hereditary proximal colonic cancer

Hereditary Proximal Colonic Cancer *

PATRICK m'. LYNCH, J.D., HENRY W. LYNCH, M.D., RANDALL E. HARRIS, PH.D.

From the Department of Preve~li~e Medicine~Public Health, Creighton University, Omaha, Nebraska

HEREDITARY COLONrC CANCER differs in several significant respects from the sporadic variety. For instance, the hereditary variety is characterized by early onset and an excess of multiple primary cancer.~2 It is also frequently associated with gastrointestinal polyps (as in the several familial polyposis coli syndromes), as well as with cancers at other specific anatomic sites (such as tlm endometrium in the cancer family syndrome), t5 In light of such distinctions, might it not be reasonable to anticipate other, heretofore unexpected, differences between hereditary colonic cancer and the estimated 80 to 90 per cent that occur sporadically'? One possible discriminant that may be worthy of attention is the specific anatomic location of cancer in the colon.

The purpose of this report is to docu- ment fully the site distribution of colonic cancers in ten cancer-prone families. These families manifest hereditary syndromes that d.iffer from familial adenomatous polyposis coli (FPC) in that none of the patients wieh histologically verified colonic cancer have evidenced multiple polyposis of the colon.

Material and Methods

Medical genetic studies have been con- ducted on ten families prone to adeno-

* Received for publication March 16, 1977. Supported in part by The National Cancer In-

stitute, Grant No. 5 RO1 CA18408-02, and The- Fraternal Order of Eagles.

Address reprint requests to Dr. Henry T. Lynch: Chairman, Department of Preventive Medicine, Creighton University School of Medicine, 2500 California Street, Omaha, Nebraska 68178.

Dis. CoI. & Rect. Nov.-Dec. 1977

carcinoma of the colon. Nine of these families show findings consistent with the cancer family syndrome, which is characterized by an excess of adenocarinomas, predom- inantly of the colon and endometrium, an increase in multiple primary cancer, early age of onset, and an autosomal dominant mode of inheritance, t4, is The tenth family (the one that initially aroused our attention in terms of possible unusual site distribution of colonic cancer) is characterized by site-specific colonic cancer early age of onset, excess of multiple primary colonic cancers, and an atttosomal dominant mode of inheritance, ta Ahhough no member of any of these families showed cutaneous or colonic manifestations of any of the FPC syndromes, a majority of those relatives hav- ing colonic Cancer did have one or more solitary' adenomatous polyps. 16

The probands and close relatives from each family were personally interviewed, when possible, in order to obtain detailed genealogy and medical history, with par- ticular attention given to cancer occurrences. Questionnaires were then circulated to all available relatives. A signed permis- sion form allowed us to secure primary medical documents from physicians, hos- phals and pathology laboratories. In most cases this enabled ascertainment of the specific anatomic area of the colon affected with cancer. Occasionally, death certificates were sufficiently detailed to yield the sites 0{ colonic cancer occurrences when verifica- tion through primary sources could not be obtained.

The basic data resource analyzed com- prised I l l cases of anatomic site-docu-

661 Volume 20 Number 8

669 L Y N C H , E T A L . Dis. Col. & Reef. Nov.-Dec. 1977

TAttLE 1. Proximal ColorTic Cance~" Freq~encies Among Ten Kindreds

First Occurrence at Proximal Colon

P e r N Number Cent

Family l 6 6 100 Family 33 27 II 40.7 Family 51 6 3 50 Family 120 7 5 71.4 Family 196 I 1 4 36.4 Family 200 7 6 85.7 Families 30, 35, 115 8 7 87.5 Family 198" 26 21 80.8

TOTAL 98 63 64.3

* Site-specific colonic cancer. All others are consistent with the cancer family syndrome.

mented colonic cancer f rom the ten subject kindreds. Consistent with known differences in physiology and vascular supply, the proximal colon is defined to include the cecum, ascending colon, hepatic flexure, and transverse colon; while the distal colon includes the splenic flexure, descending colon, sigmoid and rectosigmoid colon, and rectum.

