Behçet's Disease Associated with Malignancies. Report of Two Cases

Behçet’s disease associated with malignancies. Report of two cases and review of the literature

V.G. Kaklamani1, A. Tzonou2, P.G. Kaklamanis3

1Feinberg School of Medicine, Northwest- ABSTRACT Introduction ern University, Chicago, USA; 2Depart- Objective. To investigate the incidence Behçet’s disease (BD) is a chronic, re- ment of Hygiene and Epidemiology, Med- of malignancies in a cohort of Behçet’s lapsing multi-system disorder. T h e ical School, Athens University, Greece; disease patients and review the world principal manifestations are: oral apht- 3Department of Rheumatology, Athens Medical Center, Athens, Greece. literature. hous ulcers, genital ulcers, skin lesions, Methods. Our database of 128 patients eye, joint, neurological and vascular Vir ginia G. Kaklamani, MD, DSc, As s i s t a n t Professor in Haematology/Oncology; was searched and the age standardized manifestations (1-3). Rare clinical find- Anastasia Tzonou, Associate Professor, rate (ASR) for cancer was calculated. ings include: cardiac, pulmonary and De p a r tment of Hygiene and Epidemiology; F u rt h e r m o re, we performed a MED - renal disorders (1-3), as well as, epidi- Phaedon G. Kaklamanis, MD, Emeritus LINE search from 1970 through 2003, dymoorchitis (4). The epidemiology of Professor of Internal Medicine. as well as, a search in the proceedings BD in most parts of the world has re- Please address correspondence to: of international conferences for cases cently been reviewed (5-7). The patho- Phaedon Kaklamanis, MD, 61 Ipsilantou of malignancies associated with Beh - genesis of the disease has not been elu- St., Athens 11521, Greece. çet’s disease. cidated (1,2,8), although genetic fac- E-mail: Virginia @hol.gr Results. Two of our 128 patients with tors, environmental agents and immune Received on September 30, 2004; accepted B e h ç e t ’s disease were found to have aberrations have been implicated (1, 2, in revised form on April 1, 2005. solid tumors. One male had lung can - 9). Immune abnormalities, particularly Clin Exp Rheumatol 2005; 23 (Suppl. 38): cer and the other female had kidney increased production of some antibod- S35-S41. cancer. The ASR for cancer cases in ies have been reported in patients with © Copyright CLINICALAND EXPERIMEN- our population was investigated and it BD (9). However, Raynaud’s phenom- TAL RHEUMATOLOGY 2005. was found to be 1,600 per 100,000 in enon, polyserositis, Sjögren’s syndro- Key words: Behçet’s disease, 10 years. The ASR for cancer cases in me, neutrophil, antiphospholipid and malignancies. Greece according to WHO is 272.51 antinuclear antibodies, which charac- per 100,000 per year and there f o re terize an autoimmune disease, have not 2,725 per 100,000 in 10 years. been associated with BD (10,11). Sev- In the world literature 112 cases of ma - eral studies have shown that arterial and lignancies associated with Behçet’s di - venous involvement of all size vessels sease were found: Sixty five cases were are characteristic findings of the dis- of male patients and 46 of female with ease (12-16). Given the above vas- 1 case of unknown gender. The solid culitic manifestations, BD is classified malignancies associated with Behçet’s among the wide spectrum of systemic disease included cases of bladder, vasculitides (14). b reast, uterus, thyroid and stomach In autoimmune and vasculitic disorders cancer, whereas haematological malig - the risk of malignancies has been ex- nancies included leukemia, myelodys - tensively studied. In patients with rheu- plastic syndrome, lymphoma, multiple matoid arthritis (RA), both solid and myeloma, Hodgkin’s disease and lym - haematopoietic malignancies have been phosarcoma. The treatment administer - reported (17,18). In Western Europe ed in these patients with their disease is and in the United States the risk is re- also reported. lated primarily to the development of Conclusion. The age standardized rate haematopoietic neoplasms, whereas in of cancer in our population was lower Japanese patients oropharyngeal malig- than that of the general population in nancies are more commonly seen (19). G reece, although the difference was The discrepancy may have to do with not statistically significant. However, environmental and dietary differences there is discrepancy in the world litera - between the different regions. Patients ture and the possibility of development with systemic lupus erythematosus of malignancies in Behçet’s disease pa - (SLE) have increased risk of develop- tients should not be ignored. ing both solid tumors and haematologic

