Department of Medicine, Division of Nephrology, Helsinki University Hospital, Helsinki, Finland
Sir,
AA amyloidosis is a well known cause of nephrotic syndrome and renal failure. The most common underlying conditions are inflammatory diseases such as rheumatoid arthritis or ancylosing spondylitis, and infections such as tuberculosis, or in association with bronchiectasis. Malignant aetiologies have also been reported, a typical example being renal adenocarcinoma. We here report a case of a rare gastrointestinal malignancy leading to renal AA amyloidosis.
Case.
A 59-year-old male was admitted to the Department of Surgery for an operation because of a pelvic tumour. He had a history of massive obesity for years (body mass index 48), and was diagnosed as having type 2 diabetes mellitus and gout in 1989. Four years prior to the current medical problem the patient was examined for morbid obesity. The C-reactive protein (CRP) concentration (2140 mg/l) as well as the erythrocyte sedimentation rate (ESR) (4252 mm/h) were constantly elevated, but no infections were found. At that time ultrasound examination of the upper abdomen was normal, as were the serum creatinine level (92 µmol/l) and urine dipstick test. In 1998 the patient developed bladder retention. Abdominal ultrasound examination revealed a pelvic mass. Serum creatinine level was normal but mild proteinuria was seen in the dipstick test (+/+++). The ESR remained constantly elevated (52 mm/h). At surgery, a large tumour mass was found to be tightly adherent to the rectum, bladder and the prostate. Total cystoprostatectomy and mesorectum excision with Bricker's ileocutaneostomy and permanent sigmoideostomy were performed. Pathological examination showed that the tumour, 8.5 cm in diameter, infiltrated the rectal muscle wall but not the bladder or the prostate, and consisted of a necrotic and cystic inner part. The tumour was highly cellular, and the nuclei varied in size and form. There were also plenty of mitoses (15/10 HPF), and the neoplasm displayed no clear structure. Since immunohistochemical examination showed that the cells stained positive for myeloid stem cell antigen (CD-34) and c-kit proto-oncogene (CD117), the diagnosis of a gastrointestinal stromal tumour (GIST) could be made, and the tumour was considered malignant because of multiple necrotic lesions and high mitotic activity.
Pre-operative laboratory tests displayed a normal serum creatinine (94 µmol/l) but the proteinuria was increased in the dipstick test (+++/+++). CRP level was slightly elevated (36 mg/l). Perioperative bleeding amounted to 12700 ml. On the fourth post-operative day the patient presented with polyuria of 5000 to 6000 ml/day. Two weeks after the operation, the serum creatinine level rose from 94 to 321 µmol/l, serum albumin concentration declined from 24.8 to 7.0 g/l and urinary protein excretion increased to 34 g/24 h. In the renal biopsy massive glomerular amyloidosis with small amounts of amyloid in vessel walls and interstitium were observed. The amyloid stained strongly with anti-AA but not with anti- or anti-
antiserum (Figure 1
). Immunofluorescence remained unspecific. Congo-red staining performed on the removed tumour bulk showed positivity in small vessel walls of the bladder and rectum.
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Comment.
GISTs represent relatively rare (about 1% of gastrointestinal neoplasms) lesions showing minor if any differentiation, and they are thought to arise from mesenchymal elements located along the entire length of the gut. GISTs occur primarily in middle age with the peak incidence in the fifth and sixth decades. They are rare in patients under 40 years, but may be more malignant at younger age. Benign GISTs are much more common than malignant GISTs, while the incidence of the latter has been approximated to 4/1 000 000. Risk factors and the aetiology are not known. Furthermore, no clear gender difference has been shown [1].
Microscopically, two different histological patterns occur in GISTs: spindle cell and epitheloid. GISTs have a typical immunohistochemical profile. They are positive for CD34 and CD117. Less than 2 mitoses/10 high power fields (HPF) are usually prognostic for benign behaviour, whereas GISTs with mitotic counts higher than 5/10 HPF are considered histologically malignant [1,2]. It is of note that approximately 10% of all GISTs display malignant behaviour.
In AA (secondary) amyloidosis, the major infiltrative protein is the amino terminal end of serum amyloid A, an acute-phase reactant whose synthesis by the liver increases under the influence of cytokines. Its accumulation in serum and subsequent deposition in tissues occur in a wide variety of chronic infections, inflammatory, genetic (familial Mediterranean fever) and neoplastic (e.g. Hodgkin disease, renal cell carcinoma) disorders.
Several studies have reported an increase of serum amyloid A (SAA) in malignancy [4]. Certain tumours, especially lung cancer, seem to produce a very high SAA titre. Also malignancies of the stomach, colon and rectum have been shown to induce a rise in SAA level. There seems to be a positive correlation between the SAA concentration and the stage of malignancy. A lower initial SAA titre has been shown to correlate with survival, and remission after treatment has been observed to parallel a decrease in SAA [4]. There are, but few, reports of systemic AA amyloidosis in association with malignancy-induced elevation of SAA.
Our patient had had type 2 diabetes mellitus at least for 9 years, and renal function measured by serum creatinine level and urine dipstick was normal until a few weeks before hospitalization. Although the patient developed overt nephrotic syndrome and renal insufficiency the clinical course was not suggestive of diabetic nephropathy and the post-operative renal biopsy revealed AA amyloidosis.
We are not aware of the SAA level of our patient, but his CRP concentration had been elevated for at least 4 years prior to the current medical problem. Serum C-reactive protein and SAA correlate highly [5] and, given the association between malignancies and serum amyloid A concentrations, a plausible hypothesis for the origin of our patient's AA amyloidosis would be a high SAA titre produced by the massive gastrointestinal stromal tumour.
In conclusion, we hereby report a case of a rare gastrointestinal malignancy leading to renal AA amyloidosis, an association not previously reported in the medical literature.
References