Modern Rheumatology
ISSN: 1439-7595 (Print) 1439-7609 (Online) Journal homepage: http://www.tandfonline.com/loi/imor20
Multiple malignancies in a patient with limited granulomatosis with polyangiitis without immunosuppressive therapy Yun-Hong Cheon, Min-Gyo Kim, Ji-Eun Kim, Chang Yoon Ha, Sang-Il Lee & Hyun-Ok Kim To cite this article: Yun-Hong Cheon, Min-Gyo Kim, Ji-Eun Kim, Chang Yoon Ha, Sang-Il Lee & Hyun-Ok Kim (2014): Multiple malignancies in a patient with limited granulomatosis with polyangiitis without immunosuppressive therapy, Modern Rheumatology To link to this article: http://dx.doi.org/10.3109/14397595.2014.891494
Published online: 19 Mar 2014.
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Date: 05 November 2015, At: 18:18
http://informahealthcare.com/mor ISSN 1439-7595 (print), 1439-7609 (online) Mod Rheumatol, 2014; Early Online: 1–4 © 2014 Japan College of Rheumatology DOI: 10.3109/14397595.2014.891494
CASE REPORT
Multiple malignancies in a patient with limited granulomatosis with polyangiitis without immunosuppressive therapy Yun-Hong Cheon1, Min-Gyo Kim1, Ji-Eun Kim2, Chang Yoon Ha1, Sang-Il Lee1, and Hyun-Ok Kim1 1Department of Internal medicine and Institute of Health Science, Gyeongsang National University School of Medicine, Jinju, South Korea and
Modern Rheumatology
2Department of Radiology, Gyeongsang National University School of Medicine, Jinju, South Korea
Abstract
Keywords
Here, we report the case of a 69-year-old man with limited granulomatosis with polyangiitis (GPA; formerly Wegener ’s granulomatosis) who developed papillary thyroid cancer, adenocarcinoma of the stomach, and myelodysplastic syndrome following glucocorticoid treatment. This is the first report to present multiple malignancies in a patient with limited GPA without immunosuppressive treatment. Thus, our report supports the notion that limited GPA itself can be associated with the development of malignancy.
ANCA, Granulomatosis with polyangiitis, Malignancy, Myelodysplastic syndrome, Vasculitis
Introduction Granulomatosis with polyangiitis (GPA) is a rare, systemic autoimmune disease with an unknown etiology characterized by pathologically granulomatous inflammation and systemic necrotizing vasculitis that predominantly affects the small vessels [1]. This condition primarily involves the upper and lower respiratory tracts and kidneys, but any organ system may be affected [1,2]. An antineutrophil cytoplasmic antibody specific for proteinase 3 (PR3-ANCA) is detected in approximately 95% of patients with generalized GPA [2]. Furthermore, detection of c-ANCA and the specific antigen of ANCA using immunofluorescence and enzymelinked immunosorbent assay (ELISA) is the most useful approach for diagnosing GPA and monitoring disease activity [3]. Several studies have indicated a link between GPA and cancers such as bladder cancer, renal cell carcinoma, papillary thyroid cancer (PTC), and hematopoetic cancer [4–6]. However, most of these cancers have been attributed to exposure to immunosuppressive drugs such as cyclophosphamide, and few reports have been made of cancers in patients with granulomatosis with polyangiitis following glucocorticoid treatment or prior to the administration of immunosuppressive drugs [7]. Here, we report the case of a patient who developed PTC, gastric adenocarcinoma, and myelodysplastic syndrome (MDS) after receiving a diagnosis of limited GPA and receiving treatment without immunosuppressive drugs; we also conducted a literature review.