S-35 Behçet's disease and malignancies / V.G. Kaklamani et al. malignancies (19-23). In patients with genital ulcers appeared. These lesions of search headings of «Behçet’s dis- progressive systemic sclerosis (sclero- were recurrent. Pathergy test was posi- ease», «Behçet’s syndrome», «Adaman- derma) increased risk of malignancy tive and the diagnosis of BD was estab- tiades-Behçet’s disease», «cancer» and was found (24), particularly bronchoal- lished. He was treated with colchicine «malignancy». Cases from proceedings veolar carcinoma (23). The incidence and prednisolone 30 mg/d which was of international conferences in BD of malignancy in dermatomyositis and tapered slowly to 7.5 mg/d. Since then were also included in the analysis. polymyositis (DM,PM) has been the every 3-4 months most of the clinical subject of multiple publications (25- manifestations would recur and the Statistical section 29). Among 618 patients with DM and dose of prednisolone would be increas- We wanted to determine whether the PM, 198 cases of cancer were reported ed. The time of cancer diagnosis he incidence of malignancy in our BD pop- (26), pointing toward a predisposition presented with small oral aphthae, one ulation was similar to that of the gener- to the development of malignant disor- genital ulcer and arthritis of the right al population. For this we had to stan- ders in such patients. Wegener’s granu- knee. In March 1999 he presented with dardize our population since the age di- lomatosis (30), Henoch-Schönlein pur- neurological symptoms and a brain stribution of our population was not si- pura (31) and other vasculitides (32) MRI showed a solid mass measuring milar to that of the general population. have also been associated with increas- 3.5 cm at the lower left parietal area. We calculated the age standardized rate ed risk of malignancies. In BD patients This was a metastatic tumor originating (ASR) for cancer cases in our popula- more than hundred cases associated from his lung and a biopsy of the lung tion which was 1,600 per 100,000 in 10 with malignancies have been publish- tumor showed to be a microcytic type years. We used the following formula ed. However, the direct relationship adenocarcinoma with large cells. The for calculating ASR: ASR = S cases with BD has not been proved. patient was treated with carboplatin, (age group)/population (age group) x The development of malignancies in paclitaxel and radiotherapy. Several 100,000 world standard population autoimmune diseases and vasculitides months later he died. The patient devel- (age group)/world standard population. could be related to abnormalities in im- oped lung cancer 10 years after the According to the WHO the ASR for mune regulation, T cell deficiency, or diagnosis of BD. He had a 40 pack/year cancer cases in Greece is 272.51 per the overproliferation of B cells, which smoking history. 100,000 per year and therefore 2.725 may trigger a malignant transformation per 100,000 in 10 years (36). After per- of cells (33). The association of malig- Case 2 forming a c 2 test to assess the signifi- nancies with BD may represent a para- A 60-year-old housewife at the age of cance, we found that there was no sta- neoplastic syndrome (34) or may be re- 17 developed oral and genital ulcers. tistically significant difference between lated to the above mentioned distur- They were followed by arthritis of the the two populations. Furthermore, we bances (33). Furthermore, medications lower extremities. At the age of 20 calculated the annual incidence of ma- that BD patients are chronically on those symptoms recurred several times lignancy in our population of 128 pa- may also predispose to the develop- and anterial uveitis was diagnosed. tients with BD and found it to be 156 in ment of neoplastic diseases. Five years later erythema nodosum and 100,000. Our primary aim in this report is to recurrences of oral and genital ulcers share our own experience on the asso- developed. Pathergy test was negative Review of the literature ciation of malignant neoplasms and BD and she had HLA B5 (51). The dia- A variety of solid tumors have been re- by searching our database of 128 pa- gnosis of BD was established and be- ported in the world literature including tients with a median follow up of 10 gan treatment with prednisolone 30 two of our own. The diagnosis of BD years. Furthermore, we will review the mg/d and chlorambucil 6-10 mg/d for 3 was established according to the crite- cases of malignancies associated with years. Two years later hypopyon iritis ria reported (96). In a few cases the dis- BD present in the scientific literature. was diagnosed and received predni- ease onset was defined as the time solone 20 mg/d and azathioprine 100- when the patient developed the first Material and methods 200 mg/d for 8 years. At the time of symptom, while in others when the dia- Our BD patient cohort has been pros- diagnosis of cancer she suffered from gnostic criteria were fulfilled. pectively collected since 1990, during chronic uveitis, recurrent erythema no- which time we have enrolled 128 pa- dosum and oral aphthae. At the age of 1. Solid tumors (references: (33, 34, tients. All patients met the International 59 she developed haematuria and an in- 37, 39, 46, 51, 56-58, 61, 62, 65, Study Group (ISG) criteria for BD filtrating carcinoma of the left kidney 73, 82, 85-88, 92, 94) (35). In 2000, two of our patients died. stage IV was diagnosed 43 years after Among the 54 cases, 33 were male and the diagnosis of BD. She had a 30 21 female with a median age of 38.9 Case 1 pack/year smoking history. She refused years (range 13-69). In 51 out of 54 A 4 4 - y e a r-old man at the age of 34 any treatment and died two months cases BD preceded the diagnosis of developed oral aphthous ulcers and later with multiple metastases. solid tumor with a median duration of pseudofolliculitis. Four weeks later an- In addition, a MEDLINE search from 9.5 years (range 2 months-43 years). In terior uveitis was diagnosed and two 1970 to 2003 was performed by the use only two patients malignancy preceded

