| Japanese Journal of Clinical Oncology | Pages |
Possible Associations of Rectal Carcinoma with Schistosoma japonicum Infection and Membranous Nephropathy: a Case Report with a Review
Introduction
Case Report
Discussion
References
Possible Associations of Rectal Carcinoma with Schistosoma japonicum Infection and Membranous Nephropathy: a Case Report with a Review
We report the first case of rectal carcinoma associated with S. japonicum and membranous nephropathy. A 57-year-old Japanese man noticed narrowing of his feces. He had lived in Yamanashi prefecture, an endemic area of S. japonicum. He had suffered from nephrotic syndrome for about 1 year. Barium enema study showed a severe stricture in the upper rectum and biopsy specimens from the tumor demonstrated well differentiated adenocarcinoma and many ova of S. japonicum. Sonography of the liver showed a network pattern and a linear high echoic area. Low anterior resection with incisional biopsy of the liver and the right kidney was performed. Histopathological findings showed well differentiated adenocarcinoma and schistosomal ova. The total number of ova in the resected colon amounted to 15 133, consisting of 2243 inside and 12 890 outside the carcinoma. The nearer to the carcinoma the area was, the higher was the density of ova. The findings of light microscopy and electron microscopy of the biopsy specimen from the kidney were compatible with membranous nephropathy (stage II). This case suggests that schistosomal ova have some effect on carcinogenesis and nephrotic syndrome. In patients with nephrotic syndrome of unknown cause, especially in inhabitants of endemic areas of S. japonicum, gastrointestinal malignancy should be ruled out as an etiological factor. Sigmoidoscopy would be useful for colorectal carcinoma surveillance in S. japonicum patients.
Key words: Schistosoma japonicum - rectal carcinoma - membranous nephropathy - distribution of ova
INTRODUCTION
Adult worms of Schistosoma japonicum live in the mesenteric veins in pairs and lay many eggs in the intestine (3000/day/pair). Many papers have been published about colorectal carcinoma cases associated with S. japonicum infection (1-11). However, it remains to be determined whether this association is significant or not.
Several researchers have reported the possible association between colorectal carcinoma and membranous nephropathy and that immune complexes derived from colorectal carcinoma might induce renal lesions (12-14) However, this issue is also controversial.
Here we report the first case of rectal carcinoma associated with S. japonicum and membranous nephropathy, with a review of the literature, and discuss the causal relation between these conditions.
CASE REPORT
A 57-year-old Japanese man noticed narrowing of his feces in April 1998. Fecal occult blood test was positive. For 18 years after his birth, he had lived in Yamanashi prefecture, an endemic area of S. japonicum, and worked as a farmer. He had been to Hong Kong and Guam Island. He had no family history of colorectal carcinoma. He had suffered from nephrotic syndrome for about 1 year. A barium enema study showed a severe stricture in the upper rectum and colonoscopy revealed a circumferential tumor at 10 cm from the anal verge. Biopsy specimens from the yellow-colored round wall demonstrated well differentiated adenocarcinoma and many ova of S. japonicum (Fig. 1). Biopsy specimens from white spots, 1 cm distal to the tumor edge, demonstrated a few ova of S. japonicum. Abdominal computed tomography (CT) showed linear calcification in the liver. Sonography of the liver showed a network pattern and a linear high echoic area, which corresponded to the CT findings (Fig. 2). Table 1 shows the laboratory data on admission. These data fulfilled the diagnostic criteria of nephrotic syndrome (urine total protein/day >3.5 g, TP <6.0 g/dl, Alb <3.0 g/dl). No drugs had been administered for his nephrotic syndrome. Renal biopsy had not been performed, so the cause of nephrotic syndrome was unclear.
Figure 1. Biopsy specimen from the round wall showing yellow color demonstrating well differentiated adenocarcinoma and ova of S. japonicum (black arrow heads) (hematoxylin-eosin staining, ×100).
Figure 2. Sonography of the liver showed a network pattern and a linear high echoic area (white arrow head) which corresponded to calcification.
