acromegalia y cancer

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Acromegaly and Gastrointestinal CancerElaine Ron, PhD ,* Gloria Gridley, MS,* Zdenek Hrubec, S cD,*William Page, PhD,t Sho bhit Arora, and Joseph F. F raum eni Jr , MD*A cohort of 1041 men who were discharged from the hospital with a diagnosis ofacromegaly were examined for subsequent cancer. With a mean follow-up time of8.3 years, an increased rate of cancers of the digestive organs was observed (27cases; standard incidence ratio [SIR],2.0; 95% confidence interval [CI], 1.3 to 2.9).Rates were elevated for cancers of the esophagus (7 cases; SIR, 3.1), stomach (4cases; SIR, 2.51, and colon (1 3 cases; SIR, 3.1). The increased risk of colon cancer inacromegaly is consistent with previous clinical reports and suggests opportunitiesfor etiologic research and early cancer detection. It would seem prudent to alsoevaluate this risk in current research on the use of growth hormone in olderindividuals to increase muscle mass and reduce body fat.Cancer 68:1673-1677,1991.

C R O M E G A L Y is a rare but distinct clinical disease ofA somatic growth and metabolic derangements causedby increased secretion of growth hormone. It usually re-sults from a benign pituitary somatotrophic tumo? thatis often present for 10 to 20 years before diagnosis. Inrecent years, several clinical and case re-ports6- have suggested an increased incidence of coloncancer among subjects with acromegaly. In addition, therehave been case reports of acromegaly associated withmultiple myeloma, bone cancer, and malignant pitu-itary tumor. A follow-up study of 166 patients with ac-romegaly reported an increased number of cancer deathsoverall, but n o instances of colon cancer were found.12To clarify the cancer experience associated with acro-megaly, we evaluated the risks arising in a sizable cohortof patients with acromegaly who were discharged fromall Veterans Administration (VA) hospitals between 1969and 1985.

MethodsA cohort of 12 I 2 patients with acromegaly (diagnosiscode 253.0 in the eighth and ninth revisions of the Inter-national Classification of Diseases) was identified from acomputer-based file: of 4,364,184 persons discharged be-

From the *Epidemiology and Biostatistics Program, National Canc erInstitute. Bethesda, Maryland; an d the ?Medical Follow-up Agency, Na-tional Academy of Sciences, Washington, DC.Address for reprints: Gloria Gridley. MS, National Cancer Institute,EP N 443. Bethesda, M D 20892.Accepted for publication June 24 , 1991.

tween July 1, 1969 and September 30, 1985 from all VAhospitals in the United States. Due to the small numberof female patients, the study population was restricted to1190 male veterans. An additional 149 patients with ac-romegaly were excluded for the following reasons: theydied during their first admission for acromegaly (43 pa-tients); they were older than 100 years of age at first ad-mission ( 1 patient); they had a diagnosis of cancer alongwith or before their first diagnosis of acromegaly in theVA system (8 7 prevalent cancers); or they were notwhite or black (1 8 patients). The final acromegaly cohortconsisted of 1041 male patients (859 were white and 182were black).Statistical analyses used standardized incidence ratios(SIR) (ratios of observed to expected events) in which theexpected numbers of cases of cancers were determined byapplying internally generated incidence rates. These rateswere obtained by following through the VA hospital sys-tem all 3.7 million first admissions among white and blackmale veterans between the ages of 18 and 100 years (ex-cluding, as mentioned above, patients who died or whohad a diagnosis of cancer on their first visit, but not ex-cluding the patient with acromegaly). The expected num-ber of cases of cancer was calculated by applying 5-yearage and 5-year calendar-time and race-specific cancer in-cidence rates from the 3.7 million patients of the VA hos-pitals to the person years at risk of the acromegaly cohort.Person years at risk were computed for each patient fromthe date of first hospital discharge (for the acromegalycohort, the reported date of first discharge with a diagnosisof acromegaly was used) to the date of first admission for

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1674 CANCER ctober 15 1991 Vol. 68TABLE . Selected Characteristics of Men Diagnosed WithAgromegaly and a 1 % Sample o f All Male Veterans Discharged FromVeterans Administration Hospitals, 1969-1985