S-36 Behçet's disease and malignancies / V.G. Kaklamani et al.

Table I. Immunosuppressive drugs admin- nocarcinoma were found in 2 patients months to 10 years), while in 9 the de- istered for BD before the diagnosis of solid treated with cyclosporine A. Chemo- velopment of malignancy preceded the tumors and heamatological malignancies. therapy was administrated in two pa- diagnosis of BD with a median dura- tients with BD who developed bladder tion of 4.1 years (range 4 months-6 Drug No of patients cancer and malignant histiocytosis. years). In 1 patient both diseases were Cyclophosphamide 17 Uterine adnexia teratoma was found in diagnosed simultaneously. Cyclophosphamide + cyclosporine A 1 a patient who was treated with IFN-a. Myelodysplastic syndrome was diag- Chlorambucil 3 Colchicine and corticosteroids each nosed in 18 patients associated with Chlorambucil + cyclosporine A 1 one alone or in combination with other BD 11 of which were male and 7 fe- Chlorambucil + azathioprine 3 medications in 30% and 43% respec- male with a median age of 49.1 years Azathioprine + cyclosporine A 1 tively was administrated in patients (range 34-72 years ). + Interferon–a Cyclosporine A+ azathioprine 2 who developed various malignancies. Behçet’s disease preceded the MDS in Cyclosporine A 2 A variety of tumors were diagnosed in 7 patients with a median duration of 5 Chemotherapy 3 10 patients in whom the treatment was years (range 5 months-8 years) and the Interferon–a 3 not reported. Furthermore, two more malignancy preceded the diagnosis of Azathioprine + interferon–a 1 patients with solid tumors (ovarian BD in 9 patients with a median dura- cancer, breast cancer) did not received tion of 3.33 years (range 4 months-13 any drug. years). In 2 cases both diseases were the diagnosis of BD, by 4 and 5.6 years The drugs given for BD before the de- diagnosed simultaneously. respectively. In one patient both dis- velopment of solid tumor are reported Malignant lymphoma associated with eases developed nearly simultaneously. (Table I). BD was reported in 13 patients, 7 of A great variety of solid tumors were re- which were male and 6 female. Their ported: bladder (7), breast (5), thyroid 2. Haematological malignancies (ref- median age was 7.57 years (range 4 (4), stomach (4), uterus (3), liver (3), erences: 33, 38, 40-45, 47-50, 52- months-20 years) and the locations of lung (3), colon (3), pancreas (2), ovary 54, 55, 59, 60, 62-64, 66-72, 74-81, the lymphoma were: nasal, intracranial, (2), basal cell cancer (2), Kaposi sarco- 83, 84, 87, 89-94) gastric and intestinal. One patient with ma (2), renal (2), malignant histiocy- Sixty cases of BD associated with hae- lymphosarcoma was also reported. toma (2) and pheochromocytoma (2). matological malignancies were report- Most of these cases are from Japan and Furthermore, other malignancies such ed in the world literature of which 32 in all patients BD preceded the deve- as pharyngeal, malignant rhabdoid tu- males and 27 females, whereas in one lopment of lymphoma. mor, seminoma, teratoma of the uterus, patient age