Table 1. Laboratory data on admission
| Hematology: | Markers: | ||
| WBC | 5600/mm3 | HBs Ag | (-) |
| (eosinophil: 0) | HCV-Ab | (-) | |
| RBC | 531×104/mm3 | CEA | 2.6 ng/ml |
| Hb | 17.0 g/dl | CA 19-9 | 20 ng/ml |
| Ht | 49.9% | ||
| Platelets | 20.4×104/mm3 | Complement: | |
| CH50 | 41.1 [uarr] | ||
| Coagulation tests: | C3 | 94 | |
| PT | 100% | C4 | 40 |
| aPTT | 28.8 s | ||
| Immunological test (ELISA): | |||
| Blood chemistry: | S. japonicum | ||
| TP | 5.3 g/dl [darr] | Eggs: IgG [ge] 1:50(+) | |
| Alb | 2.8 g/dl [darr] | Adults: IgG [ge] 1:50(+) | |
| T. Bil | 0.8 mg/dl | ||
| GOT | 36 U/l | Urinalysis: | |
| GPT | 44 U/l [uarr] | Prot | 4+ |
| LDH | 204 U/l [uarr] | Glu | (-) |
| ALP | 174 U/l | Bil | (-) |
| [gamma]-GTP | 92 U/l [uarr] | Urob | ± |
| BUN | 15.8 mg/dl | Blood | 1+ |
| Crea | 0.9 mg/dl | ||
| Na | 139 mEq/l | Urine total protein | 4.2 g/day [uarr] |
| K | 4.4 mEq/l | ||
| Cl | 106 mEq/l | Ccr | 81 ml/min |
| T. Chol. | 250 mg/dl [uarr] | ||
| ICG 15 min | 13.1% | ||
| Serological test: | |||
| CRP | 0.3mg/dl |
On August 24, 1998, low anterior resection with incisional biopsy of the liver and the right kidney was performed. At laparotomy, the liver showed a linear contraction and many small white spots. Histopathological findings of the surgical specimen were as follows: well differentiated adenocarcinoma, type 2, 35 × 30 mm in size, with subserosal invasion, moderately lymphatic and mild vessel invasion, and positive lymph nodal metastasis (3/10), Dukes C. Schistosomal ova were detected in the rectosigmoid colonic wall, lymph nodes and liver (Figs 3-5). No dysplastic epithelium was detected around the advanced carcinoma. We counted the number of schistosomal ova in hematoxylin-eosin stained specimens. Outside the carcinoma, ova were separately observed in the mucosa, submucosa, muscularis propriae and subserosa. The total number of ova amounted to 15 133, of which 2243 were inside and 12 890 outside the carcinoma (Table 2). Ova were predominantly located in the submucosa outside the carcinoma. The distribution and density, the number of ova per centimeter, are illustrated in Fig. 6. A large difference was observed among different areas. The area where apparently many ova were located showed diffuse small spots with a yellowish color. As shown in Fig. 7, the nearer to the carcinoma the area was, the higher was the density of ova.
Figure 3. Resected specimen after formalin fixation.
Figure 4. Photomicrograph at the black arrow in Fig. 3 showed many ova both inside the carcinoma and in the submucosa outside the carcinoma.
Figure 5. Schistosomal ova in the liver (hematoxylin-eosin staining, ×100).
Table 2. Number of schistosomal ova in different areas
| No. of ova | |
| Inside carcinoma | 2243 (14.8%) |
| Outside carcinoma | |
| Mucosa | 144 (1.0%) |
| Submucosa | 12200 (80.6%) |
| Muscularis propriae | 181 (1.2%) |
| Subserosal area | 365 (2.4%) |
| Total | 15133 (100.0%) |
Light microscopy of the biopsy specimen from the kidney showed segmental proliferation of endothelial cells, thickening of the basement membrane, spike formation and splitting of the membrane in some glomeruli (Fig. 8). Immunohistochemical study showed IgG(+), C3(+), IgA(±) and IgM(±). Electron microscopy demonstrated thickened basement membrane with electron-dense subepithelial deposits, swollen epithelial cells and obliteration of epithelial cell foot processes (Fig. 9). These findings were compatible with membranous nephropathy (stage II).
Figure 6. Distribution of density of schistosomal ova in the resected specimen.
Figure 7. Correlation between density of schistosomal ova and distance from carcinoma.
The postoperative course was uneventful; however, nephrotic syndrome remained unchanged for 4 months after the rectal carcinoma was removed.