Characterstic Acromegaly 1% SampleNo. of men identified from admissions

records 1041 37036Person years of follow-up 8619 314141Mean years of follow-up 8.3 8. 5Mean age at study entry (yr) 52.7 50.1Mean age at end of follow -up (yr) 61.0 58.6Mean year of cancer diagnosis 1979.3 1979.7

cancer, the date of death, age of 100years, or the end offollow-up (September 30,1989, whichever occurred first.Patients were assumed to be alive and free of cancer unlessdeath or cancer were documented in the VA hospital re-cord. Exact 95% confidence intervals (CI) for the SIR were

Because the findings for white patients andblack patients were essentially the same, the results werecombined for this report.A 1% systematic sample of the white male patients andthe black male patients of the VA hospitals (37,000 pa-tients) was used as a comparison group for demographiccharacteristics, multiple cancer patterns, and prevalenceof malignant and benign disorders. Statistical significancewas assessed by Fishers exact test.

Hospital records of patients with digestive, pituitary,and brain tumors, as well as a small, randomly selectedsample of patients with acromegaly without cancer, werereviewed to validate diagnoses of cancer and acromegaly.Because the confirmation rate for acromegaly was similarfor patients with and without cancer, we did not adjustthe SIR presented.

ResultsThe 1041 patients with acromegaly had a total of 8,6 19

person years of follow-up (mean follow-up time, 8.3 years)(Table 1). The mean ages at study entry and at the endof follow-up were 52.7 and 61O years, respectively, ap-proximately 2 years older than a 1% sample of patientsadmitted to VA hospitals during this time. For the patientswith acromegaly, the mean calendar years of entry anddiagnosis of cancer were 1976.0 and 1979.3, respectively.

Altogether, 116 patients had a diagnosis of cancer sub-sequent to acromegaly, compared with the expectednumber of 72.3 (SIR, 1.6; 95% CI, 1.3 to 1.9) (Table 2).The increased incidence of cancer was attributable to sig-nificantly increased numbers of cases of cancer of thedigestive organs (SIR, 2.0), pituitary gland (SIR, 135.0),and brain and other nervous system components (SIR,3.6). As shown in Table 3, the increased incidence of can-cer of the digestive organs was mainly caused by an in-crease in the number of casesof cancer of the colon (SIR,3. l), esophagus(SIR, 3.l) , and stomach (SIR, 2.5). Blackpatients and white patients had a similar increased inci-dence of these tumors, although the risk of esophagealcancer was slightly higher among black patients and therisk of colon cancer was greater among white patients.Only one cancer of the rectum was observed, but 2.24cases were expected. Exclusion of patients whose diagnosisof acromegaly was ever coded as uncertain (192 patients)did not reduce the SIR for colon or stomach cancers, butsomewhat decreased the SIR for esophageal cancer (SIR,2.3; CI, 0.6 to 5.9).Table 4 shows that the risk of gastrointestinal cancersdecreased with time after the first admission for acro-

TABLE . Standardized Incidence Ratios of Cancers After the D iagnosis of Acromegaly Compared W ith Those for All Male VeteransDischarged From Veterans Administration Hospitals, 1969-1985Observed ExpectedCancer site cancers cancers SIR 95% CI

A11 cancers 116*.t 72.28 1.6 1.3-1.9Buccal cavity, pharynx (140-9) 7 6.94 1 o 0.4-2.0Digestive organs, peritoneum ( 1 50-9) 27 13.50 2.0 1.3-2.9Respiratory system (160-5) 22 25.41 0.9 0.6-1.3Connective tissue ( I7 1) 2 0.77 2.6 0.4-8.6Bone (170) 0 0.45 0.0 0.0-6.6Melanoma (172) 3 0.90 3 .3 0.7-9.7Male genital and urinary ( 1 85-9) 15 14.50 1 o 0.6-1.7Brain & other nervous system ( I9 1, 192) 5* 1.38 3.6 1.3-8.0Pituitary gland (194.3) 27t 0.20 135.0 91-193Il l defined, unspecified (195, 199) 0 2.10 0.0 0.0- 1.42Multiple myeloma (203) 1 0.82 1.2 0.1-6.0Leukemia (204-208) 2 I .70 1.2 0.2-3.9

Thyroid (193) I 0.23 4.3 0.2-2 1.4

Lymphoma (200-202) 4 1.95 2.0 0.6-4.9

SIR: standardized in cidence ratio; CI: confiden ce interval.* Two of the three hospital charts of brain cancer were reviewed and t Eighteen charts of pituitary cancer were reviewed and all tumorswere found to be benign.both tumors were found to be benign pituitary tumors.


