Radiation-induced Carcinoma of the Rectum*

ANTONIO MARTINS, M.D., STEPHEN S. STERNBERG, M.D., FADI F. ATTIYEH, M.D.

Martins A, Sternberg SS, Attiyeh FF. Radiation-induced car- cinoma of the rectum. Dis Colon Rectum 1980;23:572-575. Car- c inomas and sarcomas are known to develop after radiation therapy. A complete review of the literature regarding appear- ance of carcinoma of the rectum following radiation therapy to the pelvis was undertaken. The average interval between irradia- tion and diagnosis of the rectal cancer was 15.2 years, the range being from one year, two months to 33 years. We present a case of carcinoma of the rectum arising as two separate primaries 46 years after irradiation for an epidermoid carcinoma of the cervix. There were many pathologic changes related to the radiation therapy. [Key words: Carcinoma, rectal; Radiotherapy, cancer subsequent to; Rectum, carcinoma]

CARCINOMAS AND SARCOMAS are k n o w n to deve lop fo l lowing r ad i a t i on t he r apy for b e n i g n or m a l i g n a n t lesions. T h e y have been r e p o r t e d to occur in skin, thyroid , b o n e mar row, bone , lung , breast , co lon a n d rec tum, b l a d d e r a n d salivary gland.* With the a d v e n t o f s u p e r v o l t a g e r a d i o t h e r a p y as well as m o d e r n c h e m o t h e r a p y , a new era is b e g i n n i n g in which we migh t see more t u m o r s a r i s ing in pat ients who ha d the i r ini t ia l n e o p l a s m c o n t r o l l e d by r a d i o t h e r a p y ,

c h e m o t h e r a p y or both. T h e e lapsed t ime is insuff i - c ient to indica te the ex ten t o f this p rob lem.

Th i s p a p e r p resen t s a case r e p o r t of two closely associated bu t separa te a d e n o c a r c i n o m a s of the rec- t u m in a pa t i en t previous ly t r ea t ed with r ad i a t i on t he r apy for c a r c i n o m a of the cervix.

R e p o r t o f a C a s e

A 73-year-old white woman had been treated in February 1932, for a fungating, exophytic tumor of the cervix that measured 3.5 cm in diameter. There had been no parametrial involvement but the tumor apparently extended into the proximal vagina. Biopsy had revealed a grade II epidermoid carcinoma of the cervix. She had received high kilovolt external radiation for a total of 1500 mCi/hr and a va~nal tandem radiation application of 3000 mCi/ hr. She had been followed regularly without evidence of disease up to 1965, when she disappeared from our clinic follow-up.

In April 1978 (46 years after the initial admission), she came to Memorial Hospital with a history of increase in the number of bowel movements and decrease in the caliber of the stools of four months' duration. On admission, results of the general physical examination were within normal limits except for telangiectasis over the suprapubic region. Rectal examination revealed a barely

* Received for publication April 7, 1980. Address reprint requests to Dr. Attiyeh: 1275 York Avenue,

New York, New York 10021.

From tke Memori.l Sloan-Kettering Cancer Center, New York, New York

palpable mass m the upper rectum. On proctosigmoidoscopy a polypoid tumor of the rectum was seen 10 cm from the anal mar- gin. Biopsy revealed an adenocarcinoma. Pelvic examination showed no abnormality except for radiation changes wkh atrophy of the upper vagina and cervix.

Anterior resection of the rectum, bilateral salpingo- oophorectomy and appendectomy were performed. She did well postoperatively and was discharged two weeks later. There is no evidence of recurrence in over two years of fk)llow-up.

P a t h o l o g y

G r o s s E x a m i n a t i o n : T h e 20-cm s e g m e n t of co lon c o n t a i n e d two separa te a n d d is t inc t ra ised mucosa l masses which were cen t ra l ly necrot ic . T h e first mass was 9 cm f rom the distal m a r g i n of r e sec t ion a n d m e a s u r e d 4 x 3 cm. T h i s was gray-whi te a n d ex- t e n d e d into the muscu la r i s p rop r i a . T h e s econd mass was 5 cm f r o m the distal m a r g i n of r e sec t ion a n d m e a s u r e d 2 • 1.5 x 1 cm with in f i l t r a t ion in to the u n d e r l y i n g muscle . T h e per icol ic fat b e n e a t h b o t h

masses was p u c k e r e d a n d dep re s sed . T h e m u c o s a be- tween the masses was intact , t h i ckened , a n d e d e m a t -

ous. T h e r e m a i n i n g bowel a p p e a r e d n o r m a l . T h e r ight ovary m e a s u r e d 2.5 x 1.5 x 1 cm a n d

consis ted ma in ly of mu l t ip l e smal l cysts. T h e tube ap- pea red e d e m a t o u s . T h e left ovary m e a s u r e d 2.5 x 2 x 2 cm a nd cons is ted of a th in -wa l l ed cyst f i l led with clear fluid. T h e tube was n o r m a l .

