Journal of Surgical Oncology Supplement 221-23 (1991)
Clinical Staging and Pathological Correlation in Colorectal Cancer F. MAZZEO, MD, L. BUCCI, MD, M. GENTILE, MD, G . BENASSAI, MD, A N D ) . NIRO, MD From the Department of General Surgery I / , The University of Naples School of Medicine, Naples, Italy
KEYWORDS:residual tumor, imaging techniques, clinical staging
INTRODUCTION The role of surgery in the treatment of large bowel cancer is still preeminent, influencing both the immediate and longer term outcome of the disease. The examination of surgical specimens, i.e., what we agree as a traditional staging, cannot leave out of our consideration the clinical preoperative evaluation of the disease and the definition of the residual tumor or “R”, in order to get a more punctual staging of the tumor. The free serosal surface and adjacent organ invasion play a primary role in determining the “R[ 121”. If a laparotomic staging is always satisfactory it is not the fullest-proof for colonic cancer and imaging techniques play a significant role in not-operative staging of rectal cancer allowing to choose an adequate surgical procedure and assisting a rational selection of preoperative adjunctive treatment. A warning comes from the increasing number of non-operative imaging techniques makes it necessary to schedule a rational sequence of imaging procedures to keep the financial costs for patients as low as possible. An accurate clinical staging includes the degree of local invasion, the lymph nodal involvement, and the detection of hepatic metastases together with the age and the anatomical (sphincters and pelvis) and risk evaluation. All these factors must always be weighed in balance [61. Above the peritoneal reflection, traditional not-operative imaging techniques give information about the size and the degree of obstruction; computerized tomographic (CT) scan and urographic examination can better define the stage of a large fixed mass, and the anatomical and functional abnormalities of urinary tract [ 11. Under the peritoneal reflection, or for those tumors localized within the lower 10 cm of the rectum, assessing local invasion is fundamental because an inappropriate or incomplete surgery could be followed by local recurrences particularly difficult to manage. A digital rectal examination is essential to define the degree of invasion, assessing the size, the fixity, and the extent of the lesion within the 0 1991 Wiley-Liss, Inc.
pelvis. The tip of the fingers must explore all rectal walls, posteriorly the sacrum, pelvic, and perineal muscles [2,81. York Mason [5] proposed a clinical staging system based on digital rectal examination defining as CS I, a fully mobile tumor; CS 11, there is some resistance to movement; CS 111, an adherent but still mobile tumor; CS IV, a fixed tumor. Freely mobile tumors are those where invasion is confined to mucosae and sub-mucosae only. Tumors are mobile when the disease penetrates the muscularis mucosae but not progress beyond it. When tumors penetrate into the muscularis propria they can be defined as adherent, and greater degrees of fixity can indicate an involvement of adjacent organs such as the prostate or muscle-skeletal organs. Digital staging was tested, prospectively, in 1982 by Nicholls et al. [4], showing an accuracy of prediction in around 80% of the cases, if the examination was performed by an expert registrar. The percent of accuracy decreases for Dukes stage C or N+ . CT may be useful for evaluating extensive local invasion as in CS 111-IV; whereas endosonography (ES) of the rectum can be performed in CS 1-11 if the lesion is really confined to the rectal wall. There is a general agreement that five layers can be identified by ES as follows: the first, hyperechoic, the interface between the balloon and the mucosal surface; the second, hypoechoic, the mucosae and the muscularis mucosae; the third, hyperechoic, the interface between sub-mucosae and the muscularis propriae; the fourth, hypoechoic, the muscularis propriae; and the fifth layer, hyperechoic, the interface between the muscularis propriae and perirectal fat. ES examination has an accuracy around 90%, is easy to perform, is relatively cheap, and the major problems are stenotic tumors [3]. Rifkin and Wechsler [ 151 in 1986 Accepted for publication May 30, 1991. Address reprint requests to Dr. F. Mazzeo, Department of General Surgery 11, The University of Naples School of Medicine, Via S . Pansini, 80131, Naples, Italy.