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No . 8 ACROMEGALY N D G A S T R O IN TE S T IN A L . C A N C E R * Ron ef a/ . 1675T A B L E . Standardized Incidence Ratios of Gastrointestinal CancerSubsequent to Acromegaly Diagnosis Compared With Those for AllMale Veterans Discharged From Veteran AdministrationHospitals. 1969-1985

Observed ExpectedCancer site cancers cancers SIR 95 % CIEsophagus ( I 50 ) 7 2.29 3.1 1.3-6.0Stomach ( I 5 I ) 4 I .62 2 .5 0.8-6.0Small intestine ( I 52 ) I 0.16 6.2 0.3-30.8Colon ( 1 53 ) 13 4.2 2 3.1 1.7-5.1Rectum ( 154) 1 2.24 0.4 0.0-2.2Liver ( I 55) 0 0.83 0.0 0.0-3.6Gallbladder ( I 56) 0 0.24 0.0 0.0-17.1Pancreas ( 157) I I .76 0.3 0.0-2.8Other ( I 59 ) 0 0.17 0.0 0.0-17.6

SIR: standardized incidence ratio: CI: confidence interval.

megaly, but remained elevated throughout the study pe-riod. For colon can cer, the largest increase in risk occurredin the 5 years after the diagnosis of acromegaly, but atwofold (although not sign ificant) increase in risk persisteduntil the end of follow-up.

A number of the patients with acromegaly had con-comitant pituitary disorders (20%)or polyglandular syn-dro m e (170). After exclusion of these patients from theanalysis, the SIR for esophageal cancer remained constant(SIR, 3.4; CI, 1.2 to 7.3) but the SI R for total gastroin-testinal cancers (SIR, 1.8;CI, 1. to 2.8) and colon cancer(SIR, 2.7; CI, 1.2 to 5.2) were reduced slightly. The in-crease in stomach cancer incidence disappeared totally(SIR, 0.8; CI,0.0 to 4.4).Significant increases in the num -ber of cases of colon cancer still occurred in the 5 yearsafter the diagnosis of acromegaly (< 1 year SIR, 5.7: 1 to4 year SIR, 4.1 , but only two cases of colon cancer ap-peared after 5 years (SIR, 1.2).

A review of the medical charts was attempted for allpatients with cancers of the gastrointestinal tract, pituitarygland, and brain and other central nervous system com-ponents, as well as a sample of patients without cancer.Of the 89 (59 patients with cancer an d 30 without cancer)charts requested, 66 (74%) were obtained. Of the 2 1 chartsofgastrointe stinal canc er that were reviewed, all cases wereconfirmed, although one stomach cancer was diagnosedbefore the acromegaly. A review of the charts of 20 pi-tuitary and brain cancers showed that all tumors werebenign. O ne tum or coded to the central nervous systemturned out to be a malignant astrocytoma, whereas an-other was a meningioma. Of the 66 charts received, thediagnosis of acromegaly was definite in 50 (76%) cases,probable in 9, and uncertain in 7.To explore whether gastrointestinal cancer and acro-megaly might reflect an underlying syndrome, we ex-amined the frequency of a number of conditions reportedin the acromegaly cohort compared with a I % sample ofwhite male patients and black male patients of the VA

hospitals. N o unusual combination of malignant neo-plasms was observed in the acromegaly coh ort. There wasa significant increase in the number of patients with li-poma in the acromegaly cohort, along with an insignifi-ca nt increase in the nu m be r of colon polyps, benign pros-tatic hypertrophy, and nonmelan oma skin cancer. How-ever, none of these conditions was found to cluster inpatients with acromegaly with cancer overall or withdigestive or colon cancer.

