Systemic AA amyloidosis and nephrotic syndrome associated with small cell carcinoma of the bladder

Ozkan Kanat1, Turkkan Evrensel1, Gulaydan Filiz2, Mehmet Usta3, Emel Baskan4, Kamil Dilek3 and Osman Manavoglu1

Uludag University Medical Faculty 1Medical Oncology 2Pathology 3Nephrology 4Dermatology Bursa Turkey Email: ozkanat{at}uludag.edu.tr

Sir,

Amyloidosis is a well-known cause of nephrotic syndrome and renal failure, which is usually associated with chronic inflammatory disease (e.g. rheumatoid arthritis), chronic infections (e.g. tuberculosis and bronchiectasis) or familial Mediterranean fever (FMF). All of these conditions are associated with elevated circulating levels of serum amyloid A (SAA). SAA is one of the acute phase proteins in inflammation and is a precursor of AA amyloid. AA amyloidosis has also been described in association with some tumours [13]. We report here the first case of small cell carcinoma (SCC) of the bladder complicated with nephrotic syndrome and renal failure due to systemic AA amyloidosis.

Case. A 57-year-old male was referred to our hospital because of generalized oedema and intermittent macroscopic haematuria of 2 months duration. He had no history of fever, recurrent infections or chronic inflammatory disease. He had neither a family history nor a clinical presentation compatible with FMF or familial amyloidosis. Systemic physical examination was found to be normal except for marked, pitting oedema on both legs.

The haemoglobin level was 11 g/dl (normochromic normocytic anaemia), the white blood cell count was 6120/mm3 and the platelet count was 254 000/mm3. The erythrocyte sedimentation rate (ESR) (120 mm/h) and C-reactive protein (CRP) (6.93 mg/dl) were elevated, but no source of infection was found. Blood chemistry was as follows: urea 90 mg/dl, creatinine 6 mg/dl, total serum protein 4.2 g/dl, albumin 1.4 g/dl, triglycerides 355 mg/dl, total cholesterol 300 mg/dl, glucose 85 mg/dl, AST 20 U/l and ALT 25 U/l, with normal serum electrolyte levels. Serum protein and immunoelectrophoresis revealed hypoalbuminaemia with no monoclonal gammopathy.

Serum IgA was 349 mg/dl (normal 93.2–445), IgG 1177 mg/dl (normal 802–1760), IgM 125 mg/dl (normal 65–280), C3 89.1 mg/dl (normal 52.6–120) and C4 37.9 mg/dl (normal 20.5–49). The urine was 4+ for protein and 10–15 red blood cells were observed per high power field. Twenty-four hour urinary protein excretion was 12 g; Bence-Jones proteinuria was not present. Serological tests for ANA, HBsAg, anti-HBsAg, anti-HCV, anti-HIV, VDRL, p-ANCA, c-ANCA, cryoglobulins, rheumatoid factor as well as tuberculin skin test were all negative.

A computerized tomography (CT) of the abdomen and pelvis showed a 4 x 3 cm solid mass on the left lateral bladder wall with no evidence of lymphadenopathy or metastasis. Cystoscopy revealed a solitary friable tumour. Transurethral resection was performed. The histopathological examination of the transurethral specimens revealed SCC of the bladder invading muscularis propria. CT of the chest, MRI of the brain and bone scan showed no evidence of metastasis. The tumour was staged as T2N0M0 and the patient underwent pelvic radiotherapy.

Proteinuria, hypoalbumin and other laboratory data suggested that our patient had nephrotic syndrome. Because of the suspicion of systemic amyloidosis, a rectal biopsy was performed, which revealed AA-type amyloid deposition. Renal biopsy also demonstrated glomerular amyloid deposition of AA type.

After transurethral resection of the tumour and pelvic irradiation (6600 cGy), urinary protein excretion decreased to 4 g/24 h, serum albumin concentration increased to 2.5 g/dl and generalized oedema partially regressed. ESR decreased to 40 mm/h and serum CRP level to 1.26 mg/dl. The patient was then treated with a combination chemotherapy regimen including cyclophosphamide, adriamycin and vincristin. Cyclophosphamide dosage was adjusted according to creatinine clearance. A total of four cycles of chemotherapy were administered. Laboratory parameters of renal function and proteinuria remained stable during chemotherapy.

Six months after the last cycle of chemotherapy, haemodialysis was started because of end-stage renal disease. The patient died without evidence of local recurrence or distant metastasis 13 months after the diagnosis of SCC of the bladder.

Comment. AA amyloidosis may occur as a complication of neoplastic disorders [13]. Secondary amyloidosis in malignancies should be diagnosed after exclusion of other formerly mentioned disorders. Several studies have reported increased SAA levels in malignancy. In cancer patients, SAA concentrations are increased due to several pro-inflammatory mediators, particularly tumour necrosis factor alpha and interleukin-6. Secondary amyloidosis in malignancies may be caused by the overproduction of SAA. Although certain tumours, such as lung and renal cell carcinoma, produce very high SAA titres [4], progression to amyloidosis occurs rarely, suggesting the role of other unknown mechanisms in the development of AA amyloidosis in malignancy.

SCC of the bladder is a rare tumour and represents <1% of all bladder neoplasms [5]. The biological behaviour and prognosis of bladder SCC is similar to that of lung SCC. The overall 5 year survival rate for all reported cases has been estimated as 8.3% [5]. To the best of our knowledge, the association of AA amyloidosis and SCC of the bladder have not been described previously. Our patient had systemic amyloid deposition proven by rectal and renal biopsies. We could not measure the serum SAA level in this patient. Although rare, the absence of any sign of a chronic inflammatory, infectious or autoimmune disease in our patient that could lead to secondary amyloidosis led us to postulate a direct correlation of secondary amyloidosis with bladder SCC.

Based on this observation and literature reports, we speculate that the prognosis of AA amyloidosis secondary to malignancy depends on the development of end-stage renal disease. If the underlying condition is cured or controlled, deposition of AA fibrils may be halted and perhaps even reversed. Thus, surgical removal of the tumour bulk may result in a marked decline in proteinuria and prevent the development of renal failure [1,3,6].

In conclusion, we presume that the concurrent presence of systemic amyloidosis, as in our case, may adversely affect survival. We suggest that SCCB be included in the list of neoplastic diseases predisposing to AA amyloidosis.

Conflict of interest statement. None declared.

References

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  3. Agha I, Mahoney R, Beardslee M, Liapis H, Cowart RB, Juknevicius I. Systemic amyloidosis associated with pleomorphic sarcoma of the spleen and remission of nephrotic syndrome after removal of the tumor. Am J Kidney Dis 2002;40: 411–415[CrossRef][ISI][Medline]
  4. Biran H, Friedman N, Neumann L, Pras M, Shainkin-Kestenbaum R. Serum amyloid A (SAA) variations in patients with cancer: correlation with disease activity, stage, primary site, and prognosis. J Clin Pathol 1986;39: 794–797[Abstract]
  5. Trias I, Algaba F, Condom E et al. Small cell carcinoma of the urinary bladder: presentation of 23 cases and review of 134 published cases. Eur Urol 2001;39: 85–90[CrossRef][ISI][Medline]
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