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

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, 69120 Heidelberg, Germany e-mail: Frank_Autschbach@med.uni-heidelberg.de 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

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

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

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)

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

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.

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

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

38 Frank Autschbach References Adam IJ, Mohamdee MO, Martin IG, Scott N, Finan PJ, Johnston D, Dixon MF, Quirke P (1994) Role of circumferential margin involvement in the local recurrence of rectal cancer. Lancet 344:707 711 Birbeck KF, Macklin CP, Tiffin MJ, Parsons W, Dixon MF, Finan PJ, Johnston D, Quirke P (2002) Rates of circumferential margin involvement vary between surgeons and predict outcomes in rectal cancer surgery. Ann Surg 235:449 457 Cawthorn SJ, Parums DV, Gibbs NM, A Hern RP, Caffarey SM, Broughton CIM, Marks CG (1990) Extent of mesorectal spread and involvement of lateral resection margin as prognostic factors after surgery for rectal cancer. Lancet 335:1055 1059 Compton C, Fenoglio-Preiser CM, Pettigrew N, Fielding LP (2000) American Joint committee on cancer prognostic factors consensus conference colorectal working group. Cancer 88:1739 1757 DeHaas-Kock DFM, Baeten CGMI, Jager JJ, Langendijk JA, Schouten LJ, Volovics A, Arends JW (1996) Prognostic significance of radial margins of clearance in rectal cancer. Br J Surg 83:781 785 Hall NR, Finan PJ, Al-Jaberi T, Tsang CS, Brown SR, Dixon MF, Quirke P (1998) Circumferential margin involvement after mesorectal excision of rectal cancer with curative intent. Predictor of survival but not local recurrence? Dis Colon Rectum 41:979 983 Goldstein N, Soman A, Sacksner J (1999) Disparate surgical margin lengths of colorectal resection specimens between in vivo and in vitro measurements. Anat Pathol 111:349 351 Heald RJ (1988) The holy plane of rectal surgery. J Royal Soc Med 81:503 508 Heald RJ, Ryall RDH (1986) Recurrence and survival after total mesorectal excision for rectal cancer. Lancet 1:1479 1482 Heald RJ, Husband EM, Ryall RDH (1982) The mesorectum in rectal cancer surgery the clue to pelvic recurrence? Br J Surg 69:613 616 Heald RJ, Moran BJ, Ryall RDH, Sexton R, MacFarlane JK (1998) Rectal cancer. The Basingstoke experience of total mesorectal excision, 1978 1997. Arch Surg 133:894 899. Hermanek P, Gall FP (1981) Der aborale Sicherheitsabstand bei der sphinctererhaltenden Rektumresektion. Chirurg 52:25 29 Hermanek P, Guggenmoos-Holzmann, Gall FP (1989) Prognostic factors in rectal carcinoma. A contribution to the further development of tumor classification. Dis Colon Rectum 32:593 599 Hermanek P, Wiebelt H, Riedl S, Staimmer D, Hermanek P, und die Studiengruppe Kolorektales Karzinom (SGKRK) (1994) Langzeitergebnisse der chirurgischen Therapie des Coloncarcinoms. Ergebnisse der Studiengruppe Kolorektales Karzinom (SGKRK). Chirurg 65:287 297 Hermanek P, Wiebelt H, Staimmer D, Riedl S, and the German Study Group Colo-Rectal Carcinoma (SGCRC) (1995) Prognostic factors of rectum carcinoma experience of the German multicentre study SGCRC. Tumori 81 Supplement:60 64 Hermanek P, Hermanek P Hohenberger W, Klimpfinger M, Köckerling F, Papadopoulos T (2003) The pathological assessment of mesorectal excision: implications for further treatment and quality management. Int J Colorectal Dis 18:335 341 Hohenberger W, Schick CH, Göhl J (1998) Mesorectal lymph node dissection: is it beneficial? Langenbeck s Arch Surg 383:402 408 Jass JR, Atkin WS, Cuzick J, Bussey HJ, Morson BC, Northover JM, Todd IP (1986) The grading of rectal cancer: historical perspectives and a multivariate analysis of 447 cases. Histopathology 10:437 459 Kapiteijn E, Marijnen CAM, Nagtegaal ID, Putter H, Steup WH, Wiggers T, Rutten HJT, Pahlmann L, Glimelius B, Van Krieken HJM, Leer JWH, Van de Velde CJH, for the Dutch Colorectal Cancer Group (2001) Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 345:638 646 Köckerling F, Reymond MA, Alterdorf-Hofmann A, Dworak O, Hohenberger W (1988) Influence of Surgery on metachronous distant metastases and survival in rectal cancer. J Clin Oncol 16:324 329 Kwok SPY, Lau WY, Leung KL, Liew CT, Li AKC (1996) Prospective analysis of the distal margin of clearance in anterior resection for rectal carcinoma. Br J Surg 83:969 972 Maurer CA, Renzulli P, Meyer JD, Büchler MW (1999) Rektumkarzinom. Optimierung durch partielle oder totale Mesorektumentfernung. Zentralbl Chir 124:428 435

