Premalignancy of the Mucosal Polyp in the Large Intestine: 1I. E s t i m a t i o n o f t h e P e r i o d s R e q u i r e d f o r M a l i g n a n t Transformation of Mucosal Polyps* SADAO KOZUKA, M.D.,J- MOKICHI NOGAKI, M.D.,+ TAKEO OZEKI, M.D.,$ SHIGEKI MASUMORI, M.D.++

Nagoya, Japan

THE

CONCEPT OF

PREMALIGNANCY Of

adenoma in the large intestine is widely accepted 4-6, 11, 12, 15, 16, 20, 22-24,29, 33-35 in spite of some opposition,7, 30, 31 while controversy concerning a transition between hyperplasia and adenoma still remains. 2, 10, la, 20, 21, 2a, 25, 32, 33 T h e previous paper described criteria for histologic gradation of mucosal polyps in the large intestine on the basis of epithelial pseudostratification and indicated that most mucosal polyps consist of glandular epithelium of two or more grades. A general review of a total of 230 polyps and 130 invasive cancers suggested a gradual transition from normal to invasive adenocarcinoma through hyperplasia and adenoma. These results led us to the hypothesis that if cancer in the large intestine develops gradually through the processes of hyperplasia and adenoma, the average age of the patient should increase with the advance of histologic atypism in the polyps, to reach a maximum that might be represented by the average age of the patients in whom invasive carcinoma is * Received for publication January 24, 1975. ]-Department of Pathology, Nagoya University School of Medicine. + Nogaki Hospital for Proctorial Diseases. Address reprint requests to Dr. Kozuka: Department of Pathology, Nagoya University School of Medicine, 65 Tsurumaicho, Showaku, Nagoya, 466, Japan.

identified at autopsy. In order to substan.tiate the above hypothesis, the relationship between the age of the patient and histologic gradation of the mucosal polyps and invasive cancer was studied. Materials and Methods Histologic specimens of mucosal polyps and invasive carcinomas of the colon and rectum were collected from the file of surgical biopsy specimens at the Second Department of Pathology, Nagoya University School of Medicine, during the years 1968 to 1974. Many of our specimens, a total of 331 mucosal polyps from 324 patients and 261 invasive carcinomas, were provided by the Nogaki Hospital for Proctorial Disease. Histologic gradation was based on epithelial pseudostratification; the details are described in the previous paper. Grade 0 is an excrescence of normal colonic mucosa. Grade I is almost the same as grade 0 except for enlargement of the glandular lumens; Grade II shows crowding of tall and narrow epithelial cells without epithelial pseudostratification. Grade III shows apparent pseudostratification of the glandular epithelial cells, but the level of nuclear positions is limited to the basal half of the epithelial height. In grade IV there is severe pseudostratification of glandular epithe-

494 Dis. Col. &Rect. September 1975

Number 6 Volume 18

MALIGNANT TRANSFORMATION

Volume 18 Number 6

TABLE l,

OF M U C O S A L POLYPS

495

Average Ages of Patients with Polyps and Invasive Cancer

Age Difference from N u m b e r of Patients

Average Age

(Years)

Were Found at Autopsy (Years)

43.6 _____15.5 40.7 • 14.1 45.6 ~: 13.7 47.3 ~ 14.9 50.4 +___14.6 55.1 ~ 15A

15.1 18.0 13.1 IlA 8.3 3.6 3.1

Patients

Male Grade

0

13

I

36

I1 Ill 1V V

63 55 45 28

(2) (5) (1)

Female 3 10 18 (1) 20 (1) 21 19

Total 16 46 81 (3) 75 (6) 66 (1) 47

Patients Whose ~ancers

Invasive cancer

in surgical specimen Invasive cancer found at autopsy Parentheses

147

114

261

55.6 ~ 14.7

1,857

1,321

3,178

58.7 + 15.2

indicate n u m b e r s of patients less t h a n

lium, but the uppermost part of the glandular epithelium contains no scattering of nuclei except for mitotic figures. Grade V is characterized by extremely severe pseudostratification of the glandular epithelium. Nuclei are scattered throughout the height of glandular epithelium. Individual mucosal polyps usually contained glands of two or more grades of pseudostratification. Therefore, gradation of each polyp was based on the most advanced grade in the poIyp. Polyps of grades 0 to I I pseudostratification correspond to so-called "hyperplasia," and those of grades I I I to V are adenoma, although polyps of grade V are premalignant or carcinoma in

situ. T h e term "invasive carcinoma" in this study includes ulcerative carcinomas as well as mucosal polyps in which foci of adenocarcinoma invade the stalk. T h e ages at death of individuals in whom carcinomas in the rectum and colon were detected at autopsy (total 5,i78) were calculated from the Annual of the Pathologic Autopsy Cases in Japanw for the years 1964 to 1971. w

by the Japanese Pathologic Society,

Tokyo. Volumes 8--15, 1966--1973.

