International Journal of Rheumatic Diseases 2014; 17: 573–577
APLAR GRAND ROUND CASE
Anaplastic large cell lymphoma in a patient with systemic onset juvenile arthritis: case report and review of literature Bharat K. SINGH,1 Paul T. ANTONY,1 Surendra K. VERMA,2 Debdutta BASU2 and Vir S. NEGI1 1
Departments of Clinical Immunology, and 2Pathology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India
Abstract The association of malignancy with autoimmune rheumatic diseases has been a subject of investigation. It has been shown that there is increased risk of malignancies, mainly non-Hodgkin lymphoma, in patients with autoimmune disorders. There is scarcity of data about malignancy in juvenile idiopathic arthritis (JIA). We report the occurrence of anaplastic large cell lymphoma in a patient with systemic onset juvenile idiopathic arthritis treated with low dose methotrexate (MTX). A relationship between MTX treatment and the occurrence of lymphoma in autoimmune diseases has been suggested. The hypothesis that MTX has a role in the aetiology of lymphoproliferative disorders is supported by the observation of spontaneous remission of lymphoma in few cases on cessation of MTX therapy. However, systemic onset juvenile idiopathic arthritis patients receiving MTX must be periodically examined for the development of lymphoproliferative disorder especially if the disease is difficult to control or patient develop new symptoms on therapy. Key words: anaplastic large cell lymphoma ALK negative, methotrexate, systemic onset juvenile idiopathic arthritis.
INTRODUCTION The association of malignancy with autoimmune rheumatic diseases has been a subject of investigation for years. It has been shown that there is increased risk of malignancies, mainly non-Hodgkin lymphoma (NHL), in patients with autoimmune disorders such as rheumatoid arthritis (RA), primary Sj€ ogren syndrome (pSS) and systemic lupus erythematosus (SLE). There are few and conflicting data about malignancy in juvenile idiopathic arthritis (JIA).1,2 However, because of the paucity of information regarding baseline cancer risk in JIA, it is unclear whether cancer risk after antitumor necrosis factor (TNF)-a or immunomodulator
Correspondence: Dr Vir S. Negi, Professor and Head, Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry 605006, India. Email: [email protected]
treatment is truly related to the drugs or if it is related to underlying risk conferred by JIA itself. We report the occurrence of anaplastic large cell lymphoma (ALCL) in a patient with systemic onset juvenile idiopathic arthritis (SOJIA) treated with low-dose methotrexate (MTX). To the best of our knowledge, this is the first such report.
CASE REPORT A 21-year-old woman was diagnosed as having SOJIA 10 years ago based on fever, polyarthritis, cutaneous rash, raised inflammatory markers and negative rheumatoid factor (RF), antinuclear antibodies (ANA) and anti-citrullinated peptide antibodies (ACPA). She received steroids and non-steroidal anti-inflammatory drugs (NSAIDs) for her illness. As a result she developed deformities of the joints of both upper and lower limbs. Over the previous 2 years she was being treated
© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
B. K. Singh et al.
with low-dose MTX (15 mg/week) and hydroxychloroquine (200 mg/day). In March 2013, the patient was admitted with fever, cough, breathlessness and worsening joint symptoms of 1-week duration, to the emergency medical services (EMS) department of Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, a tertiary care hospital in southern India. Fever was intermittent, high-spiking and not associated with chills, rigor or perspiration. The cough was associated with nonpurulent mucoid expectoration. The joint pains were associated with joint swelling and significant early morning stiffness. On examination, the patient was anemic, febrile with a temperature of 39.7°C (103.6°F). Her vital signs were stable. She had enlarged cervical, axillary and inguinal lymph nodes, nontender but firm (maximum size 2 cm). Abdominal examination revealed nontender, firm moderate splenomegaly. Cardiac examination was normal except for mild tachycardia. Mild jugular venous distension was noted. Soft rales were heard over the right lung base. She also had active and deforming arthritis involving bilateral elbow, wrist, knee and ankle joints. Examination for other organ systems was unremarkable. Chest X-ray showed cardiomegaly and right parapneumonic pleural effusion. In view of her clinical picture suggestive of pneumonia with sepsis, she was treated with broad-spectrum third generation cephalosporine after taking blood and sputum cultures. MTX was stopped. Hematological investigations revealed bicytopenia, normocytic normochromic anemia and hyperferritinemia (Table 1). Bone marrow aspiration performed to rule out macrophage activation syndrome showed hypercellular marrow. No atypical cells were seen. Computed tomography (CT) scan of the abdomen and thorax revealed pericardial effusion with areas of pericardial thickening, right pleural effusion with underlying consolidation and lymphadenopathy of paratracheal, para-aortic, retoperitoneal and external iliac regions (Fig. 1a,b). Pleural and pericardial fluid was transudative and negative for malignant cells. Diagnostic work-up for tuberculosis in the form of sputum for Ziehl–Neelsen staining, Mantoux test and interferon-c releasing assays was negative. Lung biopsy could not be done. However, she continued to have persistent high-grade fever and cough requiring addition of antibiotics (vancomycin and levofloxacin) empirically for Gram-positive and atypical organisms, which was also not effective in controlling fever. Considering the possibility of disease flare in view of serositis, fever, lymphadenopathy, splenomegaly
574
Table 1 Laboratory data Variable Hb (g/dL) WBC (mm3) Neutrophils (%) Lymphocytes (%) Eosinophils (%) Basophils (%) Platelets (mm3) ESR (mm/h) HsCRP (g/dL) Peripheral smear
Patient value
Reference range: adults
7.8 12 730 84 13 2 1 47 000 80 130 Microcytic hypochromic, neutrophilic leucocytosis and thrombocytopenia 15 0.5
12.0–16.0 4000–11 000 40–70 22–44 0–8 0–3 150 000–400 000 < 20 < 3.34 NA
BUN (mg/dL) Creatinine (mg/dL) Uric acid (mg/dL) Bilirubin (mg/dL) BilirubinDirect (mg/dL) AST (IU/dL) ALT (IU/dL) Total protein (g/dL) Albumin (g/dL) Globulin (g/dL) Alkaline phosphatase (IU/L) LDH (IU/L) Ferritin (ng/mL) ANA (IF)
600 1650 Negative
ANCA (IF)
Negative
RF (IU/mL) Complement C3 (g/L) Complement C4 (g/L) IgG (g/L) IgM (g/L) IgA (g/L) EBV nuclear antigen
8–20 0.7–1.2
6.6
1.5–6.0
1.1
0.4–1.2
0.4
0.1–0.4
32 33 5.3 2.8 2.5 152
0–40 0–40 6.3–8.3 3.5–5.5 2.5–3.5 30–125
5.8 1.1
60–200 29–248 Negative at 1 : 40 dilutions Negative at 1 : 40 dilutions < 15.9 0.9–1.8
0.12
0.1–0.4
16 2.1 3.2 Negative
7–16 0.4–2.3 0.7–4 Negative
ALT, alanine aminotransferase; ANA, antinuclear antibodies; ANCA, antineutrophil cytoplasmic antibodies; AST, aspartate aminotransferase; EBV, Epstein–Barr virus; LDH, lactate dehydrogenase; NA, not applicable; RF, rheumatoid factor.
International Journal of Rheumatic Diseases 2014; 17: 573–577
ALCL and systemic JIA
and arthritis, intravenous corticosteroids were started to which her fever and arthritis improved transiently to reappear again after a few days. In view of the possibility of infectious, hematologic and neoplastic etiologies, lymph node biopsy was performed. The histopathology showed partial effacement of the lymph node architecture with sinusoidal pattern of infiltration by large atypical lymphoid cells with multilobulated nucleus and prominent nucleoli (Fig. 2). On immunostaining these cells were positive for CD3 and CD30 (Fig. 3a,b) but negative for CD20, anaplastic
(a)
(b)
Figure 1 Computed tomography (CT) scan of the abdomen. (a) Axial view showing para-aortic lymphadenopathy. (b) Coronal section showing para-aortic lymphadenopathy (arrow).
