Clinical Research
Copyright ©The Author(s) 2005. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 21, 2005; 11(27): 4215-4219
Published online Jul 21, 2005. doi: 10.3748/wjg.v11.i27.4215
Clinical analysis of multiple primary malignancies in the digestive system: A hospital-based study
Hui-Yun Cheng, Cheng-Hsin Chu, Wen-Hsiung Chang, Tzu-Chi Hsu, Shee-Chan Lin, Chuan-Chuan Liu, An-Ming Yang, Shou-Chuan Shih
Hui-Yun Cheng, Chuan-Chuan Liu, An-Ming Yang, Shou-Chuan Shih, Health Evaluation Center, Mackay Memorial Hospital, Taipei, Taiwan, China
Hui-Yun Cheng, Cheng-Hsin Chu, Wen-Hsiung Chang, Shee-Chan Lin, An-Ming Yang, Shou-Chuan Shih, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan, China Tzu-Chi Hsu, Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan, China
Cheng-Hsin Chu, Shou-Chuan Shih, Mackay Medicine, Nursing and Management College, Taipei, Taiwan, China
Correspondence to: Dr. Shou-Chuan Shih, Department of Internal Medicine, Mackay Memorial Hospital, No. 92, Section 2, Chung Shan North Road, Taipei, Taiwan, China. hychey@ms1.mmh.org.tw
Telephone: +886-2-25433535-2860
Received: November 5, 2004
Revised: December 3, 2004
Accepted: December 8, 2004
Published online: July 21, 2005

Abstract

AIM: To analyze the characteristics of multiple primary malignancies (MPMs) of digestive system; including incidence, types of tumor combinations, time intervals between development of multiple tumors, clinical course, and prognostic factors affecting survival and mortality.

METHODS: Data from a total of 129 patients treated from January 1991 to December 2000 for pathologically proved MPMs, including at least one originating from the digestive system, were reviewed retrospectively.

RESULTS: Among 129 patients, 120 (93.02%) had two primary cancers and 9 (6.98%) had three primary cancers. The major sites of MPMs of the digestive system were large intestine, stomach, and liver. Associated non-digestive cancers included 40 cases of gynecological cancers, of which 31 were carcinoma of cervix and 10 cases of genitourinary cancers, of which 5 were bladder cancers. Other cancers originated from the lung, breast, nasopharynx, larynx, thyroid, brain, muscle, and skin. Reproductive tract cancers, especially cervical, ovarian, bladder, and prostate cancers were the most commonly associated non-GI cancers, followed by cancer of the lung and breasts. Forty-three cases were synchronous, while the rest (86 cases) were metachronous cancers. Staging of MPMs and treatment regimes correlated with the prognosis between survival and non-survival groups.

CONCLUSION: As advances in cancer therapy bring about a progressively larger percentage of long-term survivors, the proportion of patients with subsequent primary lesions will increase. Early diagnosis of these lesions, based on an awareness of the possibility of second and third cancers, and multidisciplinary treatment strategies will substantially increase the survival of these patients.

Key Words: Multiple primary malignancies, Digestive system


Citation: Cheng HY, Chu CH, Chang WH, Hsu TC, Lin SC, Liu CC, Yang AM, Shih SC. Clinical analysis of multiple primary malignancies in the digestive system: A hospital-based study. World J Gastroenterol 2005; 11(27): 4215-4219
INTRODUCTION

Many types of cancer, when treated early and aggressively, can be cured. The potential, however, for cancer to occur independently a second time, or more often, in the same patients remains an ever present risk. Interest in multiple primary malignancies (MPMs) is long-standing since Warren and Gates in 1932. He proposed that each suspected primary tumor (1) must be clearly malignant as determined by histological evaluation; (2) must be geographically separate and distinct. The lesion should be separated by normal appearing mucosa. If a secondary neoplasm is contiguous to the initial primary tumor or is separated by mucosa with intraepithelial neoplastic changes, the two should be considered as confluent growth rather than multi-centric carcinomas; and (3) the possibility that the second neoplasm represents a metastasis should be excluded. The observation that the invasive carcinoma arises from an overlying epithelium, which demonstrates a transition from carcinoma in situ to invasive carcinoma, is helpful, and when the separate foci have significant differences in histology, the diagnosis of separate primary cancers is appropriate[1,2].

