Cancer Incidence in Patients With Acromegaly: A Cohort Study and Meta-Analysis of the Literature
J Clin Endocrinol Metab, June
Cancer Incidence in Patients With Acromegaly: A Cohort Study and Meta-Analysis of the Literature
Jakob Dal 0
Michelle Z. Leisner 1
Kasper Hermansen 2
D o?ra Ko? rmendin e? Farkas 1
Mads Bengtsen 0
Caroline Kistorp 3
Eigil H. Nielsen 4
Marianne Andersen 5
Ulla Feldt-Rasmussen 6
Olaf M. Dekkers 1 7
Henrik Toft S?rensen 1
Jens Otto Lunde J?rgensen 0
0 Department of Endocrinology and Internal Medicine, Aarhus University Hospital , 8000 Aarhus , Denmark
1 Department of Clinical Epidemiology, Aarhus University Hospital , 8200 Aarhus , Denmark
2 Department of Medicine , Sydvestjysk Sygehus, 6700 Esbjerg , Denmark
3 Department of Internal Medicine, Copenhagen University Hospital , 2730 Herlev , Denmark
4 Department of Endocrinology, Aalborg University Hospital , 9000 Aalborg , Denmark
5 Department of Endocrinology, Odense University Hospital , 5000 Odense , Denmark
6 Department of Endocrinology, National University Hospital Rigshospitalet , 2100 Copenhagen , Denmark
7 Department of Clinical Epidemiolgy and Metabolism, Leiden University Medical Centre , 2333 ZA Leiden , The Netherlands
Context: Acromegaly has been associated with increased risk of cancer morbidity and mortality, but research findings remain conflicting and population-based data are scarce. We therefore examined whether patients with acromegaly are at higher risk of cancer. Design: A nationwide cohort study (1978 to 2010) including 529 acromegaly cases was performed. Incident cancer diagnoses and mortality were compared with national rates estimating standardized incidence ratios (SIRs). A meta-analysis of cancer SIRs from 23 studies (including the present one) was performed. Results: The cohort study identified 81 cases of cancer after exclusion of cases diagnosed within the first year [SIR 1.1; 95% confidence interval (CI), 0.9 to 1.4]. SIRs were 1.4 (95% CI, 0.7 to 2.6) for colorectal cancer, 1.1 (95% CI, 0.5 to 2.1) for breast cancer, and 1.4 (95% CI, 0.6 to 2.6) for prostate cancer. Whereas overall mortality was elevated in acromegaly (SIR 1.3; 95% CI, 1.1 to 1.6), cancerspecific mortality was not. The meta-analysis yielded an SIR of overall cancer of 1.5 (95% CI, 1.2 to 1.8). SIRs were elevated for colorectal cancer, 2.6 (95% CI, 1.7 to 4.0); thyroid cancer, 9.2 (95% CI, 4.2 to 19.9); breast cancer, 1.6 (1.1 to 2.3); gastric cancer, 2.0 (95% CI, 1.4 to 2.9); and urinary tract cancer, 1.5 (95% CI, 1.0 to 2.3). In general, cancer SIR was higher in single-center studies and in studies with ,10 cancer cases. Conclusions: Cancer incidence rates were slightly elevated in patients with acromegaly in our study, and this finding was supported by the meta-analysis of 23 studies, although it also suggested the presence of selection bias in some earlier studies. (J Clin Endocrinol Metab 103: 2182-2188, 2018)
Aof growth hormone (GH), usually from a pituitary
cromegaly is a rare disease caused by hypersecretion
adenoma, with an annual incidence of 4 cases per million
individuals and a prevalence of 85 per million individuals
). Continuous hypersecretion of GH induces the hepatic
and peripheral production of insulinlike growth factor 1
(IGF-1). Both GH and IGF-1 are implicated in cancer
promotion, based on experimental and epidemiological
), and acromegaly has been linked with elevated
risk of cancer, both in general and with thyroid and
*Shared first authorship.