10 years old.

Results

T h e relationship between average ages of the patients and histologic gradation of mucosal polyps and invasive carcinoma in the surgical series, as well as in the autopsy series, is demonstrated in Figures 1 (male patients) and 2 (female patients). T h e ages of the patients had a very wide distribution, but the average age increased gradually with the advance of histologic atypism. Female patients had slightly younger average ages than males among the grades I to IV groups and in the surgical series of invasive carcinoma. In the autopsy series, however, the average ages of both sexes were the same, 58.7 years, although the peak incidences were found in men 65 to 70 years old and in women 60 to 65 years old. Average ages are shown in T a b l e 1. T e n patients less than 10 years old have not been included in the calculations of average age in T a b l e l and Figures 1 and 2, because only large polyps manifesting obvious symptoms were collected from the patients less than 10 years old in this study. Except for grade 0, the average age increased steadily from 40.7 years for patients who had grade I polyps to 58.7 years for patients in the autopsy series.

496

K O Z U K A , E T AL.

Dis. CoL & Reef+ September 197S

Male

__[--J

70

60

10

30

20

10

,g ,

~

,p

?

! II [] IV Histological Grade of Mueosal Polyp

I

V

l

In+asive Cancer in Surgery

II

I

L

1

100

200 31)0 Number of t'ases Invasive Cancer in Autol~y

FIG. 1. R e l a t i o n s h i p between ages of m a l e patients a n d gradation of mucosM polyps a n d invasive cancer in surgical biopsy a n d autopsy specimens. Circles show average age a n d solid lines indicate s t a n d a r d deviation, b u t patients less t h a n 10 years old are excluded f r o m calculation of average age. T h e age incidence of invasive cancer in the a u t o p s y series is s h o w n in intervals of 5 years.

Discussion

Ages o[ patients with cancer as well as rnucosal polyps in the large intestine ranged very widely, from newborn to more than 95 years (Figs. 1 and 2). The average age of the patien:ts increased steadily with the advance of histologic atypism from grade 0 or I polyps to invasive cancers, reaching 58.7 years in the autopsy series. Correa e t al. 9 also reported that hyperplastic polyps tended to appear around the fourth decade of life, earlier than adenomatous polyps, and their prevalence did not increase appreciably with age, while adenomatous polyps increased in prevalence with age.

From the difference in the average ages among the patients with polyps of each grade and invasive carcinomas in both the surgical series and the autopsy series, it might be possible to estimate approximately the average periods before the polyps of each grade would become malignant and cancers would kill the patients. Estimation of exact periods of expected survival, however, would require a vast number of cases and also the hypothesis that almost all mucosal neoplasms in the large intestine develop gradually from normal tissue to adenocarcinoma through the stages of hyperplasia and adenoma in response to persistence of carcinogenic stimulation. T h e

MALIGNANT TRANSFORMATION

Volume 18 Number 6

OF M U C O S A L POLYPS

497

Female

9O |

&

8O

T

O

~

7O

?

im

_

6O

50

~

4O

:1" 39 _ O

20

•

9

|

O

:

9 9

-

U

z

t

-

| s

s

O

I0

......

