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Int. J. Cancer: 71, 517–520 (1997)
r 1997 Wiley-Liss, Inc.
Publication of the International Union Against Cancer
Publication de l’Union Internationale Contre le Cancer
CANCER RISK AFTER RENAL TRANSPLANTATION IN JAPAN
Yoshihiko HOSHIDA1, Hideaki TSUKUMA2, Yutaka YASUNAGA1, Ning XU1, Masaki Q. FUJITA1, Takaomi SATOH3, Yasuji ICHIKAWA4,
Kenji KURIHARA5, Masaaki IMANISHI6, Tsuyoshi MATSUNO7 and Katsuyuki AOZASA1,*
1Department of Pathology, Osaka University Medical School, Suita, Osaka, Japan
2Department of Field Research, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan
3Department of Surgery, Sendai Shakai Hoken Hospital, Sendai, Miyagi, Japan
4Department of Urology, Hyogo Prefectural Nishinomiya Hospital, Nishinomiya, Hyogo, Japan
5Department of Pathology, Uwajima City Hospital, Uwajima, Ehime, Japan
6Department of Urology, Kinki University, Sayama, Osaka, Japan
7Department of Surgery, Okayama University, Okayama, Japan
Excess of cancer in patients receiving renal transplantation
is well-known in Western countries, but information in Japan
remains limited. Our study examined whether excess risk is
found in patients receiving renal transplantation in Japan.
Between 1970 and 1995, 1155 males and 589 females underwent renal transplantation in 6 hospitals, and a total of 12,982
person-years of observation was accumulated. Malignancies
developed in 2.6% of patients; O/E ratio was 2.78. Median
interval from renal transplantation to tumor development
was 58 months. The interval in the patients receiving medication with cyclosporine-A (CyA) (median, 42.5 months) was
significantly shorter than that with non-CyA (median, 95.5
months). Median age at the diagnosis of malignancy was 40
years, which is much younger than that in the general
population. Relative risk was highest in renal cancer, followed
by thyroid cancer, malignant lymphoma and uterine cancer.
A distribution of malignancies was different from that reported from Western countries. These findings showed the
excess risk of malignancies in Japan with renal transplants,
especially in male patients, similar to that observed in Western countries, though the types of malignancy were different.
Int. J. Cancer 71:517–520, 1997.
r 1997 Wiley-Liss, Inc.
Excess of cancer in patients receiving renal transplantation is
well known in Western countries: the frequency of cancer development was reported to be 6% in the United States (Penn, 1994) and
8.3% in the Nordic countries (Birkeland et al., 1995). These studies
showed a 4.5- to 6.3-fold increase in risk for cancer compared with
the general population. Depression of immune surveillance owing
to the use of immunosuppressive agents was considered to cause
cancer development (Kinlen et al., 1979). In the countries mentioned, cancers of the skin and lips (non-melanotic) and malignant
lymphoma were the commonest malignancies. In Japan, though
information on malignancies after renal transplants remains limited, some studies have suggested a pattern of cancer development
different from that in Western countries, gastric cancer being the
commonest malignancy (Ochiai et al., 1987; Gunji et al., 1990). In
these studies, however, histologic diagnoses of malignancies were
not confirmed, and relative risk for cancer development was not
shown.
In order to qualify and quantify the risk for cancer associated
with renal transplants, a nation-wide study in Japan was carried out
in 1995 and 1996. We reviewed all the histologic specimens of
developed cancers, and examined the excess risk of malignancies.
PATIENTS AND METHODS
Study subjects
Renal-transplant patients in 6 hospitals in Japan (Osaka University Hospital, Sendai Shakai Hoken Hospital, Hyogo Prefectural
Nishinomiya Hospital, Uwajima City Hospital, Kinki University
Hospital and Okayama University Hospital) were studied regarding
the O/E ratio of developing malignancies. These hospitals were
representative institutes for renal transplantation in Japan, the
number of transplant patients in each hospital being 417, 381, 285,
316, 144, and 201, respectively. Patients were admitted to the
hospitals during the period 1970 to 1995; all patients were followed
up to the end of 1995 for vital status and development of
malignancies. No special methods for detection of cancer were
used if the patients were without symptoms. Diagnosis of malignancy was made on the basis of histologic examination of biopsy
materials in each hospital. All the histologic specimens were
collected, and reviewed by one of us (Y.H.). Consequently, all the
original histologic diagnoses were confirmed.