22
Mazzeo et al.
found the sensitivity for detection of perirectal fat infiltration to be 83% for ES and 55% for CT and the sensitivity for malignant lymph nodes involvement to be 55% and 23%, respectively. Thus, neither CT nor ES is capable of detecting lymph node metastases with sufficient accuracy, mainly because the techniques cannot distinguish normal gland tissue from tumor tissue, irrespective of the size of the glands. Perhaps preoperative transcutaneous ultrasound (US) and magnetic resonance imaging (MRI), as time progresses, will be able to improve the reliability of preoperative staging of rectal cancer. As Nicholls et al. [4] emphasized during the International Workshop on Colorectal cancer held in Rome in 1989, ES cannot define the degree of perirectal fat invasion. Dukes stage B or T3 [18] includes different infiltrative tumors having very different prognoses. Hermanek et al. [7] proposed a T3 restaging, introducing a T3a-T3b-T3c classification in order to get a better assessment of the wall. Pathologists play a fundamental role in improving the staging of Dukes B or T3 of the rectum since those tumors are related to a metastatic spread to lateral ileopelvic lymph nodes. A correlation between York Mason’s [5] classification and the incidence of lymph nodal metastatic involvement could be the following: CS I, 0% of N + ; CS 11, 10% of N + , CS 111, f 50%; CS IV, >50%. Digital examination, ES, or CT scan can detect enlarged reactive lymph nodes in most cases (60%) except for locally really advanced tumors [2]. ES can detect nodes of 0.5 cm in diameter or greater, with an accuracy of around 80%. Nodes are seen as hypoechoic rounded lesions and are easily distinguished from pelvic blood vessels. CT scan can detect lymph node enlargement of 1 cm but it is not specific for nodal metastases [3]. By using traditional techniques and comparing the scans with the histopathology of resected specimens, reliable mesorectal node imaging is now possible [lo]. In this field we introduced, in 1982, an important technique to evaluate the lymphatic flow, but not the metastases, of lymph nodes located along the hemorrhoidal and inferior mesenteric vessels, by the injection of Tc sulfur colloid into the rectal sub-mucosa. Also, the injection of Tc, either underneath Waldeyer’s fascia or in the perirectal space, as Ege proposed [14], allows us to evaluate the lymphatic flow of lateral and iliac lymph nodes by ileopelvic lymphoscintigraphy [ 131. Both these techniques can be improved by using monoclonal antibodies as tumor-positive markers, as we have done L9,lOI. Diagnostic techniques were applied in our experience in 72 patients. In 61 patients lymphoscintigraphy by Tc99 was utilized whereas immuno-lymphoscintigraphy by anticarcinoembryonic antigen (CEA) marked with I 131
was performed in 11 patients. Two doses of 3 mCi of Tc99 or marked antibodies, in 3 ml, were injected through a proctoscope, with a 21G needle into the rectal sub-mucosae [ 111. Scintigraphic scans were performed by gamma-camera at regular intervals of 30 minutes for a period of 3 hours in patients who underwent lymphoscintigraphy and at 24, 36,48, 72, and 96 hours after the injection of monoclonal marked antibodies. Rectal lymphoscintigraphy visualized epirectal and pararectal lymph nodes and nodes of the middle hemorrhoidal artery; in Dukes stage A (6 patients) the spread of radionuclide was more rapid than in the control group (16 patients). In Dukes stage B (23 patients) the drainage was delayed and in stage C (16 patients) was incomplete after 3 hours. Eight out of 23 Dukes stages B, with a large pelvic invasion, showed a delayed drainage as in Dukes stages C. The results of immuno-lymphoscintigraphy emphasized that marked antibodies do not progress beyond the point of injection. In patients with rectal cancer high dose of antibodies were evidenced in the site of injection, in the site of the tumor, and later in a synchronous sigmoid cancer. Recently, Derksen et al. [17], administered in patients with rectal cancer antibody fragments by injection into the rectal sub-mucosa, and evaluation of the counts per-area increased the sensitivity and the accuracy of the method. Arnaud et al. [I61 re-evaluated the method showing a complete cranial lymphatic drainage in 100% of patients, whereas internal iliac nodes were visible in 50% of cases. Results were correlated with histological examination of dissected lymph nodes resulting in 85% for sensitivity, 58% for specificity, 76% for accuracy, 71% positive predictive value, and 83% negative predictive value. Although we first introduced this technique, our results are not so encouraging as in Arnaud et al.’s experience, and we hope to get improvements of lymphoscintigraphy and of immuno-lymphoscintigraphy by kinetic studies more than by imaging. In comparing lymphoscintigraphy with histopathological results, radiotherapy plays a fundamental role by reducing the number of involved lymph nodes as does lymphatic dissection, even if it is never extended to lateral and pelvic nodes. The future usefulness of lymphoscintigraphy and of immuno-lymphoscintigraphy can be tested only by prospective studies. At present the injection of the radionuclide either into the rectal sub-mucosa or underneath Waldeyer’s fascia is still the only means to detect the involvement of nodes of the first level in rectal cancer.