Abbreviations: CI, confidence interval; DCR, Danish Cancer Registry; GH, growth hormone;
ICD, International Classification of Diseases; IGF-1, insulinlike growth factor 1; SA,
somatostatin analog; SD, standard deviation; SIR, standardized incidence ratio.
colorectal cancer in particular (
). However, not all
studies have found this association (
acromegaly has been associated consistently with increased
), it remains uncertain whether death from
cancer is also increased.
A major reason for the inconsistent epidemiological
data on cancer risk is differences in study design, and the
need for population-based studies persists (
databases provide an opportunity to conduct a study with
virtually complete follow-up, using valid population-based
data, rather than at a single-center or multicenter level.
We therefore conducted a nationwide population-based
cohort study to examine the long-term risk of cancer
incidence and mortality in patients with acromegaly. We also
conducted a meta-analysis of the literature on cancer
standardized incidence ratios (SIRs) in acromegaly.
Materials and Methods
Population-based Danish cohort study
The source population comprised the cumulative
population of Denmark, with ~8.1 million inhabitants during the
period 1991 to 2010. The Danish National Health Service
provides tax-supported health care, with universal free access
to hospital-based and primary medical care, including care for
acromegaly. To ensure unambiguous data linkage, we used the
Danish Civil Registration System, which assigns a unique
personal identifier, the civil personal registration number, to
each Danish resident at time of birth or upon immigration. We
identified members of the acromegaly cohort from the Danish
National Patient Registry, which contains records on all
hospitalizations since 1 January 1977, together with primary
and secondary diagnoses coded according to the International
Classification of Diseases (ICD) (
). The Eighth Revision
(ICD-8) was used until 1993 and then replaced by the Tenth
Revision (ICD-10). To identify cancers among patients with
acromegaly, we used the Danish Cancer Registry (DCR),
which has recorded all cases of incident cancer in Denmark
since 1943 (
). ICD-10 codes are used in the DCR?s current
format. Finally, we identified causes of mortality from the
Danish Registry of Causes of Death, which contains individual
digitalized classification of causes of death in accordance with
World Health Organization rules and, since 1994, by ICD-10
We validated each individual acromegaly diagnosis as
previously described (
). Briefly, hospital records and charts for each
possible patient with acromegaly were reviewed by an expert
endocrinologist. All patients with validated acromegaly diagnoses
who resided in Denmark between 1978 and 2010 were eligible for
our cohort study. Those who received a cancer diagnosis before
their acromegaly diagnosis were excluded from the study.
Disease-specific clinical variables were retrieved from patient
records, including pituitary tumor size (maximal diameter),
serum GH and IGF-1 levels (at diagnosis, 1 year after diagnosis,
and 2 years after diagnosis), and acromegaly treatment modality
[surgery only, somatostatin analog (SA) treatment with and
without surgery, and irradiation with and without other
treatment]. These biochemical and treatment-related data were
available only for patients diagnosed after 1991.
All incident cancers were identified in the DCR between the
index date (date of acromegaly diagnosis) and 30 November
2013. Cancer types of specific interest were colorectal cancer,
breast cancer, lung cancer, thyroid cancer, gastric cancer, and
prostate cancer. Cancer of any type and colorectal, breast, and
lung cancers were classified further as localized or nonlocalized.
Aggregated groupings were created for urinary tract cancers
and hematological cancers. Causes of death were categorized as
cancer, cardiovascular disease, other conditions not including
cancer, and unknown. Each patient was followed from the date
of the acromegaly diagnosis until first occurrence of a cancer
diagnosis, death, emigration, or end of the study period (30
November 2013), whichever came first.
SIRs were used to compare the number of cancers observed
in patients with acromegaly with the expected number,
calculated from national cancer incidence rates obtained from the
). Patients with incident acromegaly were not
excluded from the general population before calculation of SIRs.
For all SIRs, 95% confidence intervals (CIs) were also
calculated. All estimates were standardized to the general
population by age, sex, and calendar period (5-year intervals). To
reduce the risk of surveillance bias, cancer cases identified
within the first year after the acromegaly diagnosis were not
included in the primary analysis. However, in a sensitivity
analysis, we included cancer cases diagnosed within the first
year after the acromegaly diagnosis.
