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acromegaly is 2 to 3 times the expectedrate, mostly due to cardiorespiratorydisease, hypertension, diabetes mellitus,and cancer.2 The excess mortality rate inacromegalics due to cancer was shownin a large multicenter retrospectivestudy of 1362 patients in which therewas a 2.4 fold increase in the mortalityrate of colorectal cancer, and an almosttwo-fold increase in breast cancer.2 3

CASE REPORTSPatient AIn this 61 year old man presenting withtypical acromegalic features (Figure 1) alarge carcinoma of the descending colonwith infiltration of the psoas muscle andthe lateral abdominal wall was diag-nosed. Colonoscopy revealed severalmore colonic polyps. In his medical his-tory there was a right-sided pyelolitho-tomy due to nephrolithiasis.Subsequently, he suffered from recur-rent kidney stones, which once weretreated by extracorporeal shock wavelithotripsy (ESWL). Seven years ago hewas operated on for bilateral carpaltunnel syndrome. A large euthyroidmultinodular goitre was removed oneyear ago. Because of low back pain, amagnetic resonance imaging (MRI) ofthe lumbar spine was performed andshowed an infiltrating process withinthe psoas muscle eventually leading tothe diagnosis of colorectal cancer. Left-

Acromegaly and Colorectal CancerBeat R. Buehler, MD*

Christoph M. Henzen, MD†

Maria Teresa de Zulueta, MD‡

Rudolf A. Joss, MD§

*Department of Oncology, Kantonsspital Luzern, Luzern, Switzerland†Consultant Endocrinology, Kantonsspital Luzern, Luzern, Switzerland‡Department of Oncology, Kantonsspital Luzern, Luzern, Switzerland§Department of Internal Medicine, Kantonsspital Luzern, Luzern, Switzerland

KEY WORDS: acromegaly, colon cancer, IGF-1, pituitary adenoma

ABSTRACTAcromegaly results from an excessivesecretion of growth hormone. Recently,a 2.4 fold increased mortality rate of col-orectal cancer was shown in acromegal-ics. Over a 2-year period 186 new casesof colorectal cancer were diagnosed atour institution, and acromegaly wasdiagnosed in 3 (males) of 182 patients,yielding a prevalence of 1.6%. Clinicalpresentation and diagnosis ofacromegaly are discussed.

INTRODUCTIONAcromegaly results from a prolonged,excessive secretion of growth hormone(GH), mostly due to a GH-secretingadenoma of the anterior pituitary gland.Rarely acromegaly is caused by exces-sive secretion of growth hormone-releasing hormone (GHRH) byhypothalamic tumors, ectopic GHRHsecretion by nonendocrine tumors suchas carcinoid tumors or small-cell lungcancers, and ectopic secretion of GH bynonendocrine tumors. The incidence ofacromegaly is 3 to 4 cases per millionpersons, and the prevalence is 50 to 70cases per million, equally occurring inboth sexes.1

The mortality rate of patients with

sided hemicolectomy was performedand chemotherapy with capecitabinewas initiated.

An MRI of the skull demonstrated amacroadenoma of the pituitary gland.The assessment of the pituitary functionrevealed elevated IGF-1 and prolactinlevels, a normal thyroid axis, hypogo-nadotrophic hypogonadism, and a par-tial insufficiency of thehypothalamic-pituitary-adrenal axis(Table 1).

Patient BThis 56-year-old male patient wasreferred to our outpatient clinicsbecause of poorly controlled diabetesmellitus type 2, that was diagnosed 6years ago and complicated by diabeticretinopathy and nephropathy. There wasa history of non-metastatic colorectalcancer 4 years ago that was treated byright-sided hemicolectomy only. Oncolonoscopic routine follow up 3 yearsago, several colonic polyps wereremoved. Two years ago obstructivesleep apnea was diagnosed and treat-

ment with nasal continuous positive air-way pressure (CPAP) was installed suc-cessfully.

On physical examination he present-ed with typical acromegalic features(Table 2), and the diagnosis was con-firmed by excessively high levels of IGF-1 and growth hormone, and amacroadenoma of the pituitary glandwas demonstrated by MRI. The labora-tory findings are summarised in Table 1.

Patient CIn this 68-year-old male patient,colonoscopy was performed because ofrefractory iron deficiency anemia.Colorectal cancer with liver metastasisand peritoneal carcinosis was diagnosed.Right-sided hemicolectomy was per-formed and chemotherapy with irinote-can, 5-fluorouracil, and calciumfolinatewas initiated. In his medical history uvu-loplasty was performed 11 years ago,due to obstructive sleep apnea syn-drome.On admission the patient reported thathis feet had been growing over the past

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Table 1. Laboratory Findings*

Patient A Patient B Patient C

IGF-1 (5.7-41.6 nmol/L) 96.4 139.1 84.5

TSH (0.2-4.2 mU/L) 1.6 0.85 1.5

fT4 (12-22 pmol/L) 13.8 11.8 16.1

Cortisol, stimulated (>550 nmol/L) 520 223 519

LH (1.7-8.6 U/L) 3.4 1.1 2.8

Free testosterone (19-66 pmol/L) 11.5 10.2 24.3

Prolactin (2-16 µg/L) 23.6 284 8.9*TSH indicates thyroid-stimulating hormone; fT4, free thyroxine (T4); and LH, luteinizing hormone.