and sex were not reported. The treatment administered for BD adenocarcinoma of unknown origin, Their median age was 44.1 years before the development of neoplasia is mesenchymal tumor, small cell carcin- (range 21-72 years). reported (Table I). oma of the lung and cancer of the testis Behçet’s disease was associated in 24 Four patients with BD were treated have been reported. The majority of cases with leukemia, 18 with myelody- with cyclophosphamide and developed these cases (44/54) were published splastic syndrome (MDS) and 13 with acute leukemia, chronic myeloid leu- within the past 13 years (1991-2003). lymphoma. Multiple myeloma (2), kemia, non Hodgkins lymphoma, Hod- Thirteen BD patients who developed Hodgkins disease (2) and lymphosar- gkins disease. One patient was treated solid tumors were treated with cyclo- coma (1) were also reported. In 39 ca- with cyclophosphamide and cyclospo- phosphamide. Among them 5 had blad- ses, BD preceded the diagnosis of mali- rine A and developed non-Hodgkins der cancer and the other a variety of gnancy with a median duration of 6.1 lymphoma. Chlorambucil was admin- other tumors (malignant granuloma of years (range 3 months-41 years). Mali- istrated in a patient who developed pharynx, malignant histiocytosis, pan- gnancy preceded the diagnostis of BD MDS. Two patients one with acute leu- creas adenocarcinoma, rectum adeno- in 18 cases, 9 with MDS and 9 with kemia and another with high grade carcinoma, breast cancer, thyroid can- leukemia with a median duration of 6.5 lymphoma were treated for their BD cer and seminoma, malignant mesen- years (range 3 months–20 years). In 3 with chlorambucil and azathioprine. chymal tumor (the last one received cases both diseases were diagnosed Another one on chlorambucil and cy- also IFN-a ). Two patients, one with ade- nearly simultaneously. closporine A developed MDS. Two pa- nocarcinoma of unknown origin and When examining the different haema- tients treated with azathioprine and cy- the other with pulmonary cancer were tological malignancies separately, we closporine A developed MDS. Azathio- treated with chlorambucil. Renal carci- found that leukemia was diagnosed in prine and interferon-a was given in a noma was diagnosed in a patient treat- 24 patients, 11 male and 12 female. In patient who developed chronic myeloid ed with chlorambucil and azathioprine. 1 patient the sex was not available. The leukemia. Two patients with chronic Kaposi sarcoma was diagnosed in a pa- median age was 40.1 years (range 21- myeloid leukemia were treated with in- tient who received azathioprine, cy- 62 years). In 14 patients BD preceded terferon-a . Another with acute myeloid closporine A and interferon-a . Malig- the diagnosis of malignancy with a me- leukemia was treated with chemother- nant rhabdoid tumor, and pancreas ade- dian duration of 3.8 years (range 3 apy. Levamisole, busulfan, hydroxyur-

S-37 Behçet's disease and malignancies / V.G. Kaklamani et al.

Table II. Cases of Behçet’s disease associated with malignancies in the world (country, year and number of cases).