To explore whether variation in clinical variables (pituitary
tumor size and GH and IGF-1 levels before and 1 to 2 years after
diagnosis) predicted the outcomes of cancer incidence, cancer
mortality, and overall mortality, we used a Cox proportional
hazards model to calculate hazard ratios with 95% CIs. All
analyses were performed in SAS version 9.4 (SAS Institute Inc.,
To identify published studies on the risk of cancer in
acromegaly, we searched the PubMed and Scopus databases in
January 2018 for publications in English, Danish, Dutch,
Norwegian, and Swedish (languages spoken by the authors).
The search string focused on acromegaly AND overall cancer or
specific cancers. Studies were chosen that provided data
permitting calculation of SIRs for cancer in patients with
acromegaly compared with a control population. Initial selection of
studies by title and abstract was performed by one reviewer
(M.B.). Selected studies were retrieved for closer scrutiny by
three reviewers (M.B., J.O.L.J., and O.M.D.), and
disagreements were resolved by consensus.
SIRs were computed by dividing the number of observed
events by the number of expected events in the selected studies.
The meta-analysis of SIRs used a random-effects model (
and heterogeneity was assessed via x2 tests and I2 statistics (
Funnel plots were used when $10 studies were available for
analysis. All statistical analyses were performed in
Comprehensive Meta-Analysis version 3.3 (Biostat, Englewood, NJ).
Five hundred twenty-nine patients with acromegaly
(51% male) were included in the cohort study. The mean
age [standard deviation (SD)] at acromegaly diagnosis
was 47.4 (14.2) years, and of these, 25% (n = 132)
received a diagnosis of acromegaly between 35 and
44 years of age and 13% (n = 67) after the age of 65
(Table 1). Regarding prevalence of comorbid conditions
at the time of diagnosis, 8.3% presented with diabetes,
7.8% with hypertension, and 3.0% with chronic
obstructive pulmonary disease. As treatments, 46%
received SA treatment, 34% underwent surgery only, and
17% underwent radiation therapy (with and
without additional treatment). In total, 90 patients with
acromegaly (17%) were diagnosed with cancer during
the follow-up period. The mean follow-up time was
13.6 (8.3) years, and the mean age at cancer diagnosis
was 63.5 (12.5) years.
Within the first year after the diagnosis of acromegaly,
nine patients were diagnosed with cancer and excluded
from subsequent SIR analysis to reduce surveillance bias.
The SIR of all cancers was 1.1 (95% CI, 0.9 to 1.4)
(Table 2). Inclusion of the nine cases diagnosed within the
first year after an acromegaly diagnosis increased the
overall cancer risk marginally [SIR 1.2 (95% CI, 1.0 to
1.5)] (Supplemental Table 1). The SIR for colorectal
cancer was 1.4 (95% CI, 0.7 to 2.6), slightly elevated. The
estimates as regards associations between pituitary tumor
size and biochemical biomarkers (GH and IGF-1 levels)
and cancer risk were imprecise, with wide CIs, and
therefore are not reported.
During the follow-up period, 141 patients died, of
whom 46 were ,55 years old. Cancer was the cause of
death for 16% (n = 22) and cardiovascular disease for
30% (n = 42). Mortality risk in acromegaly was 1.4 times
higher than in the general population (95% CI, 1.1 to
1.6); mortality risk after exclusion of the first year was
1.3 (95% CI, 1.1 to 1.6) (l). Mortality was elevated in the
small group of patients who were not treated for
acromegaly (n = 16) (data not shown). No difference in
mortality was detected when different treatment groups
were compared (data not shown).
Meta-analysis and literature review
Our initial search yielded 5365 publications, of which
5333 were excluded based on title or abstract.
