Histopathological Regression of Systemic AA Amyloidosis After Surgical Treatment of a Localized Castleman’s Disease

By Shimojima, Yasuhiro; Takei, Yo-Ichi; Tazawa, Ko-Ichi; Gono, Takahisa; Et al

Keywords: Amyloid regression, AA amyloidosis, Castleman’s disease

Abbreviation: CD = Castleman’s disease

Abstract

Previously, we reported a case of localized plasma cell type Castleman’s disease with severe hepatomegaly and reactive systemic AA amyloidosis. The amyloid deposits were demonstrated in both the hepatic tissue and in the gastric mucosa. Surgical resection of an isolated extra-hepatic tumor was performed. The laboratory findings, including SAA and IL-6, remained within normal limits and the patient’s hepatomegaly subsequently showed regression. Nine years after the operation, no amyloid deposition was seen in the gastric mucosa and the patient’s liver was of normal size. Our findings with long-term follow up in this case indicated that the cessation of SAA production was the probable cause of histopathological regression of AA amyloid deposits in this patient.

Introduction

Previously, we reported a case of Castleman’s disease (CD) with systemic reactive AA amyloidosis [1]. With the exception of hepatomegaly, all clinical manifestations and laboratory abnormalities improved after surgical excision of a large rctroperitoneal Iymphoid mass with pathological findings of plasma cell type of CD. Here, we report remarkable hisiopathotogical regression of tissue amyloid deposits and reduction of hepatomegaly during a 9-year follow-up after the operation.

Case report and follow-up

As reported previously [1], the patient initially presented to our hospital at age 21 with a 3-month history of exhaustion and epigastric discomfort. Her physical findings showed macroglossia and remarkable hepatomegaly without splenomegaly. Laboratory findings demonstrated increased inflammatory appearance in serum levels of C reactive protein (CRP; 13.7mg/dL), IL-6 (96.9 pg/mL, normal value <4.0 pg/mL), and SAA (422 g/mL, normal value <8.0 g/mL). Computed tomography (CT) showed an isolated mass lesion in the retroperitoneum on the border of the caudate lobe of the liver. Her enlarged liver volume calculated from abdominal CT as reported previously [2] was 4005 cm^sup 3^.

Liver and gastric mucosal biopsies were carried out with informed consent and these biopsy specimens were stained with alkaline Congo red. Liver tissue showed severe and diffuse amyloid deposits in the parenchymal sinusoidal space (Figure 1A). Her gastric mucosa also showed severe amyloid deposits with apple-green birefringence under a polarizing microscope (Figure 1B). Surgical resection of the isolated extra-hepatic tumor was performed 3 months later with a diagnosis of plasma cell type CD. The gall bladder was also removed simultaneously, and amyloid deposits on the gall bladder showed specific immunostaining with an anti-AA antibody [1]. Within 3 months after surgery, her abnormal laboratory findings decreased to within the normal ranges [1]. In addition, various clinical symptoms causing discomfort showed gradual improvement.

Nine years after the operation, laboratory examination, abdominal CT, and second gastric mucosal biopsy were performed with the patient’s informed consent. Her serum SAA and IL-6 were within the respective normal ranges (SAA: <2.5 g/mL, IL-6: 0.368 pg/mL). Neither amyloid deposition nor birefringence were seen in the gastric mucosa with alkaline Congo red staining (Figure 1C,D), and no immunoreactivity with anti-AA antibody was detected. The patient's hepatomegaly showed marked regression (Figure 2A,B) and the liver volume calculated from CT was from 4005 to 1126 cm^sup 3^. The patient did not consent to a second liver biopsy.

Discussion

Surgical resection of a pathogenic isolated proliferating lymphoid mass is ideal therapy for unicentric Castleman’s disease, effectively suppressing circulating IL-6 [3]. The hepatocytes stimulated by IL-6 produce circulating SAA, which is the precursor of AA-type amyloid fibrils [4], IL-b is also thought to act as a hepatocyte growth factor inducing hepatic proliferation that leads to hepatomegaly [5]. Liver biopsy could not be performed to confirm the decrease in amyloid deposition, while complete regression of amyloid deposits was observed on the gastric mucosa. These histopathological findings suggest that gradual regression of AA amyloid deposits occurred in the involved visceral organs in this case. The marked reduction of hepatomegaly may have been due not only to the decrease in IL-6 activity, but also to the regression of amyloid deposition within the hepatic parenchyma.

Figure 1. (A) Liver (alkaline Congo red staining, bar = 100 m). Severe amyloid deposits were seen in the parenchymal sinusoidal space of the liver tissue. (B) Gastric mucosa (alkaline Congo red staining, bar = 100 m). Apple-green birefringence in the muscular mucosa was seen under polarized light. (C,D) Second biopsy tissue of gastric rnucosa (alkaline Congo red staining; C, bar = 500 m; D, bar = 100 m). No amyloid deposition was seen.

There have been a number of previous reports of systemic AA amyloidosis associated with CD, but only two reports referred to the histopathotogical regression of renal AA amyloidosis [6,7].

Experimental AA amyloidosis can be induced easily in rodents by inflammatory stimuli, but this amyloid deposition is known to be resolved after cessation of amyloidogenic stimuli [8]. An electron microscopic study demonstrated the presence of activated macrophages in the periphery of degrading amyloid nodules, where intact appearing amyloid fibrils were seen in the cytoplasmic phagolysosomes of these macrophages [9]. However, the detailed mechanism of the regression of tissue amyloid deposits is not yet completely understood.

Figure 2. (A) Magnetic resonance imaging (MRI) of the abdomen before surgery. The enlarged right lobe of the liver reached into the pelvic space (calculated CT liver volume before surgery: 4005 cm^sup 3^). (B) CT findings of the liver 9 years after the operation, The liver volume was significantly reduced (1126 cm^sup 3^), and the lower edge of the right lobe was apparently elevated.

Our findings in this case indicated that the cessation of SAA production was the most likely cause of histopathological regression of AA amyloid deposits seen with long-term follow-up in this patient.

References

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YASUHIRO SHIMOJIMA1, YO-ICHI TAKEI1, KO-ICHI TAZAWA1, TAKAHISA GONO1, TOMOHISA FUSHIMI1, MASAYUKI MATSUDA1, YOSHINOBU HOSHII2, & SHU-ICHI IKEDA1

1 Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan, and 2 Department of Pathology, Yamaguchi University School of Medicine, Yatuaguchi, Japan

Correspondence: Dr Yo-ichi Takei, Department of Internal Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoro MO-8621, Japan. Tel: +81 263 17 2673. Fax: +81 263 37 3427. E-mail: y-takei@hsp.md.shinshu-u.ac.jp

Copyright Taylor & Francis Ltd. Sep 2006

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