Frequencies of proximal and distal co- Ionic cancers were est imated for each family and for the ten families pooled. T h e frequency of proximal colonic cancer in our resource was compared with popula t ion expectations using a chi-square test. s

R e s u l t s

Table I shows the frequency dis t r ibut ion of cancer in the proximal colon for the ten families studied. In de te rmin ing these frequencies, only 98 patients whose first cancer occurred in the colon are considered. T h e frequency of proximal colonic cancer in the subject families differs significantly (P < .001) f rom the colorectal cancer dis t r ibut ion expected in the general popula t ion, where the frequency of proximal colonic cancer is only 15 to 35. 22, 2s

A m o n g the cases studied, there are many examples of mul t iple p r imary cancer. Venn diagrams i l lustrat ing tile frequencies o[ m,.dtiple p r imary ma l ignan t neoplasms o[ tile proximal and distal colon in males, and of the endomet r ium, proximal colon, and distal colon in females are presented in Figures 1 and g, respectively.

T h u s far, 28 males have had cancer at the proximal colon wi thou t a subsequent pr imary mal ignancy in the distal colon (Fig. 1). T h e same n u m b e r has been affected at the distal co!on wi thou t a later pr imary in the proximal colon. O[ the 13 males who have had carc inoma at b o t h

sites, nine were first affected at the proximal colon and two had synchronously occur r ing cancers of the r ight and left colon. Thus , of the 59 males with colonic cancer, :34 (57.6 per cent) had carcinomas of the p rox imal colon occurr ing exclusive of, p r io r to, or synchronously with, distal colonic cancer.

T h e clinical onset o[ p roximal colonic cancer has typically occurred at an earlier age than distal colonic cancer in males affected only once (.89.9 versus 48.8 years, P < .025) while males with p r imary lesions of both colonic sites show an in termediate age of f rs t onset (43.4 years). Overall , the first onset of colorectal cancer in these 59 men (43.9 years) occ~n'red more than 90 years earlier than one would expect based on popula t ion figures. 2s

Relative frequencies of p rox imal and distal colonic cancers a m o n g females of the ten families are i l lustrated in Figure 2. Since nine of the ten families s tudied manifest the cancer family syndrome, cases involving endometr ia l carc inoma are included. If one considers only the por t ion of the Venn d iagram involving colonic cancer, these results indicate a higher frequency of proximal colonic cancer in

women than was observed a m o n g men. Specifically, of the 52 females who had co-

Ionic cancer at some time, 88 (73.1 per cent) had proximal colonic cancer occur r ing ex-

Volume 20 HEREDITARY PROXIMAL COLONIC CANCER 6 6 ~ Number 8

Proximal On ly

N = 23 (39%)

39.9 y r s

Prox imal & Distal

N = 13 (22%)

43.4 yrs

Distal On ly

N = 23 (39%)

48.3 yrs

Site-sequence N

Proximal only 23 Distal only 23 Proximal followed by distal 9 Distal followed by proximal 2 Synchronous proximal and distal 2

59

Fro. 1, Frequencies of proximal colonic cancer and distal colonic cancer intersection, and age of onset for each in males.

Mean age @ onset

39.9 48.3 44.4 48.5 33.5 43.9

(including the rectum), their

clusive of, p r i o r to, or synchronous ly with, d is ta l co lonic cancer.

