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Pathology of Cancer of the Colon and Rectum: Classification and Modes of Spread
Pathology of Cancer of the Colon and Rectum Classification and Modes of Spread F. A.
DE
PEYSTER, M.D., F.A.C.S.
R. K. GILCHRIST, M.D., F.A.C.S.
THE key to the therapy of malignant lesions arising in the colon and rectum is a knowledge of their pathological behavior. Although the cause of cancer is unknown, its behavior is predictable. Intensive study of rectal and colon cancer in recent years, particularly with regard to the influence of such factors as the gross appearance, location, degree of cellular differentiation and the manner of dissemination, has yielded information which, when pieced together, provides a reasonably accurate basis for determining the prognosis and the type of therapy indicated. Consideration of these factors constitutes the basis of this presentation. INCIDENCE AND CLASSIFICATION
About 12 per cent of all malignant tumors of the human body and 75 per cent of intestinal cancers originate in the colon, rectum or anus, causing more than 32,000 deaths annually~22 Figure 377 illustrates the incidence and distribution of cancer arising in the large bowel. Cancer of the colon and rectum is predominantly confined to the white race (95 per cent),2 affecting males more commonly than females in a ratio'of about 3:2. Large bowel cancer is generally considered a disease of middle life with the greatest incidence of occurrence between the fourth and sixth decades. However, the significant incidence in the younger age groups is shown by a recent survey of gastrointestinal tumors in persons of military age. 12 From 1941 through 1945, 813 tumors were reviewed at The Army Institute of Pathology. Three hundred and forty-two of these occurred in the colon, rectal and anal areas. To date, 53 cases of carcinoma of the colon occurring in children have been reported. 24 An histological classification of colon and rectal malignancies appear in Table 1. From the Department oj Surgery, Presbyterian Hospital, Chicago, affiliated with the University oj IUinois.
1295
F. A. de Peyster, R. K. Gilchrist
1296
DISTRIBUTION BY TYPES AND GRADE
It is generally accepted that carcinoma of the colon and rectum grows relatively slowly and may metastasize late. About two-thirds of the large bowel lesions fall into the lower two grades (Broders) of cellular anaplasia (Tablf> 2). Although the prognosis is closely related to the degree
Fig. 377. Percentage distribution of the lesion in 4975 cases of colon carcinoma (Compiled from Popper. 19) Table 1 HISTOPATHOLOGICAL CLASSIFICATION OF PRIMARY MALIGNANT TUMORS OF THE COLON AND RECTUM
I. Epithelial Tissue (Carcinoma) 1. Epithelioma a. Basal cell b. Squamous cell 2. Carcinoid argentaffinoma 3. Adenocarcinoma a. Medullary b. Scirrhous c. Papillary d. Villous e. Mucoid f. Melanoma
II. Connective Tissue (Sarcoma) 1. Lymphosarcoma a. Reticulum cell b. Fibrosarcoma 2. Leiomyosarcoma
of malignancy (Broders) an accurate index of dissemination of the malignant process is not obtained. Dukes' method10 based on bowel wall penetration with or without lymph node involvement and subsequent modification1 • 17 (Fig. 378) provide a more practical method in planning
Pathology of Cancer of the Colon and Rectum
1297
the operation and estimating prognosis. However, the combined use of Broders' and Dukes' classification is most desirable, since together they provide the best guide for estimating the pathology, selecting the operation and rendering a prognosis. Table 2 PERCENTAGE DISTRIBUTION OF GRADES OF MALIGNANCY, 2877 RESECTED NEOPLASMS (FIVE STUDIES, 1928-1952)
Rankin and Broders, 1928 .... Dukes, 1937 ................ Broders, Buie and Laird, 1940. Broders, 1940 ............... Phillips and colleagues, 1952 ..
TOTAL NO. OF CASES
Grade 1
598 • 600 432 580 667
17.6 6.0 16.9 14.6 29.3
PERCENTAGE Grade Grade Grade 2 3 4 50.0 54.0 55.8 51.8 47.1
23.5 26.0 23.1 24.5 21.2
8.9 2.0 4.2 9.1 2.2
Colloid
12.0
Grade 1 includes those lesions in which 100 to 75 per cent of the cells are differentiated; Grade 2, from 75 to 50 per cent; Grade 3, from 50 to 25 per cent, and Grade 4, from 25 to 0 per cent. (From Broders.' )
With Negative Nodes
With Positiv.e Nodes
Fig. 378. Diagram illustrating modified Dukes classification: In type A the lesion is confined to the mucosa; BI, the lesion extends into the muscularis mucosa, but not through it with negative nodes; B 2, the lesion extends through the muscularis mueosa without involved nodes; CI, the lesion is type BI or Bz limited to the wall with involved nodes. Cz, the lesion extends through all wall layers with positive nodes.17· 1 MODES OF DISSEMINATION
Cancer of the colon and rectum spreads by direct extension, by lymphatic, vascular and perineural channels, and by local implantation. The most common sites of visceral metastases are the liver, lung, adrenal gland, thyroid gland, kidney and spleen. Direct spread by cancer of the colon and rectum most commonly involves the peritoneum, vagina, bladder, sacrum, uterus, pancreas and duodenum.
F. A. de Peyster, R. K. Gilchrist
1298
Direct Extension-Intra:mural Spread
Carcinoma has already penetrated through all muscle layers of the bowel wall in more than three-fourths of the patients coming to operation. 5 The size of the lesion is not a reliable index of its malignancy. A punched-out ulcer tends to be more malignant than the fungating type of cancer. Carcinoma of the colon and rectum arises in the mucosa, Table 3 MURAL PENETRATION IN RELATION TO GRADE OF MALIGNANCY DEGREE OF MURAL PENETRATION
No.
