Malignant Peritoneal Mesothelioma in a Hemodialysis Patient with Familial Mediterranean Fever: A Case Report and Literature Review

E Sengul¹, K Yildiz², Y Topcu³, A Yilmaz¹ 

1. Department of Internal Medicine, Division of Nephrology

2. Department of Pathology

3. Department of Internal Medicine

Faculty of Medicine, University of Kocaeli, 41380, Kocaeli, Turkey

 Corresponding author:Erkan Sengul, M.D. Division of Nephrology, University of Kocaeli, 41380 Umuttepe yerleskesi/Kocaeli/TURKEY  E-mail: dr.erkansengul@hotmail.com

SMJ 2008 53(4): 10

Abstract

Malignant mesothelioma is a rare tumor. The most common localization of mesothelioma is pleura. It rarely arises from the peritoneum. It has been suggested that familial Mediterranean fever (FMF) may cause the development of peritoneal mesothelioma. We describe a case of malignant peritoneal mesothelioma in a hemodialysis patient with FMF. The patient was a 56 year old female. A history of FMF was present since her childhood. She did not use colchicine and suffered from recurrent ascites. To the best of our knowledge, this is the seventh case of FMF diagnosed as having malignant peritoneal mesothelioma in the medical literature.

Keywords: familial Mediterranean fever, inflammation, malignant peritoneal mesothelioma

Introduction  

Malignant peritoneal mesothelioma is a tumor arising from the mesothelial lining of the peritoneum. It is a relatively rare neoplasm, representing approximately one fifth to one third of all mesotheliomas.¹ The primary cause of malignant mesothelioma is asbestos exposure.² Radiotherapy has also been postulated to cause malignant mesothelioma.³ Cosmetic talk, mica, diffuse lymphocytic lymphoma are reported as other risk factors.⁴ It is also suggested that inflammation has an important role in the pathogenesis of malignant mesothelioma in patients exposed to asbestos.⁵

Familial Mediterranean fever (FMF) is a hereditary disease, and mainly affects certain ethnic groups including Jews, Anatolian Turks, the Arabs of the Middle East, and Armenians. The frequency of the mutant gene leading to FMF in these populations is very high and it is known that there are more than 100 000 patients with FMF in the worldwide. It is characterized by self-limited recurrent attacks of fever and serositis. The development of amyloidosis is the most serious complication in FMF. Amyloidosis usually affects the kidneys, and leads to chronic renal failure.^{6, 7}

FMF is not an autoimmune disease, but an inflammatory disease. Laboratory findings are consistent with nonspecific inflammation. The levels of some inflammatory mediators including serum amyloid A, fibrinogen, erythrocyte sedimentation rate (ESR), serum C-reactive protein (CRP) and white blood cell count are increased during acute FMF attacks.⁵ Furthermore, there is evidence of inflammatory activity between attacks.⁸ Therefore, it is possible to suggest that chronic inflammatory activity is a factor leading to malignant mesothelioma in these patients.

Six case of malignant peritoneal mesothelioma associated with FMF have been described in the medical literature up to now.^{4, 9-12} Our case is the seventh report supporting a possible link between malignant peritoneal mesothelioma and FMF. Pleural mesothelioma has been also reported in a patient with FMF.¹³

Case Report 

A 56 year old female of Turkish ancestry was admitted due to a history of decreased appetite, progressive weight loss, abdominal enlargement and pain for six months. At age 46, she was investigated due to recurrent ascites but any laboratory and radiologic findings could not be obtained about the etiology of ascites formation. At that time asked cautiously, she described episodes of abdominal pain and fever recurring three-five times a year from age 9 until age 46. Those episodes generally lasted 24-48 hours and spontaneously subsided.

The diagnosis of FMF was made based on recurrent abdominal pain, fever and unexplained ascites. She was investigated for mutations causing FMF and was established to be heterozygous for both M694V and R761H mutations by reverse hybridisation.