Years Japan Turkey Iran Korea China USA Greece Tunisia France Spain Germany Italy England Total

1961-1970 1 1 1971-1980 3 3 1 7 1981-1990 13 1 3 1 2 1 1 22 1991-2000 13 7 11 10 6 1 4 1 1 3 3 1 61 2001-2003 21 1 1 23 Total 30 29 11 10 9 6 4 4 3 3 3 1 1 114

References: Japan: 37, 39, 40, 44, 46, 53-59, 61, 63, 66, 68-70, 74-79, 82. Turkey: 47, 73, 80, 85, 88, 92, 94. Iran: 87. Korea: 33. China: 45, 50, 52, 62. USA: 38, 41, 42, 49, 86, 91. Greece: 81, 90. Tunisia: 51, 71, 93. France: 35, 43, 60. Spain: 64,67,72. Germany: 65, 84, 89. Italy: 83. England: 48. ea were given in other patients with Turkey with a 15 year follow up there than in the standardized general popu- malignancies. Corticosteroids and col- were no reported malignancies (95). lation. However, our results did not chicine each one alone or in combina- The authors stated that BD may be pro- reach statistical significance. tion with other medications, were ad- tective against the development of ma- A factor, which may be associated with ministrated in 38% and 25% of patients lignancy and hypothesized that BD pa- neoplasia in BD, is trisomy 8. In 9 out respectively who subsequently devel- tients may possess a protective HLA of 14 patients with BD-associated neo- oped various malignancies. In 18 pa- subtype against malignant transforma- plasia, trisomy 8 was found (79). This tients with various haematological ma- tion (95). However, in another study chromosomal abnormality is found in lignancies the treatment given for BD from Turkey, which included 400 pa- 8.9-18.4% of patients with MDS (77, was not reported by the investigators. tients followed-up for a median of 9.8 96,97). Thus, the percentage of chro- Combination of treatment with corti- years, 13 cases of malignancy were re- mosomal abnormalities in patient with costeroids and or colchicine was very ported (3.25%) (92). BD associated MDS is markedly high- frequent. The incidence of malignancy in BD pa- er than in those with MDS alone (77). The countries and the year of publica- tients compared with the general popu- Trisomy 8 has not been associated with tions of BD associated with malignan- lation has been reported in only 2 stud- BD. However, in 9 of 18 patients in the cies are presented in Table II. ies. Cengiz et al. (92) found 13 cases of literature MDS preceded the develop- malignancies in 400 BD patients, with ment of BD with a median period of Discussion a median follow up of 9.8 years, which 3.3 years (range 4 months-13 years), We have presented 114 cases of malig- did not differ statistically (x2test) from whereas in 7 patients BD preceded the nancy- associated BD. This is, to the the crude annual incidence of malig- development of MDS and in two cases best of our knowledge, the most com- nancies in the general population in Tur - both diseases were diagnosed simulta- plete review.A recent review article in- key. In the second study (94), among neously (79). Therefore, there is an included at total of 40 cases of malignan- 387 BD patients 8 developed ma- direct evidence that trisomy 8 may pre- cies in patients with BD (92). The onset lignancies, in a 20-year follow up pe- dispose to BD in a subgroup of MDS of malignancy may precede, coincide riod. This gives the annual incidence patients (79). with, or follow the diagnosis of BD. rate of 103 in 100,000 with a crude Immune mechanisms may also contri- So far most of the data on malignancies yearly cancer incidence of 90 in bute in the development of malignant in patients with BD come from case re- 100,000 among the general population disorders in patients with BD. More ports. In our patient population of 128 in Turkey in 1995. None of these stud- specifically it has been shown that dur- BD patients, 2 developed solid tumors ies however have taken into account ing the course of BD there is an in- during a 10-year follow up. In other the age difference between the BD po- creased number of gd+ and ab +T cells, studies the frequency of malignancy in pulation and the general population. In probably due to a microbial agent, BD varied. In 100 patients with BD our study of 128 patients with BD and a which induces the expression of heat from China 6 developed malignancies 10-year follow up period, 2 of our pa- shock protein 65 (HSP65) (98). Lym- (62). In 4,130 patients with BD from tients developed a malignant disorder phocytes, macrophages and neutrophils Iran only 11 cases were associated with and therefore the annual incidence in are activated, and therefore may be res- malignancies (87). Similarly, a study our population was 156 in 100,000. In ponsible for the abnormal clones and from Korea including 5,000 patients Greece according to the WHO, in the the development of B-cell lymphoma with BD reported only 10 cases of ma- year 2000 there were 36,747 incidence (93). lignancies (33). Furthermore, in a more cases of malignancy, making the inci- Patients with BD are treated, particu- recent study of 387 patients with BD, dence rate of malignancy in Greece 345 larly the refractory cases, with immu- followed-up for 20 years, 8 cases of per 100,000. When standardizing our nosuppressive drugs (99) most of them malignancy were reported (2%) (94) population for age we also found the have been implicated in the develop- and in 400 patients with BD from incidence of malignancy to be lower ment of malignancies. However, there