Group A ........... Group B ........... Group C ...........
7 3 9
TOTAL ...........
19
1
GRADE OF MALIGNANCY (BRODERS) 2 4 3 % No. % No. %. No 70.0 14.3 10.1
2 15 55
20.0 71.4 61.8
72
1 2 20 23
10.0 9.5 22.5
0 1 5
TOTAL
% 0 4.8 5.6
6
10 21 89 120
Dukes' Classification: Group A includes cancer confined to the mucosa; Group Bcancer has penetrated into but not through muscularis; Group C-cancer has penetrated through muscularis and into sUbperitoneal tissue. (From Simpson. 21)
Tab.e 4 DISTRIBUTION OF COLON AND RECTAL LESIONS ACCORDING TO MODIFIED DUKES' CLASSIFICATION IN SPECIMENS FROM PATIENTS OPERATED UPON IN YEARS 1940 THROUGH 1944 WITH 5 YEAR SURVIVAL CLASS
NO. OF CASES
PER CENT OF. TOTAL
PER CENT 5 YEAR SURVIVAL
A B-1 B-2 C-l 0-2
1 48 164 14 125
0.28 13.64 46.59 3.98 35.51
100 66.6 53.9 42.8 22.4
Class A lesions were limited to the mucosa; Class B-1 lesions were confined to but not through the muscular mucosa; Class B-2 lesions extended through the muscle coats without positive nodes; Class C-llesions were limited to the wall with positive nodes; Class C-2 lesions extended through all layers with positive nodes. (From Astler. 1)
destroying th~ mucous membrane slowly. Dukes has ~stimated that six months are required for the tumor to encircle one-fourth of the bowel circumference. The degree of cellular anaplasia (Broders) directly influences the depth of penetration (Table 3). The plane of greatest longitudinal spread varies but usually occurs in the submucosa. 5 Most authors report that longitudinal spread is not great, usually less than 2 cm. in either direction from the tumor margin. The peritoneum sets a temporary
Pathology of Cancer of the Colon and Rectum
1299
barrier to cancer spread. When the bowel wall has been penetrated, intraperitoneal seeding or fixation and direct invasion of contiguous structures may occur. This spread by direct extension occurs most readily from lesions below the peritoneal reflexion. The patient's prognosis as originally demonstrated by Dukes in 193210 may be directly correlated with the depth of bowel wall penetration, if nodes were not involved. Recent classifications1 • 17 based on microscopic examination of tumor penetration in the bowel wall provide a refinement of Dukes' original work (Table 4; Fig. 37S). LYlDphatic Spread-ExtralDural
Lymph node involvement by carcinoma is primarily embolic, following a definite pattern with a predictable course. Tumors arising on the mesI I
I I
I I
I I I
23'cm. I I
Peritonea I---+-"i-.i!'il;r,c~~ ---reflection
I I I
I
Tu~or , I I I I
_-Tumor
I
I
·...........:::.---+-M ucocutoneous lin"'~==------~-
A
B
Fig. 379. A, Drawing of cleared rectal specimen showing distant node involvement with intervening negative nodes. B, Drawing of cleared rectal specimen showing 4 cm. retrograde node involvement in advanced carcinoma. The extent of node replacement by tumor is shown in black.
enteric border do not seem to metastasize to nodes more readily than tumors located on the antimesenteric border. Tumor emboli enter the subcapsular space of the lymph node and spread in the depth. Nodes, where cancer has lodged, prevent further spread until the node is completely overwhelmed by tumor. When this occurs, further spread is by way of new tumor emboli to the collateral lymph channels. Metastases growing in lymph nodes do not break through the capsule until extensive and overwhelming growth has occurred. Gross detection of involved lymph nodes is not possible with any degree of certainty, nor is there any constant correlation between the size of the node and the extent of its involvement. Not infrequently, positive nodes may lie out of continuity of spread
F. A. de Peyster, R. K. Gilchrist
1300
Fig. 380. Drawing showing nodes and distribution of the extramural lymphatic network of the colon, which tend to follow blood supply.
Para-aortic nodes Sup. hemorrhoidal
rotor node tor ani muscle
--In9uinal nodes
Fig. 381. Drawing illustrating the extramural lymphatic network of the rectum. Note the dual lymph drainage from the middle and inferior rectal segments.
and at some distance from the tumor with normal nodes intervening (Fig. 379, A). Where lymph node channels are mechanically blocked by tumor, inflammation or a previous operative wound, retrograde metastases (incidence 4.6 per cent) may occur at distances more than 4 cm.
Pathology of Cancer of the Colon and Rectum
1301
below the tumor margin (Fig. 379, B). These two facts constitute the fundamental reasons for wide en bloc excision of the primary lesion together with the dependent lymph node drainage. The chief lymphatic pathways of the colon and rectum follow their· principal blood supply and are illustrated in Figures 380 and 381. Additional pathways to adjacent organs recently have been demonstrated by Weinberg using vital dye techniques. 23 Cancer arising in the upper third of the rectum (intraperitoneal portion) spreads superiorly, principally along the lymphatics adjacent to the superior hemorrhoidal vessels. Cancer arising in the middle and inferior rectal regions (extraperitoneaI) not only spreads superiorly, but metastasizes laterally in the lymphatics accompanying the middle and inferior hemorrhoidal vessels. The presence of this dual lymph drainage is one Table 5 INCIDENCE OF LYMPH NODE METASTASES IN TUMORS OF RIGHT COLON AS COMPARED WITH THOSE OF THE LEFT COLON
NUMBER
Tumors of Right GoWn AU With Resection and Ileotransverse GoWn Anastomoses13 Alive 5 years. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Had involved nodes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. With involved nodes, alive 5 years. . . . . . . . . . . . . . . . . . . . Postoperative deaths. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Had no follow-up. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tumors of Left GoWn AU With Obstructive Resections Alive 5 years. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Had involved nodes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . With involved nodes, alive 5 years. . . . . . . . . . . . . . . . . . . . Postoperative deaths. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Of 10 without nodes, alive 5 years. . . . . . . . . . . . . . . . . . . . .