T h e a p p e n d i x m e a s u r e d 5 • 0.5 cm a n d ha d only a p i n p o i n t l u m e n .

M i c r o s c o p i c F i n d i n g s : T h e l a rge r mass was an

a d e n o c a r c i n o m a , g rade I I I , which e x t e n d e d t h r o u g h the nmscu la r i s p r o p r i a a n d in to the pericolic fat (Fig. 1). T h e smal le r mass, also an a d e n o c a r c i n o m a g rade I l i , e x t e n d e d deeply in to bu t no t b e y o n d the mus- cularis p ropr ia . T e n l y m p h nodes were f o u n d a n d were free of metastases.

T h e s u b m u c o s a be t w e e n the t u m o r s a n d tha t distal to the second mass was e d e m a t o u s . T h e s u b m u c o s a l

vessels in all s egmen t s showed t h i c k e n i n g a n d sclerosis o f ar ter ies a n d ar ter io les (Fig. 9_). T h e vessels i m m e d i -

ately a d j a c e n t to the two t u m o r s a n d those in the wall be tween the t u m o r s a p p e a r e d to be m o r e severely i n v o l v e d t h a n e l s ewhere . T h e m u s c u l a r i s p r o p r i a

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Dis. Col. & Rect. 574 MARTINS, ET AL. Nov.-Dec. 1980

TABLE 1. Rectal Carcinoma Reported in Patients Having Had Pr;.or Radiotherapy

Reference

Interval from Radiotherapy

N u m b e r of Age (years) to Cancer Patients at Diagnosis (years)

Palmer and Spratt, 1956 a 7 (benign No data 10.7 (average) conditions)

2 (cervical No data No data cancer)

Slaughter and Southwick, 1957 ~ 2 63 3 & 11 No data

Rubin et aL, 1961 ~ 5 49-61 4-12

Smith, 1962 s 3 57-68 19-22

Black and Ackerman, 19657 I 72 16

Quan, 1968 s 2 63 & 84 18 & 21

DeCosse et aL, 1969 ~s 1 71 31

MacMahon and Rowe, 19719 6 44-70 1.2-25

Dickson, 1972 ~5 8 No data No data

Cunn ingham and Wilhoite, 1973 ~~ I 49 17

Castro et al., 1973 ~ 26 47-86 5-30

Qizilbash, 1974 ~-~ 1 61 24

Greenwald et at., 1978 la 1 53 9

O 'Connor et al., 1979 ~4 9 62 & 78 16 & 33

showed areas of fiber separa t ion and fibrosis. T h e pericolic fat conta ined scat tered nests o f lymphoctyes and few foci o f fibrosis and hyperemia .

Both ovaries conta ined simple cysts. T h e r e was very little r emain ing ovar ian tissue, and this was atrophic. T h e fal lopian tubes were normal . T h e append ix was fibrosed. T h e r e were no changes in these s t ructures to suggest a radia t ion effect.

Rev iew of the Literature

Substantial da ta on radia t ion carcinogenesis comes f r o m pa t ien ts g iven r a d i o t h e r a p y for a n k y l o s i n g spondyli t is . 2 R a d i a t i o n - i n d u c e d c a r c i n o m a of the colon and rec tum is a rare p h e n o m e n o n , and the majority of the r epo r t ed cases involve the rec tum.

TABLE 2. lnte~,al Between Radiotherapy and Development of Rectal Carcinoma*

Patients

N um ber Per Cent

<~ 10 years It5 32 11-20 years 20 40 21-30 years 12 24 ~> 31 years 2 4

*Exc ludes patients on w h o m there was insufficient data to classify.

In 1956, Pa lmer and Sprat t 3 reviewed 721 patients who had received radia t ion the rapy for benign pelvic disease and 471 patients who had received radia t ion therapy for carc inoma of the cervix. Seven patients f r o m the first g roup and two f rom the second g roup developed carc inoma of the rectum; this was more than the expec ted incidence. T h e y raised the quest ion that low dose radiat ion therapy was at least partially responsible for the subsequent a p p e a r a n c e of car- c inoma of the rec tum. Since then, n u m e r o u s repor ts have appeared , 4-1a and the most recent r epo r t was published by O ' C o n n o r et al . 14 in 1979.