DISCUSSION
The schistosome parasite is a thread-like minute trematode parasite measuring 10-15 mm in length in males and about 22 mm in females. The adult worms are found in blood vessels in pairs. Female worms hugged by male worms in the gynecophoric canal lay eggs in the intestinal mucosa. Ova deposited in tissues develop to the larval stage, the miracidium, within 1 week. The embryonated eggs are delivered through the feces into fresh water, miracidia hatch from the eggs and then they find an intermediate snail host, Oncomelania hupensis nosophora, in the case of S. japonicum, and multiply in an asexual manner (Fig. 10). Developed larvae with a tail, cercariae, swim in fresh water to find mammalian hosts including humans and penetrate the skin and shed their tails to become a schistosomule. The schistosomule migrates to grow in the host and finally male worms form a pair with female worms in blood vessels to lay many eggs in the intestine (3000/day/pair). Some eggs are carried through the portal vein into the liver and cause egg embolism. The major pathogenic processes in schistosomiasis japonica are caused by eggs, not by adult worms, in the blood vessels. Eggs in the intestine cause damage to the mucous membrane. Egg embolism in the liver leads to more serious sequelae; egg granuloma formation finally induces fibrosis, leading to liver cirrhosis.
Figure 8. Light micrograph of the kidney showing global thickening of the glomerular basement membrane and segmental proliferation of endothelial cells (periodic acid-Schiff stain, ×100).
Figure 9. Electron micrograph demonstrating remarkable spike formation of the basement membrane with electron-dense deposits (black arrow heads) and effacement of epithelial cell foot processes.
Figure 10. Life cycle of Schistosoma japonicum.
Several reports have been published about the relation between colorectal carcinoma and S. japonicum infection. Chen et al. (11) reported that schistosomal infection was found to play an etiological role in bowel malignancy in patients having diffuse involvement of the large intestine and a history of colitic symptoms of 10 years or more, in their study of 454 colorectal carcinoma colectomy specimens. In a following study, Chen et al. (15) found that 36 of 60 surgical specimens had mild to severe grades of colonic epithelial dysplasia. They regarded these dysplastic changes in schistosomal colitis as a premalignant lesion. In the present case, however, no dysplasia was observed around the carcinoma. Amano (16) examined 1458 surgical specimens collected in three hospitals during 9 years in the Kofu area. Schistosomal eggs were detected in 78/456 (16.8%) malignant tumors and in 94/967 (9.6%) non-malignant specimens (p < 0.005). The ratio of colorectal carcinoma to gastric carcinoma in Yamanashi prefecture (1:3.5) was higher than the national average (1:6.6). He suggested that schistosomal eggs might act as a promoting factor in intestinal tumor development. Inaba (17) studied the cause of death of 2067 inhabitants in Yamanashi Prefecture and reported that S. japonicum was an important risk factor for colon carcinoma in females. Xu and Su (18) also found a positive correlation between S. japonicum infection and colorectal (especially rectal) carcinoma. The sites of carcinoma associated with S. japonicum were compared with those of controls (Table 3) (1-11,19). Both in Japan and in China, the frequency of rectal carcinoma in S. japonicum cases was higher than that in controls. Ninomiya (20) studied the distribution of schistosomal ova in 36 human cases and 16 rabbits. He reported that the number of ova was larger in the rectum than in the colon. The present report is the first attempt to analyze the correlation between the density of ova and the distance from the carcinoma in many serial sections, demonstrating that the nearer to the carcinoma the area is, the more ova tend to be detected. These data suggest that schistosomal ova have some effect on carcinogenesis.