Case report A 69-year-old man visited our hospital for an evaluation of persistent anemia. Two years previously, he had been admitted to our hospital with abdominal pain and diarrhea. The colonoscopy revealed inflammatory colitis in the descending and sigmoid colon. On abdominal computed tomography (CT), there was evidence Correspondence to: Hyun-Ok Kim, Department of Internal medicine and Institute of Health Science, Gyeongsang National University School of Medicine 79 Gangnam-ro, Jinju 660-702, South Korea. Tel: 82-55-7508069. Fax: 82-55-758-9122. E-mail: [email protected]
History Received 19 July 2013 Accepted 1 February 2014 Published online 11 March 2014
of multiple lymph node enlargement. Microscopic findings from a mesenteric lymph node biopsy showed granulomatous inflammation and necrotizing vasculitis with small-sized vessels. Immunological analysis revealed that the patient was positive for both antinuclear antigen at a titer of 1:160 and cytoplasmic antineutrophil antibodies (c-ANCA) at a titer of 1:640. He was diagnosed with limited GPA and treated with glucocorticoid alone [8]. Prior to discharge, esophagogastroduodenoscopy (EGD) was performed, which showed diffuse and mucosal nodularity on the body and antrum of the stomach. The microscopic findings were consistent with hyperplastic polyps and chronic duodenitis. There was no sign of gastric cancer. In the first year of ongoing treatment, the patient was readmitted to the hospital due to dyspnea upon exertion. His vital signs were within the normal range, with a blood pressure of 125/84 mmHg, pulse rate of 92/min, respiratory rate of 23/min, and body temperature of 36.8°C. His laboratory findings were as follows: white blood cell count, 4,660/mm3; hemoglobin, 7.2 g/dL; platelet count, 175,000/mm3; serum glucose, 76 mg/dL; cholesterol, 102 mg/dL; albumin, 3.1 g/dL; total bilirubin, 0.53 mg/dL; aspartate aminotransferase, 11 IU/L; alanine aminotransferase, 5 IU/L; blood urea nitrogen, 20.3 mg/dL; creatinine, 1.20 mg/dL; C-reactive protein, 120 mg/dL; and erythrocyte sedimentation rate, 12 mm/h. Serum viral markers were normal, with negative results for HBsAg, positive results for anti-HBs, and negative results for anti-HCV and anti-HIV. Neither proteinuria nor hematuria was observed during the urinary microscopic examination. On physical examination, there were goiter-like masses in his neck. The thyroid function test showed the following results: TSH, 0.01 mIU/L; T3, 137.80 ng/dL; Free T4, 4.37 ng/dL; thyroglobulin antibody, 11.24 IU/mL; and anti-TPO, 6.32 IU/mL. A thyroid scan revealed diffuse mild goiters with decreased uptake (1.9%). The patient was diagnosed with destructive thyroiditis and instructed to begin treatment with a beta-blocker. EGD was repeated to evaluate the cause of new-onset anemia, and the results revealed an elevated mucosal modular lesion at the lower body of the gastric lesser curvature and antrum; the microscopic findings showed moderately differentiated adenocarcinoma (Figure 1). The patient
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Mod Rheumatol, 2014; Early Online: 1–4
of the thyroid (Figure 4) and lymph nodes were consistent with PTC and its metastasis. Finally, the patient was diagnosed with gastric adenocarcinoma, PTC, MDS, and limited GPA. He is now undergoing iodine radiotherapy for PTC and oral chemotherapy for MDS.
Discussion
Modern Rheumatology
Figure 1. An adenocarcinoma was detected at irregular branching glands lined by pseudostratified columnar cells (100).
was diagnosed with gastric adenocarcinoma, underwent subtotal gastrectomy, and was discharged after receiving ferrous sulfate and vitamin B12 medications. After 1 year of regular follow up, new onset cytopenia was developed and unexplainable anemia persisted despite adherence to medication and surgery. Therefore, the patient was readmitted to determine the additional causes for his cytopenia and anemia (Figure 2). Bone marrow examination was performed, which revealed erythroid dysplasia and megakaryocyte dysplasia consistent with MDS (Figure 3). To evaluate additional hidden malignancies, positron emission tomography (PET)-CT was performed, and the results showed hot uptake on the left lobe of the thyroid gland and left supraclavicular lymph nodes. Fine needle aspiration was performed for the left lobe of the thyroid gland, and the microscopic findings were consistent with PTC. Thus, total thyroidectomy was performed. The microscopic findings from a surgical specimen
Here, we reported the case of a patient who developed gastric adenocarcinoma, PTC and MDS after being diagnosed with limited GPA and receiving treatment with glucocorticoid alone. Several previous studies have demonstrated an increased risk of cancer in patients with ANCA-associated vasculitis, including GPA [4,6,9]. However, only one previous case reported multiple malignancies (spinocellular carcinoma, basal cell carcinoma, Kaposi sarcoma, and urinary bladder carcinoma) in a patient with GPA. Although these multiple malignancies were related to immunosuppressive treatment [10], this was unlikely the case for our patient. Therefore, this is the first report to present multiple malignancies in a patient with limited GPA without immunosuppressive treatment. Edgar et al. first reported the finding that ANCA-associated systemic vasculitis was associated with malignant tumors [11]. The relationship between vasculitis and malignancy remains unclear, although some researchers have suggested that a dysfunctional immune system, treatment with cytotoxic drugs, common genetic susceptibility, chronic stimulation of the immune system, and autoantibody formation against various autoantigens may play roles in this association [9,12,13]. Many reports have also demonstrated that solid cancers such as bladder cancer, renal cancer, and hematologic malignancies can develop in patients with systemic GPA, although these malignancies have been largely associated with the use of cyclophosphamide [5,13,14]. However, in the present case, our patient received a diagnosis of limited GPA and was treated with steroid alone; subsequently, he was diagnosed with papillary thyroid cancer, gastric adenocarcinoma, and MDS during regular follow up. This finding supports the notion that limited
Figure 2. The Clinical course of the patient.