T h e m e a n ages at first onset of endo- me t r i a l a n d p r o x i m a l co lonic cancers in females were s imi la r (45.0 and 47.6 years). I n contras t , females wi th d is ta l colonic cancers exclusive of the o the r two sites showed a s ignif icant ly (P < .01) l a te r onset

(58.0 years). T h i s difference in ages of onset be tween e n d o m e t r i a l / p r o x i m a l colonic cancer and d i s ta l colonic cancer in women is of the same o r d e r of m a g n i t u d e as the difference in ages of onset be tween p r o x i m a l and dis ta l co lon ic cancers in m e n (Figures 1 and 2). Overa l l , the mean onset of c o l o r e c t a l / e n d o m e t r i a l cancer in w o m e n

664 LYNCH, ET AL. Dis. Col. &Reet. Nov.-Dec. 1977

E ndometrium Only

N = 39 (42.4%)

45.0 yrs

N = 4 (4.4%)

45.2 yrs

PIE

N = 9 (9.9%)

44.1 yrs

P/D/E

N = 4 (4.4%)

P/D

N = 4 (4.4%)

51.75 yrs

Proximal Colon O n l y

N = 24 (26.4%)

47.6 yrs

Distal Colon Only

N = 7 (7.7%)

58.9 yrs

Site-sequence N Mean age @ onset

Proximal only 24 47.6 Distal only 7 58.9 Endometrium only 39 45.0 ProximaI--Endometrium 4 (two were synchronous) 45.0 Endometrium-Proximal 5 43.4 Proximal-Distal 2 (one was synchronous) 57.5 Distal-Proximal 2 4 6 . 0

Endometrium-Distal 2 50.0 DistaI-Endometrium 2 (one was synchronous) 40.5 ProximaI-Endometrium-Distal 2 (in both, the proximal colon 46.5

and endometrium cancers were synchronous)

Endometrium-ProximaI-Distal Endometrium-Distal--Proximal

1 55.0 1 55.0

91 47.2

FIG. 2. Frequencies of proximal colonic cancer, distal colonic cancer (including the rectum), and endo- metrial cancer, their intersection, and age of onset for each in females.

Volume 20 H E R E D I T A R Y P R O X I M A L C O L O N I C C A N C E R 665 Number 8

TABLE 2. Chances of Second Primary Cancer and Death (Exclusive of Second Primary Cancer) Within Five Years o/First Cancer

Risk (Per Cent) + SD

Sit of First Second Primary Cancer Occurrence Sex Cancer

Death without Second Primary Cancer

Proximal colon Male 17.5 +_ 7.9 42.9 ~ 9.4 Female 46.2 -+- 9.8 30.0 ___ 10.2 Male/female 32.7 • 6.7 37.5 + 7.0

Distal colon Male 30.8 ___ 12.8 66.7 -4- 10.3 Female 20.0 ___ 17.9 70.0 ___ 14.5 Male/female 27.8 -+- 10.6 67.7 + 8.4

Endometrium Female 6.0-+- 4.1 34.1 • 7.2

is somewha t la te r than the onset of co lonic cancer in men of the ten famil ies (47.2 versus 43.4 years, P < .05).

T a b l e 2 presents es t imates of the r isk for subsequen t p r i m a r y cancer a n d the chance of dea th wi th classif icat ion for the site of first cancer occurrence. D e a t h rates are ad- ju s t ed for poss ible effects of second pri- m a r y cancer by de l e t ing years at r isk subsequen t to thei r d i agnoses ) Consequent ly , these rates are p r e s u m e d to reflect m o r t a l i t y due to metas tas is or o the r effects of the in i t i a l tumor . These figures ind ica te a sig- n i f icant ly g rea te r chance of dea th due to the in i t i a l t u m o r a m o n g i n d i v i d u a l s wi th d is ta l colonic cancer than those wi th p r o x i m a l colonic cancer (68 versus 38 per cent, P < .01). T h e co r r e spond ing risk for dea th in women wi th a first e n d o m e t r i a l cancer is s imi lar to that for i nd iv idua l s wi th an in i t i a l p r o x i m a l colonic cancer. T h u s , based on these figures, pa t i en t s first diagnosed wi th p r o x i m a l co lonic cancer or endomet r i ca l cancer show be t t e r five-year survival t han pa t i en t s first d i agnosed wi th d is ta l colonic cancer.