PER CENT
9 13 7 3 1
60.0 86.6 53.8
11 8 3 0 8
61.1 44.4 37.5 80.0
of the reasons why the highest incidence of local recurrence and the lowest survival rates of patients with carcinoma of the large bowel occur in the extraperitoneal portion of the rectum. About two-thirds of patients explored for an "operable carcinoma" already have lymph node metastases. A considerably higher incidence of lymph involvement is encountered in cancer of the right colon as compared to the left colon. Despite this fact, the over-all prognosis for patients with right-side lesions remains more favorable (Table 5). Venous DissenIination
Microscopic evidence of venous invasion is found in from 14 to 36 per cent of surgically removed specimens of bowel cancer.16 Employing new techniques, Barringer3 and Madison18 have been able to demonstrate
F. A. de Peyster, R. K. Gilchrist
1302
tumor invasion of the veins in 38 per cent and 43 per cent, respectively, of surgically removed specimens. When applied clinically, the significance of venous invasion by tumor assumes added importance. About onethird of patients operated upon for bowel cancer have gross evidence of liver metastases at the time of surgery. Tumors arising in the rectum have a greater propensity to invade veins than tumors elsewhere in the colon. 16 Gross vein involvement has been demonstrated in 12 per cent of the left-sided and 6 per cent of the right-sided colon lesions. ll Venous involvement may take place at any stage in the development of the cancer. The incidence of venous invasion increases directly with greater cellular anaplasia or deeper wall penetration, as seen in the punched-out ulcer. Dukesll found no evidence of venous invasion in Table 6 FIVE YEAR RESULTS: VEIN INVASION AND MURAL PENETRATION; COLON AND RECTUM Patients Surviving Operation Five Years or Dying of Cancer in That Period NO VEIN INVASION Per Cent Total 5 Year 5 Year Cases Survival Survival
TOTAL CASES
Group A: Group B: Group C:
17 47 69
17 32 33
16 28 18
133
82
62
94 88 55
VEIN INVASION Per Cent Total 5 Year 5 Year Cases Survival Survival
15 36
9 10
51
19
60
28
Group A lesions have not penetrated the muscle wall; Group B, extend to the perirectal or pericolic tissues without node involvement; Group C, lesions exhibit wall involvement with metastases. (After Grinnell,15)
Class A tumors (limited to the mucosa); but 16.4 per cent in Class B tumors (extending through the wall without involved nodes) and 21.9 per cent in Class C tumors (extending through the wall with involved lymph nodes). These facts indicate that vein invasion probably takes place from the primary tumor site and is not only independent of lymphatic spread but may even occur before the nodes are involved. In the absence of demonstrable portal system spread, central nervous system metastases may occur via the paravertebral veins described by Batson. 4 Table 6 shows the relation of mural penetration to vein invasion and five year survival. Perineural Spread
Seefeld and Bargen20 have demonstrated the high incidence of perineural invasion of rectal cancer in resected specimens. In 100 surgically removed rectal specimens studied, they observed that 47 per cent had
Pathology of Cancer of the Colon and Rectum
1303
lymphatic involvement, 30 per cent perineural spread, and in 20 per cent the veins were involved. The extent of perineural invasion may be correlated with the degree of cellular anaplasia, but does not seem to be related to site of the lesion in the bowel. Local recurrence of cancer is more than twice as likely to take place when nerve infiltration by tumor can be demonstrated than in those cases without demonstrable perineural infiltration. Local Im.plantation-Consideration of Local Recurrence
Relation of Tumor Site to Peritoneal Reflection. Cancer lying below the peritoneal reflection has a consistently greater local recurrence rate than intraperitoneal rectal or colon lesions. According to Gilchrist and David, 13 in 55 cases of surgically treated intraperitoneal rectal and sigmoid tumors, 18 per cent of the patients died of recurrent tumors within five years; 3.6 per cent exhibiting local recurrence. In contrast, of 122 patients with extraperitoneal rectal cancer, 43.5 per cent were dead within five years of recurrence, 23 per cent of whom had developed local recurrence. The incidence of lymph node involvement in both groups was similar, i.e., 62 per cent and 63 per cent respectively. Similar observations have been made by Wangensteen and Coller.9 This evidence suggests that factors other than lymph node involvement may be responsible for the high local recurrence rate observed when cancer is located below the peritoneal reflection. Factors contributing to this increased rate of local recurrence are the lack of a protective peritoneal wall, allowing ready spread to fat and adjacent structures, and the rich plexus of veins and nerves. Finally, the presence of a large tumor cradled in a rigid pelvis hinders exposure and makes a wide resection difficult. Under these conditions, added massage of the tumor liberates showers of intravascular emboli, or local seeding is caused by directly breaking into the tumor itself. Significance of Suture Line Recurrence. The relation of implantation to local recurrence at the suture line was suggested in 1935 by GordonWatson and his associates. 14 Recently Cole 7 has observed, in 55 consecutive patients who had a portion of the colon resected, a 16 per cent incidence of local recurrence. In two-thirds of these patients the recurrent lesion was at the suture line, where he thought implantation occurred by the suturing process. He found viable malignant cells lying free within the resected bowel lumen for distances up to 35 cm. from the tumor. Fourteen to 56 per cent of smears from the proximal ends of the resected bowel segments, and 43 to 76 per cent taken from the distal segments, were positive for viable cancer cells. However, negative smears were obtained when occlusive ligatures were placed to isolate the tumor prior to resection. 8 In our experience, when recurrent cancer is found at the suture line, it appears like an "iceberg," with the major portion lying outside the
'I'
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F. A. de Peyster, R. K. Gilchrist
bowel wall and the smaller portion projecting into the suture line. This suggests that the recurrence originates outside the layers of the bowel wall. This and other documented evidence16 emphasizes the possibility of cancer spread by implantation. A surgical procedure for cure of bowel cancer must be devised (1) to prevent manipulative venous spread; (2) to prevent implantation; (3) to excise sufficient bowel to include maximum intramural spread and (4) to remove the cancer by "en bloc" excision with the dependent echelons of lymph node spread. REFERENCES 1. Astler, V. B. and Coller, F. A.: The Prognostic Significance of Direct Extension
2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.