Modern Rheumatology
DOI 10.3109/14397595.2014.891494
Multiple malignancies in limited granulomatosis with polyangiitis 3
Figure 3. (A) Relative erythroid hyperplasia and dysplasia, including nuclear–cytoplasmic ratio asynchrony and binucleated cells, were noted. (B) Megakaryocytic dysplasia was noted; in particular, small, mononuclear megakaryocytes or megakaryocytes with separate nuclei were frequently noted.
vasculitis itself can be associated with the development of malignancy, although further study on the association between limited vasculitis and malignancy will increase our understanding of this complex relationship. PTC is a common malignancy of the endocrine system, and the incidence of this condition is increasing. Several cases of thyroid malignancy have been reported in patients with GPA, including papillary thyroid cancer, mixed papillary and follicular cancer, and anaplastic carcinoma [7,15–17]. However, the relationship between limited GPA and thyroid cancer is not clear. One study demonstrated that the coexistence of ANCA-associated vasculitis
and autoimmune thyroid disease was associated with MPO-ANCA [18], and another study revealed that patients with GPA had a higher likelihood of developing thyroid disease (Grave’s disease and thyroiditis), especially in cases of severe GPA [19]. Furthermore, many reports support the hypothesis that Grave’s disease [20] and thyroiditis [21] can increase the risk of thyroid cancer. Upon second admission, our patient was diagnosed with destructive thyroiditis, and after 1 year of follow up, he was diagnosed with papillary thyroid cancer. It is possible that ANCA-positive vasculitis may have triggered the development of thyroiditis and papillary thyroid cancer, and further study should investigate the potential relationship between ANCA-positive vasculitis, including cases of limited GPA, and the development of papillary thyroid cancer. Approximately 5% of patients with vasculitis develop malignant tumors, and in such patients, numerous malignant tumors are often found [4]. Furthermore, gastric adenocarcinoma is one of the most common malignancies worldwide [22], although the occurrence of gastric adenocarcinoma has rarely been reported in patients with GPA. In 2006, one study investigated the prevalence of autoantibodies among Omani patients with gastric cancer. In this study, anti-proteinase 3 levels were significantly higher in patients with gastric cancer than in the control groups [23], which suggests that ANCA-positive vasculitis may be associated with gastric adenocarcinoma, although the pathogenesis of the development of gastric adenocarcinoma in limited GPA is not yet clear. Our report also supports the possibility of a hidden relationship between these two diseases. MDS is considered to be a preleukemic condition and is likely to progress to acute myeloblastic leukemia. In particular, MDS should be suspected as a possible cause of unexplained anemia in elderly patients [24]. Vasculitis may develop simultaneously or precede the clinical onset of hematologic disorders such as MDS. In 1981, Pirayesh et al. reported the first case of MDS associated with vasculitis [25], and a study by Savige et al. demonstrated that ANCA could be associated with myelodysplasias such as MDS [26]. In a retrospective study of 82 MDS patients, 10 patients (12%) with MDS had immune-mediated complications; of the 10 patients there were 5 cases of skin vasculitis,1 case each with temporal arteritis/polymyalgia rheumatic, necrotizing panniculitis, Hashimoto’s thyroiditis, autoimmune thrombocytopenia, and Sweet’s syndrome [27]. Because our patient had unexplained anemia even after subtotal gastrectomy, we examined his bone marrow and then diagnosed him with MDS. MDS might lead to the defect of immunosurvaillance and aberrant DNA methylation and Ciavatta et al. recently revealed the hypomethylation of PR3 and MPO loci in patients with ANCA-associated vasculitis [28–30]. It seems difficult to discover which disease precede one another, however taking above studies into consideration, we think there is possible relationship between limited GPA and MDS. In conclusion, we report a case of limited GPA with gastric adenocarcinoma, PTC, and MDS in a single patient. Our report supports the notion that ANCA-associated vasculitis, including limited granulomatosis with polyangiitis, may increase the risk of the development of malignancies. Therefore, physicians should be aware of the risk of cancer and must pay attention to symptoms suggestive of malignancy and the possibility of hematologic malignancies, such as MDS, in patients with limited GPA.