International Journal of Rheumatic Diseases 2014; 17: 573–577
lymphoma kinase (ALK)1, paired box (PAX)5, Epstein– Barr virus latent membrane protein and CD5. Ki67 labeling index was 67%. These features were consistent with ALK-negative anaplastic large cell lymphoma, stage III with B symptoms (Ann Arbor classification). She had a very rapid downhill course and succumbed before initiation of chemotherapy (duration of stay, 20 days).
DISCUSSION Systemic onset juvenile idiopathic arthritis is a systemic inflammatory disease classified within the spectrum of JIA. The incidence of SOJIA is approximately 0.4–0.9/ 100 000.3 This disorder is unique in terms of clinical manifestations, prognosis and lack of response to conventional immunosuppressants. A relationship between MTX treatment and the occurrence of lymphoma in autoimmune diseases such as RA has been suggested. This observation was supported by reversibility of lymphadenopathy in some patients after stopping MTX. The most commonly observed lymphoma in RA patients who have been receiving lowdose MTX is B-type NHL.4,5 Only a few RA cases6,7 in which ALCL developed under MTX treatment have been reported so far. ALK-negative (ALCL-ALK ) variant of ALCL is defined as a CD30+ peripheral T-cell neoplasm that is not reproducibly distinguishable on morphological grounds from ALCL-ALK+, but lacks the ALK protein. Most cases express T-cell-associated markers and cytotoxic markers. The main differential diagnoses are primary cutaneous ALCL, other subtypes of CD30+ T or
Figure 2 Lymph node biopsy showing infiltration by large cells with hyperlobulated pleomorphic nuclei and prominent nucleoli present mainly in the sinuses.
575
B. K. Singh et al.
(a)
(b)
Figure 3 (a) Large cells showing CD3 positivity. (b) Large cells showing CD30 positivity.
B-cell lymphoma with anaplastic features, and classical Hodgkin lymphoma. ALCL, systemic type, represents 2–3% of NHL and 12% of T-cell NHL. Among all systemic ALCLs, ALK-negative constitutes 15–50% of cases. It affects adults with a slight predominance in males. The median age at diagnosis is approximately 55– 60 years. It usually involves lymph nodes at diagnosis (49% of cases) and, less frequently, extranodal sites (20% of cases). The most frequent extranodal sites in ALCL-ALK are skin, liver and lung involvement compared with bone and soft tissue in ALCL-ALK+. Peripheral blood dissemination (as leukemic phase) is rare.8 At presentation, ALCL-ALK is often widespread (stages III–IV), with B symptoms, high International Prognostic Index (IPI) score, high serum lactate dehydrogenase (LDH) levels, and an aggressive course. The prognosis of patients with ALCL-ALK is poor, with a 5-year overall survival of 30–49 versus 70–86% in ALCL-ALK+.9 Recent studies showed that autoimmune disorders may contribute to the risk of T-cell ALCL development. Coeliac disease and psoriasis have been associated with increased risk of systemic T-cell ALCL, suggesting a possible pathogenic mechanism of chronic antigenic stimulation with local antigenic drive, ultimately leading to the development of lymphoma.10 The hypothesis that MTX has a role in the etiology of lymphoproliferative disorders is supported, at least in part, by the observation of spontaneous remission of lymphoma on cessation of MTX therapy.11 This has been reported in at least eight adult patients.12 Resolution of peripheral adenopathy, but not of thoracic or abdominal lymph node and spleen involvement, was noted in one child with JIA and Hodgkin’s disease on withdrawal of MTX.13 In another case a 10-year-old boy with polyarticular JIA treated with lowdose MTX for 2 years and 8 months developed nonHodgkin’s B cell (T-cell rich) lymphoma.14
576
The role of EBV virus infection in the pathogenesis of lymphoproliferative disorders in patients treated with MTX is unclear. It may be speculated that MTX interferes with the handling of EBV by T-cells, and allows the subsequent proliferation of EBV-infected lymphocytes. EBV may lead to aberrant cytotoxicity and lymphoproliferation, especially in patients with perforin deficiency or poor lymphocyte exocytosis.15 Evaluation for EBV was negative in our patient. It is still difficult to suggest that MTX treatment causes the development of ALCL, or systemic onset JIA itself paves the way to this disease. However, the development of ALCL in RA cases while being treated with MTX places this drug under suspicion.11 Methotrexate is an established and effective treatment for polyarthritis in children.16 It is not clear how physicians caring for children with polyarthritis should interpret these isolated case reports, as there is no epidemiological or proven causal association between therapeutic immunosuppression and the development of lymphoproliferative disorders. However, systemic onset JIA patients receiving MTX must be periodically examined for the development of lymphoproliferative disorder especially if the disease is difficult to control or patients develop new symptoms on therapy. In conclusion, vigilant clinical observation for the development of lymphoproliferative disorder is recommended as a routine part of the clinical follow-up of all children with JIA treated with weekly low-dose MTX.
