Case 18-2004 — A 61-Year-Old Man with Rectal Bleeding and a 2-cm Mass in the Rectum
http://www.100md.com
《新英格兰医药杂志》
Presentation of Case
A 61-year-old man was referred to this hospital for treatment of a low rectal adenocarcinoma. He had been well until five months previously, when he occasionally began to note blood in his stool. A stool guaiac test was positive. Three weeks before the patient's referral, a colonoscopy was performed at another hospital. A sessile polyp, 10 mm in diameter, was removed from the right side of the colon and was determined to be a tubular adenoma; a sessile polyp, 4 mm in diameter, was found 80 cm into the left side of the colon; it was excised and found to be associated with a hyperplastic polyp containing carcinoma in situ. A friable, sessile lesion, 15 to 20 mm in diameter, was identified very low in the rectum; examination of a biopsy specimen of the lesion disclosed adenocarcinoma. Nine days later, another colonoscopy was performed with ink injection; biopsy specimens were obtained at the 80-cm site and were found to contain no residual neoplasm. A polyp, 3 to 4 mm in diameter, was found 110 cm into the colon; it was removed and found to be a tubular adenoma.
Computed tomographic (CT) scanning of the abdomen and pelvis performed after the administration of contrast material showed no evidence of metastatic carcinoma.
The patient was referred to this hospital. There was a history of mild, intermittent fecal incontinence, diabetes mellitus that was controlled with diet, and kidney stones that had been treated by lithotripsy 10 years earlier. He had a 40-pack-year smoking history but had discontinued smoking five years previously. On physical examination, he appeared well. An examination of his heart and lungs showed no abnormalities. The patient was moderately obese, and the abdomen was free of palpable masses. During a digital rectal examination, a mobile, soft mass was found low in the left lateral portion of the rectum. Examination by flexible sigmoidoscopy to 20 cm showed a sessile polyp, 0.5 cm in diameter, at 12 cm, and an exophytic, friable mass, 1 by 3 cm, with its lowest edge at 6 cm.
The patient sought a second opinion at another hospital. Transanal ultrasound examination at that hospital showed that the mass was either a stage T1 or possibly early stage T2 tumor, and two lymph nodes of normal size were identified in the perirectal area. Another biopsy of the mass was performed at that hospital, and examination of the specimen showed a moderately to poorly differentiated adenocarcinoma.
The results of laboratory tests, including a complete blood count and measurements of electrolytes, blood urea nitrogen, creatinine, and carcinoembryonic antigen, were within normal ranges. A chest radiograph showed that the lungs were clear, without evidence of metastases, and that the cardiac, hilar, mediastinal pleural, and bony structures were normal.
Discussion of Management
Dr. Paul C. Shellito: Dr. Brugge, will you review the ultrasound examinations?
Dr. William Brugge (Gastroenterology): Endoscopic ultrasonography is used for the staging of rectal cancers according to the tumor–node–metastasis classification system (Figure 1A). T1 lesions involve the mucosa with variable invasion into the submucosa; T2 lesions invade, but do not completely penetrate, the muscularis propria; T3 lesions are transmural and involve all layers of the rectum, including the serosa; and T4 lesions involve adjacent structures, such as the bladder. Ultrasound examination permits visualization of the normal layered structure of the gastrointestinal tract wall, revealing alternating black and white bands that correspond to the histologic layers. The muscularis propria appears as a thick black band and is our reference point for determining whether the lesion is superficial or invades or completely penetrates the muscularis propria. The extent of invasion through the muscularis propria can be assessed by looking at the outside border of this layer. A smooth border is indicative of a T1 or T2 lesion, whereas an irregular border indicates transmural invasion.
Figure 1. Transanal Ultrasonographic Staging of Rectal Cancer.
The tumor–node–metastasis classification system (Panel A) is based on the depth of invasion by a lesion through the layers of the gastrointestinal wall. These layers appear as alternating dark and light bands on an ultrasonogram. In this patient (Panel B), the ultrasonogram shows a mass, 8 mm thick, in the mucosa that extends through the submucosa into the muscularis propria, which is seen as a dark band. The external contour of the muscularis is smooth (arrows), suggesting that the tumor does not infiltrate beyond the muscularis propria. The bright area in the lower part of the field is perirectal fat.
A transanal endoscopic ultrasonographic examination performed at this hospital (Figure 1B) shows an infiltrative mass, 8 mm thick, in the rectum. The tumor has invaded the mucosa, submucosa, and muscularis propria. However, the outside border of the muscularis propria appears smooth. Several lymph nodes are visible, but they are not enlarged and have normal echogenicity. Therefore, the lesion was classified as a T2N0 lesion — one that invades but does not completely penetrate the muscularis propria, and that is not accompanied by pathologically enlarged lymph nodes.
Dr. Paul Russell (Surgery): Do you get the same information from other types of scans?
Dr. Brugge: CT and magnetic resonance imaging (MRI) scans do not provide nearly the degree of resolution as ultrasonography. However, new techniques involving the use of rectal coils may enhance the details of the rectum on MRI scanning.
Dr. Shellito: This patient was a moderately obese man with a small tumor situated very low in the rectum; he was unusually anxious about his diagnosis and treatment and was very determined to avoid a colostomy. Although I frequently refer patients with rectal carcinoma for preoperative radiation and chemotherapy, on initial evaluation this cancer did not seem to be locally advanced, so I focused on surgery as the first therapeutic step. The options for surgical treatment of low rectal cancer are abdominoperineal resection with a permanent colostomy, low anterior resection with or without the creation of a colon pouch, and local ablation, usually with a transanal local excision.
Local excision is the preferred option because it enables the patient to avoid major surgery and a colostomy. The procedure removes just a small portion of the full thickness of the rectal wall, so it is appropriate only for cancers that are less than 2 to 3 cm in diameter and that are limited to the rectal wall and those not accompanied by lymph-node metastases. The tumor should be mobile on digital rectal examination, exophytic, well or moderately well differentiated, and located low in the rectum. Tumors classified as T1 are the best candidates for local excision; it is controversial whether or not excision is appropriate for T2 tumors,1,2,3 since the risk of spread to the lymph nodes is higher than it is with T1 tumors. There is no reliable preoperative imaging technique for detecting lymph-node metastases. The rate of local recurrence after local excision has ranged from 5 to 20 percent, depending on how carefully patients were selected.3 About half of such local recurrences can be salvaged by radical resection, giving an ultimate long-term survival rate of 80 to 90 percent. This survival rate compares favorably with that of patients who undergo initial abdominoperineal resection, although randomized, controlled trials to compare the two approaches are not possible.
I initially considered local excision for this patient because his tumor was small, mobile, and exophytic and because of his anxieties about surgery and a colostomy. Nevertheless, I changed my mind when the biopsy specimens from the other hospital were reported to show a moderately to poorly differentiated tumor. Also, although ultrasound examination at the other hospital was interpreted as showing only a T1 or perhaps a superficial T2 tumor, the transanal ultrasound study performed here showed a T2 tumor. Thus, ultimately, I advised the patient to undergo radical resection instead of local excision.