REFERENCES I . Phillips RKS, Hittinger R , Fielding LP: Preoperative urography in large bowel cancer surgery-A useless investigation? J Exp Clin Cancer Res 255, 1983.
Clinical Staging of Colorectal Cancer 2. Sugarbaker PH: Clinical evaluation of symptomatic patients. In Glenn Steele Jr, Osteen RT (eds): “Colorectal Cancer.” New York: Marcel Dekker, Inc., 1986, pp 59-98. 3. Mortensen N: New thoughts and methods in colorectal cancer. In Hadfield J , Hobsley M, Treasure T (eds): “Current Surgical Practice.” London: Edward Arnold, 1990, pp 113-127. 4. Nicholls RJ, York Mason A, Morson BC: The clinical staging of rectal cancer. Br J Surg 69:404-409, 1982. 5 . York Mason A: Rectal cancer: the spectrum of elective surgery. Proc R Soc Med 69:237-244, 1976. 6. Fielding LP: Clinical-pathologic staging of large-bowel cancer. A report of the ASCRS Committee. Dis Colon Rectum 31:204-209, 1988. 7. Hermanek P, Guggenmoos-Holzmann I, Gall FP: Prognostic factor in rectal carcinoma. A contribution to the further development of tumor classification. Dis Colon Rectum 32:593-599, 1989. 8. Benyon NJ, Mortensen McC, Foy DMA, Channer L, Virjee J, Goddard P: Pre-operative assessment of local invasion in rectal cancer: digital examination, endoluminal sonography or computed tomography? Br J Surg 73:1015-1017, 1986. 9. Mazzeo F. Bucci L, Benassai G: Prognostic factors in colorectal cancer. J Exp Clin Cancer Res 8:3 (suppl.), 1989. 10. Bucci L, Mazzeo F: Rectal lymphoscintigraphy. Dis Colon Rectum 27:370-375, 1984. 11. Bucci L, Mazzeo F: F(AB‘) anti-CEA immunoscintigraphy in
23
prestaging and early detection of recurrences in colorectal cancer. Med Chir Dig 16:267-269, 1987. 12. Fielding LP, Chapuis PH, Dent 0, Gathright B, Hardcastle JD, Hermanek P, Jass JR, Newland RD: Clinicopathological staging for colorectal cancer: an international comprehensive anatomical terminology (ICAT). Working Party Reports 1990, pp 5 7 4 2 . 13, Kaplan DW: lleopelvic lymphoscintigraphy. Semin Nuclear Med 13142-53, 1983. 14. Ege GN: Augmented ileopelvic lymphoscintigraphy: application in management of genitourinary malignancy. J Urol 127:265-269, 1982. 15. Rifkin MD, Wechsler RJ: A comparison of computed tomography and endorectal ultrasound in staging rectal cancer. Int J Colorect Dis 1:21&223, 1986. 16. Arnaud JP, Bergamaschi R, Schloegel M, Ollier JC, Haegele P, Grob JC, Adloff M: Progress in the assessment of lymphatic spread in rectal cancer. Rectal endoscopic lymphoscintigraphy . Dis Colon Rectum 335,338401, 1990. 17. Derksen EJ, Roos JC, van Lingen A, der Hollander W, Mejer S, Teule JJ: Submucosally administered antibody-fragments in patients with rectal carcinoma: visual discrimination or curve analysis? In abstract Fifth Congress of The European Society of Surgical Oncology, Brussels, Belgium, 1990, p 165. 18. Spiessel B, Schiebe 0 , Wagner G: UlCC TNM Atlas. New York: Springer-Verlag, 1982.