REFERENCES 1 Bernatsky S, Rosenberg AM, Oen KG et al. (2011) Malignancies in Juvenile Idiopathic Arthritis: a Preliminary Report. J Rheumatol 38, 760–3. 2 Beukelman T, Haynes K, Curtis JR et al. (2012) Rates of malignancy associated with juvenile idiopathic arthritis and its treatment. Arthritis Rheum 64, 1263–71. 3 Modesto C, Ant on J, Rodriguez B et al. (2010) Incidence and prevalence of juvenile idiopathic arthritis in Catalonia (Spain). Scand J Rheumatol 39, 472–9. 4 Moseley AC, Lindsley HB, Skikne BS, Tawfik O (2000) Reversible methotrexate-associated lymphoproliferative disease evolving into Hodgkin’s disease. J Rheumatol 27, 810–3. 5 Miyazaki T, Fujimaki K, Shirasugi Y et al. (2007) Remission of lymphoma after Withdrawal of methotrexate in rheumatoid arthritis: relationship with type of latent Epstein-Barr virus infection. Am J Hematol 82, 1106–9. 6 Kim SK, Kim IS, Jun JB (2006) Anaplastic large cell lymphoma in a patient with rheumatoid arthritis taking lowdose methotrexate. Rheumatol Int 26, 775–6.
International Journal of Rheumatic Diseases 2014; 17: 573–577
ALCL and systemic JIA
7 Bes C, Bes ZS, Vardı S, Soy M (2011) Anaplastic large cell lymphoma in a patient with Rheumatoid arthritis. Rheumatol Int 31, 533–5. 8 Medeiros LJ, Elenitoba-Johnson KS (2007) Anaplastic large cell lymphoma. Am J Clin Pathol 127, 707–22. 9 Stein H, Foss HD, D€ urkop H et al. (2000) CD30(+) anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features. Blood 96, 3681–95. 10 Ekstr€ om Smedby K, Vajdic CM, Falster M, Engels EA, Martınez-Maza O, Turner J (2008) Autoimmune disorders and risk of non-Hodgkin lymphoma subtypes: a pooled analysis within the Inter Lymph Consortium. Blood 111, 4029–38. 11 Salloum E, Cooper DL, Howe G et al. (1996) Spontaneous regression of lymphoproliferative disorders in patients treated with methotrexate for rheumatoid arthritis and other rheumatic diseases. J Clin Oncol 14, 1943–9.
International Journal of Rheumatic Diseases 2014; 17: 573–577
12 Georgescu L, Paget SA (1999) Lymphoma in patients with rheumatoid arthritis. Drug Saf 20, 475–87. 13 Londino AV Jr, Blatt J, Knisely AS (1998) Hodgkin’s disease in a patient with juvenile rheumatoid arthritis taking weekly low dose methotrexate. J Rheumatol 25, 1245–6. 14 Cleary AG, McDowell H, Sills JA (2002) Polyarticular juvenile idiopathic arthritis treated with methotrexate complicated by the development of non-Hodgkin’s lymphoma. Arch Dis Child 86, 47–9. 15 Machaczka M, Klimkowska M, Chiang SCC et al. (2013) Development of classical Hodgkin’s lymphoma in an adult with biallelic STXBP2 mutations. Haematologica 98, 760–4. 16 Giannini EH, Brewer EJ, Kuzmina N et al. (1992) Methotrexate in resistant juvenile rheumatoid arthritis—results of the USA-USSR double-blind, placebo-controlled trial. N Engl J Med 326, 1043–9.