Table 2. Acromegalic features

Patient A Patient B Patient C

Acral growth + + +

Hyperhydrosis + + +

Pathologic glucose tolerance - + -

Carpal tunnel syndrome + - -

Systemic hypertension + + +

Goitre + + -

Sleep apnea syndrome + + +

Loss of libido + - -

few years and that his rings had to beenlarged. The acromegalic features andthe laboratory findings are summarisedin Table 1. The MRI showed macroade-noma of the pituitary gland with a diam-eter of 1.5 cm.

DISCUSSIONOver a 2-year period 182 new cases ofcolorectal cancer have been diagnosedat our institution. The diagnosis ofacromegaly has been made in 3 of them,suggesting a prevalence of 1.6%. In all 3patients the diagnosis of colorectal can-cer preceeded the diagnosis ofacromegaly by one to 4 years. However,the typical acromegalic features and themedical history suggested the diagnosisof acromegaly much earlier. Our find-ings concur with several studies thatdemonstrated an increased risk of col-orectal cancer in acromegalics.2 4 Theprevalence of 1.6% of acromegaly in ourpatients with colon cancer is consider-ably high, compared to the prevalence offamilial adenomatous polyposis of lessthan 1% and to the prevalence of hered-itary non-polyposis colorectal cancer of

5 to 8%.5

Excessive secretion of growth hor-mone (GH) leads to the increased syn-thesis of IGF-1, which is mainlyproduced in the liver and, by the activa-tion of a tyrosine kinase, and leads tothe phosphorylation of several intracel-lular structures ultimately resulting inthe stimulation of cell growth, proteinsynthesis, cell proliferation, cell differen-tiation, and inhibition of apoptosis.6

The initial step in adenoma forma-tion is an increased cell proliferationthat also entails the risk of oncogenicmutation. Actively dividing cells arefound at the bottom of the coloniccrypts and move toward the luminal sur-face, where they eventually becomeapoptotic. In acromegaly the increasedproliferation of the colonic epitheliumcorrelates to the serum IGF-1 level, sup-porting the clinical findings that adeno-matous colonic polyps occur morefrequently in patients with acromegalyand behave more aggressively withaccelerated progression to malignancy.3

Moreover, IGF-1 reduces apoptosis byimpairing the function of antiapoptoticproteins and by inadequate induction oftranscription.7

Recently, screening guidelines forcolorectal cancer and polyps in patientswith acromegaly have been published.Following these guidelines regularcolonoscopic screening should beoffered to these patients from the age of40 years. The interval of colonoscopyshould depend on the original findingsand the activity of the acromegaly, forinstance, patients with an adenoma or anelevated IGF-1 level should be screenedat 3-year intervals. In patients with nega-tive findings screening at 5-year inter-vals should be offered. Totalcolonoscopy is required but may beassociated with technical difficulties. Inthese patients the colon is of increasedlength and circumference with a morethan doubled transit time. Therefore

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Figure 1. Typical acromegalic changes inpatient A.

twice the standard bowel preparation isrequired.8

Considering the surprisingly highproportion of acromegaly in our patientswith colorectal cancer, physicians shouldbe aware of acromegalic features in thepatients with colorectal cancer, and IGF-1 levels should be measured if there is ahigh index of suspicion.

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3. Jenkins PJ, Besser M. Acromegaly and can-

cer: A problem. J Clin Endocrinol Metab.2001;86:2935-2941.

4. Ron E, Gridley G, Hrubec Z, Page W, AroraS, Fraumeni JF. Acromegaly and gastrointesti-nal cancer. Cancer. 1991;68:1673-1677.

5. Lynch HT, de la Chapelle A. Genetic suscep-tibility to non-polyposis colorectal cancer. JMed Genet. 1999;36:801-818.

6. LeRoith D, Werner H, Beitner-Johnson D,Roberts CT. Molecular and cellular aspects ofthe insulin-like growth factor 1 receptor.Endocr Rev. 1995;16:143-163.

7. Remacle-Bonnet MM, Garrouste FL, HellerS, André F, Marvaldi JL, Pommier GJ.Insulin-like growth factor 1 protects coloncancer cells from death factor-induced apop-tosis by potentiating tumor necrosis factor α-induced mitogen-activated protein kinase andnuclear factor κβ signaling pathways. CancerRes. 2000;60:2007-2017.

8. Jenkins PJ, Fairclough PD. Screening guide-lines for colorectal cancer and polyps inpatients with acromegaly. Gut. 2002;51(suppl5):V13-14.

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