of Carcinoma of the Colon and Rectum. Ann. Surg. 139: 846-851 (June) 1954. Bacon, H. E.: Anus-Rectum-Sigmoid Colon: Diagnosis and Treatment. Vol. II, 3rd Ed. Philadelphia, J. B. Lippincott Co., 1949. Barringer, P. L., Dockerty, M. B., Waugh, J. M. and Bargen, J. A.: Carcinoma of the Large Intestine. A New Approach to the Study of Venous Spread. Surg., Gynec. & Obst. 98: 62-72 (Jan.) 1954. Batson, O. V.: The Function of Vertebral Veins and Their Role in the Spread of Metastases. Ann. Surg. 112: 138-149, 1940. Black, W. A. and Waugh, J. M.: The Intramural Extension of Carcinoma of the Descending Colon, Sigmoid and Rectosigmoid. Surg., Gynec. & Obst. 87: 457-464 (Oct.) 1948. Broders, A. C. Sr., Phillips, C. and Stinson, J. C.: Neoplasms of the Large Bowel. S. CLIN. NORTH AMERICA 32: 1-19 (Oct.) 1952. Cole, W. H.: Recurrence in Carcinoma of the Colon and Proximal Rectum Following Resection for Carcinoma. A.M.A. Arch. Surg. 65: 264 (Aug.) 1952. Cole, W. H., Packard, D. and Southwick, H. W.: Carcinoma of the Colon with Special Reference to Prevention and Recurrence. J.A.M.A. 155:1549-1553 (Aug. 25) 1954. Coller, F. A., Kay, E. B. and MacIntyre, R. S.: Regional Lymphatic Metastasis of Carcinoma of the Rectum. Surgery 8: 294--311 (Aug.) 1940. Dukes, C. E.: The Classification of Cancer of the Rectum. J. Path. & Bact. 35: 323-332, 1932. Dukes, C. E. and Bussey, H. J. R.: Venous Spread in Rectal Cancer.P~oc. Roy. Soc. Med. 34: 571-574 (July) 1941. Ehrlich, J. C. and Hunter, O. B. Jr.: Tumors of the Gastrointestinal Tract. Surg., Gynec. & Obst. 85: 98, 1947. Gilchrist, R. K. and David, V. C.: Prognosis in Carcinoma of the Bowel. Surg, Gynec. & Obst. 86: 359-371 (March) 1948. Gordon-Watson, C.: Origin and Spread of Carcinoma of the Rectum in Relation to Surgical Treatment. Lancet 1: 239-245 (Jan. 29) 1938. Grinnell, R. S.: The Spread of Carcinoma of the Colon and Rectum. Cancer 3: 641-652 (July) 1950. Guiss, R. L.: The Implantation of Cancer Cells Within a Fistula in Ano. Surgery 36: 136-139, July, 1954. Kirklin, J. W., Dockerty, M. B. and Waugh, J. M.: The Role of the Peritoneal Reflection in the Prognosis of Carcinoma of the Rectum and Sigmoid Colon. Surg., Gynec. & Obst. 88: 326-331, 1949. Madison, M. S., Dockerty, M. B. and Waugh, J. M.: Venous Invasion in Carcinoma of the E.ectum as Evidenced by Venous Radiography. Surg., Gynec. & Obst. 99: 17Q-178 (Aug.) 1954. Popper, Hans: Newer Aspects of the Pathology of the Colon. J. Internat. Coll. Surgeons 17: 286-296 (March) 1952. Seefeld, P. H. and Bargen, J. A.: The Spread of Carcinoma of the Rectum: Invasion of the Lymphatics, Veins and Nerves. Ann. Surg. 118: 76-90 (July) 1943.
Pathology of Cancer of the Colon and Rectum
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21. Simpson, W. C. and Mayo, C. W.: The Mural Penetration of the Carcinoma Cell in the Colon-Anatomic and Clinical Study. Surg., Gynec. & Obst. 68: 872-877 (May) 1939. 22. United States Department of Health, Education and Welfare, Public Health Service, National Office of Vital Statistics: Vital Statistics of the United States 3: 63 (Table 51) 1951. 23. Weinberg, J. and Movius, H. J.: Vital Staining of the Lymphatics in Surgery of Carcinoma of the Large Intestine. West. J. Surg. 61: 528-534 (Sept.) 1953. 24. Williams, C. Jr.: Carcinoma of the Colon in Childhood. Ann. Surg. 139: 816-825 (June) 1954. 59 E. Madison Street Chicago 3, Illinois
DE
PEYSTER, M.D., F.A.C.S.