This left the option of performing either abdominoperineal resection or low anterior resection. A consideration of the volume of tissue that must be removed to obtain clear resection margins will often determine whether a sphincter-saving operation is possible and appropriate. The vascular supply and lymphatic drainage of the rectum are contained within a supralevator compartment known as the mesorectum.4 The mesorectum is a fatty envelope around the lateral and posterior rectum, which is surrounded by a thin fascia propria (Figure 2). The mesorectum tapers and disappears as the rectum passes inferiorly through the levator hiatus. Distal spread of rectal cancer is unlikely to occur beyond a point 1 to 2 cm below the tumor, but distal intramesorectal lymphatic spread may occur as far as 3 to 4 cm below it.5 6 Resection of 4 to 5 cm of the rectum and mesorectum distal to the tumor is required for upper rectal cancers, and resection of the entire rectum and mesorectum down to the levatores should be performed for lower rectal cancers. In either instance, the mesorectum with its fascia propria should be excised en bloc with the rectum. This procedure, known as total mesorectal excision, has produced impressive results in nonrandomized trials (5 to 10 percent rates of local recurrence),7 and there is a growing consensus among surgeons that this technical aspect of radical rectal resection is important. If the tumor does not invade the sphincters, an adequate resection can usually be achieved with a total mesorectal excision, sparing the anus. Not all low rectal cancers require an abdominoperineal resection.
Figure 2. Diagram of the Mesorectum and Total Mesorectal Excision.
The mesorectum is a fatty envelope around the lateral and posterior rectum, which is surrounded by a thin fascia propria. It contains the blood and lymphatic vessels that supply and drain the rectum, as well as the regional lymph nodes. Total mesorectal excision removes this entire structure with the rectum to ensure adequate resection of a rectal cancer.
To spare the sphincter after very low radical resection, a coloanal anastomosis must be created. The anastomosis may be hand-sewn through the perineum after the mucosal lining is stripped from the dentate line up to the point of rectal transection (a technique known as "pull-through"). Alternatively, the low rectum or upper anal canal may be stapled and divided at the levator hiatus and an anastomosis then created with the use of a circular stapler (a technique known as "double stapling"), which is most often preferable.8 Constructing a J pouch from the proximal colon improves functional results by adding capacitance, especially in the first one to two years after surgery (Figure 3).9,10 Usually, a temporary ileostomy or transverse colostomy is created to divert the fecal stream away from the area of reconstruction.
Figure 3. Reconstruction of the Rectum after Low Anterior Resection with a Colonic J Pouch.
Two 5-to-6-cm lengths of colon are sutured together (top left portion of the figure). An incision is made in the apex of the pouch, and a stapler is inserted to join the two portions of the pouch. The anvil of a circular stapler (top right, shaded area) is inserted into the apex of the pouch; the remainder of the stapler is inserted through the rectum, and the shaft is pierced through the transverse staple line and joined to the anvil. The stapler is closed and fired, joining the apex of the pouch to the rectal stump (bottom).
This patient's tumor was quite low (6 cm from the anal verge), and he was male and moderately obese — all factors that make pelvic surgery, especially low anterior resection, technically difficult. Nevertheless, the tumor did not invade the sphincters (the anal canal, and thus the sphincters, extend from the anal verge 4 or 5 cm proximally), so I believed it was reasonable to attempt a sphincter-saving radical resection. Furthermore, the patient was able to lose an appreciable amount of weight before the operation.
I performed a very low anterior resection of the rectum with mobilization of the splenic flexure, and created a colonic J pouch, coloanal anastomosis, and a divided-loop ileostomy. There were no apparent intraabdominal metastases. The entire mesorectum was excised down to the levatores, with 1.5 cm of distal rectal wall below the cancer (a measurement made without traction on the bowel) as a resection margin. There were no postoperative complications.
Pathological Discussion
Dr. Aaron P. Caplan: The rectal biopsy specimen obtained at the other hospital contains a dense, complex proliferation of glands (Figure 4A). The glands are irregular in contour and densely packed, in contrast to normal mucosal glands (Figure 4B), which have open lumina and a parallel arrangement of epithelial cells. The nuclei are hyperchromatic, irregular, and stratified, in contrast to those of normal glands, which are bland, round, and located basally. Because of the superficial nature of the biopsy specimens, the extent of invasion of the submucosa could not be assessed. We interpreted the findings as indicative of at least high-grade dysplasia, with features (the complexity and density of the glandular proliferation) suggestive of invasion.
Figure 4. Biopsy Specimen of the Rectal Lesion (Hematoxylin and Eosin).
Examination of the rectal biopsy at low magnification shows a proliferation of irregularly shaped and complex glands that are crowded in a back-to-back arrangement (Panel A, x10). At a higher magnification, pseudostratification of the nuclei and nuclear hyperchromasia are evident in comparison with an uninvolved gland (upper left) (Panel B, x40).
Examination of the resected rectum and sigmoid showed a mass, 3 by 2 by 0.5 cm, that was a moderately differentiated adenocarcinoma with transmural invasion into the perirectal fat (Figure 5), extending to within 0.2 cm of the distal resection margin. There was invasion of blood and lymphatic vessels in the submucosa and extramurally, and four of nine lymph nodes contained cancer. The local-tumor stage was PT3N2MX (pathologically T3, with more than one positive node and unevaluable metastases); the extent of invasion was scored as pT3b; that is, there was invasion into the perirectal soft tissues less than 0.5 cm beyond the muscularis propria. The surgical clearance was 0.2 cm from the closest radial margin.
Figure 5. Photomicrographs of the Resected Rectum (Hematoxylin and Eosin).
Examination of the resection specimen at low power (Panel A, x2.5) shows a proliferation of well-formed but architecturally complex glands, similar in appearance to those seen in the biopsy specimen. The tumor extends from the colonic surface through the lamina propria and into the submucosa. Another view (Panel B, x2.5) shows that the tumor focally extends beyond the muscularis propria, into the perirectal fat (left portion of the panel). Lymphatic invasion was easily identified (Panel C, x20). Metastatic deposits of adenocarcinoma were present (Panel D, x10) within a regional lymph node.
Dr. Shellito: Because of the pathological findings of a deeply invasive tumor with positive lymph nodes, I referred the patient for consideration of postoperative adjuvant radiation and chemotherapy.
Discussion of Management, Continued
Dr. Christopher G. Willett: Nineteen days after discharge, the patient was seen in our clinic for consideration for further therapy. Radiation therapy is used in the management of rectal carcinoma in three settings: as adjuvant therapy after the local excision of carcinomas that have a favorable prognosis (typical stage, T2NXM0), as adjuvant or neoadjuvant therapy for more advanced lesions, such as clinical T3 carcinomas, and as preoperative therapy for fixed and unresectable tumors (T4) to facilitate resection. With regard to clinical stage T3 carcinoma, a long-standing debate exists about the merits of adjuvant (postoperative) strategies as compared with neoadjuvant (preoperative) strategies. For more than 30 years, clinical trials have evaluated combinations of surgery, radiation therapy, and chemotherapy. One of the chief advantages of postoperative adjuvant therapy is that the decision making can be based on operative and pathological findings that allow the rational selection of patients for this treatment.