T h e chances of d e v e l o p i n g a second primary cancer a p p e a r to differ somewhat for females, d e p e n d i n g u p o n the site of the first lesion ( T a b l e 2). Specifically, females first affected at the p r o x i m a l or d is ta l co lon

have a s ignif icant ly g rea te r chance of de- v e l o p m e n t of a second p r i m a r y cancer than females first affected at the e n d o m e t r i u m . N e i t he r sex showed a s ignif icant difference in risk for subsequen t p r i m a r i e s as a func- t ion of the colonic site first affected, at least d u r i n g the in i t i a l five years af ter d iagnos is

and t r ea tment . T h e overa l l f r equency of male co lonic

cancer pa t i en t s wi th m u l t i p l e p r i m a r y ma- l ignancies is s imi la r to tha t a m o n g females wi th colonic a n d / o r e n d o m e t r i a l cancers. Of the 59 m e n wi th colonic cancers, 24 (40.7 per cent) h a d at least one e x t r a p r i m a r y ma l ignancy of e i the r the colon or a n o t h e r ana tomic site. Of 91 w o m e n wi th colonic or e n d o m e t r i a l cancers, 35 (38.5 pe r cent) had at least one o t h e r p r i m a r y cancer. T h e s e f requencies are m u c h h igher than the r e p o r t e d p o p u l a t i o n figures, wh ich range f rom 2 to 5 p e r cent. 19 D e t a i l e d dis-

cussion of r isk for m u l t i p l e p r imar i e s in fami l ia l cancer has been p resen ted else- where. 14

Discussion

C a r c i n o m a of the co lon in the genera l p o p u l a t i o n shows a p r e d i l e c t i o n for the left colon (65 to 85 per cent) w i th the greates t n u m b e r occu r r ing in the d is ta l p o r t i o n of the descend ing colon, the r ec tos igmoid

666 L Y N C H , E T AL. D{s. CoL & Rect. Nov.-Dec. 1977

colon, and the rectum22, 2s Environmental factors, part icularly diet, have been sug- gested to be of pr imary etiologic significance in causing the high frequency of distal versus proximal colonic cancers.2 The pre- dilection to cancer at the distal colon and rectum also occurs in FPC. Bussey a found only 16.3 per cent of 286 patients with FPC from the St. Mark 's Hospital series to have cancer occur at the proximal colon. Gardner 's syndrome and generalized gastrointestinal polyposis also appear to have similar (predominant ly distal) site distribu- tions of colonic cancer, a l though this has not been as well documented.

The frequency of proximal colonic cancers (64.3 per cent) observed in the ten kindreds studied differs significantly from that expected in the general populat ion of the Uni ted States (P < .001). Even more striking is the disparity between this esti- mate and the frequency of proximal colonic cancer in FPC, with which these kindreds share a genetic predisposition to colonic cancer, though the component of mult ipl e adenomatous polyps is lacking.

Our results also reveal significantly better five-year survival for patients first diagnosed with proximal colonic cancer, as opposed to distal colonic cancer. In light of the inac- cessibility of the proximal colon to routine screening procedures, compared with the distal colon, the earlier age at diagnosis and enhanced survival of proximal colonic cancer patients is somewhat surprising. While further research will obviously be required tO clarify the meaning of these observations, we suggest that the phenomena may be characteristic of the colonic cancer syndrome in the families under study.

During the past two decades a number of kindreds that show clustering of colorectal cancer in the absence of FPC have been reported.X, 6-11, 17, 18. 20, 21, 23, 24, 2~ A genetic

factor has been persistently a l leged (typically autosomal dominant) despite dogged

criticism by some that such cancer dusters

were chance occurrences or the result o[ shared environmental or dietary influences.

