Elsevier

Human Pathology

Volume 41, Issue 12, December 2010, Pages 1749-1757
Human Pathology

Original contribution
Tumor necrosis is a new promising prognostic factor in colorectal cancer

https://doi.org/10.1016/j.humpath.2010.04.018Get rights and content

Summary

The prognostic significance of tumor necrosis in colorectal cancer is unclear. Our study aimed to analyze the prognostic value of tumor necrosis with respect to progression-free and cancer-specific survival and to relate findings to expression of proteins involved in the control of cancer cell death, such as p53 and bcl-2. A total of 381 colorectal cancer specimens were retrospectively reevaluated. The extent of tumor necrosis was semiquantitatively assessed and recorded as either absent, focal (≤10% of the tumor area), moderate (10%-30%), or extensive (≥30%). Expression of p53 and bcl-2 was assessed immunohistochemically and recorded as either positive (using a cutoff value of 10%) or negative. In addition, mismatch repair protein status was assessed by immunohistochemistry using antibodies directed against hMLH1, hMSH2, and hMSH6. Tumor necrosis was observed in 365 (96%) cases, with 180 (47%) tumors showing focal necrosis, 119 (31%) moderate necrosis, and 66 (17%) extensive necrosis, respectively. Extent of necrosis was significantly associated with high T classification (P < .001), high N classification (P = .005), high International Union Against Cancer stage (P < .001), poor tumor differentiation (P < .001), large tumor size (P < .001), and blood vessel invasion (P = .01). No association of tumor necrosis with expression of p53, bcl-2, and mismatch repair protein status was observed. Tumor necrosis proved to be an independent prognostic variable with respect to progression-free and cancer-specific survival. In conclusion, tumor necrosis showed significant impact on prognosis of colorectal cancer patients. Its presence is readily assessable in hematoxylin and eosin–stained sections and should therefore routinely be commented upon in the pathology report.

Introduction

The incidence of colorectal cancer (CRC) ranks fourth in men (after lung, prostate, and stomach) and third in women (after breast and cervix uteri), accounting for about 1 million new cancer cases occurring every year worldwide, with a similar number of cases in men and women for colon cancer and a male prevalence for rectal cancer [1]. In the United States, CRC accounts for approximately 10% of annual new cancer cases. About 150 000 newly diagnosed cases and nearly 50 000 deaths of the disease have been estimated for 2008 [2].

Tumor stage reflected by the American Joint Committee on Cancer/International Union Against Cancer (UICC) TNM system is currently regarded as the strongest prognostic parameter for affected patients [3]. The TNM classification discriminates patients with early-stage disease from those with advanced disease, but is less able to predict the prognosis of patients with intermediate levels of tumor invasion and is therefore unsatisfactory with respect to prognostication of affected patients [4]. In fact, patients with tumors of the same pathologic stage may experience considerably different clinical outcomes. Moreover, according to a comprehensive study analyzing the Surveillance, Epidemiology, and End Results database, patients with stage IIIA tumors appear to be associated with a significantly improved survival compared with patients with stage IIB disease [5].

In routine histology, no reliable marker capable of selecting high-risk stage II patients who might benefit from adjuvant treatment has been established. In fact, patients are still selected for therapy based solely on TNM stage, a tool that has changed little since Dukes' [6] original description published more than 70 years ago. Because of the reported suboptimal risk stratification of the TNM system, however, identification of additional prognostic markers that are readily available in routine hematoxylin and eosin (H and E)–stained sections is warranted [7].

It is generally accepted that tumor necrosis, a common feature of solid tumors, is a consequence of chronic ischemic injury due to rapid tumor growth. Accordingly, the extent of necrosis is thought to reflect the level of intratumor hypoxia [8], [9]. Increased cellular hypoxia correlates with increased metastatic potential and worse prognosis in solid tumors as well as resistance to radiotherapy and chemotherapy [8], [10]. Moreover, tumor necrosis has been reported as an indicator of poor prognosis in lung [8], breast [11], and renal malignancies, including both renal cell carcinoma [12], [13] and upper urinary tract urothelial carcinoma [9], but also in mesenchymal tumors, such as gastrointestinal stromal tumors [14] and Ewing sarcoma [15].

Literature data regarding the prognostic significance of tumor necrosis in CRC are rare. However, presence of tumor necrosis has been related to intra-/peritumoral inflammation and microsatellite status [16], [17], [18].

Our analysis aimed to evaluate the prognostic impact of tumor necrosis with regard to both progression-free and cancer-specific survival, including univariate and multivariate analyses. In addition, we correlated histologic findings with mismatch repair (MMR) proteins status and biomarkers involved in the control of cell death, such as p53 and bcl-2.

Section snippets

Case selection

During the period from January 1, 1984, to December 31, 2005, a total of 7909 CRCs from 7564 patients (4095 male, 3469 female; ratio 1.2:1) were identified in the Colorectal Cancer Database of the Institute of Pathology, Medical University of Graz, Austria. Of these, 400 (5%) patients were randomly sampled from January 1992 through December 2000 with the aim of obtaining identical adjuvant treatment modalities (see below) as well as at least 5 years' follow-up.

The following patients were

Tumor characteristics

Tumors were located in the cecum in 49 (13%) patients, in the ascending colon in 27 (7%), at the hepatic flexure in 18 (5%), in the transverse colon in 13 (3%), at the splenic flexure in 13 (3%), in the descending colon in 15 (4%), in the sigmoid colon in 82 (22%), at the rectosigmoid junction in 15 (4%), and in the rectum in 149 (39%) patients, respectively. Thus, according to our definition, 107 tumors (28%) were right-sided colon cancers, 110 (29%) left-sided colon cancers, and 164 (43%)

Discussion

The current standard of care for CRC patients is primarily based on TNM stage [26]. Approaches that are not yet standard practice but may improve prognostication of CRC patients include the analysis of additional histopathologic parameters that are easily assessable on routine H and E–stained sections, such as tumor necrosis. These parameters might facilitate the identification of patients who are at high risk of adverse outcome and who might therefore benefit from adjuvant treatment.

We noted

Acknowledgment

The authors are grateful to Mrs E. Grygar, Ms A. Kaps, and Ms M. Schuller for excellent technical support.

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