S-38 Behçet's disease and malignancies / V.G. Kaklamani et al. are several cases of BD associated ma- BD, treatment with immunosuppres- 12. KOK Y, GÜLLÜ I, AKPEK G et al.: Vascular lignancies in patients who had never re- sive drugs may coincide with the de- involvement in Behçet’s disease. J Rheumatol 1992; 19: 402-10. ceived immunosuppressive therapy. In velopment of malignant disorders al- 13. LIE JT:Vascular involvement in Behçet’s dis- a patient with pheochromocytoma, cor- though there is no convincing evidence ease: arterial and venous and vessels of all ticosteroids were administered, while for this. Another implicating factor sizes. J Rheumatol 1992; 19: 341-3. in another patient with the same malig- may be the immune mechanism behind 14. EHRLICH GE: Vasculitis in Behçet’s disease. Intern Rev Immunol 1997; 14: 81-8. nant disorder, there was no history of the pathogenesis of BD. 15. RIZZI R, BRUNO S, DAMMACCO R: Behçet’s use of immunosuppressive agents. Both Since most cases of BD associated with disease: an immune-mediated vasculitis in- cases may represent a coincidental find- malignancies were reported in the last volving vessels of all sizes. Int J Clin Lab Res ing whereas it is plausible that some 13 years, it is unclear whether this re- 1997; 27:225-32. 16. KRAUSE I, WEINBERGER A : Va s c u l o - B e h- basic pathophysiologic connection be- presents a true increase in the incidence çet’s disease. IMAJ 2002; 4: 636-7. tween the two disorders may exist (86). or whether there has been increased 17. TENNIS P, ANDREWS E, BOMLARDIER C et Furthermore chlorambucil and cyclo- awareness, leading researchers to re- al.: Record linkage to conduct an epidemiolo- gic study on the association of rheumatoid phosphamide, may perhaps be the only port such cases. As more potent agents arthritis and lymphoma in the province of drugs used in patients with BD, with are being used in the treatment of BD, Saskatchewan, Canada. J Clin Epidemiol convincing evidence for the develop- it is possible that those patients live 1993; 46: 685-95. ment of neoplasia. longer than before, making the deve- 18. MORITOMO H, UEDA T, HIYAMA T, HOSONO N, MORI S, KOMATSUBARA Y: The risk of Immunosuppressive drugs can induce lopment of malignant disorders more cancer in rheumatoid arthritis patients in Ja- malignancy by two possible mecha- likely. However, our observations do pan. Scand J Rheumatol 1995; 24: 157-9. nisms (84). not support the hypothesis that BD pre- 19. CARSONS S: The association of malignancy 1. By the direct effect of the drug on disposes to malignancy. Large prospe- with rheumatic and connective tissue diseases. Seminars in Oncology 1997; 24: 369- DNAreplicatation. ctive international studies will be able 72. 2. By an indirect effect on cellular re- to answer this question. 20. GREEN J A, DAWSON AA, WALKER W: Syste- gulatory effects. mic lupus erythematosus and lymphoma. 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