Table 3 presents relevant abstracted por- tions of" these reports, describing the colonic cancers by site distribution and age of onset. The results regarding site distr ibution are strikingly similar to our own. In 11 reports whose results we have pooled, 51 of 76 colorectal cancer patients (67.1 per cent) for whom adequate descriptions are given were first affected at the proximal colon. While the difference between the mean ages at onset (40.4 years for p roximal colon and 39.9 years for distal colon) is not as great as in the series we present, each figure is still significantly lower than popula t ion expectations. 2s Since the authors cited gen- erally did not note the high frequency of proximal colonic cancer in their reported kindreds, it is not likely that their ascer- ta inment of the kindreds was biased by the presence of such cases.

Support for a possible integrat ing relationship between the observed early onset of colonic cancer and excess occurrence in the right colon in cancer-prone families can be seen in populat ion studies. For example, the T h i r d Nat ional Cancer Survey's incidence figures published in 1975, 25 reveal that more than half (51.5 per cent) of colonic cancer patients whose cancers were diagnosed before the age of 40 years were affected at the proximal colon. Although the popula t ion affected in this age range was quite small (1.9 per cent of all cases in the series), the frequency of proximal colonic involvement was higher than for any older age group.

T h e site distr ibution of colonic cancer as a function of age in FPC patients reveals a pat tern that is inversely related to that observed in our series, and may be incon- sistent with frequencies f rom the T h i r d Nat ional Cancer Survey as well. Among patients comprising the St. Mark's Hospital series, Bussey 3 found the mean age at onset

of proximal colonic cancers to be 46.2 years,

Volume 20 H E R E D I T A R Y P R O X I M A L C O L O N I C C A N C E R 667 Number 8

TABLE 3. Reported Kindreds Manifesting Site-Specific Colonic Cancer in the Abse~tce of Familial Polyposis of the Colon, wi th Site Distr ibut ion and Age o[ Onset o] Colorectal Cancer

Proximal Colon Distal Colon (Including Rectum)

Number Mean Age at Number Mean Age at Reference (Per Cent) Onset (Years) (Pet- Cent) Onset (Years)

Lovett (1976) n (England)

Miller, et al. (1976) TM (U.S.)

Mathis (1962) ~z (Switzerland)

Dunstone and Knag~ (1972)" (England)

Fielding (1969) ~ (England)

Kluge (1964) ~~ (Norway)

Stemper, et al. (1975) "-'~ (U.S.) Peltokallio and Peltokatlio

(1966) ~~ (Finland)

Giidzie and Petrodc (1968):" C~'ugoslavia)

Savage (1956):' (England)

Bieler and Helm (1965)~ (Switzerland)

TOTAL

4 66.7)

3 75.0) 5* 71.4)

13 56.5) 4 S0.0)

_~ 40.0)

5 (100)

5t

6 ( 8 5 . 7 )

2 (66.7)

2 (100)

51 (~7.l)

40.25 2 (33.3) 41 35.6 1 (25.0) 35

38 2* (28.6) 39.5

- lO (43.5) -

40.25 1 (20.0) 42 48 3 (60.0) 41.3

37.6 0 ( 0 ) - -

29.2 4j- 33.5

47.2 1 (14.3) 26

50.5 1 (33.3) 76

51.0 0 ( 0 ) -

40.4 25 (32.9) 39.9

Wootf, et al. (1955), -~" Smith (1970), ~-3 and Heinzelmann (1964) '~ have reported similar pedigrees; however. colonic cancer sites and onset were not cited.

