CHANGING PATTERNS OF COLORECTAL CARCINOMA

BLAKE CADY, MD, ALFRED V. PERSSON, MD, DAVID 0. MONSON, MD,

AND DON L. MAUNZ, MD

Over the 40 years 1928-1967, 5,807 surgical specimens of large bowel adeno- carcinoma treated b y resection were accumulated. These specimens were ana- lyzed for maximum tumor diameter, incidence of lymph node metastases, loca- tion within the Iarge bowel, and compared by decade. During this 40-year period, several trends in clinical presentation of disease were noted. Com- paring the first to the last decade, the incidence of right colon cancer in- creased significantly from 7% to 22% of cases, while the relative incidence of sigmoid, rectosigmoid, and rectal carcinomas fell significantly from 80% to 62%. The size of the increasingly frequent right colon cancers was unchanged in recent years, and the incidence of lymph node metastases was constant during the decades studied. I n contrast, there was a significant trend toward earlier disease in the sigmoid, rectosigmoid, and rectal cancers, manifested by a statistically significant decrease in the size of the primary cancers, a significant increase to 65% in the frequency of cases without lymph node metastases, and a decrease, to 9%, of cases with metastases to more than three lymph nodes. These trends are explained by the early detection techniques of sig moidoscopy and rectal examination in recent years, by the more aggressive treatment of polyps within the reach of the sigmoidoscope, and by the greater susceptibility of the right colon to cancer in recent decades.

LTHOUGH THE INCREASING INCIDENCE OF A carcinoma of the right colon has been noted by Moss10 and 0thers5~~~QJl in the United States and other developed countries, and an epidemiologic model for this shift in location of colorectal carcinoma has been outlined by Haenszel and Correa,' this trend remains largely unrecognized by American physicians and surgeons. A review of all the colorectal pathologic material accumulated over a 40- year period by the Lahey Clinic Foundation and the New England Deaconess Hospital Laboratory of Pathology has clearly demon- strated this trend and has outlined other as- pects of the changing presentation of carci- noma of the large bowel. We have published a similar presentation of disease variations with time for carcinoma of the breast.3

Presented at the Twenty-Sixth Annual Meeting of the James Ewing Society, Louisville, Kentucky, April

From the Department of Surgery, Lahey Clinic Foun- dation, Boston, Massachusetts.

Address for reprints: Blake Cady, MD, 605 Common- wealth Ave., Boston, MA 02215.

Received for publication August 28, 1973.

26-28, 1973.

METHODS

All pathologic diagnoses of colonic or rectal adenocarcinoma or polyps registered at the New England Deaconess Hospital Laboratory of Pathology from its inception in 1928 to 1967 were examined; 5,807 cases of surgically resected colonic and rectal specimens were ob- tained in which a diagnosis of adenocarci- noma was made. In recent years, a small per- centage of these consisted only of a surgically resected polyp in which very early carcinoma was discovered; all the remainder were actual segments of large bowel that had been surgi- cally excised. Biopsy specimens alone or ne- cropsy material was not utilized. This selec- tion of material was chosen to give an over- view of the surgical aspects of this disease. Data from each pathologic specimen, regard- ing the maximum diameter of the primary carcinoma as measured in the fresh state by the pathologist, the location within the large bowel, the total number of lymph nodes dis- sected, and the number of lymph nodes dis- playing metastases, were recorded. T h e actual

422

No. 2 COLORECTAL CARCINOMA - Cady et al. 423

techniques of analysis of lymph node speci- mens have previously been described.3

Definitions as to location were: right co- lon-any carcinoma of the cecum or ascending colon; transverse colon-carcinomas arising in either hepatic or splenic flexure or the inter- vening transverse colon; left colon-a lesion arising from below the splenic flexure to the beginning of the sigmoid colon as defined by the assumption of a significant mesenteric at- tachment near the pelvic brim; and rectosig- moid carcinoma-all those carcinomas arising within the entire extent of the sigmoid colon on a mesenteric attachment or below that area in regions commonly called rectosigmoid and rectum. The term “rectosigmoid” is used with such a connotation for simplicity, recognizing the difference from customary usage but stress- ing the feature of distal colonic as contrasted to proximal colonic pathology. In this fashion, a truer contrast was offered between right- sided and terminal colonic adenocarcinomas.

Data were analyzed for all decades when there were more than 100 cases, and when at least 90% of patients had specific statements about the factor in question. These restric- tions were made to produce more meaningful data and did not produce any obvious bias.