She was treated with colchicine. However, she didn’t take colchicine regularly. The clinical and laboratory findings of patient revealed to develop chronic renal failure after six years. A rectal biopsy was positive for amyloid. She underwent routine hemodialysis for 4 hours 3 times a week for 4 years. 

On physical examination, she had abdominal distention. Hepatomegaly, splenomegaly, ascites, and palpable irregular masses at right inguinal and suprapubic areas were noted. Abdominal ultrasonography showed increased liver and spleen sizes (17 cm and 16 cm respectively), multiple mesenteric tumoral masses, multiple mesenteric and paraaortic lymph nodes, and marked ascites. Magnetic resonance imaging confirmed the ultrasonographic findings. Predialysis laboratory analysis showed that blood urea nitrogen (BUN) was 56 mg/dL, creatinine was 5.9 mg/dL, potassium was 5.5 mEq/L, calcium was 9.7 mg/dL, uric acid was 6.3 mg/dL, albumin was 3.5 g/dL, iron was 36 μg/dL, iron binding capacity was 232 μg/dL, transferrin saturation was 15.51 %, ferritine was 4078 ng/mL, CRP was 4.3 mg/dL, ESR was 59 mm/h, Hematological data revealed that hemoglobin was 9.3 g/dL, white blood cell count was 9330 /mm³, platelet count was 235.000/mm³. Kt/V was 1.83, urea reduction ratio (URR) was 76 %. Pathological specimens were obtained by computed tomography guided biopsy because she did not approve laparoscopic procedure. Histological examination was concordant with malignant mesothelioma. Immunohistochemical studies demonstrated strongly positive staining of the neoplastic cells for calretinin and cytokeratin (Figure 1A, B). Immunohistochemical findings were very suggestive of malignant mesothelioma. She was a nurse and there was not a history of asbestos exposure. The patient did not approve any therapy and died after four months.

Discussion 

We report a case of malignant peritoneal mesothelioma in a hemodialysis patient with FMF. The medical literature is also reviewed to investigate whether there is a possible association between malignant peritoneal mesothelioma and FMF. Malignant peritoneal mesothelioma is a rare tumor of the peritoneum, arising both from visceral and parietal peritoneum. It is usually diagnosed in advanced stages and regarded as a fatal disease. The origin of mesotheliomas often is pleura and only 20% to 33% of all mesotheliomas arise from the peritoneum. The role of asbestos as a cause of peritoneal mesothelioma is less established than pleural mesothelioma.^{1, 2, 14}

FMF is an autosomal recessive disease. The mutations in MEFV gene have been demostrated to cause FMF. This gene was described on chromosome 16. It encodes a 781 aa protein called pyrin. Pyrin is likely to be a nuclear factor that controls the inflammatory response in differentiated polymorphonuclear leukocytes (PMNs). A mutated pyrin probably leads to uncontrolled inflammation by the production of interleukine-1 and the inhibition of apoptosis of leukocytes. FMF attacks are characterized by a massive influx of PMNs into the affected compartment.^{6, 7}

FMF is characterized by recurrent febrile episodes of sterile peritonitis, pleuritis, and arthritis. Abdominal pain is the most common presenting feature of FMF.⁵ There are two different phenoypic expressions in FMF patients. Type I FMF usually presents with recurrent episodes of peritonitis, pleuritis, and arthritis. In type II FMF, the major feature is the development of systemic AA-amyloidosis particularly affecting the kidneys. In many cases, amyloidosis precedes the abdominal symptoms and may be only manifestation of the disease.¹⁰

Colchicine has significantly changed the course of FMF. Most patients become asymptomatic with colchicine.⁵ However, Lachmann et al showed that substantial subclinical inflammation occured during clinical quiescence in patients with FMF.⁸ In another study, Notarnicola et al demostrated that cytokine expression at the transcriptional level were increased in attack-free FMF patients than in controls and that there was no significant difference according to colchicine treatment.¹⁵

Encapsulating peritonitis, massive recurrent ascit, intestinal volvulus and necrosis have been reported as the FMF related complications.^16-18 FMF is also suggested as a possible risk factor for malignant peritoneal mesothelioma. This opinion are supported by the unusual localization of malignant mesothelioma in FMF patients and the presence of subclinical inflammation between attacks.