Conflicts of interest None.
References Figure 4. The tumor revealed a complex branching papillary structure. The papillae were covered by tumor cells with an eosinophilic cytoplasm. The nuclei of neoplastic cells had irregular contours (100).
1. Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, et al. 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013;65(1):1–11.
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2. Lamprecht P, Gross WL. Wegener’s granulomatosis. Herz. 2004; 29(1):47–56. 3. Hagen EC, Daha MR, Hermans JO, Andrassy K, Csernok E, Gaskin G, et al. Diagnostic value of standardized assays for anti-neutrophil cytoplasmic antibodies in idiopathic systemic vasculitis. Kidney Int. 1998;53(3):743–53. 4. Pankhurst T, Savage COS, Gordon C, Harper L. Malignancy is increased in ANCA-associated vasculitis. Rheumatology. 2004;43(12):1532–5. 5. Heijl C, Harper L, Flossmann O, Stücker I, Scott DGI, Watts RA, et al. Incidence of malignancy in patients treated for antineutrophil cytoplasm antibody-associated vasculitis: follow-up data from European Vasculitis Study Group clinical trials. Ann Rheum Dis. 2011;70(8):1415–21. 6. Knight A, Askling J, Ekbom A. Cancer incidence in a population‐based cohort of patients with Wegener’s granulomatosis. Int J Cancer. 2002;100(1):82–5. 7. Araki R, Shima T, Goto H, Imoto I, Baba M, Misaki M, Suzuki S. Wegener’s granulomatosis with papillary adenocarcinoma of the thyroid. Intern Med (Tokyo, Japan). 1992;31(8):1065–8. 8. Jeong YG, Kim TH, Lee CM, Shim KS, Moon IK, Lee SI, et al. A case of limited Wegener’s granulomatosis with gastroenteritis and mesenteric lymphadenopathy. Korean J Gastroenterol. 2010;55(5):331–5. 9. Kermani TA, Warrington KJ, Amin S. Malignancy risk in vasculitis. Ther Adv Musculoskel Dis. 2011;3(1):55–63. 10. Hoff M, Rodevand E. Development of multiple malignancies after immunosuppression in a patient with Wegener’s granulomatosis. Rheumatol Int. 2005;25(3):238–40. 11. Edgar JDM, Rooney DP, Mc Namee P, Mc Neill TA. An association between ANCA positive renal disease and malignancy. Clin Nephrol. 1993;40(1):22–5. 12. Matteson EL, Abu-Hilal MA. Rheumatic manifestations in malignancy. Curr Rheumatol Rev. 2008;4(1):50–8. 13. Emadi A, Jones RJ, Brodsky RA. Cyclophosphamide and cancer: golden anniversary. Nat Rev Clin Oncol. 2009;6(11):638–47. 14. Faurschou M, Sorensen IJ, Mellemkjaer L, Loft AGR, Thomsen BS, Tvede N, Baslund B. Malignancies in Wegener’s granulomatosis: incidence and relation to cyclophosphamide therapy in a cohort of 293 patients. J Rheumatol. 2008;35(1):100–5. 15. Villa ML, Mukherjee JJ, Tran NQ, Cheah WK, Howe HS, Lee KO. Anaplastic thyroid carcinoma with destructive thyrotoxicosis in a patient with preexisting multinodular goiter. Thyroid. 2004;14(3):227–30. 16. Miyahara H, Sato T, Ueda G, Okudaira Y. A case of Wegener’s granulomatosis with cancers of the thyroid gland and the cervix
