The Pathological Assessment of Total Mesorectal Excision: What Are the Relevant Resection Margins?

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1 The Pathological Assessment of Total Mesorectal Excision: What Are the Relevant Resection Margins? Frank Autschbach F. Autschbach ( ) Institute of Pathology, Heidelberg University, Im Neuenheimer Feld 220/221, Heidelberg, Germany [email protected] Abstract An accurate pathological reporting of rectal cancer specimens has important implications concerning patients prognosis and further clinical management. Since locoregional recurrence and prognosis in rectal cancer is especially influenced by the extent of extramural tumor spread into the mesorectal lymphovascular fatty tissue, systematic investigation of the status of the circumferential mesorectal resection margin is a point of major importance to determine the completeness of tumor resection. Careful macroscopic assessment of the resection specimen should be performed to monitor the quality of mesorectal excision. Introduction Locoregional recurrence and distant metastasis are two major factors which determine a patient s prognosis following curative resection of rectal cancer. While the occurrence of distant metastasis can only indirectly be influenced by surgery and is largely determined by tumor-related factors such as tumor grade and stage, the principal aim of surgical treatment is the prevention of local recurrent disease. Recurrent tumor growth often occurs within the first two years after the operation and mostly presents as a pelvic mass within the excised tumor bed. A number of studies suggest that a major cause of such recurrences is a failure of complete local removal of the tumor. In this context, the quality of the operative procedure performed by the individual surgeon represents one of the most important prognostic factors (Hermanek et al. 1989, 1994, 1995; Hohenberger et al. 1998; Köckerling 1988). The concept of total mesorectal excision (TME), introduced by Heald et al. (Heald et al. 1982; Heald and Ryall 1986), constituted important progress in thesurgicaltreatmentofrectalcancer.tmeconsistsofacompleteremovalof the rectum together with its surrounding mesorectal lymphovascular fatty tissue (mesorectum) by precise sharp dissection along the visceral pelvic fascia ( holy plane ) (Heald 1988), to minimize the residual tumor load. It has been shown that Recent Results in Cancer Research, Vol. 165 c Springer-Verlag Berlin Heidelberg 2005

2 The Pathological Assessment of Total Mesorectal Excision: What Are the Relevant Resection Margins? 31 careful adherence to this procedure can significantly reduce the rate of locoregional recurrences in rectal cancer. Types of Resection Margins in Rectal Cancer Specimens An accurate pathological reporting of rectal cancer resection specimens has important implications for the clinical management and the individual prognosis of the patient. The determination of the completeness of tumor resection is based on the assessment of resection margins by the pathologist. Principal sites which must be considered are the proximal and distal resection margins as well as the deep antiluminal (mesorectal) margin within the plane of dissection, called the lateral, radial, or circumferential resection margin (CRM). Proximal Resection Margin Due to the relatively wide proximal safety distance in most rectal cancer specimens (length of resected gut proximal to the tumor usually >15 cm, proximal ligation of the inferior mesenterial artery), involvement of the proximal resection margin by tumor is exceptionally rare. Therefore, this site is generally nonproblematic. Distal Intramural Resection Margin The distal resection margin in rectal cancer specimens is more critical, depending on the localization of the tumor (distance from the dentate line). With regard to the question of an adequate distal tumor clearance, two different aspects must be considered: intramural as well as extramural distal tumor spread, including lymphatic spread. Concerning the former type of spread, it has been shown that distal intramural extension is rather uncommon in rectal carcinoma (Shirouzu et al. 1995). In over 95% of cases it is limited to a length of about 1 to 2 cm distal to the endoluminally visible tumor. A distal mural safety margin in this range can thus be considered appropriate for most cases (Maurer et al. 1999; Pollett and Nicholls 1983; Riedl et al. 1995; Shirouzu et al. 1995; Williams et al. 1983). It should be kept in mind that formaldehyde fixation induces a significant shrinkage of the bowel (about twofold), which might result in an underestimation of the length of distal tumor clearance (Goldstein et al. 1999; Hermanek and Gall 1981; Kwok et al. 1996). It is recommended to take measurements on the freshly obtained, native specimen (if possible) and/or to pin the tissue on corkboard before fixation to minimize shrinkage. If the tumor macroscopically approaches the distal mural margin of the specimen, frozen section diagnostics might be considered for pathohistological assessment. Using such precautions, direct involvement of the distal intramural resection margin by tumor is a rare event (Birbeck et al. 2002; Ng et al. 1993). It is noteworthy that even a narrow range of distal mural clearance has no adverse influence on locoregional recurrence rates. However, if distal mural extension is