R. K. GILCHRIST, M.D., F.A.C.S.
THE key to the therapy of malignant lesions arising in the colon and rectum is a knowledge of their pathological behavior. Although the cause of cancer is unknown, its behavior is predictable. Intensive study of rectal and colon cancer in recent years, particularly with regard to the influence of such factors as the gross appearance, location, degree of cellular differentiation and the manner of dissemination, has yielded information which, when pieced together, provides a reasonably accurate basis for determining the prognosis and the type of therapy indicated. Consideration of these factors constitutes the basis of this presentation. INCIDENCE AND CLASSIFICATION
About 12 per cent of all malignant tumors of the human body and 75 per cent of intestinal cancers originate in the colon, rectum or anus, causing more than 32,000 deaths annually~22 Figure 377 illustrates the incidence and distribution of cancer arising in the large bowel. Cancer of the colon and rectum is predominantly confined to the white race (95 per cent),2 affecting males more commonly than females in a ratio'of about 3:2. Large bowel cancer is generally considered a disease of middle life with the greatest incidence of occurrence between the fourth and sixth decades. However, the significant incidence in the younger age groups is shown by a recent survey of gastrointestinal tumors in persons of military age. 12 From 1941 through 1945, 813 tumors were reviewed at The Army Institute of Pathology. Three hundred and forty-two of these occurred in the colon, rectal and anal areas. To date, 53 cases of carcinoma of the colon occurring in children have been reported. 24 An histological classification of colon and rectal malignancies appear in Table 1. From the Department oj Surgery, Presbyterian Hospital, Chicago, affiliated with the University oj IUinois.
1295
F. A. de Peyster, R. K. Gilchrist
1296
DISTRIBUTION BY TYPES AND GRADE
It is generally accepted that carcinoma of the colon and rectum grows relatively slowly and may metastasize late. About two-thirds of the large bowel lesions fall into the lower two grades (Broders) of cellular anaplasia (Tablf> 2). Although the prognosis is closely related to the degree
Fig. 377. Percentage distribution of the lesion in 4975 cases of colon carcinoma (Compiled from Popper. 19) Table 1 HISTOPATHOLOGICAL CLASSIFICATION OF PRIMARY MALIGNANT TUMORS OF THE COLON AND RECTUM
I. Epithelial Tissue (Carcinoma) 1. Epithelioma a. Basal cell b. Squamous cell 2. Carcinoid argentaffinoma 3. Adenocarcinoma a. Medullary b. Scirrhous c. Papillary d. Villous e. Mucoid f. Melanoma
II. Connective Tissue (Sarcoma) 1. Lymphosarcoma a. Reticulum cell b. Fibrosarcoma 2. Leiomyosarcoma
of malignancy (Broders) an accurate index of dissemination of the malignant process is not obtained. Dukes' method10 based on bowel wall penetration with or without lymph node involvement and subsequent modification1 • 17 (Fig. 378) provide a more practical method in planning
Pathology of Cancer of the Colon and Rectum
1297
the operation and estimating prognosis. However, the combined use of Broders' and Dukes' classification is most desirable, since together they provide the best guide for estimating the pathology, selecting the operation and rendering a prognosis. Table 2 PERCENTAGE DISTRIBUTION OF GRADES OF MALIGNANCY, 2877 RESECTED NEOPLASMS (FIVE STUDIES, 1928-1952)
Rankin and Broders, 1928 .... Dukes, 1937 ................ Broders, Buie and Laird, 1940. Broders, 1940 ............... Phillips and colleagues, 1952 ..
TOTAL NO. OF CASES
Grade 1
598 • 600 432 580 667
17.6 6.0 16.9 14.6 29.3
PERCENTAGE Grade Grade Grade 2 3 4 50.0 54.0 55.8 51.8 47.1
23.5 26.0 23.1 24.5 21.2
8.9 2.0 4.2 9.1 2.2
Colloid
12.0
Grade 1 includes those lesions in which 100 to 75 per cent of the cells are differentiated; Grade 2, from 75 to 50 per cent; Grade 3, from 50 to 25 per cent, and Grade 4, from 25 to 0 per cent. (From Broders.' )
With Negative Nodes
With Positiv.e Nodes
Fig. 378. Diagram illustrating modified Dukes classification: In type A the lesion is confined to the mucosa; BI, the lesion extends into the muscularis mucosa, but not through it with negative nodes; B 2, the lesion extends through the muscularis mueosa without involved nodes; CI, the lesion is type BI or Bz limited to the wall with involved nodes. Cz, the lesion extends through all wall layers with positive nodes.17· 1 MODES OF DISSEMINATION
Cancer of the colon and rectum spreads by direct extension, by lymphatic, vascular and perineural channels, and by local implantation. The most common sites of visceral metastases are the liver, lung, adrenal gland, thyroid gland, kidney and spleen. Direct spread by cancer of the colon and rectum most commonly involves the peritoneum, vagina, bladder, sacrum, uterus, pancreas and duodenum.
F. A. de Peyster, R. K. Gilchrist
1298
Direct Extension-Intra:mural Spread
Carcinoma has already penetrated through all muscle layers of the bowel wall in more than three-fourths of the patients coming to operation. 5 The size of the lesion is not a reliable index of its malignancy. A punched-out ulcer tends to be more malignant than the fungating type of cancer. Carcinoma of the colon and rectum arises in the mucosa, Table 3 MURAL PENETRATION IN RELATION TO GRADE OF MALIGNANCY DEGREE OF MURAL PENETRATION
No.