RESULTS

Table 1 demonstrates the marked changes in incidence of both right colon and rectosig- moid carcinomas. This table assumes that the surgical specimens unspecified as to the exact location within the large bowel fell almost en- tirely in the category of transverse and left colon. Such an assumption is logical since

right colon lesions were categorized accurately because of the small bowel attached to the right colectomy specimen, and rectosigmoid le- sions were accurately classified because of at- tached anal skin or demonstration of extraper- itoneal rectosigmoid or rectum. In addition, transverse and left colon cases are underre- ported in our series, compared to others, by approximately the amount unspecified by lo- cation.

Table 1 also analyzes those specimens pre- cisely labeled and eliminates unspecified loca- tions. The slope by decade for the incidence of carcinoma of the right colon is +5.48, while that for rectosigmoid is -7.09, both highly sig- nificant figures when analyzed by regression on time with the technique of Snedecor and Cochran.12

Maximum diameter was recorded in most cases of carcinoma of the right colon (96.3%,

1967). It was not apparent that the measure- ment omissions represented any bias in sam- pling, but only the relative thoroughness of individual prosectors. Table 2 indicates that the mean maximum diameter of carcinoma of the right coion did not change in a consistent or significant way during the three decades analyzed. This table also demonstrates a sig- nificant trend toward smaller-sized lesions oc- curring in the rectosigmoid with time. Nearly all cases in this location were accurately meas- ured (96.6%, 1928-1937; 95.8%, 1938-1947; 96.1%, 1948-1957; and 94.7%, 1958-1967), reinforcing the implications of the size changes with time.

Analysis of the changes in lymph node me- tastases in time was undertaken for the last

1938-1947; 94.6%, 1948-1957; 90%, 1958-

TABLE 1. Change in Location by Decade

1928-1937 1938-1947 1948-1957 1958-1967 No. Percent No. Percent No. Percent No. Percent Slope t Value

Rightcolon 39 6 .7 191 10.5 258 13.7 316 21.4 Rectosigmoid 462 79.6 1,401 74.6 1,334 70.8 908 61.6 Transverse,

left and unspecified 79 13.6 286 15.0 290 15.4 249 16.9

TOTAL 580 1,878 1,882 1,473

Precise Specification Rightcolon 39 7.4 191 11.5 258 15.3 316 23.7 +5.48 10.41*

Transverse, Rectosigmoid 461 88.0 1,401 84.9 1,334 79.1 908 68.2 -7.09 11.98*

left colon 24 4 . 6 57 3 . 4 93 5.5 107 7.9 $1.61 4.89* TOTAL 524 1,649 1,685 1,331

* Significant.

424 CANCER February 1974 VOl. 33

TABLE 2. Change in Mean Maximum Diameter by Decade 1928-1937 1938-1947 1948-1957 1958- 1967

Right colon Number 184 244 285 Mean maximum diameter, cm 6.37 6.46 6.23 Standard deviation 2.50 2.53 2.68

Slope: -0.05 cm/decade F: < 1

Rectosigmoid Number Mean maximum diameter, cm Standard deviation Slope: -0.20 cm/decade F: 37.55

446 5.37 1.97

1,342 5.23 1.86

1,282 5.11 1.98

860 4.76 1.95

three decades where at least a 90% completion in description of nodal pathology was ob- tained. Table 3 demonstrates that there has been no statistically appreciable change in cases without lymph node metastases, with only one to three lymph node metastases, or with more than three lymph node metastases in carcinomas of the right colon. There is ac- tually a slight increase in the number of cases with multiple node metastases and a decrease in those without node metastases, but not in a consistent fashion or at the level of statistical significance. By contrast, carcinomas of the rectosigmoid area have undergone an appreci- able and significant change with time toward cases with fewer lymph node metastases. Thus, there is an increase in the number of cases with no lymph node metastases significant to the 5% level of confidence, and a decrease in the number of cases with more than three lymph node metastases, the worst prognostic group. Because of relatively few numbers, this slope is not statistically significant, but the trend is clear.

In addition, there has been a small, gradual, but consistent rise over time of cases with muscularis involvement as the deepest level of bowel wall penetration in the rectosigmoid area, which was not seen in the right colon area. Because of the large number of cases not categorized for maximum depth of invasion, however, significant figures were not analyzed for this factor.

DISCUSSION

Haenszel and Cornea7 reviewed extensive epidemiologic data for colorectal cancer and noted clear incidence variations which led

them to propose an epidemiologic model. In low incidence areas, disease tends to be con- centrated in the cecum and ascending colon, and occurs more frequently in women than in men. As incidence increases, the bulk of the increase is in sigmoid carcinomas among men, with a time lag before the incidence of sig- moid carcinoma increases in women. “As ex- posures to the etiologic factor become more intense and prolonged, a later phase is charac- teristically a rise in cecum and ascending colon cancer. . . . T h e changes for cecum and ascending colon are accompanied by similar transitions in the transverse and descending colon, so that the upward displacement in male cases may appear sequentially in time as involving successive segments of the colon moving from the rectosigmoid junction to the cecum.” Although we did not record sex data, the shift in cases noted in this study corre- sponds closely to the suggested model.

