Japanese Journal of Clinical Oncology Advance Access originally published online on September 19, 2005
Japanese Journal of Clinical Oncology 2005 35(10):617-621; doi:10.1093/jjco/hyi156
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© 2005 Foundation for Promotion of Cancer Research
Case Report |
Secondary Amyloidosis and Eosinophilia in a Patient with Uterine Leiomyosarcoma
1 First Department of Internal Medicine, 2 Department of Gynecology and Obstetrics and 3 Department of Pathology, Ehime University School of Medicine, Ehime and 4 Department of Internal Medicine, Ehime Prefectural Imabari Hospital, Ehime, Japan
For reprints and all correspondence: Sachiko Onishi, First Department of Internal Medicine, Ehime University, Toon, Ehime 791-0295, Japan. E-mail: osachiko{at}csc.jp
Received February 12, 2005; accepted August 8, 2005
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Abstract |
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We report a rare case demonstrating the relationship between secondary amyloidosis and uterine leiomyosarcoma. A 59-year-old female with high fever was referred to our hospital. Laboratory tests revealed increased white blood cells, eosinophilia and an accelerated erythrocyte sedimentation rate. Endoscopic examination of the stomach and colon revealed amyloid deposits in their mucosa. The patient showed no symptoms that suggested amyloidosis. No other organs or tissues were surveyed for amyloid deposition. Ga scintigraphy, computed tomography and magnetic resonance imaging suggested necrotic infectious leiomyoma of the uterus, which was considered to be the cause of the fever. The patient underwent total hysterectomy. The histological diagnosis of the mass revealed a low-grade uterine leiomyosarcoma with necrosis. Amyloid deposits in the gastric mucosa disappeared 1 year after the operation. In this case, amyloid deposition was detected by endoscopic biopsy before clinical manifestations. The deposition was reversible and was successfully treated. Thus, it is logical and useful to undertake endoscopic mucosa biopsy to check for amyloid deposition in patients with systemic inflammation, whose serum amyloid A protein level has been high for several months. In addition, peripheral eosinophilia was also detected in this case. Although eosinophilia associated with malignant tumor has been recognized, it is an uncommon occurrence.
Key Words: leiomyosarcoma • uterus • secondary amyloidosis • serum amyloid A protein
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INTRODUCTION |
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Secondary amyloidosis has been reported in relation to chronic inflammation. Prominent causes of secondary amyloidosis are rheumatoid arthritis and inflammatory bowel diseases. Tuberculosis, bronchiectasis and osteomyelitis have also been reported as major causes of chronic inflammatory and secondary amyloidosis (1). The former diseases can be successfully controlled these days, whereas the latter have become less frequent. Therefore, there has been a decrease in the number of cases of secondary amyloidosis. While the relationship between secondary amyloidosis and malignancy has been described, reports are still limited. In addition, peripheral eosinophilia, which is unusual to accompany malignant tumors, was also detected in this case.
We report a case of uterine leiomyosarcoma, complicated with secondary amyloidosis and eosionphilia, which disappeared after a total hysterectomy. Eosinophilia of unknown etiology should be considered as a sign of malignancy.
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CASE REPORT |
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A 59-year-old female with lumbago and high fever was admitted to a hospital. The patient had both anemia and an increased white blood cell count. She was referred to another hospital for further examination. The white blood cell count was 18 500/µl with 15% eosinophil, hemoglobin level was 8.5 g/dl and platelet count was 48.1 x 104/µl. Autoantibody tests, including those for myeloperoxidase antineutrophil cytoplasmic antibodies and proteinase 3 antineutrophil cytoplasmic antibodies were negative. Bone marrow examination revealed myeloid hyperplasia and an increase in the number of megakaryocytes and eosinophils with normal chromosomes. The abdominal computed tomographic scan indicated no abnormalities besides the uterine tumor that had been diagnosed as uterine myoma by the gynecologist. The patient's temperature remained above 38°C. She had no asthma or other allergy symptoms such as skin rashes. She was referred to our University Hospital for further examination.
Laboratory examinations performed are listed in Table 1. The patient's urinary sediment consisted of 10 red blood cells/high-power field, no white blood cells, bacteria and casts. The urinary protein level was 264 mg/24 h. Creatinine clearance was 75 ml/min.