Statistical analysis
The observed number (O) of malignancies developed following
renal transplants was compared with the expected number (E) in
the general population, according to the selected site of malignancy
and number of years elapsed since transplantation. The relative risk
(RR) was shown by the O/E ratio. Each individual was considered
to be at risk from the date of the first renal transplantation until
death. The expected number of cases with malignancies was
calculated by applying age- and calendar-year-specific incidence
rates from Osaka Cancer Registry, which was founded in 1962 for
the purpose of registering all malignant tumors and benign
intracranial tumors arising in Osaka Prefecture, Japan (1990
Census population, 8.7 millions). A computer program developed
by Monson (1984) was used for these calculations. The significance of the O/E ratio was tested by Poisson-distribution analysis
(Bailar et al., 1954), while 95% confidence intervals (CI) were
calculated using the CIA statistical package (Gardner et al., 1989).
The interval between renal transplantation and tumor development
in patients medicated with CyA and with non-CyA was evaluated
by the Chi-squared test.
Histological and immunohistochemical analysis
Histologic specimens obtained by biopsy or autopsy were fixed
in 10% formalin and routinely paraffin-embedded. Histologic
sections, 6-µm thick, were stained with hematoxylin and eosin.
Immunohistochemical procedures were performed for cases of
malignant lymphoma with monoclonal antibodies Mx-panB (CD20)
(Kyowa Medex, Tokyo, Japan, diluted at 1:50), MB-1 (Bioscience,
Emmenbrucke, Switzerland, diluted at 1:50), MT-1 (CD43) (Bioscience, diluted at 1:50), UCHL-1 (CD45RO) (Dakopatts, Glostrup,
Denmark, diluted at 1:100), and OPD4 (Dakopatts, diluted at
1:100). Mx-panB and MB-1 react with human B lymphocytes and
MT-1, UCHL-1, and OPD4 with T lymphocytes.
RESULTS
In all, 1155 males and 589 females underwent renal transplantation during the period 1970 to 1995 in 6 hospitals. Up to December
Contract grant sponsor: Ministry of Education, Science and Culture;
Contract grant numbers: 08457061, 08670202, and 08770126.
*Correspondence to: Department of Pathology, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka 565, Japan. Fax: 81-6-879-3719.
Received 12 September 1996; revised 13 December, 1996
HOSHIDA ET AL.
518
31, 1995, 229 patients had died, 1441 patients were alive, and 74
patients were lost to follow-up. When these 74 patients were
included among the living patients, a total of 12,982 person-years
of observation were accumulated. Ages of patients at transplantation ranged from 3 to 65 (median 36) years. As immunosuppressive
agents, cyclosporine A (CyA) was used in 1166 patients, and other
agents (non-CyA) in 578.
O/E ratios of tumor development
At 6 hospitals, 46 of 1744 patients (2.6%) were diagnosed as
having malignancies (Table I). The O/E ratios according to the
elapsed years from renal transplantation are shown in Table II; risk
of tumor development in transplant patients was 2.78-fold higher
than in the general population ( p , 0.01). Except for uterine
cancer, only male patients showed increased risk. Risk is highest in
the first year after transplantation and decreases through the time
course. The O/E ratios by site of malignancy are shown in Table III.
RR was highest in renal cancer (79.96, p , 0.01), followed by
thyroid cancer (12.43, p , 0.01), malignant lymphoma (11.10,
p , 0.01) and uterine cancer (4.12, p , 0.05). Age of patients at
transplantation and at diagnosis of malignancy ranged from 15 to
51 (median 36) years and from 19 to 63 (median 40) years
respectively.