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uteri (author’s transl)]. Nihon Jibiinkoka Gakkai kaiho. 1976;79(11): 1368–74. Lim C, Mahar A, Clark JR, McGuigan L, Felbel W, Murali R. Concurrent involvement of thyroid gland by Wegener’s granulomatosis and papillary thyroid carcinoma. Pathology. 2011;43(4):381–3. Tanaka A, Maeda K, Sawai K, Okuda J, Sugawara A, Kuwahara T. Concealed hypothyroidism in patients with myeloperoxidase antineutrophili cytoplasmic autoantibodies-(MPO-ANCA) positive renal disease. Clin Nephrol. 1999;52(2):91–5. Stone JH. Limited versus severe Wegener’s granulomatosis: baseline data on patients in the Wegener’s granulomatosis etanercept trial. Arthritis Rheum. 2003;48(8):2299–309. Belfiore A, Russo D, Vigneri R, Filetti S. Graves’ disease, thyroid nodules and thyroid cancer. Clinical endocrinology. 2001;55(6):711–8. Repplinger D, Bargren A, Zhang Y-W, Adler JT, Haymart M, Chen H. Is Hashimoto’s thyroiditis a risk factor for papillary thyroid cancer? J Surg Res. 2008;150(1):49–52. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin.2011;61(2):69–90. Al-Shukaili AK, Al-Jabri AA, Al-Moundhri MS. Prognostic value of auto-antibodies in the serum of Omani patients with gastric cancer. Saudi Med J. 2006;27(12):1873–7. Ma X. Epidemiology of myelodysplastic syndromes. Am J Med. 2012; 125(7 Suppl):S2–5. Pirayesh A, Verbunt R, Kluin PH, Meinders AE, De Meijer P. Myelodysplastic syndrome with vasculitic manifestations. J Intern Med. 2003;242(5):425–31. Savige JA, Chang L, Smith CL, Duggan JC. Anti‐neutrophil cytoplasmic antibodies (ANCA) in myelodysplasia and other haematological disorders. Aust N Z J Med. 1994;24(3):282–7. Billstrom R, Johansson H, Johansson B, Mitelman F. Immunemediated complications in patients with myelodysplastic syndromeclinical and cytogenetic features. Eur J Haematol. 1995;55(1):42–8. Das PM, Sinqal R. DNA methylation and cancer. J Clin Oncol. 2004;22(22):4632–42. Jiang Y, Dunbar A, Gondek LP, Mohan S, Rataul M, O’Keefe C, et al. Aberrent DNA methylation is a dominant mechanism in MDS progression to AML. Blood.2009;113(6):1315–25. Ciavatta DJ, Yang J, Preston GA, Badhwar AK, Xiao H, Hewins P, et al. Epigenetic basis for aberrant upregulation of autoantigen genes in humans with ANCA vasculitis. J Clin Invest. 2010;120(9): 3209–19.
ISSN: 1439-7595 (Print) 1439-7609 (Online) Journal homepage: http://www.tandfonline.com/loi/imor20
Multiple malignancies in a patient with limited granulomatosis with polyangiitis without immunosuppressive therapy Yun-Hong Cheon, Min-Gyo Kim, Ji-Eun Kim, Chang Yoon Ha, Sang-Il Lee & Hyun-Ok Kim To cite this article: Yun-Hong Cheon, Min-Gyo Kim, Ji-Eun Kim, Chang Yoon Ha, Sang-Il Lee & Hyun-Ok Kim (2014): Multiple malignancies in a patient with limited granulomatosis with polyangiitis without immunosuppressive therapy, Modern Rheumatology To link to this article: http://dx.doi.org/10.3109/14397595.2014.891494
Published online: 19 Mar 2014.