A number of prospective randomized trials have confirmed the value of postoperative radiation therapy and chemotherapy for patients with resected stage T2 or T3 rectal carcinomas. Early studies demonstrated the advantage of the combination of postoperative radiation therapy and chemotherapy over resection, radiation therapy, or chemotherapy alone. More recent trials have sought to clarify the optimal regimen of chemotherapy with radiation. One important trial demonstrated an improved overall survival benefit with the use of continuous-infusion fluorouracil throughout the course of radiation therapy as compared with bolus fluorouracil (three injections during the first and fifth weeks of irradiation).11 The results of another study showed no benefit in terms of survival or local control with the addition of leucovorin, levamisole, or both to bolus fluorouracil.12 On the basis of such data, the current practice is to offer postoperative radiation with the administration of concurrent and maintenance fluorouracil-based chemotherapy for patients with resected stage T2 or T3 rectal carcinomas.
Had the tumor stage been known preoperatively, we would have recommended neoadjuvant radiation therapy and chemotherapy. Recent randomized trials have shown that preoperative radiation therapy13 or radiation therapy and chemotherapy with fluorouracil14,15 for resectable T3 rectal cancers resulted in improved local control and sphincter preservation for patients who underwent total mesorectal excision, as compared with those who received postoperative therapy. Several single-institution studies16,17 have also indicated that neoadjuvant therapy increases sphincter preservation.
For this patient, whose tumor had already been resected, we recommended radiation therapy together with fluorouracil chemotherapy. From the 50th day to the 118th postoperative day, he received external-beam radiation by three-dimensional conformal techniques (a total dose of 58 Gy to the tumor bed in 32 fractions).
Dr. Jeffrey W. Clark: Fluorouracil is the current standard chemotherapeutic agent used in the adjuvant treatment of rectal cancer. In fluorouracil, fluorine replaces hydrogen at the position of the fifth carbon of the pyrimidine ring. Fluorouracil is converted to fluorouridine monophosphate, which inhibits thymidylate synthetase, an enzyme that is critical in the conversion of uridine to thymidine. The inhibition of thymidylate synthetase decreases the intracellular concentration of thymidine monophosphate, which in turn leads to the inhibition of DNA synthesis. Fluorouracil can be toxic to the rapidly dividing tissues of the gastrointestinal tract and, to a lesser extent, the skin and bone marrow. The severity of toxic effects varies with the dose and dosing schedule. Diarrhea and stomatitis are the most common gastrointestinal toxic effects. Nausea and vomiting are usually mild. Neutropenia is usually mild to moderate but can be severe. Palmar–plantar erythrodysesthesia (i.e., hand–foot syndrome) is more frequent, but diarrhea is less frequent, with infusional administration of fluorouracil than with bolus regimens.
A standard approach for postoperative adjuvant treatment of rectal cancer would include fluorouracil (500 mg per square meter of body-surface area per day) by rapid intravenous infusion on days 1 to 5 and days 29 to 33; combined pelvic irradiation and continuous-infusion fluorouracil (225 mg per square meter per day) for five to six weeks, starting on day 64; and two additional courses of fluorouracil alone (450 mg per square meter per day) on days 134 to 138 and days 169 to 173.11 As with all chemotherapy treatments, it is critical that doses be withheld or modified or treatment discontinued as appropriate on the basis of toxic effects. Other regimens of fluorouracil, such as other schedules or doses of fluorouracil or combinations with leucovorin, would be acceptable alternatives.
In the future, additional therapies that are now being tested may improve the outcome for a patient such as this one. Capecitabine, an oral prodrug of fluorouracil, allows the delivery of fluorouracil dosing similar to that achieved with an infusion schedule without the risk of morbidity from central venous catheters or pumps, which were used in this patient.18 Irinotecan, a topoisomerase I inhibitor, and oxaliplatin, which forms interstrand and intrastrand DNA cross-links and DNA adducts similar to those formed by other platinum compounds, have each been shown to improve survival in patients with metastatic colorectal cancer when used in combination with fluorouracil and leucovorin.19,20,21 The roles of these agents in the treatment of rectal cancer are being evaluated.
Finally, as more is learned about the biology of rectal cancer, additional therapeutic targets continue to be identified. The cyclooxygenase-2 pathway is important in the proliferation of adenomatous polyps, and preclinical studies have indicated that its inhibition can enhance the efficacy of both radiation therapy and chemotherapy against tumors.22 Inhibition of vascular endothelial growth factor or its receptors, which are important in tumor angiogenesis, also has been found in preclinical models to enhance radiation sensitivity and the activity of fluorouracil. Clinical trials are evaluating bevacizumab, the anti–vascular endothelial growth factor antibody, as well as inhibitors of the epidermal growth factor receptor, for use in combination with radiation therapy for rectal cancer.23,24,25
For this patient, infusion of fluorouracil and radiation therapy followed by adjuvant administration of fluorouracil and leucovorin were chosen. Stomatitis, oral candidiasis, abdominal pain, diarrhea, and palmar–plantar erythrodysesthesia occurred. The patient's treatment was interrupted for the management of his abdominal and pelvic pain, diarrhea, and dehydration — symptoms consistent with fluorouracil toxicity. After the completion of radiation therapy, a course of adjuvant chemotherapy with fluorouracil and leucovorin was given; this treatment was complicated by fatigue, intermittent diarrhea, nausea, and vomiting. Restaging evaluation after the initial cycle of adjuvant chemotherapy revealed no evidence of metastatic disease.
Dr. Shellito: I was surprised by the final pathology report in this case. If I had known the stage of disease preoperatively, I would have referred the patient for neoadjuvant chemotherapy and radiation therapy. In the majority of cases, the surgeon bases the judgment of whether a sphincter-sparing operation is possible on the initial evaluation. If the tumor is clearly invading the anal canal or the sphincter, the patient is not a candidate for a sphincter-sparing operation, in my view. However, if the tumor is located higher in the rectum, then a sphincter-sparing operation usually can be performed, regardless of adjuvant treatment. There is the occasional patient, such as this one, whose tumor is in a borderline location for sphincter-sparing surgery, and in that situation, if the cancer is transmural or node-positive, I would be more comfortable performing such an operation if the patient has first had neoadjuvant treatment.
Dr. Brugge: Endoscopic ultrasonographic staging of lymph nodes is based on their size and echotexture. In this patient, the lymph nodes were microscopically involved and were not enlarged. The lymph nodes we saw on ultrasonographic examination were not enlarged and had normal echogenicity. It is important to remember that in rectal cancers, there can be microscopic involvement of the lymph nodes.
Dr. Clark: Better methods for assessing lymph-node involvement are clearly needed; new agents that allow the evaluation of internal lymph-node architecture on MRI scanning may be helpful in cases such as this one.26
Dr. Andrew L. Warshaw (Surgery): Has the evaluation of mobility on digital rectal examination lost its validity now that we have transrectal ultrasonography?
Dr. Shellito: I depend heavily on the physical examination. Tumor mobility, the degree of ulceration, and size are important. Sometimes, the assessment based on physical findings is not in agreement with the endoscopic ultrasonographic assessment, and then I have to make my best judgment as to how to proceed, given the conflicting data.
Dr. Warshaw: This patient had multiple colonic polyps. At what point do you become concerned about a polyposis syndrome and the need to evaluate the upper gastrointestinal tract?
Dr. Shellito: He had three other polyps, which is rather typical for synchronous neoplasms in patients with colorectal cancer. The presence of a few synchronous polyps (2, 3, or 4) would not concern me, but 12 or 15 would make me consider attenuated familial adenomatous polyposis, and I would then evaluate the patient more thoroughly with upper gastrointestinal endoscopy.