3 32 Frank Autschbach prominent, it is usually associated with a locally advanced tumor stage and poor long-term prognosis, which is largely determined by the occurrence of distant metastasis rather than local recurrence (Pollett and Nicholls 1983; Philips et al. 1984; Shirouzu et al. 1995; Vernava and Moran 1992, Williams et al. 1983). Circumferential Resection Margin One important aspect concerning the growth pattern of rectal carcinoma is its tendency for extramural radial spread into the mesorectal lymphovascular fatty tissue. Radial tumor spread may be continuous and expansive, displaying a pushing type of the invasive margin (Fig. 1), but not rarely (>20%) also includes irregular, infiltrative, and discontinuous modes of spread with tumor deposits extending to the CRM and/or the serosa (Fig. 2). It has been shown that an infiltrative patternofgrowthiscorrelatedwithpoorprognosisincolorectalcancer(jassetal. 1986) and constitutes an adverse prognostic factor which is independent of tumor stage (Compton et al. 2000). By histology, various often co-existing modes of extramural tumor spread occur, including continuous and discontinuous infiltrates within the perirectal fatty tissue, extramural venous invasion, lymphangiosis carcinomatosa and lymph node metastasis (Fig. 3). Although most mesorectal tumor deposits are located at the level of or proximal to the cancer, discontinuous extra- Figure 1. Rectal adenocarcinoma of the expansive type displaying a rather well defined invasive tumor margin. Tumor formations (gray-white color) infiltrate the mesorectal fatty tissue (pt3), but do not approach the circumferential (mesorectal) resection margin

4 The Pathological Assessment of Total Mesorectal Excision: What Are the Relevant Resection Margins? 33 Figure 2A, B. Adenocarcinoma of the infiltrative type displaying an irregular and discontinuous mode of spread with extramural tumor deposits extending to the circumferential resection margin (bottom) and to the lateral serosal aspects (left and right) of this specimen (rectosigmoid)

5 34 Frank Autschbach Figure 3A F. Histopathological modes of mesorectal tumor spread in rectal adenocarcinoma. A Continuous spread. B Discontinuous mesorectal deposits. C Extramural venous invasion. D Lymph node metastasis. E Lymphangiosis carcinomatosa in the immediate vicinity of the circumferential resection margin (bottom). F Direct involvement of the circumferential resection margin. H&E stains

6 The Pathological Assessment of Total Mesorectal Excision: What Are the Relevant Resection Margins? 35 Figure 4. Intra- and extramural spread in rectal cancer mural tumor spread has been shown to involve also regions distal (up to 4 cm) to the main tumor mass (>10%) (Heald and Ryall 1986; Scott et al. 1995) (Fig. 4). The demonstration of significantly reduced local recurrence rates and increased patient survival after total mesorectal excision for rectal cancer (Heald et al. 1982, 1998; Heald and Ryall 1986; Heald et al. 1998; Hohenberger et al. 1998; Kapiteijn et al. 2001; Köckerling et al. 1998; MacFarlane et al. 1993; Wibe et al. 2002) strongly indicate that recurrence is mainly caused by an inadequate resection of extramural tumor deposits within the mesorectal lymphovascular fatty tissue using standard surgical procedures. One of the basic reports demonstrating the importance of lateral tumor spread and the prognostic significance of CRM involvement in rectal cancer was published in 1986 by Quirke and colleagues. They investigated a series of 52 rectal carcinomas (operated by standard procedures) where they embedded the whole tumor area after serial transverse slicing of the specimens. The extent of mesorectal spread was determined, including morphometric measurements. The outer limit of the tumor was defined as the most lateral penetration of the mesorectum, either by continuous or discontinuous tumor extension. An involvement of the CRM was considered when tumor directly infiltrated the CRM or reached this margin within a distance of less than 1 mm (Quirke et al. 1986; Quirke and Dixon 1988). The CRM was involved in 27% of the cases investigated in that study. Most importantly, those authors found that CRM involvement was associated with a local recurrence rate of 85%, in contrast to a recurrence rate of only 3% in the group of CRM-negative cases (median follow-up: 23 months). Involvement of the CRM was associated with increasing Dukes stage, decreasing tumor differentiation, and an infiltrative tumor margin. In a further study on 141 cases, these results were confirmed (Adam et al. 1994). Tumor involvement of the CRM was seen in 25% of cases with potentially curative resection, and the frequency of local recurrence was again significantly higher in CRM-positive cases compared to CRM-negative cases (78% vs. 10%, respectively; median follow-up, 5 years). The authors performed a multivariate analysis of several pathological variables and demonstrated that an involvement of the CRM is one of the most important factors independently influencing both local recurrence and survival.