Thirtytwo publications were retrieved for more detailed
evaluation, of which 21 publications were eligible, and
scrutiny of these identified 1 additional publication
4, 5, 14?33
). Only 1 of these studies (23) excluded
cancer cases diagnosed within the first year. Data from
the current study including cancer cases detected within
the first year after acromegaly diagnosis were included
in the meta-analysis. Thus, 23 studies with a total
of 9677 patients were included in the meta-analysis
(Table 3). The mean weighted age at time of
acromegaly diagnosis was 47.9 years, and the mean weighted
follow-up time was 10.1 years (range: 4.5 to 15.0 years).
The mean weighted age at time of cancer diagnosis was
62.0 years. The sex distribution was approximately
equal (male/female ratio 53:47).
In general, SIRs for overall cancer were similar
across studies, with 12 of 14 (
14?16, 18, 23, 24, 26,
27, 29, 30, 33
) reporting a SIR .1.0. The pooled SIR
for overall cancer in the meta-analysis was 1.5 (95%
CI, 1.2 to 1.8) (Fig. 1), with considerable heterogeneity
(I2 = 84%). The funnel plot was not clearly
asymmetric, and the Egger test was nonsignificant (P = 0.36)
(Supplemental Fig. 1), providing no clear evidence of
publication bias. Stratification based on study design
revealed a higher SIR for cancer in single-center studies
(pooled SIR = 3.2; 95% CI, 2.4 to 4.1) (16, 24, 26, 27,
Overall incidence of cancer in patients with acromegaly
SIR [95% CI]
30) compared with both multicenter studies (pooled
SIR = 1.2; 95% CI, 0.9 to 1.5) (
4, 5, 14, 15, 29, 33
population-based studies (pooled SIR = 1.4; 95% CI,
1.2 to 1.6) (
) (Table 4). When a partial overlap of
patients between the current study and Baris et al. (
became evident, we calculated the pooled SIR
excluding the Baris article, which did not influence the
pooled SIR (1.5; 95% CI, 1.2 to 1.9); similarly,
excluding the current study did not change the estimate
(SIR 1.5; 95% CI, 1.2 to 1.9). Exclusion of studies
reporting ,10 expected cases (
16, 24, 26, 27, 30, 33
changed the pooled SIR to 1.2 (95% CI, 1.0 to 1.5).
Stratification based on sex in 9 studies (
14, 15, 23,
24, 26, 27, 29, 30, 33
) yielded similar SIRs for men and
women: 1.5 (95% CI, 1.3 to 1.7) and 1.9 (95% CI, 1.4
to 2.5). Stratification based on study period (calendar
year) did not clearly affect the outcome (Table 4).
Stratified by cancer type, elevated risks were shown for
colorectal cancer (pooled SIR = 2.6; 95% CI, 1.7 to 4.0),
thyroid cancer (pooled SIR = 9.2; 95% CI, 4.2 to 19.9),
gastric cancer (pooled SIR = 2.0; 95% CI, 1.4 to 2.9),
breast cancer (pooled SIR = 1.6; 95% CI, 1.1 to 2.3),
and urinary tract cancer (pooled SIR = 1.5; 95% CI, 1.0
to 2.3). SIRs for other cancers were as follows: lung
cancer (0.8; 95% CI, 0.5 to 1.2), prostate cancer (1.2;
95% CI, 0.8 to 1.9), and hematological cancers (1.3;
95% CI, 0.8 to 2.3).
The increase in colorectal cancer incidence was
reported in 13 out of 14 studies (
4, 14, 16, 18?20, 22, 23,
25, 28, 29, 31
) (Fig. 2), without evidence of funnel plot
asymmetry (Egger test result; P = 0.67) (Supplemental
Fig. 2). The colorectal cancer incidence rates among
single-center studies (pooled SIR = 7.3; 95% CI, 2.6 to
16, 19, 20, 28
), multicenter studies (pooled SIR =
2.0; 95% CI, 1.3 to 3.1) (
4, 5, 14, 22, 25, 29, 31
population-based studies (pooled SIR = 2.2; 95% CI, 1.7
to 3.0) (
) were all elevated.
No major difference was observed in thyroid cancer
incidence between multicenter studies (pooled SIR = 7.6;
95% CI, 2.4 to 24.5) (
4, 5, 14, 17, 21, 29
population-based studies (pooled SIR = 8.2; 95% CI, 3.6
to 18.7) (
); only two single-center studies (
evaluated thyroid cancer incidence (SIR = 20.3; 95% CI,
1.2 to 332.0).