The O/E ratio was significantly high between 25 and 50 years of
age at the time of diagnosis of malignancy, especially between 25
and 30 years of age (Table IV). Intervals between renal transplantation and tumor development ranged from 35 days to 162 months
(median 58 months). The risk was the highest in the first year after
renal transplantation: 5 malignancies, including 2 cases of renal
cancer and one case each of malignant lymphoma, thyroid cancer,
and seminoma. The intervals in patients medicated with CyA (32
cases) and non-CyA (14 cases) ranged from 5 to 132 months
(median 42.5 months) and 35 days to 162 months (median 95.5
months) respectively. This difference in the interval was statistically significant by Chi-squared analysis ( p , 0.05). As shown in
Table V, O/E ratio was higher in patients with CyA medication than
in those with non-CyA medication, especially in renal and skin
cancers.
Histology of malignancies
Histologic types of malignancy are summarized in Table VI. All
renal cancers were renal-cell carcinomas. Gastric cancers were
classified as tubular adenocarcinoma in 5 cases and poorly
differentiated carcinoma in one case. None of the gastric cancers in
the present study showed a lympho-epitheliomatous pattern of
proliferation. The primary site of malignant lymphoma was extranodal in all 5 cases, the ileum in 2 cases, and lung, skin and spleen
in 1 case each. Histologically, all were non-Hodgkin’s lymphoma
(NHL), and 4 were diffuse lymphoma of the large-cell type, while
TABLE I – MALIGNANCIES DEVELOPED IN RENAL-TRANSPLANT PATIENTS
Type of tumor
Renal cancer
Gastric cancer
Non-Hodgkin’s
lymphoma
Uterine cancer
Thyroid cancer
Breast cancer
Bladder cancer
Sarcoma2
Other3
Total
Interval for tumor
development (months)
Number
of cases
(%)
Median
age1
(years)
Hemodialysis
Transplantation
15 (32.6)
6 (13.0)
5 (10.9)
41.0
41.0
40.0
114
140
98
35
97
57
4 (8.7)
3 (6.5)
2 (4.3)
2 (4.3)
3 (6.5)
6 (13.0)
46
31.0
38.0
43.0
43.5
40.5
40.0
40.0
99
61
117
129
75
98
97
94
33
36
63
38
58
58
1Median age at diagnosis of malignancy.–2Hepatic leiomyosarcoma
(1), hepatic osteosarcoma (1), and retroperitoneal liposarcoma (1).–
3Liver cancer (1), tongue cancer (1), salivary gland cancer (1), colon
cancer (1), seminoma (1) and skin cancer (1).
one was of the pleomorphic-cell type. Immunohistochemistry
revealed that 3 cases were B-cell type, and 2 T-cell type. All the
thyroid cancers were papillary carcinoma, and liver cancer was
hepatocellular carcinoma. There was one case of liposarcoma in the
retroperitoneal cavity and one case of leiomyosarcoma and one of
osteosarcoma primarily arising in the liver. This is extremely rare
among the general population. Among cases with uterine cancers,
one was adenocarcinoma of the endometrial-cell type arising from
the corpus, and 3 were epidermoid carcinoma of invasive type
arising from the cervix. One of the breast cancers was Paget’s
disease.
Original renal diseases in transplants
Causes of renal failure in current patients included chronic
glomerulonephritis in 27 cases (IgA glomerulonephritis in one,
others in 26), acute glomerulonephritis in 3, polycystic kidney in 2,
congenital hypoplastic kidney, chronic pyelonephritis, and iatrogenic bilateral hydronephrosis in 1 case each, and unknown causes
in 11. One of the 27 cases with chronic glomerulonephritis showed
a nephrotic syndrome.
DISCUSSION
The frequency of malignancies in current patients with renal
transplantation was 2.6%, lower than that reported from Western
countries (6–8%; Penn, 1994; Birkeland et al., 1995). The RR for
tumor development in renal transplants was 2.78-fold higher than
that in the general population in Osaka, Japan, which was also
lower than the value reported from England (6.3-fold higher) (Gaya
et al., 1995) and the Nordic countries (4.6 in males and 4.5-fold in
females) (Birkeland et al., 1995). When comparing RR in Japan
with that in Western countries, however, the following points
should be taken into account: (i) we used the expected number of
malignancies from the Osaka Cancer Registry, which is higher than
that in other districts of Japan (Parkin et al., 1992); (ii) 74 patients
lost to follow-up were conventionally included in the living
patients, resulting in an increase of person-years of observation.