Clinical Staging and Pathological Correlation in Colorectal Cancer F. MAZZEO, MD, L. BUCCI, MD, M. GENTILE, MD, G . BENASSAI, MD, A N D ) . NIRO, MD From the Department of General Surgery I / , The University of Naples School of Medicine, Naples, Italy
KEYWORDS:residual tumor, imaging techniques, clinical staging
INTRODUCTION The role of surgery in the treatment of large bowel cancer is still preeminent, influencing both the immediate and longer term outcome of the disease. The examination of surgical specimens, i.e., what we agree as a traditional staging, cannot leave out of our consideration the clinical preoperative evaluation of the disease and the definition of the residual tumor or “R”, in order to get a more punctual staging of the tumor. The free serosal surface and adjacent organ invasion play a primary role in determining the “R[ 121”. If a laparotomic staging is always satisfactory it is not the fullest-proof for colonic cancer and imaging techniques play a significant role in not-operative staging of rectal cancer allowing to choose an adequate surgical procedure and assisting a rational selection of preoperative adjunctive treatment. A warning comes from the increasing number of non-operative imaging techniques makes it necessary to schedule a rational sequence of imaging procedures to keep the financial costs for patients as low as possible. An accurate clinical staging includes the degree of local invasion, the lymph nodal involvement, and the detection of hepatic metastases together with the age and the anatomical (sphincters and pelvis) and risk evaluation. All these factors must always be weighed in balance [61. Above the peritoneal reflection, traditional not-operative imaging techniques give information about the size and the degree of obstruction; computerized tomographic (CT) scan and urographic examination can better define the stage of a large fixed mass, and the anatomical and functional abnormalities of urinary tract [ 11. Under the peritoneal reflection, or for those tumors localized within the lower 10 cm of the rectum, assessing local invasion is fundamental because an inappropriate or incomplete surgery could be followed by local recurrences particularly difficult to manage. A digital rectal examination is essential to define the degree of invasion, assessing the size, the fixity, and the extent of the lesion within the 0 1991 Wiley-Liss, Inc.
pelvis. The tip of the fingers must explore all rectal walls, posteriorly the sacrum, pelvic, and perineal muscles [2,81. York Mason [5] proposed a clinical staging system based on digital rectal examination defining as CS I, a fully mobile tumor; CS 11, there is some resistance to movement; CS 111, an adherent but still mobile tumor; CS IV, a fixed tumor. Freely mobile tumors are those where invasion is confined to mucosae and sub-mucosae only. Tumors are mobile when the disease penetrates the muscularis mucosae but not progress beyond it. When tumors penetrate into the muscularis propria they can be defined as adherent, and greater degrees of fixity can indicate an involvement of adjacent organs such as the prostate or muscle-skeletal organs. Digital staging was tested, prospectively, in 1982 by Nicholls et al. [4], showing an accuracy of prediction in around 80% of the cases, if the examination was performed by an expert registrar. The percent of accuracy decreases for Dukes stage C or N+ . CT may be useful for evaluating extensive local invasion as in CS 111-IV; whereas endosonography (ES) of the rectum can be performed in CS 1-11 if the lesion is really confined to the rectal wall. There is a general agreement that five layers can be identified by ES as follows: the first, hyperechoic, the interface between the balloon and the mucosal surface; the second, hypoechoic, the mucosae and the muscularis mucosae; the third, hyperechoic, the interface between sub-mucosae and the muscularis propriae; the fourth, hypoechoic, the muscularis propriae; and the fifth layer, hyperechoic, the interface between the muscularis propriae and perirectal fat. ES examination has an accuracy around 90%, is easy to perform, is relatively cheap, and the major problems are stenotic tumors [3]. Rifkin and Wechsler [ 151 in 1986 Accepted for publication May 30, 1991. Address reprint requests to Dr. F. Mazzeo, Department of General Surgery 11, The University of Naples School of Medicine, Via S . Pansini, 80131, Naples, Italy.