The findings from our population-based study and the
meta-analysis suggest that overall cancer risk is slightly
elevated in patients with acromegaly compared with the
Data from laboratory, animal, and human studies
strongly indicate that GH and IGF-1 are closely
associated with cancer development and progression (
Moreover, circulating IGF-1 levels within the upper
normal range have been associated with elevated risk of
breast, prostate, colorectal, and lung cancers in the
general population (
Our study has several strengths stemming from its
use of population-based nationwide data with virtually
complete follow-up. This design reduces the risk of
selection bias. This advantage is reinforced by free health
care access in Denmark, implying that care is equally and
openly accessible. Our study also excluded cancer cases
detected within the first year after an acromegaly
diagnosis, to minimize the risk of surveillance bias.
Moreover, the diagnosis of each patient in our study was
validated, as previously reported (
The results of the meta-analysis added support to
our finding of increased cancer incidence among
patients with acromegaly but also revealed potential
sources of bias. The elevated overall cancer incidence
risk in the meta-analysis was more pronounced in
single-center studies (Table 4) and was lower when we
excluded studies with ,10 cases, suggesting the
presence of selection or sample bias (
). It is possible that
the patient population in single centers represents
difficult cases with previous treatment failure and
increased comorbidity. It is also possible that the
comparator group in single-center studies derived from
screening programs, which poses the risk of healthy
user bias. This possibility is of particular relevance in
the context of colorectal cancer and breast cancer, for
which screening programs are often available. The
risks of surveillance bias or diagnostic workup bias
are also present. As mentioned, we reduced this risk
by excluding cancer cases detected within the first
year after the acromegaly diagnosis. Indeed, 9 out of
Dal et al.
Terzolo et al.14
Wolinski et al.16
Petroff et al.5
Kauppinen et al.18
Kurimoto et al.19
Matano et al.20
Terzolo et al.22
Baris et al.23
Renehan et al.25
Orme et al.4
Colao et al.28
Ron et al.29
Brunner et al.31
90 cancer cases were diagnosed within the first year in
our study. When we included these 9 cancer cases in a
sensitivity analysis, risk estimates increased for overall
cancer, colorectal cancer, and lung cancer
(Supplemental Table 1). This approach was used only in one
additional study (
), which may have introduced bias
and overestimation of cancer risks in the remaining
studies. Surveillance bias is of particular concern for
thyroid cancer, because thyroid volume is enlarged in
acromegaly, which may lead to more frequent use of
ultrasonography and subsequent overdiagnosis of
occult thyroid cancer (
), and endocrinologists are
generally more likely to focus on endocrine diseases. In
our own study, only a single case of thyroid cancer was
diagnosed (Table 2), even when the first year of
followup after acromegaly diagnosis was included
(Supplemental Fig. 1).
A possible association between colorectal cancer risk
and acromegaly has attracted particular interest and
controversy, as has been extensively reviewed (
number of biological mechanisms have been proposed in
addition to the fact that the bowel in patients with
acromegaly is ~15% to 20% longer, which by itself has
been estimated to increase bowel cancer risk by 15% to
). The meta-analysis confirmed an elevated risk of
colorectal cancer, which was more pronounced in
Taken together, our cohort study and the
metaanalysis suggest only a slightly elevated overall risk of
cancer in patients with acromegaly. This finding does not
call into question nonhuman data on the carcinogenic
effects of GH and IGF-1, nor should it deter patients or
health care professionals from adhering to current cancer
surveillance guidelines. However, our findings agree with
the previously drawn conclusion that excessive GH in
humans is not a serious cancer risk (
Financial Support: This study was supported by unrestricted
research grants from Pfizer and Ipsen to J.O.L.J. J.O.L.J. and
U.F.-R. have received grants and lecture fees from Pfizer, Ipsen,
Correspondence and Reprint Requests: Jens Otto Lunde
J?rgensen, MD, DMSc, Department of Endocrinology and
Internal Medicine, Aarhus University Hospital, Norrebrogade
44, 8000 Aarhus C, Denmark. E-mail: .