577
Copyright of International Journal of Rheumatic Diseases is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
APLAR GRAND ROUND CASE
Anaplastic large cell lymphoma in a patient with systemic onset juvenile arthritis: case report and review of literature Bharat K. SINGH,1 Paul T. ANTONY,1 Surendra K. VERMA,2 Debdutta BASU2 and Vir S. NEGI1 1
Departments of Clinical Immunology, and 2Pathology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India
Abstract The association of malignancy with autoimmune rheumatic diseases has been a subject of investigation. It has been shown that there is increased risk of malignancies, mainly non-Hodgkin lymphoma, in patients with autoimmune disorders. There is scarcity of data about malignancy in juvenile idiopathic arthritis (JIA). We report the occurrence of anaplastic large cell lymphoma in a patient with systemic onset juvenile idiopathic arthritis treated with low dose methotrexate (MTX). A relationship between MTX treatment and the occurrence of lymphoma in autoimmune diseases has been suggested. The hypothesis that MTX has a role in the aetiology of lymphoproliferative disorders is supported by the observation of spontaneous remission of lymphoma in few cases on cessation of MTX therapy. However, systemic onset juvenile idiopathic arthritis patients receiving MTX must be periodically examined for the development of lymphoproliferative disorder especially if the disease is difficult to control or patient develop new symptoms on therapy. Key words: anaplastic large cell lymphoma ALK negative, methotrexate, systemic onset juvenile idiopathic arthritis.
INTRODUCTION The association of malignancy with autoimmune rheumatic diseases has been a subject of investigation for years. It has been shown that there is increased risk of malignancies, mainly non-Hodgkin lymphoma (NHL), in patients with autoimmune disorders such as rheumatoid arthritis (RA), primary Sj€ ogren syndrome (pSS) and systemic lupus erythematosus (SLE). There are few and conflicting data about malignancy in juvenile idiopathic arthritis (JIA).1,2 However, because of the paucity of information regarding baseline cancer risk in JIA, it is unclear whether cancer risk after antitumor necrosis factor (TNF)-a or immunomodulator
Correspondence: Dr Vir S. Negi, Professor and Head, Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry 605006, India. Email: [email protected]
treatment is truly related to the drugs or if it is related to underlying risk conferred by JIA itself. We report the occurrence of anaplastic large cell lymphoma (ALCL) in a patient with systemic onset juvenile idiopathic arthritis (SOJIA) treated with low-dose methotrexate (MTX). To the best of our knowledge, this is the first such report.
CASE REPORT A 21-year-old woman was diagnosed as having SOJIA 10 years ago based on fever, polyarthritis, cutaneous rash, raised inflammatory markers and negative rheumatoid factor (RF), antinuclear antibodies (ANA) and anti-citrullinated peptide antibodies (ACPA). She received steroids and non-steroidal anti-inflammatory drugs (NSAIDs) for her illness. As a result she developed deformities of the joints of both upper and lower limbs. Over the previous 2 years she was being treated
© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
B. K. Singh et al.
with low-dose MTX (15 mg/week) and hydroxychloroquine (200 mg/day). In March 2013, the patient was admitted with fever, cough, breathlessness and worsening joint symptoms of 1-week duration, to the emergency medical services (EMS) department of Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, a tertiary care hospital in southern India. Fever was intermittent, high-spiking and not associated with chills, rigor or perspiration. The cough was associated with nonpurulent mucoid expectoration. The joint pains were associated with joint swelling and significant early morning stiffness. On examination, the patient was anemic, febrile with a temperature of 39.7°C (103.6°F). Her vital signs were stable. She had enlarged cervical, axillary and inguinal lymph nodes, nontender but firm (maximum size 2 cm). Abdominal examination revealed nontender, firm moderate splenomegaly. Cardiac examination was normal except for mild tachycardia. Mild jugular venous distension was noted. Soft rales were heard over the right lung base. She also had active and deforming arthritis involving bilateral elbow, wrist, knee and ankle joints. Examination for other organ systems was unremarkable. Chest X-ray showed cardiomegaly and right parapneumonic pleural effusion. In view of her clinical picture suggestive of pneumonia with sepsis, she was treated with broad-spectrum third generation cephalosporine after taking blood and sputum cultures. MTX was stopped. Hematological investigations revealed bicytopenia, normocytic normochromic anemia and hyperferritinemia (Table 1). Bone marrow aspiration performed to rule out macrophage activation syndrome showed hypercellular marrow. No atypical cells were seen. Computed tomography (CT) scan of the abdomen and thorax revealed pericardial effusion with areas of pericardial thickening, right pleural effusion with underlying consolidation and lymphadenopathy of paratracheal, para-aortic, retoperitoneal and external iliac regions (Fig. 1a,b). Pleural and pericardial fluid was transudative and negative for malignant cells. Diagnostic work-up for tuberculosis in the form of sputum for Ziehl–Neelsen staining, Mantoux test and interferon-c releasing assays was negative. Lung biopsy could not be done. However, she continued to have persistent high-grade fever and cough requiring addition of antibiotics (vancomycin and levofloxacin) empirically for Gram-positive and atypical organisms, which was also not effective in controlling fever. Considering the possibility of disease flare in view of serositis, fever, lymphadenopathy, splenomegaly
574
Table 1 Laboratory data Variable Hb (g/dL) WBC (mm3) Neutrophils (%) Lymphocytes (%) Eosinophils (%) Basophils (%) Platelets (mm3) ESR (mm/h) HsCRP (g/dL) Peripheral smear
Patient value
Reference range: adults
7.8 12 730 84 13 2 1 47 000 80 130 Microcytic hypochromic, neutrophilic leucocytosis and thrombocytopenia 15 0.5
12.0–16.0 4000–11 000 40–70 22–44 0–8 0–3 150 000–400 000 < 20 < 3.34 NA
BUN (mg/dL) Creatinine (mg/dL) Uric acid (mg/dL) Bilirubin (mg/dL) BilirubinDirect (mg/dL) AST (IU/dL) ALT (IU/dL) Total protein (g/dL) Albumin (g/dL) Globulin (g/dL) Alkaline phosphatase (IU/L) LDH (IU/L) Ferritin (ng/mL) ANA (IF)
600 1650 Negative
ANCA (IF)
Negative
RF (IU/mL) Complement C3 (g/L) Complement C4 (g/L) IgG (g/L) IgM (g/L) IgA (g/L) EBV nuclear antigen
8–20 0.7–1.2
6.6
1.5–6.0
1.1
0.4–1.2
0.4
0.1–0.4
32 33 5.3 2.8 2.5 152
0–40 0–40 6.3–8.3 3.5–5.5 2.5–3.5 30–125
5.8 1.1
60–200 29–248 Negative at 1 : 40 dilutions Negative at 1 : 40 dilutions < 15.9 0.9–1.8
0.12
0.1–0.4
16 2.1 3.2 Negative
7–16 0.4–2.3 0.7–4 Negative
ALT, alanine aminotransferase; ANA, antinuclear antibodies; ANCA, antineutrophil cytoplasmic antibodies; AST, aspartate aminotransferase; EBV, Epstein–Barr virus; LDH, lactate dehydrogenase; NA, not applicable; RF, rheumatoid factor.
International Journal of Rheumatic Diseases 2014; 17: 573–577
ALCL and systemic JIA
and arthritis, intravenous corticosteroids were started to which her fever and arthritis improved transiently to reappear again after a few days. In view of the possibility of infectious, hematologic and neoplastic etiologies, lymph node biopsy was performed. The histopathology showed partial effacement of the lymph node architecture with sinusoidal pattern of infiltration by large atypical lymphoid cells with multilobulated nucleus and prominent nucleoli (Fig. 2). On immunostaining these cells were positive for CD3 and CD30 (Fig. 3a,b) but negative for CD20, anaplastic
(a)
(b)
Figure 1 Computed tomography (CT) scan of the abdomen. (a) Axial view showing para-aortic lymphadenopathy. (b) Coronal section showing para-aortic lymphadenopathy (arrow).