Table 3. Sites of carcinoma with schistosomal ova in large intestine
| Reference, year | Rectum | Sigmoid | Descending | Transverse | Ascending | Cecum | Total |
| With Schistosoma japonicum | |||||||
| Japan | |||||||
| Shindo, 1976 (1) | 34 | 6 | 2 | 5 | 3 | 8 | 58 |
| Inoguchi et al., 1978 (2) | 5 | 3 | 1 | 1 | 0 | 3 | 13 |
| Naito et al., 1982 (3) | 14 | 6 | 2 | 7 | 29 | ||
| Tanabe et al., 1986 (4) | 1 | 1 | |||||
| Hashimoto et al., 1986 (5) | 1 | 1 | |||||
| Miura et al., 1987 (5) | 1 | 1 | |||||
| Abe et al., 1988 (7) | 1 | 1 | |||||
| Sekiguchi et al., 1989 (8) | 1 | 1 | |||||
| Yasunaga et al., 1992 (9) | 1 | 1 | 2 | ||||
| Okamoto et al., 1996 (10) | 1 | 1 | |||||
| Total | 57 | 18 | 5 | 6 | 4 | 18 | 108 |
| (52.8%) | (16.7%) | (4.4%) | (5.6%) | (3.7%) | (16.7%) | (100.0%) | |
| China | |||||||
| Chen et al., 1980 (11) (n = 289) | 63.4% | 15.4% | 3.4% | 8.2% | 3.1% | 6.5% | 100.0% |
| Control | |||||||
| Japan 1994 | 2881 | 2049 | 343 | 622 | 903 | 454 | 7252 |
| (39.7%) | (28.3%) | (4.7%) | (8.6%) | (12.5%) | (6.3%) | (100.0%) | |
| Chen et al., 1980 (11) (n = 165) | 43.1% | 24.6% | 3.0% | 16.2% | 7.8% | 6.5% | 100.0% |
Membranous nephropathy is reported to be associated with neoplasia such as colorectal carcinoma (12-14). Row et al. (12) suggested that the tumor might release antigen recognized as foreign and capable of evoking just the strength and type of antibody response necessary to form small complexes likely to localize in the subepithelial site. Costanza et al. (13) speculated that renal lesions were induced by soluble complexes consisting of carcinoembryonic antigen (CEA) and anti-CEA antibody. If immune complexes derived from a colorectal carcinoma cause membranous nephropathy, it would be expected to improve after the removal of tumor antigen. However, none of the four cases with colorectal carcinoma and membranous nephropathy showed any improvement of nephrotic syndrome after the carcinoma had been removed (Table 4) (12-14). These clinical results suggest that irreversible changes might have occurred in the glomeruli of these cases. There have been no clinical reports about membranous nephropathy and S. japonicum, although Tada et al. (21) have described that glomerulonephritis may be induced by the deposition of immune complexes including those due to antigen-IgE antibody interaction in monkeys experimentally infected with S. japonicum.
Table 4. Patients with membranous nephropathy and colorectal carcinoma
| Reference | No. | Gender | Age(years) | Date neoplasm diagnosed | Date nephrotic syndrome diagnosed | Site | Ova and/orparasites | CEA level(ng/ml) | Outcome | ||
| Date | Tumor | Renal lesion | |||||||||
| Row et al. (12) | 1 | F | 62 | 11/1965 | 11/1966 | Rectum | No description | No description | 8/1974 | Died of carcinomatosis | - |
| Row et al. (12) | 2 | M | 55 | 5/1972 | 5/1972 | Colon | No description | No description | 8/1974 | Carcinoma removed Still alive |
Nephrotic syndrome persists |
| Costanza et al. (13) | 3 | M | 57 | 2/1972 | 2/1972 | Sigmoid Liver metastasis | No description | 2.6 | 5/1972 | Sigmoid carcinoma removed Residual cancer in liver | Nephrotic syndrome persists |
| Couser et al. (14) | 4 | M | 60 | 11/1972 | 1/1973 | H/F | None | 10.8 | 6/1974 | Carcinoma removed Still alive |
Nephrotic syndrome persists |
| Our case | 5 | M | 57 | 7/1998 | 3/1998 | Rectum | Colon, rectumliver | 2.6 | 12/1998 | Carcinoma removed Still alive |
Nephrotic syndrome persists |
Ninomiya (20) reported that schistosomal ova were detected in the kidney in 38% (14/36) of autopsy cases of S. japonicum by a histolysis method. Andrade et al. (22) reported a correlation between renal changes and hepatosplenic schistosomiasis (S. mansoni). The life cycle of S. mansoni is similar to that of S. japonicum. Although the biopsy specimen of the kidney showed no ova, the possibility cannot be excluded that S. japonicum was involved in membranous nephropathy in the present case.
This is the first rectal carcinoma case complicated with S. japonicum infection and membranous nephropathy. In patients with nephrotic syndrome of unknown cause, especially in inhabitants of endemic areas of S. japonicum, gastrointestinal malignancy should be ruled out as an etiological factor. Sigmoidoscopy would be useful for colorectal carcinoma surveillance in S. japonicum patients.
References
Received April 21, 1999; accepted July 26 1999
For reprints and all correspondence: Keiji Matsuda, Department of Surgical Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyu-ko, Tokyo 113-8655, Japan. E-mail: matsuda-1su{at}h.u-tokyo.ac.jp
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