Rubin e t aL 11 in 1961, f ound four patients with cancer of the colon and one with cancer of the anus who had r ece ived r a d i a t i o n t h e r a p y fo r b e n i g n g y n e c o l o g i c c o n d i t i o n s , m o s t l y e n d o m e t r i a l hyperptasia. Smith, la in 1962, r epo r t ed three cases of carcinoma of the rec tum af ter i r radia t ion for car- c inoma of the cervix and pos tu la ted a cause-and- effect relationship. In 1972, Dickson ts also postula ted a relat ionship between r ad io the rapy for cancer of the cervix and late a p p e a r a n c e o f ca rc inoma o f the rec- tum. C u n n i n g h a m and Wilhoite, 1~ in 1973, r epor ted on a pat ient with a p r ima ry ca rc inoma of the trans- verse colon who had received radia t ion therapy for r e c u r r e n t pe lv ic t u m o r f o l l o w i n g an ab- dominoper inea l resection. In this pat ient the trans- verse colon was fixed in the pelvis and this represents one of the few cases in which rad ia t ion- induced car-

V o l u m e 23 X~.mber 8 RADIATION-INDUCED CANCER 5 7 5

c i n o m a was no t in the r ec tum. Castro et a l . , 11 in 1972,

reviewed the e x p e r i e n c e at Memor ia l Hosp i t a l a n d f o u n d 26 cases of r a d i a t i o n - i n d u c e d c a r c i n o m a of the r e c t u m in p a t i e n t s w i t h a p r i o r h i s t o r y o f r a d i o t h e r a p y for c a r c i n o m a of the cervix.

T h e 68 pa t ien ts in this collected series r a n g e d in age f rom 44 to 86 years, with a m e a n age of 64 years

(Table 1). T h e average in te rva l b e t w e e n r a d i a t i o n the rapy a n d diagnosis of cancer was 15.2 years, with a r a n g e f r o m one year, two m o n t h s to 33 years.

Tab le 2 shows the relative inc idence of la rge-bowel c a n c e r t a b u l a t e d a c c o r d i n g to the i n t e r v a l s ince r ad io the rapy . Most o f the cancers deve loped in the

second decade, and abou t t h r e e - q u a r t e r s o c c u r r e d

wi th in 20 years fol lowing r ad io the rapy . O u r pa t i en t is the only one we know of who devel-

oped two s y n c h r o n o u s lesions in the same s e g m e n t of bowel, wi thin the field of r ad io the rapy , a n d af ter a 46-year in terval .

D i s c u s s i o n

T h e i m m e d i a t e effects o f r ad ia t ion on the colonic mucosa have b e e n s tud ied in deta i l by Wei sb ro t et al. ~r

T h e y pos tu la ted that changes in the in tes t ina l mucosa are no t necessar i ly dose- re la ted no r are they p e r m a -

nen t , as long as the r ad i a t i on dose is kep t u n d e r 3000 rads. Roswit et al. ~s es t imated that at 4500 rads to 5000 rads, 5 per cent of the pa t ients will have u lce ra t ion , h e m o r r h a g e , s t r ic ture , a n d necrosis. Above 6000 rads the compl i ca t ion rate rises sharp ly and is re la ted to vascular and m e s e n c h y m a l changes . H e a l i n g follows with f o r m a t i o n of g r a n u l a t i o n tissue a n d sca r r ing with even tua l stenosis. These changes can occur f rom two m o n t h s u p to 30 years af ter r ad io the rapy . It is usual ly n o t e d that only abou t 5 to 10 per cen t o f the

pa t i en t s i r r a d i a t e d d e v e l o p compl i ca t i ons such as r ad ia t ion procti t is , with d ia r rhea , mucus , b lood, a nd t enesmus , or s y m p t o m s seconda ry to s t r ic ture a n d stenosis. Since large-bowel cancer has b e e n r e p o r t e d to deve lop m a n y years fo l lowing r ad i a t i on therapy , a n d with ou r pa t i en t d e v e l o p i n g cancer af ter 46 years, it becomes impe ra t i ve that l i f e long fol low-up in these pat ients be ca r r i ed out .