DiscussionTh e results of this study showed a significantly increasedrisk of cancers of the gastrointestinal tract in patients withacromegaly. Th e increase in the inciden ce of colon canceris consistent w ith several clinical report^.^-^ O ur findings,however, indicate that risk may extend to other pa rts ofthe digestive tract, including the esophagus and possibly

the sto mach. Because the epidemiologic profiles for colon,esophageal, and stomach cancer are different, it is unlikelytha t these associations reflect known risk factors. Becausesmoking and drinking are major causes of esophageal~ a n c e r , ' ~t is interesting that the p atients with acromegalyhad a smaller proportion of smoking and alcohol-relateddiagnoses than the entire V A cohort.No malignant or benign disorders were identified asclustering with the gastrointestinal cancers in the p atientswith acromegaly, but an unexpected increase in the in-cidence of lipomas was observed for the larger cohort ofpatients with acromegaly. Whether the lipomas representon e of the cutaneous manifestation of acromegaly (e.g.,fibromas or sebaceous cysts) or a chance finding is unclear.Benign colon polyps and skin tags have been previously

T A R I . I :. Standardized Incidence Ratios of Selected Cancers byYears Since First Admission for Acromegaly Compared WithThose for All Male Veterans Discharged From VeteransAdministration Hospitals, 1969-1985Years since admission for acromegaly

Cancer site < I 1-4 5-9 10+Gastrointestinal ( I 50-9)Observed 5Expected 1 . 5 1SIR 3.39 5 B CI 1.2-7.3

Observed 3Expected 0.45SIR 6.795 % CI 1.7-1 8. IObserved 0Expected 0.25SIR 095 % C I 0- 16.4

Colon ( 153)

Esophagus ( 150)

105.082.0I .O-3.5

5I .553.2I .2-7. I

30.883.4 I0.9-93

84.4 1I .80.8-3.43I .432. I0.5-5.730.773.901.0-10.6

42.45I .60.5-3.920.792.50.4-8.4I0.33.230.2-15.9

SIR: standardiicd incidence ratio:CI: confidence interval.


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1676 CANCER ctober 15 199 1 Vol. 68reported in association with a ~r om eg al y, ~ut th e increasein the number of colon polyps that we observed was notstatistically significant. Despite case reports in the litera-ture linking acromegaly with pituitary cancer,'' bonecancer," and multiple myeloma,' we foun d no increasedincidence of these malignant conditions. Furthermo re, noincrease in the incidence of leukemia was seen despiterecent reports of childhood leukem ia after the use of syn-thetic growth hormone to treat growth retardation. 6In a review of th e charts of digestive cancers, we foun dno evidence of neuroendocrine or carcinoid tumors, whichcause acromegaly in approximately I % of patients. ''.I8We also investigated the timing of acromegaly a nd diges-tive cancer. Of the 2 I charts of cancer reviewed, 20 wereincident cases that followed the diagnosis of acromegaly.However, the proportion of gastrointestinal cancersamong the 87 patients with acromegaly with prevalentcancer who were excluded from the m ain an alysis was 3times higher (18% versus 6% ) han that found among the1% samp le of prevalent cancers. Previous clinical reportshave also noted an increased incidence of digestive cancersbefore the diagnosis of a~ ror ne ga ly. ' .~ ,~ecause acromeg-aly usually cannot be diagnosed for 10 to 20 years,' it ispossible that excess produc tion of growth horm one exertsan effect on the gastrointestinal tract even before th e di-agnosis of acromegaly, although one might speculate thatboth conditions are manifestations o f an underlying syn-drom e that needs to be fully defined.For approximately 80% of patients with acromegaly,excess secretion of growth hormone is accompanied byan increase in other co mpou nds such a s prolactin or gly-coprotein.2 However, th e ex clusion of 20% of our cohortwith a complex pituitary dysfunction did not substantiallyaffect the increased incidence of gastrointestinal cancers,except for stomach cancer.This computer-based data set of more than 4 millionhospitalized veterans offers the oppo rtunity t o study com -paratively rare diseases such as acromegaly and their se-quelae. The resource provides a relatively easy methodfor generating an d testing hypotheses related to etiology,natural history, and therap y. In this analysis the increasedincidence of esophageal and stomach cancers was notpreviously reported with acromegaly an d should prom ptfurther study.This comp uter resource has its limitations. Hospitalizedmale veterans are not representative of United Statesmales in general, an d the assump tion that all ofthese menwere alive and free of cancer u ntil 1985 was not verified.These problems were handled by using internally gener-ated cancer rates. These internal rates have been comparedwith United States population-based cancer incidencerates of the Surveillance, Epidemiology, and End Resultsprogram19 and were found to be generally lower (as ex-pected because of underascertainm ent of cancers that are