The Pathological Assessment of Total Mesorectal Excision: What Are the Relevant Resection Margins? 39 MacFarlane JK, Ryall RDH, Heals RJ (1993) Mesorectal excision for rectal cancer. Lancet 341:457 460. Nagtegaal ID, Van Krieken JHJM (2002) The role of the pathologist in the quality control of diagnosis and treatment of rectal cancer an overview. Eur J Cancer 38:964 972 Nagtegaal ID, Marijnen CAM, Kranenbarg EK, Van de Velde CJH, Van Krieken JHJM, for the Pathology Review Committee and the Cooperative Clinical Investigators (2002) Circumferential margin involvement is still an important predictor of local recurrence in rectal carcinoma. Not one millimeter but two millimeters is the limit. Am J Pathol 26:350 357 Nagtegaal ID, Van de Velde CJH, Van der Worp E, Kapiteijn E, Quirke P, Van Krieken JHJM, and the Pathology Review Committee for the Cooperative Clinical Investigators of the Dutch Colorectal Cancer Group (2002) Macroscopic evaluation of rectal cancer resection specimen: clinical significance of the pathologist in quality control. J Clin Oncol 20:1729 1734 Ng IOL, Luk ISC, Yuen ST, Lau PWK, Pritchett CJ, Ng M, Poon GP, Ho J (1993) Surgical lateral clearance in resected rectal carcinomas. A multivariate analysis of clinicopathologic features. Cancer 71:1972 1976 Phillips RKS, Hittinger R, Blesovsky L, Fry JS, Fielding LP (1984) Local recurrence following curative surgery for large bowel cancer: II. The rectum and rectosigmoid. Br J Surg 71:17 20 Pollett WG, Nicholls RJ (1983) The relationship between the extent of distal clearance and survival and local recurrence rates after curative anterior resection for carcinoma of the rectum. Ann Surg 198:159 163 Quirke P (1998) The pathologist, the surgeon and colorectal cancer-get it right because it matters. Progress Pathol 4:201 213 Quirke P, Dixon MF (1988) How I do it. The prediction of local recurrence in rectal adenocarcinoma by histopathological examination. Int J Colorect Dis 3:127 131 Quirke P, Durdey P, Dixon MF, Williams NS (1986) Local recurrence of rectal adenocarcinoma due to inadequate surgical resection. Histopathological study of lateral tumour spread and surgical excision. Lancet 2:996 999 Riedl S, Wiebelt H, Bergmann U, Hermanek P (1995) Postoperative Komplikationen und Letalität in der chirurgischen Therapie des Coloncarcinoms. Ergebnisse der deutschen Multizenterstudie der Studiengruppe Kolorektales Karzinom (SGKRK). Chirurg 66:597 606 Scott N, Jackson P, Al-Jaberi T, Dixon MF, Quirke P, Finan PF (1995) Total mesorectal excision and local recurrence: a study of tumour spread in the mesorectum distal to rectal cancer. Br J Surg 82:1031 1033 Shirouzu K, Isomoto H, Kakegawa T (1995) Distal spread of rectal cancer and optimal distal margin of resection for sphincter-preserving surgery. Cancer 76:388 92 Vernava AM, Moran M (1992) A prospective evaluation of distal margins in carcinoma of the rectum. Surg Gynecol Obstet 163:101 103 Wibe A, Eriksen MT, Syse A, Myrvold HE, Soreide O. on behalf of the Norwegian Rectal Cancer Group (2002) Total mesorectal excision for rectal cancer what can be achieved by a national audit? Colorectal Disease 5:471 477 WibeA,RendedalPR,SvenssonE,NorsteinJ,EideTJ,MyrvoldHE,SoreideO,onbehalfof the Norwegian Rectal Cancer Group (2002) Prognostic significance of the circumferential resection margin following total mesorectal excision for rectal cancer. Br J Surg 89:327 334 Williams NS, Dixon MF, Johnston D (1983) Reappraisal of the 5 centimetre rule of distal excision for carcinoma of the rectum: a study of distal intramural spread and of patients survival. Br J Surg 70:150 154