I

0

I

i1

Histological Grade

m IV Y of Mucosal Polyp

tnvasive Cancer

in Surgery

100

200 300 Number of Cases lnvasive C a n c e r in Autopsy

FIo. 2. R e l a t i o n s h i p between ages of female patients a n d g r a d a t i o n of m u c o s a l polyps a n d invasive cancer in surgical biopsy a n d autopsy specimens. Circles show average age a n d solid lines indicate s t a n d a r d deviation, b u t patients less t h a n 10 years old are excluded from calculation of average age. T h e age incidence of invasive cancer in the autopsy series is shown in intervals of 5 years.

previous paper revealed that most mucosal polyps have glandular epithelium of two grades or more and a general view of all specimens studied suggested a gradual transition from normal tissue to cancer through hyperplasia and adenoma. Persisting or repetitive stimulation by carcinogens might be memorized by cells through transformation becoming integrated in the cells that ultimately become cancer, is In the large intestine, memory of carcinogenic stimulation might be stored in the form o[ hyperplasia or adenoma corresponding to the duration and strength of carcinogenic stimulation. Of course, the possibility of induction of

cancer d e n o v o from normal mucosa cannot be disregarded completely, but d e - n o v o induction of cancer seems rare, since no case could be recognized with certainty in our entire series, whereas malignant transition of the mucosal polyps was found frequently. Moreover, there was a gradual transition in the average ages of patients according to advancing atypism of the epithelium. However, there are still complicating problems. After about 30 or 40 years, the incidence of polyps or adenomas increased with advancing age. 1, 3, s, 9, 16, z6, 2s, a2 In addition, a considerable n u m b e r of polyps might be resected spontaneously,it Notwithstanding the problems mentioned

498

KOZUKA, E T AL.

above, even a rough estimate of the periods required for polyps to become malignant might contribute significantly to the effort to reduce the mortality rate of cancer. A provisional estimate of the average years before cancer will kill a patient could be obtained from Table I, in which the difference between the average age of patients with polyps of each grade and those of the autopsy series are shown. Patients with grade 0 polyps were slightly older than those whose polyps were grade I, possibly because of shortage of cases. Medical literature supports, in part, our provisional estimates. T h e average ages of patients with adenocarcinoma reported in the literature were 57.6 years (Grinnell and Lane, as 56.7 for cancer of rectum, and Grinnell,14 58.3 for colonic cancer), and 61 to 64 years (Wood36), whereas those with adenoma or polyps were younger in most of the following reports: 48.1 years (Buie and BrustS); 48 years (Wilson et aI.35); 50 years (Miller et al.22); 52 years (Rider et al.e7); 55 years (Bockus et a/.4); 59 years (Enterline et al:Z); 61.9 years (Grinnell and Lane'S). Buie and Brust s stated that the nine-year difference between the average ages of patients with adenoma and cancer, 48 and 57 years, focused suspicion upon adenomas as possible precancerous lesions. Follow-up studies of individual patients having a mucosaI polyp without resection are relatively seldom done, 17, 22.29 and most are short-term. Miller et al.Z2 reported an infiltrating carcinoma probably derived from a polyp that had been seen nine years previously and had had a pedicle long enough to prolapse through the anal canal. Scarborough 29 reported the histories of ten patients in whom a benign polyp had once existed; on re-examination two to 18 years later, a full blown annular carcinoma was present at the site of the previous polyp.

Dis, Col. & Reet. September 1975

Sato 2s studied the incidence of adenomatous polyps in the large intestine in Japan using 1,000 autopsy subjects and 170 surgical cases. In his series, analysis of the age distribution of surgical patients with adenomas revealed that satellite polyps in cancerous bowels were most numerous between 60 and 69 years of age, whereas adenomas in noncancerous bowels were most frequently observed in the 40's. He also reported that structural atypia of the adenomatous polyps increased in severity according to age in the autopsy series, but was uniformly distributed among all age groups in the surgical cases. Probably the above conflicts result from the fact that most surgeons might detect only polyps of large size and in advanced stage in patients complaining of symptoms caused by the polyp itself. On the other hand, our specimens were obtained not only from patients having symptoms of a polyp but also from the patients suffering from hemorrhoids or anal fistulas, by identified sigmoidoscopic examinadon. Therefore, our samples, including many small elevations of the mucosa, might represent a relatively natural incidence, except in children, who rarely suffer proctologic diseases. Present estimations suggested that a long p e r i o d - a n average of approximately 15 years--might be required for transition of the early stage of hyperplasia to invasive cancer. A mucosal polyp of the large intestine might change steadily during the process, which is defined as a function of the strength and duration of carcinogenic stimulation, from normal to malignant. In other words, in response to persistent or repetitive stimulation by carcinogens, there might be no absolute and permanent benignancy in the neoplasms, and benig-