What the environmental etiologic factors may be that cause large bowel cancer are not known, but Burkitt2 has offered an intriguing hypothesis related to general dietary practices and resulting stool bulk, bacterial counts, transit times, and bowel habits. Wynder et a1.17 have also suggested dietary factors. Al- though further laboratory experimentation will be essential to confirm these hypotheses, some demonstrated biochemical mechanisms already exist.13

Other factors leading to a decreasing inci- dence of rectosigmoid carcinoma may include the early treatment of polyps within reach of sigmoidoscopy. It is generally assumed that villous or papillary adenomas have an ex- tremely high incidence of later carcinoma de- velopment, and that many polypoid adenomas

No. 2 COLORECTAL CARCINOMA Cady et nl. 425 may indeed contain elements of a villous or papillary type.14 Their early treatment would certainly alter incidence rates of carcinoma in this area.

Of great interest is the distressing lack of early detection of carcinoma of the right colon as these lesions become more prevalent. Carci- noma of the right colon is relatively occult, and the usual early detection techniques cur- rently practiced have no role. In contrast, the significant decrease in mean maximum diame- ter and resultant significant decreases in inci- dence of nodal metastases in rectosigmoid carcinomas offer encouragement for more vig- orous early detection. These trends undoubt- edly represent a variety of influences-earlier reporting of symptoms by patients,l6 patient education about importance of symptoms, and more widespread use of rectal examination and sigmoidoscopy. In the future, with wide- spread application of flexible colonoscopic instruments and resultant polypectomy of benign lesions, and biopsy of early cancer at successively higher levels of the large bowel, reductions in size of higher lesions may be attainable.

T h e reported figures should also bring at- tention to the importance of comparing sur- vival figures in time. Certainly, if gross sur- vival figures are utilized for large bowel or rectal carcinomas, there may be marked biases based not on therapy utilized but on the marked changes in disease presentation in rec- tal carcinomas in contrast to the total absence of changes in carcinoma of the right colon. New treatment procedures utilized in rectal carcinomas, for instance, may erroneously he credited with increased survival, while in fact survival improvements may be related only to

improved clinical material. Furthermore, The lumping of survival figures not only by time periods but also by location within the colon may bias resultant survival figures signifi- cantly. Only by separating resdts by time period and by location within the colon and by exact metastatic nodal status can accurate estimations of true changes in results be achieved, and sophisticated conclusions about the results of changes in therapy be assessed.

While most reports accentuate survival fig- ures for the various Dukes’ classifications, it has clearly been demonstrated that there are marked changes in survival based on the ac- tual number of positive nodes, although all such cases are “Dukes’ C.”4,8 Changes in the incidence of cases with more than three nodes positive may erroneously lead to conclusions about the efficacy of changes in therapy over time, since improved results may be merely the result of gradual elimination of those cases with the worst biological survival potential.

Unfortunately, the international T N M (T, primary tumor; N, regional lymph nodes; M, distant metastases) classification does not ac- commodate sophisticated pathologic knowl- edge regarding the number of nodal metas- tases, and thus tends to obscure one of the most important measurements of survival poten tial.16

Many reports demonstrate considerably higher survival rates for all patients in car- cinomas of the right colon in contrast to rectal and rectosigmoid carcinomas.1.0 If this is so, and recognizing the gross differences in disease presentation of the primary cancers, espe- cially in later years, a distinctively less agyy‘es- sive biological behavior pattern must be poc~ 11-

lated for such right colon lesions.

TABLE 3. Change in Lymph Node Metastases by Decade

1938-1947 1948-1 957 1958-1967 No. Percent No. Percent No. Percent Slone t Value

Right colon N o node metastases 1 to 3 node metastases More than 3 node metastases TOTAL number with nodal

pathology described

Rectosigmoid No node metastases 1 to 3 node metastases More than 3 node metastases

TOTAL number with nodal pathology described

112 50 24

186

829 367 174

1,370

60 .2 154 6 1 . 8 176 57 .5 26 .8 58 23 .2 82 26 .8 12 .9 37 14 .8 48 15 .7

249 306

60 5 830 61 2 576 64 6 +0 0112 2 1 7 26 7 327 25 3 231 2.5 9 0 0020 >1 12 7 1\35 10 5 84 9 4 0 0087 >1

1,292 89 1

426 CANCER February 1974

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Vol. 33

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