International Journal of Rheumatic Diseases 2014; 17: 573–577
lymphoma kinase (ALK)1, paired box (PAX)5, Epstein– Barr virus latent membrane protein and CD5. Ki67 labeling index was 67%. These features were consistent with ALK-negative anaplastic large cell lymphoma, stage III with B symptoms (Ann Arbor classification). She had a very rapid downhill course and succumbed before initiation of chemotherapy (duration of stay, 20 days).
DISCUSSION Systemic onset juvenile idiopathic arthritis is a systemic inflammatory disease classified within the spectrum of JIA. The incidence of SOJIA is approximately 0.4–0.9/ 100 000.3 This disorder is unique in terms of clinical manifestations, prognosis and lack of response to conventional immunosuppressants. A relationship between MTX treatment and the occurrence of lymphoma in autoimmune diseases such as RA has been suggested. This observation was supported by reversibility of lymphadenopathy in some patients after stopping MTX. The most commonly observed lymphoma in RA patients who have been receiving lowdose MTX is B-type NHL.4,5 Only a few RA cases6,7 in which ALCL developed under MTX treatment have been reported so far. ALK-negative (ALCL-ALK ) variant of ALCL is defined as a CD30+ peripheral T-cell neoplasm that is not reproducibly distinguishable on morphological grounds from ALCL-ALK+, but lacks the ALK protein. Most cases express T-cell-associated markers and cytotoxic markers. The main differential diagnoses are primary cutaneous ALCL, other subtypes of CD30+ T or
Figure 2 Lymph node biopsy showing infiltration by large cells with hyperlobulated pleomorphic nuclei and prominent nucleoli present mainly in the sinuses.
575
B. K. Singh et al.
(a)
(b)
Figure 3 (a) Large cells showing CD3 positivity. (b) Large cells showing CD30 positivity.
B-cell lymphoma with anaplastic features, and classical Hodgkin lymphoma. ALCL, systemic type, represents 2–3% of NHL and 12% of T-cell NHL. Among all systemic ALCLs, ALK-negative constitutes 15–50% of cases. It affects adults with a slight predominance in males. The median age at diagnosis is approximately 55– 60 years. It usually involves lymph nodes at diagnosis (49% of cases) and, less frequently, extranodal sites (20% of cases). The most frequent extranodal sites in ALCL-ALK are skin, liver and lung involvement compared with bone and soft tissue in ALCL-ALK+. Peripheral blood dissemination (as leukemic phase) is rare.8 At presentation, ALCL-ALK is often widespread (stages III–IV), with B symptoms, high International Prognostic Index (IPI) score, high serum lactate dehydrogenase (LDH) levels, and an aggressive course. The prognosis of patients with ALCL-ALK is poor, with a 5-year overall survival of 30–49 versus 70–86% in ALCL-ALK+.9 Recent studies showed that autoimmune disorders may contribute to the risk of T-cell ALCL development. Coeliac disease and psoriasis have been associated with increased risk of systemic T-cell ALCL, suggesting a possible pathogenic mechanism of chronic antigenic stimulation with local antigenic drive, ultimately leading to the development of lymphoma.10 The hypothesis that MTX has a role in the etiology of lymphoproliferative disorders is supported, at least in part, by the observation of spontaneous remission of lymphoma on cessation of MTX therapy.11 This has been reported in at least eight adult patients.12 Resolution of peripheral adenopathy, but not of thoracic or abdominal lymph node and spleen involvement, was noted in one child with JIA and Hodgkin’s disease on withdrawal of MTX.13 In another case a 10-year-old boy with polyarticular JIA treated with lowdose MTX for 2 years and 8 months developed nonHodgkin’s B cell (T-cell rich) lymphoma.14
576
The role of EBV virus infection in the pathogenesis of lymphoproliferative disorders in patients treated with MTX is unclear. It may be speculated that MTX interferes with the handling of EBV by T-cells, and allows the subsequent proliferation of EBV-infected lymphocytes. EBV may lead to aberrant cytotoxicity and lymphoproliferation, especially in patients with perforin deficiency or poor lymphocyte exocytosis.15 Evaluation for EBV was negative in our patient. It is still difficult to suggest that MTX treatment causes the development of ALCL, or systemic onset JIA itself paves the way to this disease. However, the development of ALCL in RA cases while being treated with MTX places this drug under suspicion.11 Methotrexate is an established and effective treatment for polyarthritis in children.16 It is not clear how physicians caring for children with polyarthritis should interpret these isolated case reports, as there is no epidemiological or proven causal association between therapeutic immunosuppression and the development of lymphoproliferative disorders. However, systemic onset JIA patients receiving MTX must be periodically examined for the development of lymphoproliferative disorder especially if the disease is difficult to control or patients develop new symptoms on therapy. In conclusion, vigilant clinical observation for the development of lymphoproliferative disorder is recommended as a routine part of the clinical follow-up of all children with JIA treated with weekly low-dose MTX.