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Article views: 25
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View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=imor20 Download by: [Washington University in St Louis]
Date: 05 November 2015, At: 18:18
http://informahealthcare.com/mor ISSN 1439-7595 (print), 1439-7609 (online) Mod Rheumatol, 2014; Early Online: 1–4 © 2014 Japan College of Rheumatology DOI: 10.3109/14397595.2014.891494
CASE REPORT
Multiple malignancies in a patient with limited granulomatosis with polyangiitis without immunosuppressive therapy Yun-Hong Cheon1, Min-Gyo Kim1, Ji-Eun Kim2, Chang Yoon Ha1, Sang-Il Lee1, and Hyun-Ok Kim1 1Department of Internal medicine and Institute of Health Science, Gyeongsang National University School of Medicine, Jinju, South Korea and
Modern Rheumatology
2Department of Radiology, Gyeongsang National University School of Medicine, Jinju, South Korea
Abstract
Keywords
Here, we report the case of a 69-year-old man with limited granulomatosis with polyangiitis (GPA; formerly Wegener ’s granulomatosis) who developed papillary thyroid cancer, adenocarcinoma of the stomach, and myelodysplastic syndrome following glucocorticoid treatment. This is the first report to present multiple malignancies in a patient with limited GPA without immunosuppressive treatment. Thus, our report supports the notion that limited GPA itself can be associated with the development of malignancy.
ANCA, Granulomatosis with polyangiitis, Malignancy, Myelodysplastic syndrome, Vasculitis
Introduction Granulomatosis with polyangiitis (GPA) is a rare, systemic autoimmune disease with an unknown etiology characterized by pathologically granulomatous inflammation and systemic necrotizing vasculitis that predominantly affects the small vessels [1]. This condition primarily involves the upper and lower respiratory tracts and kidneys, but any organ system may be affected [1,2]. An antineutrophil cytoplasmic antibody specific for proteinase 3 (PR3-ANCA) is detected in approximately 95% of patients with generalized GPA [2]. Furthermore, detection of c-ANCA and the specific antigen of ANCA using immunofluorescence and enzymelinked immunosorbent assay (ELISA) is the most useful approach for diagnosing GPA and monitoring disease activity [3]. Several studies have indicated a link between GPA and cancers such as bladder cancer, renal cell carcinoma, papillary thyroid cancer (PTC), and hematopoetic cancer [4–6]. However, most of these cancers have been attributed to exposure to immunosuppressive drugs such as cyclophosphamide, and few reports have been made of cancers in patients with granulomatosis with polyangiitis following glucocorticoid treatment or prior to the administration of immunosuppressive drugs [7]. Here, we report the case of a patient who developed PTC, gastric adenocarcinoma, and myelodysplastic syndrome (MDS) after receiving a diagnosis of limited GPA and receiving treatment without immunosuppressive drugs; we also conducted a literature review.
Case report A 69-year-old man visited our hospital for an evaluation of persistent anemia. Two years previously, he had been admitted to our hospital with abdominal pain and diarrhea. The colonoscopy revealed inflammatory colitis in the descending and sigmoid colon. On abdominal computed tomography (CT), there was evidence Correspondence to: Hyun-Ok Kim, Department of Internal medicine and Institute of Health Science, Gyeongsang National University School of Medicine 79 Gangnam-ro, Jinju 660-702, South Korea. Tel: 82-55-7508069. Fax: 82-55-758-9122. E-mail: [email protected]
History Received 19 July 2013 Accepted 1 February 2014 Published online 11 March 2014
of multiple lymph node enlargement. Microscopic findings from a mesenteric lymph node biopsy showed granulomatous inflammation and necrotizing vasculitis with small-sized vessels. Immunological analysis revealed that the patient was positive for both antinuclear antigen at a titer of 1:160 and cytoplasmic antineutrophil antibodies (c-ANCA) at a titer of 1:640. He was diagnosed with limited GPA and treated with glucocorticoid alone [8]. Prior to discharge, esophagogastroduodenoscopy (EGD) was performed, which showed diffuse and mucosal nodularity on the body and antrum of the stomach. The microscopic findings were consistent with hyperplastic polyps and chronic duodenitis. There was no sign of gastric cancer. In the first year of ongoing treatment, the patient was readmitted to the hospital due to dyspnea upon exertion. His vital signs were within the normal range, with a blood pressure of 125/84 mmHg, pulse rate of 92/min, respiratory rate of 23/min, and body temperature of 