A surgeon: What is this patient's prognosis, and would it have been better if an abdominoperineal resection had been performed?
Dr. Shellito: I do not believe his prognosis would have been better with an abdominoperineal resection. When total mesorectal excision is performed and negative margins are achieved, the prognosis will not be affected by whether or not an uninvolved anus is also removed. Ordinarily, the prognosis for rectal cancer is fairly good with combination treatment, although it varies with the tumor stage. Nevertheless, I am concerned that this patient's tumor was node-positive, with florid lymphatic invasion. Although I remain cautiously optimistic, these histologic factors are unfavorable signs.
Dr. James C. Cusack, Jr. (Surgery): For the evaluation of a specimen obtained during total mesorectal excision, it has been recommended that the specimen be filled with formalin, fixed, and then sectioned to permit an accurate assessment of the completeness of the resection and a thorough inventory of any involved lymph nodes.27 Recently published histopathological criteria for evaluation of the completeness of total mesorectal resection require that at least 15 lymph nodes be included in the specimen.27 If only a few lymph nodes are identified in a resection specimen, then either an incomplete surgical resection or an inadequate search for lymph nodes has been performed.
Dr. Clark: The patient completed his adjuvant therapy 13 months after the operation. Restaging at that time disclosed no evidence of metastatic disease. His ileostomy was closed 16 months after the operation, and at his most recent follow-up examination, 19 months after the diagnosis, he reported that he has frequent soft stools, with some urgency, but that this symptom is improving. CT scanning of the chest, abdomen, and pelvis showed no evidence of recurrent or metastatic disease.
Pathological Diagnosis
Adenocarcinoma of the rectum, stage T3N2M0.
Source Information
From the Department of Surgery (P.C.S.), the Hematology–Oncology Unit, Department of Medicine (J.W.C.), the Department of Radiation Oncology (C.G.W.), and the Department of Pathology (A.P.C.), Massachusetts General Hospital; and the Departments of Surgery (P.C.S.), Medicine (J.W.C.), Radiation Oncology (C.G.W.), and Pathology (A.P.C.), Harvard Medical School.
References
Ng AK, Recht A, Busse PM. Sphincter preservation therapy for distal rectal carcinoma: a review. Cancer 1997;79:671-683.
Mellgren A, Sirivongs P, Rothenberger DA, Madoff RD, Garcia-Aguilar J. Is local excision adequate therapy for early rectal cancer? Dis Colon Rectum 2000;43:1064-1074.
Sengupta S, Tjandra JJ. Local excision of rectal cancer: what is the evidence? Dis Colon Rectum 2001;44:1345-1361.
Sterk P, Kasperk R, Opitz T, Schubert F, Klein P. Vascular organization in the mesorectum: angiography of rectal resection specimens. Int J Colorectal Dis 2000;15:225-228.
Scott N, Jackson P, al-Jaberi T, Dixon MF, Quirke P, Finan PJ. Total mesorectal excision and local recurrence: a study of tumour spread in the mesorectum distal to rectal cancer. Br J Surg 1995;82:1031-1033.
Hida J, Yasutomi M, Maruyama T, Fujimoto K, Uchida T, Okuno K. Lymph node metastases detected in the mesorectum distal to carcinoma of the rectum by the clearing method: justification of total mesorectal excision. J Am Coll Surg 1997;184:584-588.
Heald RJ, Moran BJ, Ryall RD, Sexton R, MacFarlane JK. Rectal cancer: the Basingstoke experience of total mesorectal excision, 1978-1997. Arch Surg 1998;133:894-899.
Read TE, Kodner IJ. Proctectomy and coloanal anastomosis for rectal cancer. Arch Surg 1999;134:670-677.
Dennett ER, Parry BR. Misconceptions about the colonic J-pouch: what the accumulating data show. Dis Colon Rectum 1999;42:804-811.
Ruo L, Guillem JG. Major 20th-century advancements in the management of rectal cancer. Dis Colon Rectum 1999;42:563-578.
O'Connell MJ, Martenson JA, Wieand HS, et al. Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 1994;331:502-507.
Tepper JE, O'Connell MJ, Niedzwiecki DR, et al. Adjuvant therapy in rectal cancer: analysis of stage, sex, and local control -- final report of intergroup 0114. J Clin Oncol 2002;20:1744-1750.
Kapiteijn E, Marijnen CAM, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 2001;345:638-646.
Sauer R, Fietkay R, Witteking C, et al. Adjuvant versus neoadjuvant radiochemotherapy for locally advanced rectal cancer: a progress report of a phase-III randomized trial (protocol CAO/ARO/AIO-94). Strahlenther Onkol 2001;177:173-181.
Sauer R. Adjuvant versus neoadjuvant combined modality treatment for locally advanced rectal cancer: first results of the German rectal cancer study (CAO/ARO/AIO-94). Int J Radiat Oncol Biol Phys 2003;57:Suppl:S124-S125. abstract.
Roh MS, Petrelli N, Wieand S, et al. Phase III randomized trial of preoperative versus postoperative multimodality therapy in patients with carcinoma of the rectum (NSABPR-03). Prog Proc Am Soc Clin Oncol 2001;20:123a. abstract.
Wagman R, Minsky BD, Cohen AM, Guillem JG, Paty PP. Sphincter preservation in rectal cancer with preoperative radiation therapy and coloanal anastomosis: long term follow-up. Int J Radiat Oncol Biol Phys 1998;42:51-57.
Van Cutsem E, Twelves C, Cassiday J, et al. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol 2001;19:4097-4106.
Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 2000;355:1041-1047.
Schmoll HJ. The role of oxaliplatin in the treatment of advanced metastatic colorectal cancer: prospects and future directions. Semin Oncol 2002;29:Suppl 15:34-39.
De Gramont A, Banzi M, Navarro M, et al. Oxaliplatin/5-FU/LV in adjuvant colon cancer: results of the international randomized MOSAIC trial. Prog Proc Am Soc Clin Oncol 2003;22:253. abstract.
Church RD, Fleshman JW, McLeod HL. Cyclo-oxygenase 2 inhibition in colorectal cancer therapy. Br J Surg 2003;90:1055-1067.
Zhu AX, Willett CG. Chemotherapeutic and biologic agents as radiosensitizers in rectal cancer. Semin Radiat Oncol 2003;13:454-468.
Willett CG, Boucher Y, di Tomaso E, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 2004;10:145-147.
Grunwald V, Hidalgo M. Developing inhibitors of the epidermal growth factor receptor for cancer treatment. J Natl Cancer Inst 2003;95:851-867.
Harisinghani MG, Barentsz J, Hahn PF, et al. Noninvasive detection of clinically occult lymph-node metastases in prostate cancer. N Engl J Med 2003;348:2491-2499.
Nagtegaal ID, van de Velde CJH, van der Worp E, Kapiteijn E, Quirke P, van Krieken JHJM. Macroscopic evaluation of rectal cancer resection specimen: clinical significance of the pathologist in quality control. J Clin Oncol 2002;20:1729-1734.