These factors lowered the O/E ratio of malignancies in the current
study.
The current study revealed that renal cancer (32.6%) was
commonest, followed by gastric cancer (13.0%), malignant lymphoma (10.9%) and uterine cancer (8.7%). As for detection bias,
special procedures in the detection of malignancy including renal
cancer were not employed in the current series. Earlier studies in
Japan have shown that the commonest cancer in renal-transplant
patients were hepatocellular carcinoma (18–19%) and gastric
cancer (16–18%) (Ochiai et al., 1987; Gunji et al., 1990). Although
this difference could not be explained, our current data were based
on a large number of cases with careful histologic diagnosis. As a
background, the frequency of hepatitis B- and C-virus-associated
hepatocellular carcinoma (HCC) among all HCC cases in the US
and in Japan were 38 and 27% (Yu et al., 1990) and 21 and 51%
(Tanaka et al., 1991) respectively, showing a relatively similar
frequency of combined hepatitis-B- and C-virus-associated HCC.
Gastric cancer is a common malignancy in Japan, not only in the
general population but also in renal-transplant patients. Epidemiological studies have suggested that Japanese-style dietary habits
represent a major risk factor in gastric cancer (Inoue et al., 1994).
RR for development of malignancies in the current cases was
quite different regarding primary sites from that in Western
countries (Penn, 1994; Birkeland et al., 1995; Gaya et al., 1995):
lower frequency of skin cancer, absence of Kaposi’s sarcoma, and
higher frequency of renal and thyroid cancer in Japan. Incidence
rates of non-melanotic skin cancers in males and females in the
general population are reported to be 1.2 and 0.9 in Osaka, Japan
(Parkin et al., 1992) and 144.9 and 73.3 among ‘‘Anglo-Saxons’’
(Waterhouse et al., 1976), showing much higher rates in ‘‘AngloSaxons.’’ This may underlie the lower frequency of skin cancer in
the current series. In registration of non-melanotic skin cancers,
CANCER RISK AFTER RENAL TRANSPLANTATION
519
TABLE II – OBSERVED (O) AND EXPECTED (E) NUMBERS OF MALIGNANCIES IN RELATION TO CALENDAR YEAR
FROM THE TIME OF RENAL TRANSPLANTATION
Year
Total
Males
E
O/E (95% CI)
O
5
1.46
1–4
18
5.52
5–9
16
5.61
10–14
6
3.04
3.421
(1.07–7.68)
3.082
(1.79–4.78)
3.032
(1.43–4.07)
1.97
(0.59–3.51)
0
1p
O
Females
E
O/E (95% CI)
O
E
O/E (95% CI)
4
1.01
1
0.45
14
3.84
4
1.68
11
3.89
5
1.72
4
2.30
3.941
(1.03–9.66)
3.392
(1.83–5.62)
3.082
(1.20–4.31)
1.74
(0.37–3.48)
2
0.75
2.23
(0.06–12.10)
2.38
(0.62–5.79)
2.91
(0.89–6.41)
2.68
(0.31–9.26)
, 0.05.–2p , 0.01.