36.8°C. His laboratory findings were as follows: white blood cell count, 4,660/mm3; hemoglobin, 7.2 g/dL; platelet count, 175,000/mm3; serum glucose, 76 mg/dL; cholesterol, 102 mg/dL; albumin, 3.1 g/dL; total bilirubin, 0.53 mg/dL; aspartate aminotransferase, 11 IU/L; alanine aminotransferase, 5 IU/L; blood urea nitrogen, 20.3 mg/dL; creatinine, 1.20 mg/dL; C-reactive protein, 120 mg/dL; and erythrocyte sedimentation rate, 12 mm/h. Serum viral markers were normal, with negative results for HBsAg, positive results for anti-HBs, and negative results for anti-HCV and anti-HIV. Neither proteinuria nor hematuria was observed during the urinary microscopic examination. On physical examination, there were goiter-like masses in his neck. The thyroid function test showed the following results: TSH, 0.01 mIU/L; T3, 137.80 ng/dL; Free T4, 4.37 ng/dL; thyroglobulin antibody, 11.24 IU/mL; and anti-TPO, 6.32 IU/mL. A thyroid scan revealed diffuse mild goiters with decreased uptake (1.9%). The patient was diagnosed with destructive thyroiditis and instructed to begin treatment with a beta-blocker. EGD was repeated to evaluate the cause of new-onset anemia, and the results revealed an elevated mucosal modular lesion at the lower body of the gastric lesser curvature and antrum; the microscopic findings showed moderately differentiated adenocarcinoma (Figure 1). The patient
2
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Mod Rheumatol, 2014; Early Online: 1–4
of the thyroid (Figure 4) and lymph nodes were consistent with PTC and its metastasis. Finally, the patient was diagnosed with gastric adenocarcinoma, PTC, MDS, and limited GPA. He is now undergoing iodine radiotherapy for PTC and oral chemotherapy for MDS.
Discussion
Modern Rheumatology
Figure 1. An adenocarcinoma was detected at irregular branching glands lined by pseudostratified columnar cells (100).
was diagnosed with gastric adenocarcinoma, underwent subtotal gastrectomy, and was discharged after receiving ferrous sulfate and vitamin B12 medications. After 1 year of regular follow up, new onset cytopenia was developed and unexplainable anemia persisted despite adherence to medication and surgery. Therefore, the patient was readmitted to determine the additional causes for his cytopenia and anemia (Figure 2). Bone marrow examination was performed, which revealed erythroid dysplasia and megakaryocyte dysplasia consistent with MDS (Figure 3). To evaluate additional hidden malignancies, positron emission tomography (PET)-CT was performed, and the results showed hot uptake on the left lobe of the thyroid gland and left supraclavicular lymph nodes. Fine needle aspiration was performed for the left lobe of the thyroid gland, and the microscopic findings were consistent with PTC. Thus, total thyroidectomy was performed. The microscopic findings from a surgical specimen
Here, we reported the case of a patient who developed gastric adenocarcinoma, PTC and MDS after being diagnosed with limited GPA and receiving treatment with glucocorticoid alone. Several previous studies have demonstrated an increased risk of cancer in patients with ANCA-associated vasculitis, including GPA [4,6,9]. However, only one previous case reported multiple malignancies (spinocellular carcinoma, basal cell carcinoma, Kaposi sarcoma, and urinary bladder carcinoma) in a patient with GPA. Although these multiple malignancies were related to immunosuppressive treatment [10], this was unlikely the case for our patient. Therefore, this is the first report to present multiple malignancies in a patient with limited GPA without immunosuppressive treatment. Edgar et al. first reported the finding that ANCA-associated systemic vasculitis was associated with malignant tumors [11]. The relationship between vasculitis and malignancy remains unclear, although some researchers have suggested that a dysfunctional immune system, treatment with cytotoxic drugs, common genetic susceptibility, chronic stimulation of the immune system, and autoantibody formation against various autoantigens may play roles in this association [9,12,13]. Many reports have also demonstrated that solid cancers such as bladder cancer, renal cancer, and hematologic malignancies can develop in patients with systemic GPA, although these malignancies have been largely associated with the use of cyclophosphamide [5,13,14]. However, in the present case, our patient received a diagnosis of limited GPA and was treated with steroid alone; subsequently, he was diagnosed with papillary thyroid cancer, gastric adenocarcinoma, and MDS during regular follow up. This finding supports the notion that limited
Figure 2. The Clinical course of the patient.