Related Letters:
Case 18-2004: A 61-Year-Old Man with Rectal Bleeding
Mitchell A., Panzini B., Shellito P. C., Caplan A. P.(Paul C. Shellito, M.D., J)
A 61-year-old man was referred to this hospital for treatment of a low rectal adenocarcinoma. He had been well until five months previously, when he occasionally began to note blood in his stool. A stool guaiac test was positive. Three weeks before the patient's referral, a colonoscopy was performed at another hospital. A sessile polyp, 10 mm in diameter, was removed from the right side of the colon and was determined to be a tubular adenoma; a sessile polyp, 4 mm in diameter, was found 80 cm into the left side of the colon; it was excised and found to be associated with a hyperplastic polyp containing carcinoma in situ. A friable, sessile lesion, 15 to 20 mm in diameter, was identified very low in the rectum; examination of a biopsy specimen of the lesion disclosed adenocarcinoma. Nine days later, another colonoscopy was performed with ink injection; biopsy specimens were obtained at the 80-cm site and were found to contain no residual neoplasm. A polyp, 3 to 4 mm in diameter, was found 110 cm into the colon; it was removed and found to be a tubular adenoma.
Computed tomographic (CT) scanning of the abdomen and pelvis performed after the administration of contrast material showed no evidence of metastatic carcinoma.
The patient was referred to this hospital. There was a history of mild, intermittent fecal incontinence, diabetes mellitus that was controlled with diet, and kidney stones that had been treated by lithotripsy 10 years earlier. He had a 40-pack-year smoking history but had discontinued smoking five years previously. On physical examination, he appeared well. An examination of his heart and lungs showed no abnormalities. The patient was moderately obese, and the abdomen was free of palpable masses. During a digital rectal examination, a mobile, soft mass was found low in the left lateral portion of the rectum. Examination by flexible sigmoidoscopy to 20 cm showed a sessile polyp, 0.5 cm in diameter, at 12 cm, and an exophytic, friable mass, 1 by 3 cm, with its lowest edge at 6 cm.
The patient sought a second opinion at another hospital. Transanal ultrasound examination at that hospital showed that the mass was either a stage T1 or possibly early stage T2 tumor, and two lymph nodes of normal size were identified in the perirectal area. Another biopsy of the mass was performed at that hospital, and examination of the specimen showed a moderately to poorly differentiated adenocarcinoma.
The results of laboratory tests, including a complete blood count and measurements of electrolytes, blood urea nitrogen, creatinine, and carcinoembryonic antigen, were within normal ranges. A chest radiograph showed that the lungs were clear, without evidence of metastases, and that the cardiac, hilar, mediastinal pleural, and bony structures were normal.
Discussion of Management
Dr. Paul C. Shellito: Dr. Brugge, will you review the ultrasound examinations?
Dr. William Brugge (Gastroenterology): Endoscopic ultrasonography is used for the staging of rectal cancers according to the tumor–node–metastasis classification system (Figure 1A). T1 lesions involve the mucosa with variable invasion into the submucosa; T2 lesions invade, but do not completely penetrate, the muscularis propria; T3 lesions are transmural and involve all layers of the rectum, including the serosa; and T4 lesions involve adjacent structures, such as the bladder. Ultrasound examination permits visualization of the normal layered structure of the gastrointestinal tract wall, revealing alternating black and white bands that correspond to the histologic layers. The muscularis propria appears as a thick black band and is our reference point for determining whether the lesion is superficial or invades or completely penetrates the muscularis propria. The extent of invasion through the muscularis propria can be assessed by looking at the outside border of this layer. A smooth border is indicative of a T1 or T2 lesion, whereas an irregular border indicates transmural invasion.
Figure 1. Transanal Ultrasonographic Staging of Rectal Cancer.
The tumor–node–metastasis classification system (Panel A) is based on the depth of invasion by a lesion through the layers of the gastrointestinal wall. These layers appear as alternating dark and light bands on an ultrasonogram. In this patient (Panel B), the ultrasonogram shows a mass, 8 mm thick, in the mucosa that extends through the submucosa into the muscularis propria, which is seen as a dark band. The external contour of the muscularis is smooth (arrows), suggesting that the tumor does not infiltrate beyond the muscularis propria. The bright area in the lower part of the field is perirectal fat.
A transanal endoscopic ultrasonographic examination performed at this hospital (Figure 1B) shows an infiltrative mass, 8 mm thick, in the rectum. The tumor has invaded the mucosa, submucosa, and muscularis propria. However, the outside border of the muscularis propria appears smooth. Several lymph nodes are visible, but they are not enlarged and have normal echogenicity. Therefore, the lesion was classified as a T2N0 lesion — one that invades but does not completely penetrate the muscularis propria, and that is not accompanied by pathologically enlarged lymph nodes.
Dr. Paul Russell (Surgery): Do you get the same information from other types of scans?
Dr. Brugge: CT and magnetic resonance imaging (MRI) scans do not provide nearly the degree of resolution as ultrasonography. However, new techniques involving the use of rectal coils may enhance the details of the rectum on MRI scanning.
Dr. Shellito: This patient was a moderately obese man with a small tumor situated very low in the rectum; he was unusually anxious about his diagnosis and treatment and was very determined to avoid a colostomy. Although I frequently refer patients with rectal carcinoma for preoperative radiation and chemotherapy, on initial evaluation this cancer did not seem to be locally advanced, so I focused on surgery as the first therapeutic step. The options for surgical treatment of low rectal cancer are abdominoperineal resection with a permanent colostomy, low anterior resection with or without the creation of a colon pouch, and local ablation, usually with a transanal local excision.
Local excision is the preferred option because it enables the patient to avoid major surgery and a colostomy. The procedure removes just a small portion of the full thickness of the rectal wall, so it is appropriate only for cancers that are less than 2 to 3 cm in diameter and that are limited to the rectal wall and those not accompanied by lymph-node metastases. The tumor should be mobile on digital rectal examination, exophytic, well or moderately well differentiated, and located low in the rectum. Tumors classified as T1 are the best candidates for local excision; it is controversial whether or not excision is appropriate for T2 tumors,1,2,3 since the risk of spread to the lymph nodes is higher than it is with T1 tumors. There is no reliable preoperative imaging technique for detecting lymph-node metastases. The rate of local recurrence after local excision has ranged from 5 to 20 percent, depending on how carefully patients were selected.3 About half of such local recurrences can be salvaged by radical resection, giving an ultimate long-term survival rate of 80 to 90 percent. This survival rate compares favorably with that of patients who undergo initial abdominoperineal resection, although randomized, controlled trials to compare the two approaches are not possible.
I initially considered local excision for this patient because his tumor was small, mobile, and exophytic and because of his anxieties about surgery and a colostomy. Nevertheless, I changed my mind when the biopsy specimens from the other hospital were reported to show a moderately to poorly differentiated tumor. Also, although ultrasound examination at the other hospital was interpreted as showing only a T1 or perhaps a superficial T2 tumor, the transanal ultrasound study performed here showed a T2 tumor. Thus, ultimately, I advised the patient to undergo radical resection instead of local excision.