Volume 18 Number 6

MALIGNANT TRANSFORMATION OF MUCOSAL POLYPS

n a n c y m i g h t signify only that a n e o p l a s m w o u l d take a r e l a t i v e l y l o n g p e r i o d to r e a c h malignancy. T h e r e q u i r e m e n t of m a n y years for dev e l o p m e n t of m a l i g n a n c y m i g h t suggest weakness a n d / o r i n t e r m i t t e n c e t9 of carcin o g e n i c s t i m u l a t i o n , a n d suggests an exp l a n a t i o n for the senile p r e p o n d e r a n c e in the i n c i d e n c e of the tumor. F o r p r o p h y l a c t i c purposes, we m i g h t figure the effective i n t e r v a l b e t w e e n exami n a t i o n s from tile p r e s e n t results, i n d i c a t i n g a p p r o x i m a t e l y 11.5 years on the average b e t w e e n the early stage of the m u c o s a l p o l y p (grade I p s e u d o s t r a t i f i c a t i o n ) a n d the p r e c a n c e r stage or c a r c i n o m a in situ (grade V), w h i c h is easily r e m o v e d by polypectomy, a l t h o u g h we have to try to determ i n e a m o r e e x a c t i n t e r v a l b e t w e e n grades I a n d V, u s i n g m o r e n u m e r o u s samples. O n the basis of this study, e x a m i n a t i o n a n d p o l y p e c t o m y at five-year intervals after 35 years of age m i g h t be e n o u g h to p r o t e c t most p e o p l e a g a i n s t invasive cancer of the large intestine. Conclusion T h e r e l a t i o n s h i p b e t w e e n age of the p a t i e n t a n d the histologic g r a d a t i o n of m u c o s a l p o l y p s (total 331 cases) a n d invasive c a r c i n o m a of the large i n t e s t i n e was s t u d i e d in a surgical series (261 cases) as we]l as in a n a u t o p s y series (3,178 cases). T h e average ages of the p a t i e n t s i n c r e a s e d steadily w i t h the a d v a n c e of histologic a t y p i s m from 40.7 years w i t h g r a d e I p o l y p s to 58.7 years w i t h invasive c a r c i n o m a in the a u t o p s y series. F r o m the differences in average ages of the patients, a p r o v i s i o n a l e s t i m a t i o n of the p e r i o d s w h i c h m i g h t be r e q u i r e d for p o l y p s of each g r a d e to b e c o m e m a l i g n a n t a n d to kill p a t i e n t s was att e m p t e d . T h e f o l l o w i n g figures were suggested; 3.6 years for p o l y p s of g r a d e V

499

p s e u d o s t r a t i f i c a t i o n , 8.3 years for g r a d e IV, 11.4 years for g r a d e I I I , 13.1 years for g r a d e II, a n d 18.0 years for g r a d e I. References 1. Arminski TC, McLean DW: Incidence and distribution of adenomatous polyps of the colon and rectum based on 1,000 autopsy examinat.ions. Dis Colon Rectum 7: 249, 1964 2. Arthur JF: Structure and significance of metaplastic nodules in the rectal mucosa. J Clin Pathol 21: 735, 1968 3. Blan LJ: Polyps of the colon and rectum: Incidence and distribution. Dis Colon Rectum 4: 277, 1961 4. Bockus HL, Tachd]iau V, Ferguson LK, et al: Adenomatous polyps of colon and rectum: Its relation to carcinoma. Gastroenterology 41: 225, 1961 ~5. Buie LA, Brust JC: Quoted by Turell R, Haller JD: A re-evaluation of the malignant potential of eolorectal adenomas. Surg Gynecol Obstet 119: 867, 1964 6. Buntain WL, ReMine WH, Farrow GM: Premalignancy of polyps of the colon. Surg Gynecol Obstet 134: 499, 1972 7. Castleman B, Krickstein HI: Do adenomatous polyps of the colon become malignant? N Engl J Med 267: 469, 1962 8. Chapman I: Adenomatous polypi of large intestine: Incidence and distribution. Ann Surg 157: 223, 1963 9. Correa P, Duque E, Cuello C, et al: Polyps of the colon and rectum in Call, Colombia. Int J Cancer 9: 86, 1972 i0. Crocker DW, Veith FJ: Focal primary mucosal hyperplasia of the colon: The case for its importance in the pathogenesis of cancer. Ann Surg 160: 215, 1964 11. Dockerty MB: Pathologic aspects in the control of spread of colonic carcinoma. Mayo Clin Proc 33: 157, 1958 12. Enterline HT, Evans GW, Mercudo-Lugo R, et al: Malignant potential of adenomas of colon and rectum. JAMA 179: 322, 1962 13. Goldman H, Ming S, Hickok DF: Nature and significance of hyperplastic polyps of the human colon. Arch Pathol 89: 349, 1970 14. Grinnel RS: Results in the treatment of carcinoma of the colon and return: An analysis of 2,341 cases over a 35 year period with 5 year survival results in 1,667 patients. Surg Gynecol Obstet 96: 31, 1953 15. Grinnel RS, Lane N: Benign and malignant adenomatous polyps and papillary adenomas of the colon and rectum: An analysis of 1,856 tumors in 1,335 patients. Int Abstr Surg 106: 519, 1958 16. Helwig EB: The evolution of adenomas of the large intestine and their relation to carcinoma. Surg Gynecol Obstet 84: 36, 1947