Modern Rheumatology
DOI 10.3109/14397595.2014.891494
Multiple malignancies in limited granulomatosis with polyangiitis 3
Figure 3. (A) Relative erythroid hyperplasia and dysplasia, including nuclear–cytoplasmic ratio asynchrony and binucleated cells, were noted. (B) Megakaryocytic dysplasia was noted; in particular, small, mononuclear megakaryocytes or megakaryocytes with separate nuclei were frequently noted.
vasculitis itself can be associated with the development of malignancy, although further study on the association between limited vasculitis and malignancy will increase our understanding of this complex relationship. PTC is a common malignancy of the endocrine system, and the incidence of this condition is increasing. Several cases of thyroid malignancy have been reported in patients with GPA, including papillary thyroid cancer, mixed papillary and follicular cancer, and anaplastic carcinoma [7,15–17]. However, the relationship between limited GPA and thyroid cancer is not clear. One study demonstrated that the coexistence of ANCA-associated vasculitis
and autoimmune thyroid disease was associated with MPO-ANCA [18], and another study revealed that patients with GPA had a higher likelihood of developing thyroid disease (Grave’s disease and thyroiditis), especially in cases of severe GPA [19]. Furthermore, many reports support the hypothesis that Grave’s disease [20] and thyroiditis [21] can increase the risk of thyroid cancer. Upon second admission, our patient was diagnosed with destructive thyroiditis, and after 1 year of follow up, he was diagnosed with papillary thyroid cancer. It is possible that ANCA-positive vasculitis may have triggered the development of thyroiditis and papillary thyroid cancer, and further study should investigate the potential relationship between ANCA-positive vasculitis, including cases of limited GPA, and the development of papillary thyroid cancer. Approximately 5% of patients with vasculitis develop malignant tumors, and in such patients, numerous malignant tumors are often found [4]. Furthermore, gastric adenocarcinoma is one of the most common malignancies worldwide [22], although the occurrence of gastric adenocarcinoma has rarely been reported in patients with GPA. In 2006, one study investigated the prevalence of autoantibodies among Omani patients with gastric cancer. In this study, anti-proteinase 3 levels were significantly higher in patients with gastric cancer than in the control groups [23], which suggests that ANCA-positive vasculitis may be associated with gastric adenocarcinoma, although the pathogenesis of the development of gastric adenocarcinoma in limited GPA is not yet clear. Our report also supports the possibility of a hidden relationship between these two diseases. MDS is considered to be a preleukemic condition and is likely to progress to acute myeloblastic leukemia. In particular, MDS should be suspected as a possible cause of unexplained anemia in elderly patients [24]. Vasculitis may develop simultaneously or precede the clinical onset of hematologic disorders such as MDS. In 1981, Pirayesh et al. reported the first case of MDS associated with vasculitis [25], and a study by Savige et al. demonstrated that ANCA could be associated with myelodysplasias such as MDS [26]. In a retrospective study of 82 MDS patients, 10 patients (12%) with MDS had immune-mediated complications; of the 10 patients there were 5 cases of skin vasculitis,1 case each with temporal arteritis/polymyalgia rheumatic, necrotizing panniculitis, Hashimoto’s thyroiditis, autoimmune thrombocytopenia, and Sweet’s syndrome [27]. Because our patient had unexplained anemia even after subtotal gastrectomy, we examined his bone marrow and then diagnosed him with MDS. MDS might lead to the defect of immunosurvaillance and aberrant DNA methylation and Ciavatta et al. recently revealed the hypomethylation of PR3 and MPO loci in patients with ANCA-associated vasculitis [28–30]. It seems difficult to discover which disease precede one another, however taking above studies into consideration, we think there is possible relationship between limited GPA and MDS. In conclusion, we report a case of limited GPA with gastric adenocarcinoma, PTC, and MDS in a single patient. Our report supports the notion that ANCA-associated vasculitis, including limited granulomatosis with polyangiitis, may increase the risk of the development of malignancies. Therefore, physicians should be aware of the risk of cancer and must pay attention to symptoms suggestive of malignancy and the possibility of hematologic malignancies, such as MDS, in patients with limited GPA.
Conflicts of interest None.
References Figure 4. The tumor revealed a complex branching papillary structure. The papillae were covered by tumor cells with an eosinophilic cytoplasm. The nuclei of neoplastic cells had irregular contours (100).
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