This left the option of performing either abdominoperineal resection or low anterior resection. A consideration of the volume of tissue that must be removed to obtain clear resection margins will often determine whether a sphincter-saving operation is possible and appropriate. The vascular supply and lymphatic drainage of the rectum are contained within a supralevator compartment known as the mesorectum.4 The mesorectum is a fatty envelope around the lateral and posterior rectum, which is surrounded by a thin fascia propria (Figure 2). The mesorectum tapers and disappears as the rectum passes inferiorly through the levator hiatus. Distal spread of rectal cancer is unlikely to occur beyond a point 1 to 2 cm below the tumor, but distal intramesorectal lymphatic spread may occur as far as 3 to 4 cm below it.5 6 Resection of 4 to 5 cm of the rectum and mesorectum distal to the tumor is required for upper rectal cancers, and resection of the entire rectum and mesorectum down to the levatores should be performed for lower rectal cancers. In either instance, the mesorectum with its fascia propria should be excised en bloc with the rectum. This procedure, known as total mesorectal excision, has produced impressive results in nonrandomized trials (5 to 10 percent rates of local recurrence),7 and there is a growing consensus among surgeons that this technical aspect of radical rectal resection is important. If the tumor does not invade the sphincters, an adequate resection can usually be achieved with a total mesorectal excision, sparing the anus. Not all low rectal cancers require an abdominoperineal resection.
Figure 2. Diagram of the Mesorectum and Total Mesorectal Excision.
The mesorectum is a fatty envelope around the lateral and posterior rectum, which is surrounded by a thin fascia propria. It contains the blood and lymphatic vessels that supply and drain the rectum, as well as the regional lymph nodes. Total mesorectal excision removes this entire structure with the rectum to ensure adequate resection of a rectal cancer.
To spare the sphincter after very low radical resection, a coloanal anastomosis must be created. The anastomosis may be hand-sewn through the perineum after the mucosal lining is stripped from the dentate line up to the point of rectal transection (a technique known as "pull-through"). Alternatively, the low rectum or upper anal canal may be stapled and divided at the levator hiatus and an anastomosis then created with the use of a circular stapler (a technique known as "double stapling"), which is most often preferable.8 Constructing a J pouch from the proximal colon improves functional results by adding capacitance, especially in the first one to two years after surgery (Figure 3).9,10 Usually, a temporary ileostomy or transverse colostomy is created to divert the fecal stream away from the area of reconstruction.
Figure 3. Reconstruction of the Rectum after Low Anterior Resection with a Colonic J Pouch.
Two 5-to-6-cm lengths of colon are sutured together (top left portion of the figure). An incision is made in the apex of the pouch, and a stapler is inserted to join the two portions of the pouch. The anvil of a circular stapler (top right, shaded area) is inserted into the apex of the pouch; the remainder of the stapler is inserted through the rectum, and the shaft is pierced through the transverse staple line and joined to the anvil. The stapler is closed and fired, joining the apex of the pouch to the rectal stump (bottom).
This patient's tumor was quite low (6 cm from the anal verge), and he was male and moderately obese — all factors that make pelvic surgery, especially low anterior resection, technically difficult. Nevertheless, the tumor did not invade the sphincters (the anal canal, and thus the sphincters, extend from the anal verge 4 or 5 cm proximally), so I believed it was reasonable to attempt a sphincter-saving radical resection. Furthermore, the patient was able to lose an appreciable amount of weight before the operation.
I performed a very low anterior resection of the rectum with mobilization of the splenic flexure, and created a colonic J pouch, coloanal anastomosis, and a divided-loop ileostomy. There were no apparent intraabdominal metastases. The entire mesorectum was excised down to the levatores, with 1.5 cm of distal rectal wall below the cancer (a measurement made without traction on the bowel) as a resection margin. There were no postoperative complications.
Pathological Discussion
Dr. Aaron P. Caplan: The rectal biopsy specimen obtained at the other hospital contains a dense, complex proliferation of glands (Figure 4A). The glands are irregular in contour and densely packed, in contrast to normal mucosal glands (Figure 4B), which have open lumina and a parallel arrangement of epithelial cells. The nuclei are hyperchromatic, irregular, and stratified, in contrast to those of normal glands, which are bland, round, and located basally. Because of the superficial nature of the biopsy specimens, the extent of invasion of the submucosa could not be assessed. We interpreted the findings as indicative of at least high-grade dysplasia, with features (the complexity and density of the glandular proliferation) suggestive of invasion.
Figure 4. Biopsy Specimen of the Rectal Lesion (Hematoxylin and Eosin).
Examination of the rectal biopsy at low magnification shows a proliferation of irregularly shaped and complex glands that are crowded in a back-to-back arrangement (Panel A, x10). At a higher magnification, pseudostratification of the nuclei and nuclear hyperchromasia are evident in comparison with an uninvolved gland (upper left) (Panel B, x40).
Examination of the resected rectum and sigmoid showed a mass, 3 by 2 by 0.5 cm, that was a moderately differentiated adenocarcinoma with transmural invasion into the perirectal fat (Figure 5), extending to within 0.2 cm of the distal resection margin. There was invasion of blood and lymphatic vessels in the submucosa and extramurally, and four of nine lymph nodes contained cancer. The local-tumor stage was PT3N2MX (pathologically T3, with more than one positive node and unevaluable metastases); the extent of invasion was scored as pT3b; that is, there was invasion into the perirectal soft tissues less than 0.5 cm beyond the muscularis propria. The surgical clearance was 0.2 cm from the closest radial margin.
Figure 5. Photomicrographs of the Resected Rectum (Hematoxylin and Eosin).
Examination of the resection specimen at low power (Panel A, x2.5) shows a proliferation of well-formed but architecturally complex glands, similar in appearance to those seen in the biopsy specimen. The tumor extends from the colonic surface through the lamina propria and into the submucosa. Another view (Panel B, x2.5) shows that the tumor focally extends beyond the muscularis propria, into the perirectal fat (left portion of the panel). Lymphatic invasion was easily identified (Panel C, x20). Metastatic deposits of adenocarcinoma were present (Panel D, x10) within a regional lymph node.
Dr. Shellito: Because of the pathological findings of a deeply invasive tumor with positive lymph nodes, I referred the patient for consideration of postoperative adjuvant radiation and chemotherapy.
Discussion of Management, Continued
Dr. Christopher G. Willett: Nineteen days after discharge, the patient was seen in our clinic for consideration for further therapy. Radiation therapy is used in the management of rectal carcinoma in three settings: as adjuvant therapy after the local excision of carcinomas that have a favorable prognosis (typical stage, T2NXM0), as adjuvant or neoadjuvant therapy for more advanced lesions, such as clinical T3 carcinomas, and as preoperative therapy for fixed and unresectable tumors (T4) to facilitate resection. With regard to clinical stage T3 carcinoma, a long-standing debate exists about the merits of adjuvant (postoperative) strategies as compared with neoadjuvant (preoperative) strategies. For more than 30 years, clinical trials have evaluated combinations of surgery, radiation therapy, and chemotherapy. One of the chief advantages of postoperative adjuvant therapy is that the decision making can be based on operative and pathological findings that allow the rational selection of patients for this treatment.
