Journal of Gastroenterology and Hepatology (2000) 15, 1272–1276

tion, loss of p53 or deleted in colorectal cancer on thepathogenesis of colorectal cancer at each stage of devel-opment from adenoma to cancer.7–9 Conversely, K-rasor N-ras gene mutation10–12 and abnormality of p53gene12–14 have also been reported in multiple myeloma,as have other abnormalities of genes in other hemato-logic diseases. However, to our knowledge there havebeen no reports on the relationship between hemato-logic diseases and colorectal neoplasms.

To determine the incidence of colorectal cancer inpatients with hematologic disease, we retrospectivelyinvestigated their history and endoscopic, surgical orautopsy findings.

METHODS

Seven hundred and thirty-four patients with hemato-logic disease were admitted to Nippon Medical School

INTRODUCTION

A relatively large number of patients with multiplemyeloma have been reported to develop a secondarymalignant disease: hematologic malignancies such asacute myeloblastic, myelomonocytic or monocyticleukemia, acute lymphoblastic leukemia, ery-throleukemia and chronic myelocytic leukemia, or solidmalignant tumors such as cancer of the breast, prostate,biliary system or bowel.1 An increased incidence of asecond malignancy, including solid tumors, wasobserved in patients with Hodgkin’s disease,2 primarilyafter radiotherapy alone or chemotherapy combinedwith radiotherapy.3 Gastric cancers were reported tosometimes complicate malignant lymphoma.4,5 We havedemonstrated in a recent endoscopic study that patientswith malignant lymphoma have colorectal neoplasms at an incidence higher than those with leukemia.6

Vogelstein et al.7 reported the influence of K-ras muta-

COLORECTAL ADENOMA AND CANCER

Risk of colorectal cancer in patients with hematologic disease

TERUYUKI KISHIDA, MASAOKI YONEZAWA, YOSHIAKI SHIBATA, SHU TANAKA,ISAO SHINOZAWA, TETSUO HOSHINO, ATSUSHI TATSUGUCHI, LI FENG, JUN SATO,

SHUNJI FUJIMORI, YUTAKA YOSHIDA, CHOITSU SAKAMOTO AND MASAFUMI KOBAYASHI

Third Department of Internal Medicine, Nippon Medical School,Tokyo, Japan

AbstractBackground and Aims: A relatively large number of patients with multiple myeloma have beenreported to develop a secondary malignancy such as cancer of the breast, biliary system or bowel.Methods: A retrospective study was perfomed in 734 patients with hematologic disease diagnosed atNippon Medical School Hospital between May 1984 and September 1994 to determine the incidenceof colorectal cancer in these patients based on a history review, colonoscopic findings, and surgical orautopsy data.Results: Of the 734 patients, 14 (1.9%) had colorectal cancer; two of 11 patients (18.2%) had purered cell aplasia; two of 25 patients (8%) had multiple myeloma; and three of 46 patients (6.5%) hadaplastic anemia. Patients with pure red cell aplasia, multiple myeloma or aplastic anemia had colorec-tal cancer at a significantly higher rate compared to those with leukemia (P < 0.005, P < 0.02, P < 0.01,respectively).Conclusions: It is possible that a relatively large number of patients with pure red cell aplasia, multi-ple myeloma or aplastic anemia will develop a colorectal cancer.© 2000 Blackwell Science Asia Pty Ltd

Key words: colon cancer, hematologic disease, rectal cancer.

Correspondence: Dr T Kishida, Third Department of Internal Medicine, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo 113-0022, Japan.

Accepted for publication 2 June 2000.

Colon cancer in hematologic diseases 1273

Hospital between April 1984 and September 1994(Table 1), for the diagnosis and treatment of either theunderlying hematologic disease or of infectious compli-cations. Outpatients were excluded in the study becausemost of them had iron-deficiency anemia. Among the734 patients, 341 patients had leukemia, 105 had malig-nant lymphoma, 75 had myelodysplastic syndrome(MDS), 47 had idiopathic thrombocytopenic purpura(ITP), and 46 had aplastic anemia.

The patients’ histories were reviewed from theirmedical records. Barium enema was performed in 92 ofthe 734 patients, mostly for the staging of malignantlymphoma. Colonoscopy was performed in 83 patients,mostly for the differential diagnosis of diarrhea, analbleeding or abnormal findings on barium enema, andthe diagnosis of secondary amyloidosis in multiplemyeloma. Overall, either barium enema or colonoscopywas performed in 133 patients. Some of the patients inwhom cancer was diagnosed by barium enema wereoperated upon without a prior colonoscopy. Approxi-mately 60% of patients who died were autopsied.