Group A ........... Group B ........... Group C ...........
7 3 9
TOTAL ...........
19
1
GRADE OF MALIGNANCY (BRODERS) 2 4 3 % No. % No. %. No 70.0 14.3 10.1
2 15 55
20.0 71.4 61.8
72
1 2 20 23
10.0 9.5 22.5
0 1 5
TOTAL
% 0 4.8 5.6
6
10 21 89 120
Dukes' Classification: Group A includes cancer confined to the mucosa; Group Bcancer has penetrated into but not through muscularis; Group C-cancer has penetrated through muscularis and into sUbperitoneal tissue. (From Simpson. 21)
Tab.e 4 DISTRIBUTION OF COLON AND RECTAL LESIONS ACCORDING TO MODIFIED DUKES' CLASSIFICATION IN SPECIMENS FROM PATIENTS OPERATED UPON IN YEARS 1940 THROUGH 1944 WITH 5 YEAR SURVIVAL CLASS
NO. OF CASES
PER CENT OF. TOTAL
PER CENT 5 YEAR SURVIVAL
A B-1 B-2 C-l 0-2
1 48 164 14 125
0.28 13.64 46.59 3.98 35.51
100 66.6 53.9 42.8 22.4
Class A lesions were limited to the mucosa; Class B-1 lesions were confined to but not through the muscular mucosa; Class B-2 lesions extended through the muscle coats without positive nodes; Class C-llesions were limited to the wall with positive nodes; Class C-2 lesions extended through all layers with positive nodes. (From Astler. 1)
destroying th~ mucous membrane slowly. Dukes has ~stimated that six months are required for the tumor to encircle one-fourth of the bowel circumference. The degree of cellular anaplasia (Broders) directly influences the depth of penetration (Table 3). The plane of greatest longitudinal spread varies but usually occurs in the submucosa. 5 Most authors report that longitudinal spread is not great, usually less than 2 cm. in either direction from the tumor margin. The peritoneum sets a temporary
Pathology of Cancer of the Colon and Rectum
1299
barrier to cancer spread. When the bowel wall has been penetrated, intraperitoneal seeding or fixation and direct invasion of contiguous structures may occur. This spread by direct extension occurs most readily from lesions below the peritoneal reflexion. The patient's prognosis as originally demonstrated by Dukes in 193210 may be directly correlated with the depth of bowel wall penetration, if nodes were not involved. Recent classifications1 • 17 based on microscopic examination of tumor penetration in the bowel wall provide a refinement of Dukes' original work (Table 4; Fig. 37S). LYlDphatic Spread-ExtralDural
Lymph node involvement by carcinoma is primarily embolic, following a definite pattern with a predictable course. Tumors arising on the mesI I
I I
I I
I I I
23'cm. I I
Peritonea I---+-"i-.i!'il;r,c~~ ---reflection
I I I
I
Tu~or , I I I I
_-Tumor
I
I
·...........:::.---+-M ucocutoneous lin"'~==------~-
A
B
Fig. 379. A, Drawing of cleared rectal specimen showing distant node involvement with intervening negative nodes. B, Drawing of cleared rectal specimen showing 4 cm. retrograde node involvement in advanced carcinoma. The extent of node replacement by tumor is shown in black.
enteric border do not seem to metastasize to nodes more readily than tumors located on the antimesenteric border. Tumor emboli enter the subcapsular space of the lymph node and spread in the depth. Nodes, where cancer has lodged, prevent further spread until the node is completely overwhelmed by tumor. When this occurs, further spread is by way of new tumor emboli to the collateral lymph channels. Metastases growing in lymph nodes do not break through the capsule until extensive and overwhelming growth has occurred. Gross detection of involved lymph nodes is not possible with any degree of certainty, nor is there any constant correlation between the size of the node and the extent of its involvement. Not infrequently, positive nodes may lie out of continuity of spread
F. A. de Peyster, R. K. Gilchrist
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Fig. 380. Drawing showing nodes and distribution of the extramural lymphatic network of the colon, which tend to follow blood supply.
Para-aortic nodes Sup. hemorrhoidal
rotor node tor ani muscle
--In9uinal nodes
Fig. 381. Drawing illustrating the extramural lymphatic network of the rectum. Note the dual lymph drainage from the middle and inferior rectal segments.
and at some distance from the tumor with normal nodes intervening (Fig. 379, A). Where lymph node channels are mechanically blocked by tumor, inflammation or a previous operative wound, retrograde metastases (incidence 4.6 per cent) may occur at distances more than 4 cm.
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1301
below the tumor margin (Fig. 379, B). These two facts constitute the fundamental reasons for wide en bloc excision of the primary lesion together with the dependent lymph node drainage. The chief lymphatic pathways of the colon and rectum follow their· principal blood supply and are illustrated in Figures 380 and 381. Additional pathways to adjacent organs recently have been demonstrated by Weinberg using vital dye techniques. 23 Cancer arising in the upper third of the rectum (intraperitoneal portion) spreads superiorly, principally along the lymphatics adjacent to the superior hemorrhoidal vessels. Cancer arising in the middle and inferior rectal regions (extraperitoneaI) not only spreads superiorly, but metastasizes laterally in the lymphatics accompanying the middle and inferior hemorrhoidal vessels. The presence of this dual lymph drainage is one Table 5 INCIDENCE OF LYMPH NODE METASTASES IN TUMORS OF RIGHT COLON AS COMPARED WITH THOSE OF THE LEFT COLON
NUMBER
Tumors of Right GoWn AU With Resection and Ileotransverse GoWn Anastomoses13 Alive 5 years. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Had involved nodes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. With involved nodes, alive 5 years. . . . . . . . . . . . . . . . . . . . Postoperative deaths. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Had no follow-up. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tumors of Left GoWn AU With Obstructive Resections Alive 5 years. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Had involved nodes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . With involved nodes, alive 5 years. . . . . . . . . . . . . . . . . . . . Postoperative deaths. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Of 10 without nodes, alive 5 years. . . . . . . . . . . . . . . . . . . . .