Multiple primary cancers may be synchronous or metachronous depending on the interval between their diagnosis. Synchronous cancers are diagnosed simultaneously or within an interval of about 6 mo, and metachronous cancers are secondary cancers that developed more than 6 mo after the diagnosis of primary cancers usually after treatment of primary lesions[2].

MPMs were classified into four types: (1) multicentric, if the two distinct carcinomata arise in the same organ or tissue; (2) systemic, if they arise on anatomically or functionally allied organs of the same system (colon and rectum cancers), (3) paired organs, as in the breasts, and (4) random, if they occur as a co-incidental or accidental association in unrelated sites[3].

The development of more sophisticated invasive and non-invasive diagnostic tools has made it possible to detect cancer at an early stage. Furthermore, it has contributed to the detection of synchronous occult tumors, which were formerly overlooked.

An individual developing more than one primary tumor in anatomically and functionally unrelated organs may be considered as cancer-prone. People with a family history of cancer will inherit genetic cancer susceptibility as a risk factor for cancer. Gene mutations influence cancer susceptibility through changes of metabolism and catabolism of carcinogens. Tumor suppressor genes, such as p53 and FHIT, may be candidates for target genes of these risk factors[4]. Genetic instability is also considered as a driving force behind carcinogenesis and the alterations of the length of single repetitive genomic sequences or microsatellite instability, implicating impaired DNA repair mechanism[5]. People with newly diagnosed cancers and survivors of earlier cancers who have genetic cancer susceptibility, therefore, have an increased risk of MPMs.

This study has analyzed the incidence of MPMs in digestive system, as well as the different tumor combinations, time interval between occurrence of tumors, staging, clinical course, and prognostic features of survival and non-survival groups.

The purpose of this study is to determine whether certain organs or systems are particularly susceptible to second or third primary cancers and, by clarifying this tendency, to aid in the early diagnosis of these lesions.

MATERIALS AND METHODS

Retrospective data from a total of 9 807 patients treated at the Mackay Memorial Hospital from January 1991 to December 2000 for pathologically proven cancer were reviewed from the Cancer Registry. Of these, 246 patients had multiple primary cancers, among which 129 (58 males and 71 females) had MPMs in the digestive system and were included in this study.

The histological criteria described by Warren and Gates[1] and Moertel et al.[3], were used for diagnosing multiple separate primary malignancies.

Clinical histories, diagnostic methods, histology, staging, and clinical course of each tumor were reviewed in all patients. The age at the onset of the primary cancer and the time intervals between two or more cancers were recorded. The distribution of the digestive and associated non-digestive cancers in these 129 patients was also investigated. Fifty-two patients had received previous radiotherapy or chemotherapy for their first cancers, and interval between the first and second cancers were recorded. All tumors had been staged according to the American Joint Committee on Cancer TNM staging system[6]. The prognostic factors between survival and non-survival groups were analyzed for double primary cancers.

The differences between groups were analyzed by Student’s t-test for continuous variables and the χ2 test for categorical data. A P value of < 0.05 was considered as statistical significance.