A number of prospective randomized trials have confirmed the value of postoperative radiation therapy and chemotherapy for patients with resected stage T2 or T3 rectal carcinomas. Early studies demonstrated the advantage of the combination of postoperative radiation therapy and chemotherapy over resection, radiation therapy, or chemotherapy alone. More recent trials have sought to clarify the optimal regimen of chemotherapy with radiation. One important trial demonstrated an improved overall survival benefit with the use of continuous-infusion fluorouracil throughout the course of radiation therapy as compared with bolus fluorouracil (three injections during the first and fifth weeks of irradiation).11 The results of another study showed no benefit in terms of survival or local control with the addition of leucovorin, levamisole, or both to bolus fluorouracil.12 On the basis of such data, the current practice is to offer postoperative radiation with the administration of concurrent and maintenance fluorouracil-based chemotherapy for patients with resected stage T2 or T3 rectal carcinomas.
Had the tumor stage been known preoperatively, we would have recommended neoadjuvant radiation therapy and chemotherapy. Recent randomized trials have shown that preoperative radiation therapy13 or radiation therapy and chemotherapy with fluorouracil14,15 for resectable T3 rectal cancers resulted in improved local control and sphincter preservation for patients who underwent total mesorectal excision, as compared with those who received postoperative therapy. Several single-institution studies16,17 have also indicated that neoadjuvant therapy increases sphincter preservation.
For this patient, whose tumor had already been resected, we recommended radiation therapy together with fluorouracil chemotherapy. From the 50th day to the 118th postoperative day, he received external-beam radiation by three-dimensional conformal techniques (a total dose of 58 Gy to the tumor bed in 32 fractions).
Dr. Jeffrey W. Clark: Fluorouracil is the current standard chemotherapeutic agent used in the adjuvant treatment of rectal cancer. In fluorouracil, fluorine replaces hydrogen at the position of the fifth carbon of the pyrimidine ring. Fluorouracil is converted to fluorouridine monophosphate, which inhibits thymidylate synthetase, an enzyme that is critical in the conversion of uridine to thymidine. The inhibition of thymidylate synthetase decreases the intracellular concentration of thymidine monophosphate, which in turn leads to the inhibition of DNA synthesis. Fluorouracil can be toxic to the rapidly dividing tissues of the gastrointestinal tract and, to a lesser extent, the skin and bone marrow. The severity of toxic effects varies with the dose and dosing schedule. Diarrhea and stomatitis are the most common gastrointestinal toxic effects. Nausea and vomiting are usually mild. Neutropenia is usually mild to moderate but can be severe. Palmar–plantar erythrodysesthesia (i.e., hand–foot syndrome) is more frequent, but diarrhea is less frequent, with infusional administration of fluorouracil than with bolus regimens.
A standard approach for postoperative adjuvant treatment of rectal cancer would include fluorouracil (500 mg per square meter of body-surface area per day) by rapid intravenous infusion on days 1 to 5 and days 29 to 33; combined pelvic irradiation and continuous-infusion fluorouracil (225 mg per square meter per day) for five to six weeks, starting on day 64; and two additional courses of fluorouracil alone (450 mg per square meter per day) on days 134 to 138 and days 169 to 173.11 As with all chemotherapy treatments, it is critical that doses be withheld or modified or treatment discontinued as appropriate on the basis of toxic effects. Other regimens of fluorouracil, such as other schedules or doses of fluorouracil or combinations with leucovorin, would be acceptable alternatives.
In the future, additional therapies that are now being tested may improve the outcome for a patient such as this one. Capecitabine, an oral prodrug of fluorouracil, allows the delivery of fluorouracil dosing similar to that achieved with an infusion schedule without the risk of morbidity from central venous catheters or pumps, which were used in this patient.18 Irinotecan, a topoisomerase I inhibitor, and oxaliplatin, which forms interstrand and intrastrand DNA cross-links and DNA adducts similar to those formed by other platinum compounds, have each been shown to improve survival in patients with metastatic colorectal cancer when used in combination with fluorouracil and leucovorin.19,20,21 The roles of these agents in the treatment of rectal cancer are being evaluated.
Finally, as more is learned about the biology of rectal cancer, additional therapeutic targets continue to be identified. The cyclooxygenase-2 pathway is important in the proliferation of adenomatous polyps, and preclinical studies have indicated that its inhibition can enhance the efficacy of both radiation therapy and chemotherapy against tumors.22 Inhibition of vascular endothelial growth factor or its receptors, which are important in tumor angiogenesis, also has been found in preclinical models to enhance radiation sensitivity and the activity of fluorouracil. Clinical trials are evaluating bevacizumab, the anti–vascular endothelial growth factor antibody, as well as inhibitors of the epidermal growth factor receptor, for use in combination with radiation therapy for rectal cancer.23,24,25
For this patient, infusion of fluorouracil and radiation therapy followed by adjuvant administration of fluorouracil and leucovorin were chosen. Stomatitis, oral candidiasis, abdominal pain, diarrhea, and palmar–plantar erythrodysesthesia occurred. The patient's treatment was interrupted for the management of his abdominal and pelvic pain, diarrhea, and dehydration — symptoms consistent with fluorouracil toxicity. After the completion of radiation therapy, a course of adjuvant chemotherapy with fluorouracil and leucovorin was given; this treatment was complicated by fatigue, intermittent diarrhea, nausea, and vomiting. Restaging evaluation after the initial cycle of adjuvant chemotherapy revealed no evidence of metastatic disease.
Dr. Shellito: I was surprised by the final pathology report in this case. If I had known the stage of disease preoperatively, I would have referred the patient for neoadjuvant chemotherapy and radiation therapy. In the majority of cases, the surgeon bases the judgment of whether a sphincter-sparing operation is possible on the initial evaluation. If the tumor is clearly invading the anal canal or the sphincter, the patient is not a candidate for a sphincter-sparing operation, in my view. However, if the tumor is located higher in the rectum, then a sphincter-sparing operation usually can be performed, regardless of adjuvant treatment. There is the occasional patient, such as this one, whose tumor is in a borderline location for sphincter-sparing surgery, and in that situation, if the cancer is transmural or node-positive, I would be more comfortable performing such an operation if the patient has first had neoadjuvant treatment.
Dr. Brugge: Endoscopic ultrasonographic staging of lymph nodes is based on their size and echotexture. In this patient, the lymph nodes were microscopically involved and were not enlarged. The lymph nodes we saw on ultrasonographic examination were not enlarged and had normal echogenicity. It is important to remember that in rectal cancers, there can be microscopic involvement of the lymph nodes.
Dr. Clark: Better methods for assessing lymph-node involvement are clearly needed; new agents that allow the evaluation of internal lymph-node architecture on MRI scanning may be helpful in cases such as this one.26
Dr. Andrew L. Warshaw (Surgery): Has the evaluation of mobility on digital rectal examination lost its validity now that we have transrectal ultrasonography?
Dr. Shellito: I depend heavily on the physical examination. Tumor mobility, the degree of ulceration, and size are important. Sometimes, the assessment based on physical findings is not in agreement with the endoscopic ultrasonographic assessment, and then I have to make my best judgment as to how to proceed, given the conflicting data.
Dr. Warshaw: This patient had multiple colonic polyps. At what point do you become concerned about a polyposis syndrome and the need to evaluate the upper gastrointestinal tract?
Dr. Shellito: He had three other polyps, which is rather typical for synchronous neoplasms in patients with colorectal cancer. The presence of a few synchronous polyps (2, 3, or 4) would not concern me, but 12 or 15 would make me consider attenuated familial adenomatous polyposis, and I would then evaluate the patient more thoroughly with upper gastrointestinal endoscopy.