7 36 Frank Autschbach The important prognostic significance of the circumferential margin status in rectal cancer has been confirmed independently by other groups (Cawthorn et al. 1990; DeHaas-Kock 1996; Ng et al. 1993). In a recent follow-up study from Leeds, UK (Birbeck et al. 2002), the investigators could formally validate that a tumor distance of 1 mm or less to the CRM is associated with a significantly increased riskoflocalrecurrence.allmajormodesoftumorspreadcontributedtothis increased risk, except for a CRM involvement by tumor deposits within a lymph node, a result which has also been confirmed by others (Nagtegaal et al. 2002). Since total mesorectal excision was not systematically performed in the series mentioned above, the relevance of CRM involvement in patient subgroups treated exclusively by TME has been debated. A recent study by the Norwegian Rectal Cancer Group addressed this point in a series of 686 patients who underwent TME (Wibe et al. 2002). Although the overall recurrence rate and the percentage of CRM involvement were comparably reduced (7% and 9.5%, respectively), this study proved that involvement of the CRM by a distance of 1 mm or less is associated with significantly higher rates of locoregional recurrence, distant metastasis, and tumor-related death, even after TME (22% recurrence in CRM-positive vs. 5% in CRM-negative cases; exponential increase with decreasing CRM). A further recent study from the Netherlands independently confirmed that CRM involvement in TME-treated patients is of prognostic significance with regard to local recurrence (especially TNM stage III patients), distant metastasis, and survival (Nagtegaal et al 2002). Those authors found that a tumor distance of less than 2 mm from the circumferential margin is already associated with a significantly increased recurrence risk and should be considered a CRM involvement. Macroscopic Assessment of Mesorectal Excision Since the introduction of TME surgery, it has become clear that considerable regional differences exist between surgical departments with regard to the oncological quality of resection as well as local recurrence rates. In this context, it has been proposed that a macroscopic assessment of the mesorectal excision should be included in pathology reports to monitor the surgical practice (Hermanek et al. 2003). Due to the problem of distal mesorectal spread, carcinomas of the middle and lower thirds of the rectum require a total excision of the mesorectum down to the pelvic floor. A partial TME can be considered for the treatment of carcinomas of the upper third, provided that the mesorectum is transected at least 3 cm distal to the aboral margin of the tumor (measured on the fresh non-stretched specimen, corresponding to an in situ distance of about 5 cm) and has a right-angled configuration of the transection line (avoidance of so-called coning of the mesorectum). Concerning the circumferential aspect, an optimal/complete mesorectal excision is characterized by a good bulk of mesorectum with a smooth, lipoma-like surface with no or only minor defects/incisions (not deeper than 5 mm). Suboptimal/nearly complete excisions have a moderate bulk of mesorectum with a slightly irregular surface, circumscript defects, and probably some minor degree of coning. Incomplete mesorectal excisions of poor quality are characterized by a little bulk

8 The Pathological Assessment of Total Mesorectal Excision: What Are the Relevant Resection Margins? 37 of mesorectum with a highly irregular surface, larger defects (>1 cm 2 ), or deep incisions down onto the muscularis propria and/or prominent coning (Hermanek et al. 2003; Nagtegaal and Van Krieken 2002; Nagtegaal et al. 2002; Quirke 1998). The evaluation of surface defects is facilitated by serial transverse slicing of the tumor area (photodocumentation is recommended) and might be supplemented by recently published stain marking techniques (Sterk et al. 2000). Concerning the relevance of such type of assessment, a recent study on 180 cases by the Dutch Colorectal Cancer Group (Nagtegaal et al. 2002) could demonstrate that incomplete mesorectal excision is related to advanced T-stages and is associated with a high incidence of CRM involvement (>40%). However, even in cases without demonstrated CRM involvement, significant differences in outcome between cases with a complete/nearly complete versus incomplete mesorectum were observed. These results indicate a prognostic relevance of this macroscopic parameter, which should be investigated in more detail in future studies. Conclusions The pathological reporting of rectal cancer resection specimens should adhere to standardized protocols. The quality of mesorectal excision and the status of the circumferential resection margin should receive special attention (Fig. 5). Such information has important implications concerning a patient s prognosis and further clinical management. Figure 5. Pathological reporting of rectal carcinoma

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