* Both figures include one case of synchronous tumors of proximal and distal colon at age 37 years. "t Both figures include one case of synchronous tumm's of proximal and distal colon (diagnosed 1.5

years apart). Three small families ha~e been pooled and have been included in this report, primarily because of the early ages o1~ onset observed in siblings.

compared with 38.7 years for carcinomas

of the distal colon and rectum. Crit ical analysis of family histories of pa-

tients whose cancers were diagnosed before the age of 40 years with cancers at the prox-

imal .colon (exclusive of FPC) could help subs tant ia te or refute the genetic association

observed in this study. Obviously, the ascer- t a i n m e n t of s trong family histories o[ co-

lonic cancer through such p robands would

demons t ra te that those proximal colonic

cancer cases that occur at the "younger" tail of the age d i s t r ibu t ion curve are

largely a t t r ibu tab le to genetic factors. I n this regard, i n t e rna t i ona l studies of the site

distr ib-t t ions of colonic cancers have shown

that those countr ies with the lowest overall

rates of colonic cancer have relatively higher

frequencies of cancers of the proximal large intest ine. 4 Since it is general ly held that

very low cancer rates reflect the background

genetic rate for the disease .type, such ob-

servations are in accord wi th this hypothesis. From the s t a n d p o i n t of cancer control , it

is obvious that , the usual rel iance u p o n proc- tosigmoidoscopy as a cancer-screening de-

vice will no t suffice when m a n a g i n g families of the type described herein. Rather ,

these f indings i l lus t ra te the impor t ance of ba r ium-enema examina t ion , with par t icu la r

a t t en t ion to u of the p rox imal colon as par t of the cancer survei l lance

program for these high-risk patients. Colon- oscopy would also be of immense value in

such diagnost ic eva[ua, tion. Finally, studies of the carcinogenesis of colonic cancer will

profit th rough greater a t t e n t i o n to biochem-

ical, physiologic, microbiologic, and anatomic factors in the occurrence of p rox imal

colonic cancer in th.ese kindreds .

6 ~ 8 LYNCH, ET AL. Dis. Col &Reef. Nov.-Dee. 1977

S u m m a r y

T e n f a m i l i e s p r o n e to c a n c e r of .tlle c o l o n

( in t he a b s e n c e of f a m i l i a l p o l y p o s i s col i )

h a v e b e e n i n v e s t i g a t e d . A s i g n i f i c a n t l y

g r e a t e r f r e q u e n c y of c a r c i n o m a s o f t h e p r o x -

i m a l c o l o n was e v i d e n t r e l a t i v e to n o n -

f a m i l i a l c o l o n i c c ance r s (55 p e r c e n t v e r s u s

less t h a n 35 p e r cent , P < .001). M o r e o v e r ,

f a m i l y m e m b e r s w i t h p r o x i m a l c o l o n i c

c ance r s e x p e r i e n c e d s i g n i f i c a n t l y e n h a n c e d

s u r v i v a l , c o m p a r e d w i t h f a m i l y m e m b e r s

w i t h d i s t a l c o l o n i c o r r e c t a l cancers . F i n d -

ings c o n s i s t e n t w i t h a g e n e t i c p r e d i s p o s i t i o n

i n c l u d e d ea r ly m e a n age a t o n s e t (45 years )

a n d a h i g h f r e q u e n c y (40 p e r cen t ) of m u l -

t i p l e p r i m a r y c ance r s i n t h e p a t i e n t s

s t u d i e d . T h e r e s u l t s a re i n a c c o r d w i t h re-

p o r t e d f i n d i n g s i n 11 s i m i l a r k i n d r e d s f r o m

.the l i t e r a t u r e , a n d s t r o n g l y sugges t t h e ex-

i s t ence of a h e r i t a b l e v a r i e t y of c o l o n i c

c a n c e r i n w h i c h t he p r o x i m a l c o l o n is a t

p a r t i c u l a r l y h i g h r isk. E x t r a o r d i n a r y ea r ly

d i a g n o s t i c m e a s u r e s , i n c l u d i n g c o l o n o s c o p y ,

a re i n d i c a t e d for m e m b e r s of s u c h f ami l i e s .