RESULTS

Among the 9 807 pathologically proven cancer patients, 246 had MPMs, with an incidence of 2.5%. Among these, 129 (52.43%), including 58 males (44.96%) and 71 females (55.04%), had MPMs of the digestive system. One hundred and twenty patients (93.02%) had two primary malignancies, and nine (6.98%) had three primary malignancies. The age at onset of the primary cancers ranged from 29 to 89 years (mean 60.3 ± 13.05 years) in double cancers, and 43 to 68 years (mean 50.22 ± 7.9 years) in triple cancers. Forty-three patients (35.8%) were over 65 years of age. Fifty-two patients (40.3%) had received previous radiotherapy or chemotherapy for their first cancer. The interval between the first and second cancers was 0.5-28 years (mean 8.1 ± 2.5 years) and 0.5-5 years (mean 3.2 ± 3.7 years) in the 32 patients receiving radiotherapy and the 17 patients receiving chemotherapy respectively.

The distribution and incidence of MPMs of the digestive system are shown in Table 1. The major site for MPMs of the digestive system was the large intestine (colon, 23.17%; rectum, 25.82%), followed by the stomach (23.17%) and liver (15.23%).

Table 1 Distribution of MPMs in digestive tract.
SiteNumber of MPMs Total number Incidence (%) % in GI MPMs
Esophagus83742.145.29
Stomach351 7701.9823.17
Small bowel3763.951.98
Ampulla Vater3763.951.98
Liver232 0811.1115.23
Gall bladder2583.451.32
Pancreas33030.991.98
Colon351 0103.4723.17
Rectum391 0593.6825.82

Distributions of associated non-digestive cancers in patients with MPMs are shown in Table 2. There were 40 cases (45.97%) with gynecological cancers, of which 31 cases (77.5%) were carcinoma of uterine cervix; 10 cases (11.49%) with genitourinary cancer, among which 5 (50%) had bladder cancers and 3 (30%) had prostate cancers.

Table 2 Distribution of associated non-GI cancers in patients with MPMs in digestive system.
Siten (%)%
Gynecological cancers4045.97
Cervix31/40 (77.5)
Endometrium2/40 (5)
Ovary7/40 (17.50)
Genitourinary cancers1011.49
Bladder5/10 (50)
Kidney2/10 (20)
Prostate3/10 (30)
Lung1011.49
NPC55.74
Breast1011.49
Skin44.59
Thyroid gland22.29
Neuromuscular tumor22.29
Tongue22.29
Gum11.14
Brain11.14

The most common tumor combination in double primary malignancies (both cancers originating from the digestive tract) was colon and rectum (10 cases), as shown in Tables 5-8.

The most common tumor combination in double primary malignancies (at least one originating from the digestive system) was rectum and cervical cancer (14 cases) and shown in Table 4.

Nine patients had triple cancers (Table 9). Mean time interval between diagnosis of the first and second primary cancer was 7.2 ± 3.86 years and for the second and third cancer was 5.24 ± 3.85 years. Two out of these nine patients had initial squamous cell cancers of cervix and nasopharynx and developed synchronous adenocarcinoma of rectum and colon, with disease intervals of 9.4 and 5.9 years respectively.

Most of the tumors in double or triple primary malignancies were diagnosed at stages 3 or 4. Synchronous cancers were found in 43 cases, while 86 cases had metachronous cancers, among which 13 cases developed secondary cancers more than 10 years after diagnosis of primary malignancies (Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, Table 9 and Table 10).