22
Mazzeo et al.
found the sensitivity for detection of perirectal fat infiltration to be 83% for ES and 55% for CT and the sensitivity for malignant lymph nodes involvement to be 55% and 23%, respectively. Thus, neither CT nor ES is capable of detecting lymph node metastases with sufficient accuracy, mainly because the techniques cannot distinguish normal gland tissue from tumor tissue, irrespective of the size of the glands. Perhaps preoperative transcutaneous ultrasound (US) and magnetic resonance imaging (MRI), as time progresses, will be able to improve the reliability of preoperative staging of rectal cancer. As Nicholls et al. [4] emphasized during the International Workshop on Colorectal cancer held in Rome in 1989, ES cannot define the degree of perirectal fat invasion. Dukes stage B or T3 [18] includes different infiltrative tumors having very different prognoses. Hermanek et al. [7] proposed a T3 restaging, introducing a T3a-T3b-T3c classification in order to get a better assessment of the wall. Pathologists play a fundamental role in improving the staging of Dukes B or T3 of the rectum since those tumors are related to a metastatic spread to lateral ileopelvic lymph nodes. A correlation between York Mason’s [5] classification and the incidence of lymph nodal metastatic involvement could be the following: CS I, 0% of N + ; CS 11, 10% of N + , CS 111, f 50%; CS IV, >50%. Digital examination, ES, or CT scan can detect enlarged reactive lymph nodes in most cases (60%) except for locally really advanced tumors [2]. ES can detect nodes of 0.5 cm in diameter or greater, with an accuracy of around 80%. Nodes are seen as hypoechoic rounded lesions and are easily distinguished from pelvic blood vessels. CT scan can detect lymph node enlargement of 1 cm but it is not specific for nodal metastases [3]. By using traditional techniques and comparing the scans with the histopathology of resected specimens, reliable mesorectal node imaging is now possible [lo]. In this field we introduced, in 1982, an important technique to evaluate the lymphatic flow, but not the metastases, of lymph nodes located along the hemorrhoidal and inferior mesenteric vessels, by the injection of Tc sulfur colloid into the rectal sub-mucosa. Also, the injection of Tc, either underneath Waldeyer’s fascia or in the perirectal space, as Ege proposed [14], allows us to evaluate the lymphatic flow of lateral and iliac lymph nodes by ileopelvic lymphoscintigraphy [ 131. Both these techniques can be improved by using monoclonal antibodies as tumor-positive markers, as we have done L9,lOI. Diagnostic techniques were applied in our experience in 72 patients. In 61 patients lymphoscintigraphy by Tc99 was utilized whereas immuno-lymphoscintigraphy by anticarcinoembryonic antigen (CEA) marked with I 131
was performed in 11 patients. Two doses of 3 mCi of Tc99 or marked antibodies, in 3 ml, were injected through a proctoscope, with a 21G needle into the rectal sub-mucosae [ 111. Scintigraphic scans were performed by gamma-camera at regular intervals of 30 minutes for a period of 3 hours in patients who underwent lymphoscintigraphy and at 24, 36,48, 72, and 96 hours after the injection of monoclonal marked antibodies. Rectal lymphoscintigraphy visualized epirectal and pararectal lymph nodes and nodes of the middle hemorrhoidal artery; in Dukes stage A (6 patients) the spread of radionuclide was more rapid than in the control group (16 patients). In Dukes stage B (23 patients) the drainage was delayed and in stage C (16 patients) was incomplete after 3 hours. Eight out of 23 Dukes stages B, with a large pelvic invasion, showed a delayed drainage as in Dukes stages C. The results of immuno-lymphoscintigraphy emphasized that marked antibodies do not progress beyond the point of injection. In patients with rectal cancer high dose of antibodies were evidenced in the site of injection, in the site of the tumor, and later in a synchronous sigmoid cancer. Recently, Derksen et al. [17], administered in patients with rectal cancer antibody fragments by injection into the rectal sub-mucosa, and evaluation of the counts per-area increased the sensitivity and the accuracy of the method. Arnaud et al. [I61 re-evaluated the method showing a complete cranial lymphatic drainage in 100% of patients, whereas internal iliac nodes were visible in 50% of cases. Results were correlated with histological examination of dissected lymph nodes resulting in 85% for sensitivity, 58% for specificity, 76% for accuracy, 71% positive predictive value, and 83% negative predictive value. Although we first introduced this technique, our results are not so encouraging as in Arnaud et al.’s experience, and we hope to get improvements of lymphoscintigraphy and of immuno-lymphoscintigraphy by kinetic studies more than by imaging. In comparing lymphoscintigraphy with histopathological results, radiotherapy plays a fundamental role by reducing the number of involved lymph nodes as does lymphatic dissection, even if it is never extended to lateral and pelvic nodes. The future usefulness of lymphoscintigraphy and of immuno-lymphoscintigraphy can be tested only by prospective studies. At present the injection of the radionuclide either into the rectal sub-mucosa or underneath Waldeyer’s fascia is still the only means to detect the involvement of nodes of the first level in rectal cancer.