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17. Knoernschild HE: Growth rate and malignant potential of colonic polyps: Early results. Surg Forum 14: 137, 1963 18. Kozuka S: Multisteps in the process of induction of murine hepatoma by 2,7-bisacetylaminofluorene (Jap). Trans Soc Patbol Jap 62: 159, 1973 19. Kozuka S, Sassa R: Effect of carbon tetrachloride on the induction of routine hepatoma by 2,7-bisacetylaminofluorene (Jap). Trans Soc Pathol Jap 63: 190, 1974 20. Lane N, Kaplan H, Pascal RR: Minute adenomatous and hyperplastic polyps of the colon: Divergent patterns of epithelial growth with specific associated mesenchymal changes: Contrasting roles in the pathogenesis of carcinoma. Gastroenterology 60: 537, 1971 21. Lane N, Lev R: Observations on the origin of adenomatous epithelium of the colon: Serial section studies of minute polyps in familial polyposis. Cancer 16: 751, 1963 22. Miller CJ, Day E, L'Esperance ES: The value of proctoscopy as a routine examination in preventing deaths from cancer of the large bowel. NY State J Med 50: 2023, 1950 23. Morson BC: Precancerous lesions of the colon and rectum: Clarification and controversial issues. JAMA 179: 316, 1962 24. Morson BC: Precancerous and early malignant lesions of the large intestine. Br J Surg 55: 725, 1968 25. Pagtalunan RJ, Dockerty MB, Jackman RJ, et ah The histopathology of diminutive polyps of the large intestine. Surg GynecoI Obstet 120: 1259, 1965

D~s. CoI. & Rect. September 1975

26. Potet F, Soullard J: Polyps of the rectum and colon. Gut 12: 468, 1971 27. Rider JA, Kirsner JB, Moeller HC, et al: Polyps of the colon and rectum: A four-year to nine-year follow-up study of five hundred thirty-seven patients. JAMA 170: 633, 1959 28. Sato, E: Adenomatous polyps of large intestine in autopsy and surgical material. Gann 65: 295, 1974 29. Scarborough RA: The relationship between polyps and carcinoma of the colon and rectum. Dis Colon Rectum 3: 336, 1960 30. Spratt JS Jr, Ackerman LV: Small primary adenocarcinomas of the colon and rectum. JAMA 179: 337, 1962 31. Spratt JS Jr, Ackerman LV, Moyer CA: Relationship of polyps of the colon to colonic cancer. Ann Surg 148: 682, 1958 32. Stemmermann GN, Yatani R: Diverticulosis and polyps of the large intestine: A necropsy study of Hawaii Japanese. Cancer 31: 1260, 1973 33. Swinton NW, Warren S: Polyps of the colon and rectum and their relation to malignancy. JAMA 113: 1927, 1939 34. Welch CE, McKittrick JB, Behringer G: Polyps of the rectum and colon and their relation to cancer. N Engl J Med 247: 959, 1952 35. Wilson GS, Dale EH, Brines OA: An evaluation of polyps detected in 20,847 routine sigmoidoscopic examinations. Am J Surg 90: 834, 1955 36. Wood DA: Tumors of the Intestines. Washington, Armed Forces Institute of Pathology, 1967, p 261