REFERENCES 1 Bernatsky S, Rosenberg AM, Oen KG et al. (2011) Malignancies in Juvenile Idiopathic Arthritis: a Preliminary Report. J Rheumatol 38, 760–3. 2 Beukelman T, Haynes K, Curtis JR et al. (2012) Rates of malignancy associated with juvenile idiopathic arthritis and its treatment. Arthritis Rheum 64, 1263–71. 3 Modesto C, Ant on J, Rodriguez B et al. (2010) Incidence and prevalence of juvenile idiopathic arthritis in Catalonia (Spain). Scand J Rheumatol 39, 472–9. 4 Moseley AC, Lindsley HB, Skikne BS, Tawfik O (2000) Reversible methotrexate-associated lymphoproliferative disease evolving into Hodgkin’s disease. J Rheumatol 27, 810–3. 5 Miyazaki T, Fujimaki K, Shirasugi Y et al. (2007) Remission of lymphoma after Withdrawal of methotrexate in rheumatoid arthritis: relationship with type of latent Epstein-Barr virus infection. Am J Hematol 82, 1106–9. 6 Kim SK, Kim IS, Jun JB (2006) Anaplastic large cell lymphoma in a patient with rheumatoid arthritis taking lowdose methotrexate. Rheumatol Int 26, 775–6.
International Journal of Rheumatic Diseases 2014; 17: 573–577
ALCL and systemic JIA
7 Bes C, Bes ZS, Vardı S, Soy M (2011) Anaplastic large cell lymphoma in a patient with Rheumatoid arthritis. Rheumatol Int 31, 533–5. 8 Medeiros LJ, Elenitoba-Johnson KS (2007) Anaplastic large cell lymphoma. Am J Clin Pathol 127, 707–22. 9 Stein H, Foss HD, D€ urkop H et al. (2000) CD30(+) anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features. Blood 96, 3681–95. 10 Ekstr€ om Smedby K, Vajdic CM, Falster M, Engels EA, Martınez-Maza O, Turner J (2008) Autoimmune disorders and risk of non-Hodgkin lymphoma subtypes: a pooled analysis within the Inter Lymph Consortium. Blood 111, 4029–38. 11 Salloum E, Cooper DL, Howe G et al. (1996) Spontaneous regression of lymphoproliferative disorders in patients treated with methotrexate for rheumatoid arthritis and other rheumatic diseases. J Clin Oncol 14, 1943–9.
International Journal of Rheumatic Diseases 2014; 17: 573–577
12 Georgescu L, Paget SA (1999) Lymphoma in patients with rheumatoid arthritis. Drug Saf 20, 475–87. 13 Londino AV Jr, Blatt J, Knisely AS (1998) Hodgkin’s disease in a patient with juvenile rheumatoid arthritis taking weekly low dose methotrexate. J Rheumatol 25, 1245–6. 14 Cleary AG, McDowell H, Sills JA (2002) Polyarticular juvenile idiopathic arthritis treated with methotrexate complicated by the development of non-Hodgkin’s lymphoma. Arch Dis Child 86, 47–9. 15 Machaczka M, Klimkowska M, Chiang SCC et al. (2013) Development of classical Hodgkin’s lymphoma in an adult with biallelic STXBP2 mutations. Haematologica 98, 760–4. 16 Giannini EH, Brewer EJ, Kuzmina N et al. (1992) Methotrexate in resistant juvenile rheumatoid arthritis—results of the USA-USSR double-blind, placebo-controlled trial. N Engl J Med 326, 1043–9.
577
Copyright of International Journal of Rheumatic Diseases is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