TABLE III – OBSERVED (O) AND EXPECTED (E) NUMBERS OF MALIGNANCIES BY SITE IN
RENAL-TRANSPLANT PATIENTS
Total
Site
Males
Females
O
O/E (95% CI)
O
O/E (95% CI)
O
O/E (95% CI)
All sites
46
34
6
Liver
3
Breast
2
Uterus
4
Urinary bladder
2
2.911
(1.73–3.49)
1.50
(0.42–3.02)
0.96
(0.10–2.91)
0.00
(0–369.00)
0.00
(0–0)
7.14
(0.73–21.90)
91.631
(44.20–130.00)
12.63
(0.28–61.90)
11.151
(2.95–27.70)
12
Stomach
2.781
(1.80–3.28)
1.40
(0.45–2.68)
1.36
(0.24–3.36)
1.53
(0.18–5.27)
4.122
(1.07–10.00)
6.61
(0.69–20.60)
79.961
(39.98–114.95)
12.431
(2.38–33.70)
11.101
(3.53–25.40)
2.461
(1.21–4.09)
1.05
(0.03–5.57)
8.14
(0.20–42.90)
1.53
(0.18–5.27)
4.122
(1.07–10.00)
0.00
(0–184.00)
0.00
(0–123.00)
12.332
(1.42–42.50)
10.89
(0.25–55.70)
Kidney
15
Thyroid gland
3
Malignant lymphoma
5
1p
5
2
0
0
2
15
1
4
1
1
2
4
0
0
2
1
, 0.01.–2p , 0.05.
TABLE IV – OBSERVED (O) AND EXPECTED (E) NUMBERS OF MALIGNANCIES IN RELATION TO AGE AT
DIAGNOSIS OF MALIGNANCY
Total
Male
Female
Age
(years)
O
E
O/E (95% CI)
O
E
O/E (95% CI)
O
E
O/E (95% CI)
25–30
4
0.34
2
0.20
0.14
7
0.92
5
0.50
1
0.43
35–40
7
2.01
5
1.09
2
0.92
40–45
9
2.87
7
1.68
2
1.19
45–50
8
2.63
6
1.72
9.992
(1.15–34.40)
12.101
(3.06–22.00)
4.582
(1.40–10.10)
4.171
(1.55–7.92)
3.482
(1.15–6.80)
2
30–35
11.701
(3.11–29.30)
7.591
(2.93–15.00)
3.491
(1.33–6.80)
3.131
(1.36–5.64)
3.032
(1.20–5.49)
2
0.91
14.122
(1.61–48.20)
2.35
(0.58–12.70)
2.18
(0.25–7.53)
1.69
(0.20–5.92)
2.20
(0.26–7.60)
1p
, 0.01.–2p , 0.05.
basal-cell carcinoma may not be included in some registries in
Japan. This may also lower the recorded frequency of skin cancer
in Japan.
Among normal Japanese and Western populations, the incidence
rate of renal cancer was higher in the West than in Japan, while that
of gastric cancer was higher in Japan than in the West, and that of
thyroid cancer was similar (Parkin et al., 1992); that of cancer of
the uterus was higher in Japan (Parkin et al., 1992). Sarcomas
developed in 3 patients, 2 in the liver and 1 in the retroperitoneal
cavity. Penn (1994) reported an increased incidence of sarcomas in
organ-transplant recipients.
The median interval between renal transplantation and tumor
development was 58 months. The risk was highest in the first year
after renal transplantation. No special detection procedures were
carried out and no attention was paid to development of malignancy during this period. The interval in patients receiving
medication with CyA (median 42.5 months) was significantly
shorter than that with non-CyA (median 95.5 months) ( p , 0.05),
suggesting that medication with CyA accelerates tumor development in renal-transplant patients. Tumors developed in the first year
in 3 of 32 patients (9%) and in 2 of 14 patients (14%) receiving
CyA and non-CyA medication respectively. O/E ratio in patients
with CyA medication was markedly higher for those with renal and
skin cancers than for those without.
Median age at diagnosis of malignancy in the current series was
40 years, which is much younger than that in general in Japan (64
years): fewer than 5% of cancer patients are diagnosed below 40
years of age as having the same types of malignancy as observed in
HOSHIDA ET AL.