The diagnosis of leukemia in all patients was basedon a study of peripheral blood and bone marrow films,and bone marrow biopsies when indicated. Acuteleukemia was classified on the basis of the French–American–British (FAB) classification.15 The diagnosisof malignant lymphoma was based on the histology ofthe lymph nodes. The lymphoma staging was based onthe Ann Arbor classification.16 The histology of non-Hodgkin’s lymphoma was classified on the basis of the‘Working Formulation’.17

The diagnosis of multiple myeloma and MDS wasbased on the diagnostic criteria proposed by Durie andSalmon18 and according to the classification of theMDS by the FAB Cooperative Group,19 respectively.

The patients’ ages were expressed as means (years) ±SD (range), according to hematologic diseases andcompared by c2 test.The incidence of colorectal cancerin hematologic diseases was expressed as a percentageand compared with that in leukemia by c2 test. A prob-ability (P) value less than 0.05 was considered to be sig-nificant.

RESULTS

Patients with multiple myeloma or MDS were signifi-cantly older than those with other hematologic diseases(P < 0.01 or P < 0.02, respectively; Table 1). Of the 734patients, 14 (1.9%) had colorectal cancer (Table 2);seven men and seven women with a mean age of 70.2± 10.3 years (range 48–84 years; Table 3).

The highest incidence of colorectal cancer wasobserved in patients with pure red cell aplasia (PRCA;two of 11 patients, 18.8%). This cancer had beendetected at colonoscopy in these patients. Two of 25patients (8%) with multiple myeloma had been diag-nosed with colorectal cancer either at colonoscopy orautopsy. Three of 46 patients (6.5%) with aplasticanemia had been diagnosed with colorectal cancer atcolonoscopy, based on history or at autopsy. Two of 75patients (2.7%) with MDS had been diagnosed with

Table 1 Summary of 734 patients with hematologic disease diagnosed between April 1984 and September 1994

Diseases Mean age (years) ± SD (range) M/F Total

Leukemia 48.9 ± 16.8 (16–86) 171/170 341Acute myeloid leukemia 96/104 200Acute lymphocytic leukemia 22/26 48Acute T cell leukemia 5/7 12Chronic myeloid leukemia 38/21 59Chronic lymphocytic leukemia 2/2 4Others 8/10 18

Malignant lymphoma 54.9 ± 17.4 (16–81) 71/34 105Hodgkin’s disease 17/4 21Non-Hodgkin’s lymphoma 52/29 81Others 2/1 3

Plasma cell dyscrasia 62.3 ± 10.2 (45–82) 15/12 27Multiple myeloma 63.4 ± 9.8* (45–82) 13/12 25Primary macroglobulinemia 2/0 2

Myelodysplastic syndrome 60.6 ± 15.8** (21–86) 36/39 75ITP 43.7 ± 17.1 (16–78) 16/31 47Aplastic anemia 50.2 ± 21.5 (19–86) 26/20 46Polycythemia vera 59.6 ± 11.3 (31–79) 12/9 21Pure red cell aplasia 52.6 ± 12.9 (35–74) 6/5 11Others 54.0 ± 17.6 (16–87) 33/28 61Total 51.7 ± 17.7 386/348 734

*P < 0.01, **P < 0.02 (compared with leukemia). ITP, idiopathic thrombocytopenic purpura.

1274 T Kishida et al.

colorectal cancer either at colonoscopy or at surgery.One among 47 patients (2.1%) with ITP had been diag-nosed to have colorectal cancer at colonoscopy. Two of105 patients (1.9%) with malignant lymphoma and twoof 341 patients (0.6%) with leukemia had been diag-nosed with colorectal cancer at colonoscopy, or basedon medical records and autopsy, respectively. After all,it was proven that patients with PRCA, multiplemyeloma or aplastic anemia had colorectal cancer at asignificantly higher rate compared with those withleukemia (P < 0.005, P < 0.02, P < 0.01, respectively).

DISCUSSION

Results of the study suggest that patients with somehematologic diseases may often have colorectal cancer.

So far, to our knowledge, there have been no reports on the relationship between hematologic diseases andcolorectal cancer, although we have shown in a recent endoscopic study that patients with malignantlymphoma had colorectal neoplasms (cancer andadenoma) at an incidence higher than those withleukemia.6 The present study, which is based onpatients’ histories and endoscopic, surgical or autopsyfindings, shows that patients with PRCA, multiplemyeloma or aplastic anemia have colorectal cancer at asignificantly higher rate compared to those withleukemia. Although the high incidence of cancer inpatients with dermatomyositis or polymyositis is wellknown, only less than 5% of these patients had com-plicating colorectal cancer.20–22 Compared with thisfigure, colorectal cancer may occur at a moderatelyhigher incidence in PRCA, multiple myeloma, and

Table 2 The incidence of colorectal cancer in hematologic diseases

Diseases n CRC % P value (compared with leukemia)

Pure red cell aplasia 11 2 18.2 P < 0.005Plasma cell dyscrasia 27 2 7.4

Multiple myeloma 25 2 8 P < 0.02Primary macroglobulinemia 2 0 0

Aplastic anemia 46 3 6.5 P < 0.01Myelodysplastic syndrome 75 2 2.7 NSITP 47 1 2.1 NSMalignant lymphoma 105 2 1.9 NSLeukemia 341 2 0.6 —Others 82 0 0 —Total 734 14 1.9

CRC, colorectal cancer; ITP, idiopathic thrombocytopenic purpura; NS, not significant.