It has been also suggested that MEFV functions as an oncogenic supressor gene and a mutation in this gene may lead to the development of mesothelioma.^{9, 10}

Chahinian et al. prospectively evaluated 69 patients with diffuse malignant mesothelioma. 12 were diagnosed malignant peritoneal mesothelioma and one had FMF.⁴ Gentiloni et al. described malignant peritoneal mesothelioma in a patient with FMF. FMF was diagnosed during adolesence. He did not take colchicine.¹⁰ Belange et al reported the patient with FMF diagnosed peritoneal mesothelioma. The duration of FMF was 30 years. He suffered from relapsing ascites for seven years.¹¹ Bani-Hani et al retrospectively reviewed the records of seven patients with malignant peritoneal mesothelioma. One of them had FMF. The patient did not exposure asbestos or other risk factors.¹² Hershcovici et al reported two cases of malignant peritoneal mesothelioma with FMF. Both patients were Jewish descent and homozygous for the M694V mutation. FMF was diagnosed during childhood and adolesence in these patients. One did not take colchicine. The other had peritoneal adhesions.⁹ Lidar et al reported pleural malignant mesothelioma in a patient with late onset FMF.¹³

In the present case, she had a long history of FMF and recurrent ascites. she did not use colchicine regularly. Reported cases of malignant mesothelioma associated with FMF are summarized in Table 1.

Table 1. Reported cases of malignant mesothelioma associated with FMF (1982-2008)

        Abbreviations: F= female, M= male, NR = not reported, * = the present case

In conclusion, this review has shown that malignant peritoneal mesothelioma is more common than pleural mesothelioma in FMF patients. There was no history of exposure for asbestos or other risk factors in these patients. The regular use of colchicine was described only two patients. One had profuse and recurrent ascites. All of them had a long history of FMF. These findings indicate that the long term inflammation in FMF patients may lead to the development of malignant mesothelioma. Therefore, it is advisable that FMF patients should be encouraged for using colchicine.

References 

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4- Chahinian AP, Pajak TF, Holland JF, Norton L, Ambinder RM, Mandel EM. Diffuse malignant mesothelioma. Prosspective evaluation of 69 patients. Ann Intern Med 1982; 96: 746–755.

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8- Lachmann HJ, Sengul B, Yavuzsen TU, et al. Clinical and subclinical inflammation in patients with familial Mediterranean fever and in heterozygous carriers of MEFV mutations. Rheumatology 2006; 45: 746–750.

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13- Lidar M, Pras M, Langevitz P, Livneh A. Thoracic and lung involvement in familial Mediterranean fever (FMF). Clin Chest Med 2002; 23: 505–511.

14- Bridda A, Padoan I, Mencarelli R, Frego M. Peritoneal Mesothelioma: a review.  MedGenMed 2007; 9: 32.

15- Notarnicola C, Didelot MN, Seguret F, Demaille J, Touitou I. Enhanced cytokine mRNA levels in attack-free patients with familial Mediterranean fever. Genes Immun 2002; 3: 43–    45.

16- Dabak R, Uygur Bayramicli O, Aydın DK, et al. Encapsulating peritonitis and familial Mediterranean fever. World J Gastroenterol 2005; 11: 2844-2846.

17- Cekin AH, Dalbudak N, Künefeci G, Gür G, Boyacıoğlu S. Familial Mediterranean fever with massive recurrent ascites: A case report. Turk J Gastroenterol 2003; 14: 276-279.

18- Tireli GA, Unal M, Sander S. An unusual complication of familial Mediterranean fever: intestinal volvulus and necrosis. Turk J Gastroenterol 2006; 17: 231-232.

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