Japanese Journal of Clinical Oncology 32:412-416 (2002)
© 2002 Foundation for Promotion of Cancer Research
Budding (Sprouting) as a Useful Prognostic Marker in Colorectal Mucinous Carcinoma
Department of Surgery, Koshigaya Hospital, Dokkyo University School of Medicine, Koshigaya, Saitama, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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Purpose: Budding (sprouting) along the invasive margin is reported to be associated with high malignant potential of colorectal carcinoma. We examined the prognostic significance of budding in colorectal mucinous carcinoma.
Patients and methods: Surgically resected specimens from 31 patients with colorectal mucinous carcinoma were studied. The median postoperative follow-up was 27 months. The presence of budding was examined according to Morodomi’s criteria using hematoxylin–eosin-stained sections.
Results: Budding was found in 18 lesions (58%). Budding was more frequently observed in lesions with venous invasion and lymph node metastasis than in those without (P = 0.04, P = 0.03, respectively). The incidence of budding was higher in lesions with distant metastasis than in those without (P < 0.03). Overall recurrence and peritoneal disseminated recurrence were significantly more frequent in patients with budding-positive lesions than in those with budding-negative lesions (P = 0.05, P = 0.04, respectively). The cumulative 5-year survival rate of curative resected cases was lower in patients with budding-positive lesions than in those with budding-negative lesions (25.0% versus 90.9%, P = 0.01, log-rank test). Moreover, both the univariate and multivariate proportional hazard models revealed that the presence of budding was the only significant co-factor of postoperative survival.
Conclusion: Budding is a pathological marker suggesting high malignant potential and decreased postoperative survival in patients with colorectal mucinous carcinoma.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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The characteristics of colorectal mucinous carcinoma are not yet fully clarified because of its low frequency (10–20%) among colorectal carcinomas (1–5). The prognosis of mucinous carcinoma is reportedly worse than that of well or moderately differentiated carcinoma (1,2,6–8). Symonds and Vickery reported that mucus produced by cancer cells promoted dispersion of cancer cells and that the mucopolysaccharide coating interfered with the immunological recognition of cancer cells (1). Although a number of studies compared prognosis between mucinous carcinoma and non-mucinous carcinoma, prognostic factors of colorectal mucinous carcinoma have rarely been investigated (1,6,9–11).
Budding (sprouting) refers to microscopic clusters of undifferentiated cancer cells ahead of the invasive margin of a tumor and is easily identified with hematoxylin–eosin (HE) staining (12). The association of budding with poor prognosis of colorectal carcinoma has been reported (13,14). The aim of this study was to examine whether budding represents a useful marker for the prediction of prognosis in colorectal mucinous carcinoma.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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We studied surgically resected specimens from 31 patients with colorectal mucinous carcinoma. They accounted for 31.3 out of 1100 patients (3%) with colorectal carcinoma, whose lesions were surgically resected at the Department of Surgery, Koshigaya Hospital, Dokkyo University School of Medicine, between 1985 and 2000. Patients with anal carcinoma, those with familial adenomatous polyposis and those with hereditary non-polyposis colorectal cancer syndrome, those with inflammatory bowel disease and those with synchronous or metachronous extracolonic carcinoma were excluded from this study.
Formalin-fixed and paraffin-embedded specimens were sectioned and stained with HE. According to the rules determined by the Japanese Society for Cancer of the Colon and Rectum (JS-CCR), we judged a lesion to be a mucinous carcinoma when the mucus component predominated in a lesion (>50%) (15). The presence of budding at the invasive margin was determined according to the criteria proposed by Morodomi et al., whereby budding is defined as isolated undifferentiated cancer cells or clusters of five or six cancer cells forming a microtubular structure, both of which appeared to bud from large cancerous glands (12). Fig. 1a and b show examples of lesions with budding. Other routine pathological findings were also recorded according to JS-CCR.
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Statistical analyses were carried out using the chi-squared test. One patient who died of postoperative acute hepatic failure was excluded from the analysis of postoperative recurrence or survival. The cumulative 5-year survival rate was calculated by the Kaplan–Meier method. Differences in survival were evaluated by the log-rank test. Multivariate analysis for prognostic factors was carried out using the proportional hazard model with the stepwise backward variable elimination method. Statistical significance was set at the P < 0.05 level.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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Clinicopathological Findings
The 31 patients consisted of 18 males and 13 females, with a median age of 63.0 years (range: 27–85 years). The rectum was the most common site of mucinous carcinoma (12 patients, 40%), followed by the right colon (10 patients, 30%) and then the left colon (nine patients, 30%). The median tumor size was 60.0 mm (range: 25–110 mm). The depth of wall penetration was up to the proper muscle layer (mp) in two patients, up to the subserosal or serosal layer (ss or se) in 25 patients and up to the adjacent organs (si) in four patients. Lymphatic invasion, vascular invasion and lymph node metastasis were found in 26 (83%), 14 (46%) and 17 lesions (54.8%), respectively. All the lesions contained concomitant portions of well or moderately differentiated adenocarcinoma. Budding was identified in 18 lesions (58.0%) exclusively at the invasive margin of well or moderately differentiated portions.