diagnosed outside the VA hospital sy stem). The increasedincidences that we found for stomach and colon cancerscould be partially d ue to the lower comparison rates, ifno patients with acromegaly had stom ach or colon cancersdiagnosed outside the V A system. However, the internalVA rates are 40% higher than the Surveillance, Epide-miology, and End Results program rates for buccal, la-ryngeal, and esophageal cancers, so the increased inci-dence o f esophageal cancer in our study would have beeneven greater if we had used Surveillance, Epidemiology,and End Results program rates.

A review of the m edical records disclosed other prob-lems. Although we tried to obtain 89 medical char ts, only66 (74%) could be reviewed. Although the charts con-firmed the increased incidence of gastrointestinal cancers,we found that the reported increased incidences of pitu-itary and brain cancers actually resulted from m iscodingof benign pituitary tumors.The threefold increase in the incidence rate of coloncancer, which persisted over time, provides epidemiologicevidence tha t patients with acromegaly ar e part of a high-risk group tha t should undergo periodic screening, similarto patients with a personal or family history of colorectalcancer or polyps. Our findings are of special interest inview of recent reports indicating that growth hormonemay be useful in increasing muscle mass and reducingb o d y fat in older Before such treatmentis accepted as stand ard, it would seem pruden t to considerthe potential risks pointed out by Hennine and Conda-mine.22 Although the mechanism linking acromegaly toan increased incidence of colon and perhaps other tumorsis uncertain, further studies are needed to clarify th e roleof som atomed ins (insulin-like growth factors) that mediatethe effects of growth horm one and appear t o have mito-genic or proli ferative effects on colonic e p i t h e l i ~ m . * ~ - ~ ~

REFERENCESI . Karpf DB, Braunstein G D . Current concepts in acromegaly: Etiol-ogy. diagnosis, and treatment. Compr Ther 1986: 12:22-30.2. Laws ER Jr , Scheithauer BW, Carpenter S. Randall RV. AbboudCF. The pathogenesis of acromegaly. J Neurosurg 1985; 63:35-38.3. Klein I , Parveen G, Gavaler JS. Vanthiel DH. Colonic polyps inpatients with acromegaly. An n Inlern Med 1982; 97:27-30.4. Pines A , Rozen P, Ron E, Gilat T. Gastrointestinal tumors in ac-romegalic patients. Am J Gastroenlerol 1985: 80:266-269.5. Brunner JE, Johnson C C, Zafar S, Peterson EL, Brunner JF . Mel-linger RC. Colon cancer and polyps in acromegaly: Increased risk as-sociated with family history of colon cancer . Clin Endocrinol 1990: 32:6. ltuarte EA, Petrini J , Hershman J M. Acromegaly and colon cancer.7. Ritter MM , Richter WO, Schw andt P. Acromegaly and colon can-8 . Ziel FH , Peters AL. Acrom egaly and gastrointestinal adenocarci-9. H a g E, Asplund K. Holm J . Acromegaly and multiple myeloma.10. Ratner RE. Hare JW. Association of acromegaly and chondro-

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No . 8 ACROMEGALY N D GASTROINTESTINALANCE R * Ron et d. 1677I I . Gordon DA, Hill FM, Ezrin C. Acromegaly: A review of 100cases. Can Med Assoc J 1962; 87:1106-1109.12. Bengtsson B, Eden S, Ernest I, Oden A, Sjogren B. Epidemiologyand lon g-term survival in acromeg aly.Acta Med Scand 1988: 223:327-335.13. Liddell FDK. Sim ple exact analysis of the standardized mortalityratio. J Epidemiol Commun ity Health 1984; 38:85-88.14. Miettinen 0s . Standardization of risk ratios. Am J Epidemiol15. Day NE, Muno z N. Esop hagus. In: Schottenfeld D, Fraumeni JFJr, eds. Cancer Epidemiology and Prevention. Philadelphia:W B aunders.16. Watanabe S, Yamaguchi N, Tsunematsu Y, Komiyama A. Riskfactors for leukemia occurrence among growth hormone users. Jpn J

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acromegalia y cancer

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