REFERENCES I . Phillips RKS, Hittinger R , Fielding LP: Preoperative urography in large bowel cancer surgery-A useless investigation? J Exp Clin Cancer Res 255, 1983.
Clinical Staging of Colorectal Cancer 2. Sugarbaker PH: Clinical evaluation of symptomatic patients. In Glenn Steele Jr, Osteen RT (eds): “Colorectal Cancer.” New York: Marcel Dekker, Inc., 1986, pp 59-98. 3. Mortensen N: New thoughts and methods in colorectal cancer. In Hadfield J , Hobsley M, Treasure T (eds): “Current Surgical Practice.” London: Edward Arnold, 1990, pp 113-127. 4. Nicholls RJ, York Mason A, Morson BC: The clinical staging of rectal cancer. Br J Surg 69:404-409, 1982. 5 . York Mason A: Rectal cancer: the spectrum of elective surgery. Proc R Soc Med 69:237-244, 1976. 6. Fielding LP: Clinical-pathologic staging of large-bowel cancer. A report of the ASCRS Committee. Dis Colon Rectum 31:204-209, 1988. 7. Hermanek P, Guggenmoos-Holzmann I, Gall FP: Prognostic factor in rectal carcinoma. A contribution to the further development of tumor classification. Dis Colon Rectum 32:593-599, 1989. 8. Benyon NJ, Mortensen McC, Foy DMA, Channer L, Virjee J, Goddard P: Pre-operative assessment of local invasion in rectal cancer: digital examination, endoluminal sonography or computed tomography? Br J Surg 73:1015-1017, 1986. 9. Mazzeo F. Bucci L, Benassai G: Prognostic factors in colorectal cancer. J Exp Clin Cancer Res 8:3 (suppl.), 1989. 10. Bucci L, Mazzeo F: Rectal lymphoscintigraphy. Dis Colon Rectum 27:370-375, 1984. 11. Bucci L, Mazzeo F: F(AB‘) anti-CEA immunoscintigraphy in
23
prestaging and early detection of recurrences in colorectal cancer. Med Chir Dig 16:267-269, 1987. 12. Fielding LP, Chapuis PH, Dent 0, Gathright B, Hardcastle JD, Hermanek P, Jass JR, Newland RD: Clinicopathological staging for colorectal cancer: an international comprehensive anatomical terminology (ICAT). Working Party Reports 1990, pp 5 7 4 2 . 13, Kaplan DW: lleopelvic lymphoscintigraphy. Semin Nuclear Med 13142-53, 1983. 14. Ege GN: Augmented ileopelvic lymphoscintigraphy: application in management of genitourinary malignancy. J Urol 127:265-269, 1982. 15. Rifkin MD, Wechsler RJ: A comparison of computed tomography and endorectal ultrasound in staging rectal cancer. Int J Colorect Dis 1:21&223, 1986. 16. Arnaud JP, Bergamaschi R, Schloegel M, Ollier JC, Haegele P, Grob JC, Adloff M: Progress in the assessment of lymphatic spread in rectal cancer. Rectal endoscopic lymphoscintigraphy . Dis Colon Rectum 335,338401, 1990. 17. Derksen EJ, Roos JC, van Lingen A, der Hollander W, Mejer S, Teule JJ: Submucosally administered antibody-fragments in patients with rectal carcinoma: visual discrimination or curve analysis? In abstract Fifth Congress of The European Society of Surgical Oncology, Brussels, Belgium, 1990, p 165. 18. Spiessel B, Schiebe 0 , Wagner G: UlCC TNM Atlas. New York: Springer-Verlag, 1982.