Table 3 Distribution of synchronous and metachronous MPMs in digestive system.
SiteSynchronous (n)Metachronous (n)
(1)(2)
Colon1131019
Stomach18311
Liver1617
Esophagus1011
Others1021
Double GI16300
Total434739
Table 4 Distribution of MPMs in large intestine: 42 cases1.
SubgroupLarge intestinenNon-GI cancersn
(1)Colon5Cervix1
Larynx1
Lung1
Uterus1
Left breast1
Rectum5Ovary1
Cervix2
Right breast1
Bladder1
(2)Colon7Cervix2
Ovary1
Thyroid1
Right thigh1
Bladder1
Nose1
Rectum12Cervix9
Right breast1
Thyroid1
Brain1
(3)Colon7Cervix3
Ovary4
Rectum6Cervix3
Left breast1
Lung2
Table 5 Distribution of MPMs in stomach: 22 cases1.
SubgroupStomachnNon-GI cancersn
(1)Adenocarcinoma3Right breast2
NPC1
(2)Adenocarcinoma11Cervix4
Prostate2
Bladder1
Left kidney1
Tongue1
Larynx1
NPC1
(3)Adenocarcinoma8NPC2
Lung3
Prostate1
Bladder1
Skull1
Table 6 Distribution of MPMs in liver: 14 cases1.
SubgroupLivernNon-GI cancersn
(1)Hepatoma1Bladder1
(2)Hepatoma7Cervix4
Right breast2
Right leg1
(3)Hepatoma6Gum1
Skull1
Right kidney1
Lung3
Table 7 Distribution of synchronous double GI MPMs: 16 cases.
SitenSiten
Esophagus2Stomach1
Gall bladder1
Stomach3Rectum1
Gall bladder1
Sigmoid colon1
Duodenum1Sigmoid colon1
Sigmoid colon3Appendix1
Rectum2
Rectum3Ascending colon3
Liver4Hepatic flexure1
Stomach3
Table 8 Distribution of metachronous double GI MPMs: 30 cases.
1st cancern2nd cancern
Esophagus3Stomach1
Liver2
Stomach4Rectum1
Esophagus1
Liver1
Pancreatic head1
GIST of ileum1Liver1
Ampulla Vater2Liver2
Appendix2Rectum2
Cecum2Stomach2
Colon6Liver2
Stomach1
Pancreatic head3
Rectum10Stomach1
Liver1
Transverse colon5
Esophagus3
Table 9 Sites and dates of diagnosis of triple primary cancers (nine cases).
Age (yr)/sexFirst primarySecond primaryThird primary
68/Female3/84 Cervix6/93 Rectum6/93 Sigmoid colon
46/Female9/85 Cervix8/88 Rectum8/95 Ascending colon
49/Female8/84 Ovary10/86 Cervix3/90 Rectum
47/Female8/79 Breast9/89 Cervix10/97 Liver
50/Male6/82 Stomach5/85 Skin4/91 Ascending colon
45/Male8/84 Stomach3/86 Prostate1/92 Ascending colon
43/Male3/89 Nasopharynx2/95 Sigmoid colon2/95 Rectum
46/Female1/84 Larynx4/88 Sigmoid colon3/91 Esophagus
58/Female3/71 Right breast6/82 Sigmoid colon6/92 Ascending colon
Table 10 Demographic and clinical data in survival and non-survival groups1.
Survival n = 40Non-survival n = 80P
Median age (yr)61.50 ± 13.6060.00 ± 14.780.46
(29–84)(30–89)
Gender
Male16390.18
Female24410.18
Time interval (mo)32.78 ± 27.0732.98 ± 18.580.49
Staging
Stage 1142< 0.01b
Stage 2192< 0.01b
Stage 36410.04a
Stage 41350.16
Treatment regimes2
Radical3616< 0.01b
Palliative2360.08
Supportive2280.08

There were no significant differences between the survival and non-survival groups in terms of age, gender, and time interval between first and second primary cancers. However, stage of tumor, especially stages 1-3 and radical treatment regimes correlated with prognosis in these two groups.

DISCUSSION

The presence of a single tumor does not offer immunity against the development of second, third, or additional primary malignant lesions in the same patient. Multiple primary malignant tumors in the same individual are experienced more frequently as advances in cancer treatment prolong life. Improved survival rates for patients with neoplastic disease, largely due to early diagnosis, allow more patients to survive long enough to develop subsequent primary tumors.

The incidence of MPMs has been carried out by the review of cancer registries in several countries, and ranged from 0.7 to 11%[7-10]. In our study, the incidence of MPMs was 2.21%, which was similar to the 2.6% as reported by Okamoto et al.[11].