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In order to determine the cause of the fever, the gastrointestinal tract was endoscopically examined. Gastric erosion was detected at the pyloric antrum. Five gastric biopsies, including two from the antrum and three from the corpus, were obtained. Marked deposits of eosinophilic protein were found in all specimens (Fig. 1a). These were strongly positive for Congo Red and exhibited apple-green birefringence under a polarizing microscope (Fig. 1b). The amyloidal deposits were sensitive to potassium permanganate digestion (Fig. 1b inset). Ten biopsy specimens from the terminal ileum to the rectum were obtained during colonoscopy. Amyloid deposits were also detected in the colon mucosa. In a gallium scintigram, gallium accumulation was detected in the uterus. Magnetic resonance imaging (MRI) suggested necrotic infectious uterine leiomyoma. Antibiotic treatment was started with imipenem/cilastatin 1 g/day for 1 week followed by ciprofloxacin 600 mg and clindamycin 1200 mg/day for 2 weeks until the operation.
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One month after admission, total hysterectomy with bilateral salpingo-oophorectomy was performed. Intraoperative pelvic examination was unremarkable. The uterus weighed 400 g. An intramural mass, 7 x 10 x 5 cm in size, was located in the posterior wall. The mass was filled with yellowish-brown necrotic tissue. There was a distinct boundary between the tumor and the normal uterine tissue. There was no abscess or evidence of infection in the uterus.
Histopathological examination revealed the tumor as a well-differentiated leiomyosarcoma without amyloidosis (Fig. 2). The tumor showed tangled bundles of spindle shaped cells with necrotic foci. The tumor cells revealed a marked cellular atypia, abundant mitoses (20–28/10 high-power fields). immunohistochemistry for alpha-smooth muscle actin, vimentin, CD117 (c-kit), Ki-67 and p53 was performed using the labeled polymer method with the Envision kit® (DakoCytomation, Glostrup, Denmark) (Table 2). The immunohistochemistry results revealed that the tumor was positive for vimentin, alpha-smooth muscle actin, Ki-67 (labeling index, 40%) and CD117. Numerous eosinophil and plasma cell infiltrations were evident at the boundary between the leiomyosarcoma and normal uterine muscle tissue. No amyloidosis was found in these lesions. No metastasis was observed in the resected pelvic lymph nodes.
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On the post-operative day 3, an evaluation revealed that white blood cells and eosinophils returned to the normal ranges of 5600/µl and 2%, respectively. The C-reactive protein (CRP) levels was improved to 0.35 mg/dl by day 10 and also improved was platelets count to 269 000/µl by day 20. Four months after the operation, she was discharged from the hospital after undergoing three rounds of chemotherapy (cyclophosphamide, vincristine, doxorubicin and dacarbazine). Urinalysis revealed diminished proteinuria at that time. She visited the hospital once a month for follow-up. Biopsy specimens of the gastric mucosa showed no sign of amyloidosis after 1 year. Recurrences have not been observed for 2 years.
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DISCUSSION |
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Uterine leiomyosarcoma is a rare disease and is difficult to differentiate from benign leiomyoma, even by MRI. Uterine leiomyosarcoma presents symptoms similar to leiomyoma, such as heavy uterine bleeding, urinary frequency and abdominal pain, and is frequently asymptomatic. Leibsohn et al. (2) reported that out of 1429 patients who underwent hysterectomies due to presumed benign leiomyoma, leiomyosarcoma was histopathologically diagnosed in seven patients (0.49%). The present case is uncommon because the uterine leiomyosarcoma was accompanied by inflammation and necrosis to the extent that secondary amyloidosis developed.
Secondary amyloidosis is an unusual but recognized complication of malignancy. Renal cell carcinoma is the most common solid tumor associated with secondary amyloidosis (3). In literature, we found four cases of secondary amyloidosis associated with sarcoma (Table 3). However, to the best of our knowledge, this is the first case that provides evidence confirming a relationship between uterine leiomyosarcoma and systemic secondary amyloidosis.
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Secondary amyloidosis is known to be related to serum amyloid A (SAA). SAA is an acute phase protein and a possible serum precursor of AA-type secondary amyloidosis. Secondary amyloidosis is induced by chronic inflammatory diseases, including rheumatoid arthritis, inflammatory bowel disease and chronic bacterial infections such as tuberculosis or osteomyelitis. SAA levels are elevated in these diseases, and in some patients they form amyloid substances (1). Certain tumors also increase SAA levels. In the present case, the patient's SAA levels had increased to 1110 µg/ml.
We detected no amyloidal deposition in the uterine leiomyosarcoma. Several pro-inflammatory mediators, particularly IL-1, TNF-
and IL-6 (8), are known to increase the production of SAA proteins in the liver. In the present case, IL-6 in the serum was elevated, and it may have been produced due to inflammation of the necrosing sarcoma tissue or infection. IL-6 induces B cells to differentiate into plasma cells. This may be the reason for the uterine leiomyosarcoma being infiltrated by numerous plasma cells.