The resection was microscopically curative in 20 of the 31 patients, with a curative resection rate of 64.5%. Factors by which the resection was non-curative were hepatic metastasis in four patients, peritoneal dissemination in five patients, lung metastasis in one patient and marked lymph node metastasis in one patient.
Preoperative pathological diagnosis was mucinous carcinoma in six of 29 lesions for which preoperative biopsy was carried out (20.7%). The remaining 20 lesions (68.9%) were preoperatively diagnosed as well differentiated adenocarcinoma.
Relationship Between Budding and Clinicopathological Findings
Budding was more frequently identified in lesions with venous invasion and lymph node metastasis than in those without (P = 0.04, P = 0.03, respectively). The incidence of budding was higher in lesions with distant metastasis than in those without (P = 0.03). Consequently, budding was relatively common in lesions with advanced pathological stages (P = 0.03, Table 1).
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Budding and Recurrence
Recurrence occurred in seven (36.8%) out of 19 patients who underwent microscopically curative resection. The patterns of recurrence are summarized in Table 2. Overall recurrence and peritoneal dissemination recurrence were significantly more frequent in patients with budding-positive lesions than in those with budding-negative lesions (P = 0.05, P = 0.04, respectively).
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Budding and Postoperative Survival
The overall cumulative 5-year survival rate for all of the 30 patients with colorectal mucinous carcinoma was 45.0%. The cumulative 5-year survival rate was lower in patients with budding-positive lesions than in those with budding-negative lesions (15.5 versus 76.2%, P = 0.03, Fig. 2). Additionally, the overall cumulative 5-year survival rate for 19 patients who underwent curative resection was 60.0%. The cumulative 5-year survival rate was lower in patients with budding-positive lesions than in those with budding-negative lesions (25.0 versus 90.9%, P = 0.01, Fig. 3).
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In univariate proportional hazard models, budding was the only co-factor of postoperative survival. Among other pathological findings and curability, venous invasion and distant metastasis were marginally associated with postoperative survival (0.05 < P < 0.1, Table 3). In the multivariate proportional hazard model, in which venous invasion, distant metastasis and budding were included in possibly significant prognostic co-factors, budding was the only significant prognostic co-factor (Table 4).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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Mucinous carcinoma has been reported to constitute 10–20% of colorectal carcinomas in the English literature (1–5) and 4–16% in the Japanese literature (10,16–18). The frequency of mucinous carcinoma is believed to depend on the criteria used for the pathological diagnosis. Symonds and Vickery defined mucinous carcinoma as a tumor that had at least 60% of mucinous component (1). In the present study, a lesion was diagnosed as mucinous carcinoma when mucinous component was predominant according to JS-CCR and the frequency of mucinous carcinoma was 3%.
In the present study, all the lesion specimens contained a portion of well or moderately differentiated adenocarcinoma and the mucinous component appeared at the deepest portion. The accuracy of preoperative biopsy was therefore only 20.6%. In other reports, preoperative biopsy accurately diagnosed mucinous carcinoma in 31–39.0% (10,16,19,20). Although the difference between non-mucin-producing cells and mucin-producing cells within each lesion remains unclear, the morphology and function of cancer cells may change from well or moderately differentiated adenocarcinoma to mucinous carcinoma during progression.
Budding, initially termed sprouting by Imai in 1954, is a morphological feature along the invasive margin of carcinoma (21). He reported that budding correlated with malignant potential in cancers of the tongue, larynx, breast, cervix and stomach. Yokota (13) and Hase et al. (14) reported that the presence of budding was associated with poor prognosis in patients with colorectal carcinoma. We also reported that budding in pT1 and pT2 well differentiated colorectal adenocarcinoma was a risk factor of lymph node metastasis (22).
In the present study, budding was exclusively identified at the invasive margin of concomitant well or moderately differentiated portions of mucinous carcinomas. This finding suggests that the mechanism of budding formation is different from that of mucinous change. Comparison of the molecular background between budding formation and mucinous change may further clarify the route of the progression of colorectal adenocarcinoma.
The present study revealed that postoperative survival in patients with mucinous carcinoma differed by the presence or absence of budding. Patients having budding-positive lesions had a shorter postoperative survival than those having budding-negative lesions. In addition, budding was a more significant co-factor of postoperative survival than other routine pathological findings such as lymph node metastasis and even tumor stage or curability of the resection. Therefore, it appears helpful for the prediction of prognosis of colorectal mucinous carcinoma to examine carefully the presence or absence of budding in the pathological examination of resected specimens.
The prognosis of mucinous carcinoma is reportedly worse than that of well or moderately differentiated adenocarcinoma. If a mucinous carcinoma presents budding at the invasive margin, the prognosis is likely to be very poor. Therefore, intensive postoperative adjuvant treatment may be recommended for such patients even if the resection is curative and the routine pathological findings are favorable.
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Acknowledgment |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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The work was carried out in the Department of Surgery, Koshigaya Hospital, Dokkyo University School of Medicine without any special financial support.
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FOOTNOTES |
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+ For reprints and all correspondence: Takashi Okuyama, Department of Surgery, Koshigaya Hospital, Dokkyo University School of Medicine, 2–1–50 Minami-Koshigaya, Koshigaya, Saitama 343-8555, Japan. E-mail: tokuyama@dokkyomed.ac.jp
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REFERENCES |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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Received March 15, 2002; accepted June 28, 2002
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