PER CENT
9 13 7 3 1
60.0 86.6 53.8
11 8 3 0 8
61.1 44.4 37.5 80.0
of the reasons why the highest incidence of local recurrence and the lowest survival rates of patients with carcinoma of the large bowel occur in the extraperitoneal portion of the rectum. About two-thirds of patients explored for an "operable carcinoma" already have lymph node metastases. A considerably higher incidence of lymph involvement is encountered in cancer of the right colon as compared to the left colon. Despite this fact, the over-all prognosis for patients with right-side lesions remains more favorable (Table 5). Venous DissenIination
Microscopic evidence of venous invasion is found in from 14 to 36 per cent of surgically removed specimens of bowel cancer.16 Employing new techniques, Barringer3 and Madison18 have been able to demonstrate
F. A. de Peyster, R. K. Gilchrist
1302
tumor invasion of the veins in 38 per cent and 43 per cent, respectively, of surgically removed specimens. When applied clinically, the significance of venous invasion by tumor assumes added importance. About onethird of patients operated upon for bowel cancer have gross evidence of liver metastases at the time of surgery. Tumors arising in the rectum have a greater propensity to invade veins than tumors elsewhere in the colon. 16 Gross vein involvement has been demonstrated in 12 per cent of the left-sided and 6 per cent of the right-sided colon lesions. ll Venous involvement may take place at any stage in the development of the cancer. The incidence of venous invasion increases directly with greater cellular anaplasia or deeper wall penetration, as seen in the punched-out ulcer. Dukesll found no evidence of venous invasion in Table 6 FIVE YEAR RESULTS: VEIN INVASION AND MURAL PENETRATION; COLON AND RECTUM Patients Surviving Operation Five Years or Dying of Cancer in That Period NO VEIN INVASION Per Cent Total 5 Year 5 Year Cases Survival Survival
TOTAL CASES
Group A: Group B: Group C:
17 47 69
17 32 33
16 28 18
133
82
62
94 88 55
VEIN INVASION Per Cent Total 5 Year 5 Year Cases Survival Survival
15 36
9 10
51
19
60
28
Group A lesions have not penetrated the muscle wall; Group B, extend to the perirectal or pericolic tissues without node involvement; Group C, lesions exhibit wall involvement with metastases. (After Grinnell,15)
Class A tumors (limited to the mucosa); but 16.4 per cent in Class B tumors (extending through the wall without involved nodes) and 21.9 per cent in Class C tumors (extending through the wall with involved lymph nodes). These facts indicate that vein invasion probably takes place from the primary tumor site and is not only independent of lymphatic spread but may even occur before the nodes are involved. In the absence of demonstrable portal system spread, central nervous system metastases may occur via the paravertebral veins described by Batson. 4 Table 6 shows the relation of mural penetration to vein invasion and five year survival. Perineural Spread
Seefeld and Bargen20 have demonstrated the high incidence of perineural invasion of rectal cancer in resected specimens. In 100 surgically removed rectal specimens studied, they observed that 47 per cent had
Pathology of Cancer of the Colon and Rectum
1303
lymphatic involvement, 30 per cent perineural spread, and in 20 per cent the veins were involved. The extent of perineural invasion may be correlated with the degree of cellular anaplasia, but does not seem to be related to site of the lesion in the bowel. Local recurrence of cancer is more than twice as likely to take place when nerve infiltration by tumor can be demonstrated than in those cases without demonstrable perineural infiltration. Local Im.plantation-Consideration of Local Recurrence
Relation of Tumor Site to Peritoneal Reflection. Cancer lying below the peritoneal reflection has a consistently greater local recurrence rate than intraperitoneal rectal or colon lesions. According to Gilchrist and David, 13 in 55 cases of surgically treated intraperitoneal rectal and sigmoid tumors, 18 per cent of the patients died of recurrent tumors within five years; 3.6 per cent exhibiting local recurrence. In contrast, of 122 patients with extraperitoneal rectal cancer, 43.5 per cent were dead within five years of recurrence, 23 per cent of whom had developed local recurrence. The incidence of lymph node involvement in both groups was similar, i.e., 62 per cent and 63 per cent respectively. Similar observations have been made by Wangensteen and Coller.9 This evidence suggests that factors other than lymph node involvement may be responsible for the high local recurrence rate observed when cancer is located below the peritoneal reflection. Factors contributing to this increased rate of local recurrence are the lack of a protective peritoneal wall, allowing ready spread to fat and adjacent structures, and the rich plexus of veins and nerves. Finally, the presence of a large tumor cradled in a rigid pelvis hinders exposure and makes a wide resection difficult. Under these conditions, added massage of the tumor liberates showers of intravascular emboli, or local seeding is caused by directly breaking into the tumor itself. Significance of Suture Line Recurrence. The relation of implantation to local recurrence at the suture line was suggested in 1935 by GordonWatson and his associates. 14 Recently Cole 7 has observed, in 55 consecutive patients who had a portion of the colon resected, a 16 per cent incidence of local recurrence. In two-thirds of these patients the recurrent lesion was at the suture line, where he thought implantation occurred by the suturing process. He found viable malignant cells lying free within the resected bowel lumen for distances up to 35 cm. from the tumor. Fourteen to 56 per cent of smears from the proximal ends of the resected bowel segments, and 43 to 76 per cent taken from the distal segments, were positive for viable cancer cells. However, negative smears were obtained when occlusive ligatures were placed to isolate the tumor prior to resection. 8 In our experience, when recurrent cancer is found at the suture line, it appears like an "iceberg," with the major portion lying outside the
'I'
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F. A. de Peyster, R. K. Gilchrist
bowel wall and the smaller portion projecting into the suture line. This suggests that the recurrence originates outside the layers of the bowel wall. This and other documented evidence16 emphasizes the possibility of cancer spread by implantation. A surgical procedure for cure of bowel cancer must be devised (1) to prevent manipulative venous spread; (2) to prevent implantation; (3) to excise sufficient bowel to include maximum intramural spread and (4) to remove the cancer by "en bloc" excision with the dependent echelons of lymph node spread. REFERENCES 1. Astler, V. B. and Coller, F. A.: The Prognostic Significance of Direct Extension
2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.