520
TABLE V – OBSERVED (O) AND EXPECTED (E) NUMBERS OF MALIGNANCIES
IN RELATION TO CYCLOSPORINE-A (CyA) MEDICATION
Site
All sites
CyA medication
O
30
Skin
1
Kidney
12
Thyroid gland
1
Malignant lymphoma
4
1p
O/E (95% CI)
Non-CyA medication
O
O/E (95% CI)
3.451
16
2.062
(2.13–4.51)
(1.18–3.34)
79.132
0
0.00
(2.53–557.00)
(0–369.00)
1
122.13
3
33.951
(44.30–150.00)
(5.62–79.70)
7.67
2
18.322
(0.18–39.80)
(2.06–66.15)
17.401
1
4.59
(4.36–41.00)
(0.11–24.20)
, 0.01.–2p , 0.05.
TABLE VI – HISTOLOGIC TYPES OF MALIGNANCY
Site
Tongue
Salivary gland
Stomach
Colon
Liver
Retroperitoneum
Skin
Breast
Uterus
Cervix
Corpus
Testis
Urinary bladder
Kidney
Thyroid gland
Malignant lymphoma
Total
Histologic type
Squamous-cell carcinoma
Duct carcinoma
Adenocarcinoma
Adenocarcinoma
Hepatocellular carcinoma
Leiomyosarcoma
Osteosarcoma
Liposarcoma
Squamous-cell carcinoma
Solid tubular carcinoma
Paget’s carcinoma
Squamous-cell carcinoma
Adenocarcinoma
Seminoma
Transitional-cell carcinoma
Renal-cell carcinoma
Papillary carcinoma
Non-Hodgkin’s lymphoma
Malignant lymphomas that developed in current cases shared
common features with those reported from the Western countries,
except for the rarity of lymphoma of the central nervous system:
large-cell morphology, preponderance of B-cell immunophenotype, and extranodal origin. Penn (1994) reported that treat with
CyA decreased the incidence of skin cancer, but increased that of
NHL and Kaposi’s sarcoma. In contrast, Gaya et al. (1995) reported
that the frequency of NHL was higher in patients receiving
azathioprine and prednisolone than those receiving CyA. In the
current cases, the number of patients developing NHL and renalcell carcinoma was higher in patients receiving CyA than in others.
The nephrotoxicity of CyA might be a partial reason (Klintmalm et
al., 1981).
In conclusion, our study shows increased incidence of malignancies in Japanese renal-transplant patients as observed Western
countries, although RR is lower in Japan. Types of malignancy
differ between Japanese and Western patients.
Number of cases
1
1
6
1
1
1
1
1
1
1
1
ACKNOWLEDGEMENTS
3
1
1
2
15
3
5
46
the current series (Research Group for Population-Based Cancer
Registration in Japan, 1987). In patients with renal transplants, the
risk of malignancy was higher than in the general population
between 25 and 50 years of age.
We thank the following pathologists and physicians for allowing
us to study their cases: Drs. H. Satoh (Sapporo Municipal
Hospital), T. Entani (Hiraga General Hospital), Y. Taguma and S.
Onodera (Sendai Shakai Hoken Hospital), Y. Kondo and D. Ozaki
(Chiba University), K. Hamaguchi (Sakura National Hospital), T.
Wakabayashi (Tokyo University), M. Kobayashi (Tokyo Women’s
Medical College), S. Kawamura (Toho University), T. Kameya
(Kitasato University), Y. Osamura and M. Yasuda (Tokai University), N. Itoh (Shinshu University), M. Kuroda (Fujita Health
University), S. Murakami (Social Insurance Chukyo Hospital), S.
Miwa (Toyama Prefectural Hospital), T. Yasumura and Y. Tsuchihashi (Kyoto Prefectural University), A. Okuyama (Osaka University), C. Yutani (National Cardiovascular Center), T. Uesugi (Kinki
University), H. Yasoshima (Hyogo College of Medicine), T. Kohro
(Hyogo Prefectural Nishinomiya Hospital), Y. Sadahira (Kawasaki
Medical School), K. Matsui (San-in Rosai Hospital), E. Tahara and
H. Yokozaki (Hiroshima University), M. Tsuneyoshi (Kyushu
University), and K. Irie (Saga Prefectural Hospital Koseikan). This
work was supported in part by grants from the Ministry of
Education, Science and Culture (08457061, 08670202, 08770126),
Japan.
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