R e f e r e n c e s

1. Bieler V, Heim V: Doppelkarzinom bei Gesch- wistern Familiiire Haufung von Genital-- und In testinalkarzinomen. Schweiz Med Wochenschr 95:496, 1965

2. Blot WJ, Fraumeni JF, McKay FW: Geo~aphic patterns of large bowel cancer in the United States. J Natl Cancer Inst 57:1225, 1976

3. Bussey HJ: Familial Polyposis Coli; Family Studies, Histopathology, Differential Diag- nosis, and Results of Treatment. Baltimore, The Johns Hopkins University Press, 1975, 104 pp

4. Correa P, Haenszel W: Comparative interna- tional incidence and mortality. In Schotten- feld D (ed): Cancer Epidemiology and Pre- vention: Current Concepts. Springfield, Ill., Charles C Thomas, 1975, 386 pp

5. Colton T: Statistics in Medicine. Boston, Little Brown & Company, 1974, 372 pp

6. Dunstone GH, Knaggs TW: Familial cancer of the colon and rectum. J Med Genet 9:451, 1972

7. Fielding JF: Familial non-polypotic carcinoma of colon. Br Med J 1:512, 1969

8. Glidzic V, Petrovic G: Observations sur le carac- t~re h&rditaire des cancers du colon. Bull Cancer (Paris) 55:511, 1968

9. Heinzelman F: Ober eine Krebsfamilie: Ein Beitrag zur Frage der Heredit~it des Colon- karzinoms. Heh' Chir Acta 31:316, 1964

1O. Kluge T: Familial cancer of the colon. Acta Chir Scand 127:392, 1964

11. Lovett E: Familial cancer of the gastrointestinal tract. Br J Surg 63:19, 1976

12. Lynch HT: Cancer Genetics. Springfield, Ill., Charles C Thomas, 1976, 639 pp

13. Lynch HT, Harris RE, Bardawil WA, et al: Management of hereditary site-specific colon cancer. Arch Surg 112:170, 1977

14. Lynch HT, Harris RE, Lynch PM, et ah Role of heredity in muhiple primary cancer (in press)

15. Lynch HT, Shaw MW, Magnuson CxN, et al: Hereditary factors in cancer: Study of two large midwestern kindreds. Arch Intern Med 117:206, 1966

16. Lynch PM, Lynch t-IT, Harris RE, et al: Herit- able colon cancer and solitary adenomatous polyps (in press)

17. Mathis M: Famili~ires Colonkarzinom: Ein Stammbaum arts dem Kanton Aargau. Schweiz Med Wochenschr 92:1673, 1962

18. Miller MS, Costanza ME, Li FP, et ah Familial colon cancer. Cancer 37:946, 1976

19. Momtel CG: Incidence and significance of multiple primary malignant neoplasms. Ann NY Acad Sd 114:886, 1964

20. Peltokallio P, Pelt0kallio V: Relationship of familial factors to carcinoma of the colon. Dis Colon Rectum 9:367, 1966

21. Savage D: A family history of uterine and gastro-intestinal cancer. Br Med J 2:341, 1956

'22. Smiddy FG, Goligher JC: Results of surgery in treatment of cancer of the large intestine. Br Med J 1:793, 1957

23. Smith WG: The cancer-family syndrome and heritable solitary colonic polyps. Dis Colon Rectum 13:362, 1970

24. Stemper T J, Kent TH, Summers RW: Juvenile polyposis and gastrointestinal carcinoma: A study of a kindred. Ann Intern Med 83:639, 1975

25. Thi rd National Cancer Survey: Incidence data. National Cancer Insti tute Monograph 41. Prepared by Biometry Branch, Division of Cancer Cause and Prevention, National Can- cer Institute. DHEW Pub No (NIH) 75-787, Bethesda, Maryland, March 1975, 454 pp

26. Woolf CM, Richards RC, Gardner EJ: Occa- sional discrete polyps of the colon and rectum showing an inheri ted tendency in a kindred. Cancer 8:403, 1955

hereditary proximal colonic cancer

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