The organs most often involved in secondary amyloidosis are the kidney and the liver (1). The most frequent clinical symptoms observed are proteinuria or renal insufficiency. In the present case, the patient only complained of lower abdominal pain that we believed was caused by inflammation of the sarcoma. She did not suffer from diarrhea or constipation. Urinary protein was only 264 mg/day. She had no other symptoms suggesting amyloidosis. Amyloid deposits in the stomach were discovered only after biopsy.
To confirm the diagnosis of amyloidosis, biopsy specimens obtained from rectum, kidney, stomach and bone marrow are frequently used (2). In patients with amyloidosis, 100% of the kidney biopsy specimens typically show amyloidal deposits, while >90% of the endoscopic biopsy specimens from the digestive tract are positive. The best method for diagnosing AA amyloidosis is still controversial, however. Kidney biopsy is rather invasive and requires hospitalization. As in this case, when a patient has had substantial inflammation for a sufficiently long period, secondary amyloidosis may be detected by endoscopic biopsies regardless of the occurrence of symptoms. Inflammation elevates SAA levels and induces secondary amyloidosis. Endoscopic biopsy is reliable and is the least invasive method to detect secondary amyloidosis.
It is erroneously assumed that amyloidosis is irreversible (8). The poor prognosis associated with amyloidosis is due to the fact that the condition is generally not diagnosed until substantial organ damage has reached to an irreversible stage. Gertz and Kyle (9) reported that 35 of 47 patients with secondary systemic amyloidosis were believed to have died as a direct result of amyloidosis. In contrast, Gillmore et al. (10) reported that amyloid deposits were confirmed to have regressed in 25 of 42 patients with amyloidosis whose SAA values were within the normal range (<10 mg/l). Gillmore et al. (10) also reported that the 10 year survival rate was 90% in patients with secondary amyloidosis whose SAA level was normal, whereas it was 40% in patients with SAA levels >10 mg/l. Biran et al. (11) reported that the SAA levels correlated with the progression of cancer in the patient.
In the present case, symptoms suggesting amyloidosis were not evident. A small amount of urinary protein excreted may be considered to be its very early sign. Amyloid deposits were clearly detected in the stomach and the colon. The levels of inflammatory markers improved and amyloid deposits in the gastric mucosa disappeared after the hysterectomy. Proteinuria also diminished. We are not aware of the post-operative SAA levels in our patient; however, her CRP concentration decreased after the operation. As serum CRP and SAA are highly correlated (12), we considered that the post-operative SAA level would have decreased.
The present case shows that amyloid deposition can be detected before clinical manifestations become evident. Secondary amyloidosis is reversal and can be successfully treated during the early stage of the disease. Therefore, it is logical and useful to undertake endoscopic mucosa biopsy to check for amyloid deposition in patients in whom the SAA levels is elevated for several months.
However, peripheral eosinophilia was detected in this patient and its levels returned to normal after operation. Numerous eosinophils and plasma cells had infiltrated at the leiomyosarcoma site. Isaacson and Rapoport (13) presented 34 cases of tumor-associated eosinophilia in 1946. Since then eosinophilia associated with tumor has been recognized; however, it is an uncommon occurrence.
Peripheral eosinophilia is an extremely poor prognostic sign when associated with malignant tumors (14). However, tumors associated with tissue eosinophilia appear to have a better prognosis. Tissue and peripheral eosinophilia often occur independently. Peripheral eosinophilia was responded to therapy, so it may reflect on recurrence.
The cause of eosinophilia in malignant tumor is obscure. One study attributed it to necrosis of tumor tissue producing an eosinophylotactic response. Other studies reported that bone marrow metastases stimulated eosinophilia. We could not find evidence of bone metastases, at least no abnormality was found in the patient's bone marrow. However, although we examined the levels of certain cytokines such as IL-5 and GM-CSF that are important in regulating the development of eosinophils, they did not show elevated levels.
Patients with peripheral eosinophilia of unknown etiology should be screened for malignancy. Two cases of eosinophilia associated with uterine leiomyoma have been reported that disappeared following hysterectomy (15). However, eosinophilia does not help differential diagnosis between uterine leiomyosarcoma and uterine leiomyoma.
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References |
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1 Falk RH, Skinner M. The systemic amyloidoses: an overview. Adv Intern Med 2000;45:107–37.[Medline]
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12 Falck HM, Maury CP, Teppo AM, Wegelius O. Correlation of persistently high serum amyloid A protein and C-reactive protein concentrations with rapid progression of secondary amyloidosis. Br Med J (Clin Res Ed) 1983;286:1391–3.[Medline]
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