A surgeon: What is this patient's prognosis, and would it have been better if an abdominoperineal resection had been performed?
Dr. Shellito: I do not believe his prognosis would have been better with an abdominoperineal resection. When total mesorectal excision is performed and negative margins are achieved, the prognosis will not be affected by whether or not an uninvolved anus is also removed. Ordinarily, the prognosis for rectal cancer is fairly good with combination treatment, although it varies with the tumor stage. Nevertheless, I am concerned that this patient's tumor was node-positive, with florid lymphatic invasion. Although I remain cautiously optimistic, these histologic factors are unfavorable signs.
Dr. James C. Cusack, Jr. (Surgery): For the evaluation of a specimen obtained during total mesorectal excision, it has been recommended that the specimen be filled with formalin, fixed, and then sectioned to permit an accurate assessment of the completeness of the resection and a thorough inventory of any involved lymph nodes.27 Recently published histopathological criteria for evaluation of the completeness of total mesorectal resection require that at least 15 lymph nodes be included in the specimen.27 If only a few lymph nodes are identified in a resection specimen, then either an incomplete surgical resection or an inadequate search for lymph nodes has been performed.
Dr. Clark: The patient completed his adjuvant therapy 13 months after the operation. Restaging at that time disclosed no evidence of metastatic disease. His ileostomy was closed 16 months after the operation, and at his most recent follow-up examination, 19 months after the diagnosis, he reported that he has frequent soft stools, with some urgency, but that this symptom is improving. CT scanning of the chest, abdomen, and pelvis showed no evidence of recurrent or metastatic disease.
Pathological Diagnosis
Adenocarcinoma of the rectum, stage T3N2M0.
Source Information
From the Department of Surgery (P.C.S.), the Hematology–Oncology Unit, Department of Medicine (J.W.C.), the Department of Radiation Oncology (C.G.W.), and the Department of Pathology (A.P.C.), Massachusetts General Hospital; and the Departments of Surgery (P.C.S.), Medicine (J.W.C.), Radiation Oncology (C.G.W.), and Pathology (A.P.C.), Harvard Medical School.
References
Ng AK, Recht A, Busse PM. Sphincter preservation therapy for distal rectal carcinoma: a review. Cancer 1997;79:671-683.
Mellgren A, Sirivongs P, Rothenberger DA, Madoff RD, Garcia-Aguilar J. Is local excision adequate therapy for early rectal cancer? Dis Colon Rectum 2000;43:1064-1074.
Sengupta S, Tjandra JJ. Local excision of rectal cancer: what is the evidence? Dis Colon Rectum 2001;44:1345-1361.
Sterk P, Kasperk R, Opitz T, Schubert F, Klein P. Vascular organization in the mesorectum: angiography of rectal resection specimens. Int J Colorectal Dis 2000;15:225-228.
Scott N, Jackson P, al-Jaberi T, Dixon MF, Quirke P, Finan PJ. Total mesorectal excision and local recurrence: a study of tumour spread in the mesorectum distal to rectal cancer. Br J Surg 1995;82:1031-1033.
Hida J, Yasutomi M, Maruyama T, Fujimoto K, Uchida T, Okuno K. Lymph node metastases detected in the mesorectum distal to carcinoma of the rectum by the clearing method: justification of total mesorectal excision. J Am Coll Surg 1997;184:584-588.
Heald RJ, Moran BJ, Ryall RD, Sexton R, MacFarlane JK. Rectal cancer: the Basingstoke experience of total mesorectal excision, 1978-1997. Arch Surg 1998;133:894-899.
Read TE, Kodner IJ. Proctectomy and coloanal anastomosis for rectal cancer. Arch Surg 1999;134:670-677.
Dennett ER, Parry BR. Misconceptions about the colonic J-pouch: what the accumulating data show. Dis Colon Rectum 1999;42:804-811.
Ruo L, Guillem JG. Major 20th-century advancements in the management of rectal cancer. Dis Colon Rectum 1999;42:563-578.
O'Connell MJ, Martenson JA, Wieand HS, et al. Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 1994;331:502-507.
Tepper JE, O'Connell MJ, Niedzwiecki DR, et al. Adjuvant therapy in rectal cancer: analysis of stage, sex, and local control -- final report of intergroup 0114. J Clin Oncol 2002;20:1744-1750.
Kapiteijn E, Marijnen CAM, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 2001;345:638-646.
Sauer R, Fietkay R, Witteking C, et al. Adjuvant versus neoadjuvant radiochemotherapy for locally advanced rectal cancer: a progress report of a phase-III randomized trial (protocol CAO/ARO/AIO-94). Strahlenther Onkol 2001;177:173-181.
Sauer R. Adjuvant versus neoadjuvant combined modality treatment for locally advanced rectal cancer: first results of the German rectal cancer study (CAO/ARO/AIO-94). Int J Radiat Oncol Biol Phys 2003;57:Suppl:S124-S125. abstract.
Roh MS, Petrelli N, Wieand S, et al. Phase III randomized trial of preoperative versus postoperative multimodality therapy in patients with carcinoma of the rectum (NSABPR-03). Prog Proc Am Soc Clin Oncol 2001;20:123a. abstract.
Wagman R, Minsky BD, Cohen AM, Guillem JG, Paty PP. Sphincter preservation in rectal cancer with preoperative radiation therapy and coloanal anastomosis: long term follow-up. Int J Radiat Oncol Biol Phys 1998;42:51-57.
Van Cutsem E, Twelves C, Cassiday J, et al. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol 2001;19:4097-4106.
Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 2000;355:1041-1047.
Schmoll HJ. The role of oxaliplatin in the treatment of advanced metastatic colorectal cancer: prospects and future directions. Semin Oncol 2002;29:Suppl 15:34-39.
De Gramont A, Banzi M, Navarro M, et al. Oxaliplatin/5-FU/LV in adjuvant colon cancer: results of the international randomized MOSAIC trial. Prog Proc Am Soc Clin Oncol 2003;22:253. abstract.
Church RD, Fleshman JW, McLeod HL. Cyclo-oxygenase 2 inhibition in colorectal cancer therapy. Br J Surg 2003;90:1055-1067.
Zhu AX, Willett CG. Chemotherapeutic and biologic agents as radiosensitizers in rectal cancer. Semin Radiat Oncol 2003;13:454-468.
Willett CG, Boucher Y, di Tomaso E, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 2004;10:145-147.
Grunwald V, Hidalgo M. Developing inhibitors of the epidermal growth factor receptor for cancer treatment. J Natl Cancer Inst 2003;95:851-867.
Harisinghani MG, Barentsz J, Hahn PF, et al. Noninvasive detection of clinically occult lymph-node metastases in prostate cancer. N Engl J Med 2003;348:2491-2499.
Nagtegaal ID, van de Velde CJH, van der Worp E, Kapiteijn E, Quirke P, van Krieken JHJM. Macroscopic evaluation of rectal cancer resection specimen: clinical significance of the pathologist in quality control. J Clin Oncol 2002;20:1729-1734.
Related Letters:
Case 18-2004: A 61-Year-Old Man with Rectal Bleeding
Mitchell A., Panzini B., Shellito P. C., Caplan A. P.(Paul C. Shellito, M.D., J)