Table 3 Patients with hematologic disease with complicating colorectal cancer, the methods of its diagnosis, pathology ofcancers and patients’ outcome

Colorectal cancerAge Methods of

Diseases (years) Sex diagnosis Site Dukes’ stage Histology Outcome

Pure red cell aplasia 74 F Endoscopy R B Well Alive70 M Endoscopy R C Well Died of cancer

Multiple myeloma 73 M Endoscopy S C Well Alive68 M Endoscopy D C Moderate Died of hematologic disease

Aplastic anemia 78 F Endoscopy T C Moderate Died of hematologic disease56 F Medical history R A Well Died of hematologic disease79 F Autopsy R C Well Died of hematologic disease

Myelodysplastic syndrome 84 M Endoscopy C C Well Died of hematologic disease66 M Operation S C Well Died of hematologic disease

ITP 48 F Endoscopy S C Well Died of hematologic diseaseMalignant lymphoma 59 F Endoscopy S C Well Died of cancer

72 F Endoscopy S C Well Died of cancerLeukemia 73 M Medical history R B Well Died of hematologic disease

83 M Autopsy S B Well Died of hematologic disease

ITP, idiopathic thrombocytopenic purpura; well, well-differentiated adenocarcinoma; moderate, moderately differentiated ade-nocarcinoma; R, rectum; S, sigmoid colon; D, descending colon; T, transverse colon; C, cecum.

Colon cancer in hematologic diseases 1275

aplastic anemia. Although the difference of age distrib-ution between the background cases (mean age 51.7years) and colorectal cancer cases (mean age 70.2 years)was observed in the study, patients with PRCA or aplas-tic anemia were as old statistically as those with otherhematologic diseases. However, patients with multiplemyeloma were significantly older. Therefore, strictlyspeaking, no patient with multiple myeloma may havecolorectal cancer at an incidence higher than those withleukemia.

Pure red cell aplasia has frequently been shown to beassociated with immunoglobulins or T cells that inhibitmarrow erythropoiesis. Although a variety of hemato-logic malignancies have been associated with PRCA,several non-hematologic malignancies have also beenreported to occur in patients with PRCA.23–25 However,no etiologic relationship between any of these neo-plasms and PRCA has been established.

Patients with multiple myeloma have been reportedto develop a secondary malignant disease such as cancerof the breast, prostate, biliary system or gut.1 Accord-ing to an autopsy survey conducted by Weitzel, 11 of 57patients (19.3%) with multiple myeloma who were 35years or older had had coexistent second carcinomas.26

As myeloma patients often have monoclonal gam-mopathy, are in a secondary immunosuppressive statefrom the disease itself or as a result of the dosage ofanticancer drugs, they may sometimes have second car-cinomas. Also, there may exist common carcinogens ofmyeloma and second carcinomas.7–13

Aplastic anemia has been shown to be associated withimmunologic abnormalities.27,28 However, the underly-ing events are still unknown. Hematologic malignanciessuch as MDS and myeloid leukemia are reported tooccur after immunosuppressive therapy for aplasticanemia.29–32 An increased incidence of solid cancersbesides colorectal cancer after bone marrow transplan-tation for aplastic anemia has also been suggested.32–34

Although there may be no direct relationship betweensolid cancers and aplastic anemia, it is clearly evidentthat solid cancers occur after treatment for aplasticanemia. However, the underlying mechanism remainsunclear.

An increase in the incidence of second malignancy,including solid tumors, was observed in patients withHodgkin’s disease,2 primarily after radiotherapy aloneor chemotherapy combined with radiotherapy.3 Arecent endoscopic study has shown an increased inci-dence of colorectal neoplasms in patients with malig-nant lymphoma.6 However, it is unknown whether thereis any association between malignant lymphoma andcolorectal cancer. In regard to MDS, ITP and leukemia,there have been no reports of association between thesediseases and colorectal cancer.

Our findings demonstrate that patients with hemato-logic disease have a considerably higher risk of devel-oping colorectal cancer than the general population,35

and that patients with PRCA, multiple myeloma oraplastic anemia have a significantly higher risk of de-veloping colorectal cancer compared to those withleukemia. This increased incidence may be associatedwith immunologic abnormalities and common carcino-gens of both diseases. Large-scale studies are needed to

clarify the relationship between hematologic diseasesand colorectal cancer.

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