In our study, the major site of MPMs in the digestive system was the large intestine, followed by stomach and liver. Cancers of the large intestine, particularly hereditary nonpolyposis colorectal cancers, were associated with increased frequencies of endometrial and ovarian cancers[12]. However, MPMs of large intestine in our study were most commonly associated with carcinoma of cervix (17 cases) and stomach (8 cases), while only two were associated with carcinoma of endometrium and six were with ovarian cancers. The significance of these differences may be due to the fact that carcinoma of cervix is much more common than endometrial cancer in our country. Unfortunately, no genetic evaluation was performed in our patients.

The predilection of MPMs for the large intestine is noted in numerous reports in the literatures[13-15]. In our series, 49 of 129 patients (37.98%) had colorectal malignancy as the first primary lesion. Of these, seven (14.28%) had a second primary cancer in the colon or rectum and four (8.16%) had a second primary cancer in the stomach. The interval between the diagnosis of the first primary colorectal cancer and the development of the second colorectal carcinoma averaged 7 years, and ranged from 1 to 14 years. This suggests that patients without evidence of disease for 5 years after operation of colorectal cancers still require careful follow-up studies of gastrointestinal tract.

Genitourinary cancers, especially cervical and ovarian cancers, bladder and prostate cancers were the common associated non-GI cancers, followed by cancers of lung and breast. Thus, attention should be paid to these sites during the period of post-operative follow-up of the first primary cancer.

The majority of MPMs may occur as a result of random chance[16]. Nonetheless, different mechanisms have been considered to be involved in MPMs, such as intense exposure to carcinogens, the effects of chemo- and/or radiotherapy and the influence of genetic predisposition.

Both the chemo- and radiotherapy have been shown to be carcinogenic in several reports[17,18]. In our study, 52 patients (40.3%) had received previous radiotherapy or chemotherapy for their first cancer, and the interval between the first and second cancers was 0.5-28 years (mean 8.1 years) and 0.5-5 years (mean 3.2 years) in the 32 patients receiving radiotherapy and the 20 patients receiving chemotherapy respectively. This suggests that radiotherapy and/or chemotherapy may play an important role in the development of MPMs.

The main problem in proving a correlation between antineoplastic therapies and secondary cancer may be attributable to detection bias rather than to carcinogenic therapy[19]. Beyond an increased zeal in searching, diagnostic agents and methods have improved such that the detection of cancer today is enhanced by improvements in technology, cytogenetics, and surveillance.

Based on a pooled analysis involving 316 relatives of 12 families, Lynch et al.[20], have demonstrated a 21.5% incidence of MPMs, a consistent 3% risk for a second primary cancer in each year of survival following the first onset, and a significantly higher 6.9% risk per year for the development of a third primary cancer following the second neoplasm.

In our study, there were no significant differences between the survival and non-survival groups in terms of age, gender, and time intervals between first and second primary cancers. Only stage of tumors, especially stages 1-3, and radical treatment regimes correlated with prognosis in these two groups.

Two important inferences can be obtained from our analysis: (1) the early diagnosis of a second primary lesion may alter survival rate. Hence more intensive surveillance and appropriate cytogenetic and molecular studies should be developed in order to improve strategies to detect MPMs, and (2) multidisciplinary treatment strategies are important to ameliorate quality of life and survival rates in patients with MPMs.

It is fundamental that patients who have been treated for cancers require careful follow-up studies. When symptoms and signs of tumor develop in a patient who has been treated for an initial cancer, they should not be assumed to represent metastases. The possibility of a localized and curable second primary cancer should be considered and evaluated. As advances in cancer therapy bring about a progressively large percentage of long-term survivors, the proportion of patients with subsequent primary lesions will increase. Early diagnosis of these lesions, based on an awareness of the possibility of second and third cancers, and multidisciplinary treatment will substantially increase the survival of these patients.

Footnotes

Science Editor Guo SY Language Editor Elsevier HK

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