of Carcinoma of the Colon and Rectum. Ann. Surg. 139: 846-851 (June) 1954. Bacon, H. E.: Anus-Rectum-Sigmoid Colon: Diagnosis and Treatment. Vol. II, 3rd Ed. Philadelphia, J. B. Lippincott Co., 1949. Barringer, P. L., Dockerty, M. B., Waugh, J. M. and Bargen, J. A.: Carcinoma of the Large Intestine. A New Approach to the Study of Venous Spread. Surg., Gynec. & Obst. 98: 62-72 (Jan.) 1954. Batson, O. V.: The Function of Vertebral Veins and Their Role in the Spread of Metastases. Ann. Surg. 112: 138-149, 1940. Black, W. A. and Waugh, J. M.: The Intramural Extension of Carcinoma of the Descending Colon, Sigmoid and Rectosigmoid. Surg., Gynec. & Obst. 87: 457-464 (Oct.) 1948. Broders, A. C. Sr., Phillips, C. and Stinson, J. C.: Neoplasms of the Large Bowel. S. CLIN. NORTH AMERICA 32: 1-19 (Oct.) 1952. Cole, W. H.: Recurrence in Carcinoma of the Colon and Proximal Rectum Following Resection for Carcinoma. A.M.A. Arch. Surg. 65: 264 (Aug.) 1952. Cole, W. H., Packard, D. and Southwick, H. W.: Carcinoma of the Colon with Special Reference to Prevention and Recurrence. J.A.M.A. 155:1549-1553 (Aug. 25) 1954. Coller, F. A., Kay, E. B. and MacIntyre, R. S.: Regional Lymphatic Metastasis of Carcinoma of the Rectum. Surgery 8: 294--311 (Aug.) 1940. Dukes, C. E.: The Classification of Cancer of the Rectum. J. Path. & Bact. 35: 323-332, 1932. Dukes, C. E. and Bussey, H. J. R.: Venous Spread in Rectal Cancer.P~oc. Roy. Soc. Med. 34: 571-574 (July) 1941. Ehrlich, J. C. and Hunter, O. B. Jr.: Tumors of the Gastrointestinal Tract. Surg., Gynec. & Obst. 85: 98, 1947. Gilchrist, R. K. and David, V. C.: Prognosis in Carcinoma of the Bowel. Surg, Gynec. & Obst. 86: 359-371 (March) 1948. Gordon-Watson, C.: Origin and Spread of Carcinoma of the Rectum in Relation to Surgical Treatment. Lancet 1: 239-245 (Jan. 29) 1938. Grinnell, R. S.: The Spread of Carcinoma of the Colon and Rectum. Cancer 3: 641-652 (July) 1950. Guiss, R. L.: The Implantation of Cancer Cells Within a Fistula in Ano. Surgery 36: 136-139, July, 1954. Kirklin, J. W., Dockerty, M. B. and Waugh, J. M.: The Role of the Peritoneal Reflection in the Prognosis of Carcinoma of the Rectum and Sigmoid Colon. Surg., Gynec. & Obst. 88: 326-331, 1949. Madison, M. S., Dockerty, M. B. and Waugh, J. M.: Venous Invasion in Carcinoma of the E.ectum as Evidenced by Venous Radiography. Surg., Gynec. & Obst. 99: 17Q-178 (Aug.) 1954. Popper, Hans: Newer Aspects of the Pathology of the Colon. J. Internat. Coll. Surgeons 17: 286-296 (March) 1952. Seefeld, P. H. and Bargen, J. A.: The Spread of Carcinoma of the Rectum: Invasion of the Lymphatics, Veins and Nerves. Ann. Surg. 118: 76-90 (July) 1943.
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21. Simpson, W. C. and Mayo, C. W.: The Mural Penetration of the Carcinoma Cell in the Colon-Anatomic and Clinical Study. Surg., Gynec. & Obst. 68: 872-877 (May) 1939. 22. United States Department of Health, Education and Welfare, Public Health Service, National Office of Vital Statistics: Vital Statistics of the United States 3: 63 (Table 51) 1951. 23. Weinberg, J. and Movius, H. J.: Vital Staining of the Lymphatics in Surgery of Carcinoma of the Large Intestine. West. J. Surg. 61: 528-534 (Sept.) 1953. 24. Williams, C. Jr.: Carcinoma of the Colon in Childhood. Ann. Surg. 139: 816-825 (June) 1954. 59 E. Madison Street Chicago 3, Illinois