T h e rad io therapy ' factors r e g a r d i n g dosages a n d fields used a re l ack ing in mos t of these r e p o r t s . T h e r e f o r e , it is very di f f icul t to draw conc lus ions re- g a r d i n g the s ign i f i cance of the dose in r a d i a t i o n - i n d u c e d colorectal cancers . It is also di f f icul t to de- t e r m i n e the t rue inc idence of colorectal neop l a s ms ar i s ing af ter pelvic i r r ad ia t ion . Only 69 cases have been r e p o r t e d since 1956, i n c l u d i n g o u r own. T h e

average age of pa t ien ts d e v e l o p i n g c a r c i n o m a of the

r e c t u m fol lowing r a d i o t h e r a p y for c a r c i n o m a of the cervix appea r s to be s imi lar to the age of pa t i en t s with s p o n t a n e o u s l a rge-bowel cancers .

T h e overal l survival for pat ients with cancers fol-

l owing r a d i o t h e r a p y has b e e n f o u n d to be m u c h lower, c o m p a r e d to tha t o f the gene ra l g r o u p of pa- t ients with colonic a nd rectal cancer . Cas t ro et a l . , ~

r e p o r t e d only a 20 per cen t f ive-year survival , a low rate when c o m p a r e d with tha t of the g e n e r a l popu la - t ion of colonic a nd rectal cancer . It is d i f f icul t to say if this was due in par t to a de lay in d iagnos is a n d the p resence of m o r e a d v a n c e d lesions.

R e f e r e n c e s

1. Hutchison GB. Late neoplastic changes following medical ir- radiation. Cancer 1976;37:1102-7.

2. Court Brown WM, Doll R. Mortality from cancer and other causes after radiotherapy for ankylosing spondytitis. Br Med J 1965;2:13.97,'-32.

3. Pahner JP, Spratt DW. Peivic carcinoma following irradiation for benign gynecological diseases. Am J Obstet Gynecol 1956;72:497-505.

4. Slaughter DP, Southwick HW. Mucosal carcinomas as a result of irradiation. Arch Surg 1957;74:420-9.

5. Rubin P, Ryplansky A, Dutton A. Incidence of pelvic malig- nancies following irradiation for benign gynecologic condi- tions. AJR 1961;85:503-14.

6. Smith JC. Carcinoma of the rectum following irradiation of carcinoma of the cervix. Proc R Soc Med 1962;55:701-2.

7. Black WC III, Ackerman LV. Carcinoma of the large intestine as late complication of pelvic radiotherapy. Clin Radiol 1965;16:278-81.

8. Quan SH. Fractitial proctitis due to irradiation for cancer of the cervix uteri. Surg Gvnecol Obstet 1968;126:70-4.

9. MacMahon CE, Rowe JW. Rectal reaction following radiation therapy of cervical carcinoma: particular reference to sub- sequent occurrence of rectal carcinoma. Ann Surg 1971;173:264-9.

10. Cunningham MP. Wilhoite R. Radiation-induced carcinoma o. the transverse colon: report of a case. Dis Colon Rectum !973; 16:145-8.

11. Castro EB, Rosen PP, Quan SH. Carcinoma of large intestine in patients irradiated for carcinoma of the cervix and uterus. Cancer 1973;31:45-52.

12. Qizilbash AH. Radiation-induced carcinoma of the rectum: a late complication of pelvic irradiation. Arch Pathol Lab Med 1974;98:i 18-21.

13. Greenwald R, Barkin JS, Hensley GT, Kaiser MH. Cancer of the colon as a late sequel of pel~ic irradiation. Am J Gas- troenterol 1978:69:196-8.

14. O'Connor TW, Rombeau JL, Levine HS, Turnbull RB Jr. Lain development of colorectal cancer subsequent to pelvic ir- radiation. Dis Colon Rectum 1979;22: i23-8.

15. Dickson RJ. Late results of radium treatment of carcinoma of the cervix. C!in Radiol 1972;23:528-35.

16. DeCosse j J, Rhodes RS, Wentz WB, Reagan JW, Dworken HJ, Holden WD. The natural history and management of radia- tion induced injury of the gastrointestinal tract. Ann Surg 1969;170:369-84.

17. Weisbrot IM. Liber AF, Gordon BS. The effects of therapeutic radiation on colonic mucosa. Cancer 1975;36:391-40.

!8. Roswit B Malsky SJ, Reid CB. Severe radiation injuries of the stomach, small intestine, colon and rectum. AJR 1972; l 14:460-75.