Disclosure Summary: The authors have nothing to
Dal et al
1. Dal J , Feldt-Rasmussen U , Andersen M , Kristensen LO , Laurberg P , Pedersen L , Dekkers OM , S?rensen HT , J?rgensen JO . Acromegaly incidence, prevalence, complications and long-term prognosis: a nationwide cohort study . Eur J Endocrinol . 2016 ; 175 ( 3 ): 181 - 190 .
2. Renehan AG , Zwahlen M , Minder C , O'Dwyer ST , Shalet SM , Egger M . Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis . Lancet . 2004 ; 363 ( 9418 ): 1346 - 1353 .
3. Renehan AG , O'Connell J , O'Halloran D , Shanahan F , Potten CS , O'Dwyer ST , Shalet SM . Acromegaly and colorectal cancer: a comprehensive review of epidemiology, biological mechanisms, and clinical implications . Horm Metab Res . 2003 ; 35 ( 11 -12): 712 - 725 .
4. Orme SM , McNally RJ , Cartwright RA , Belchetz PE ; United Kingdom Acromegaly Study Group. Mortality and cancer incidence in acromegaly: a retrospective cohort study . J Clin Endocrinol Metab . 1998 ; 83 ( 8 ): 2730 - 2734 .
5. Petroff D , T o?njes A , Grussendorf M , Droste M , Dimopoulou C , Stalla G , Jaursch-Hancke C , Mai M , Schopohl J , Sch o?fl C. The incidence of cancer among acromegaly patients: results from the German acromegaly registry . J Clin Endocrinol Metab . 2015 ; 100 ( 10 ): 3894 - 3902 .
6. Dekkers OM , Biermasz NR , Pereira AM , Romijn JA , Vandenbroucke JP . Mortality in acromegaly: a metaanalysis . J Clin Endocrinol Metab . 2008 ; 93 ( 1 ): 61 - 67 .
7. Holdaway IM , Bolland MJ , Gamble GD . A meta-analysis of the effect of lowering serum levels of GH and IGF-I on mortality in acromegaly . Eur J Endocrinol . 2008 ; 159 ( 2 ): 89 - 95 .
8. Renehan AG , Shalet SM . Acromegaly and colorectal cancer: risk assessment should be based on population-based studies . J Clin Endocrinol Metab . 2002 ; 87 ( 4 ): 1909 , author reply 1909 .
9. Lynge E , Sandegaard JL , Rebolj M. The Danish National Patient Register. Scand J Public Health . 2011 ; 39 ( 7 suppl) : 30 - 33 .
10. Gjerstorff ML . The Danish Cancer Registry . Scand J Public Health . 2011 ; 39 ( 7 suppl) : 42 - 45 .
11. Helweg-Larsen K. The Danish Register of Causes of Death . Scand J Public Health . 2011 ; 39 ( 7 suppl) 26 - 29 .
12. DerSimonian R , Laird N. Meta-analysis in clinical trials . Control Clin Trials . 1986 ; 7 ( 3 ): 177 - 188 .
13. Higgins JP , Thompson SG . Quantifying heterogeneity in a metaanalysis . Stat Med . 2002 ; 21 ( 11 ): 1539 - 1558 .
14. Terzolo M , Reimondo G , Berchialla P , Ferrante E , Malchiodi E , De Marinis L , Pivonello R , Grottoli S , Losa M , Cannavo S , Ferone D , Montini M , Bondanelli M , De Menis E , Martini C , Puxeddu E , Velardo A , Peri A , Faustini-Fustini M , Tita P , Pigliaru F , Peraga G , Borretta G , Scaroni C , Bazzoni N , Bianchi A , Berton A , Serban AL , Baldelli R , Fatti LM , Colao A , Arosio M ; Italian Study Group of Acromegaly. Acromegaly is associated with increased cancer risk: a survey in Italy . Endocr Relat Cancer . 2017 ; 24 ( 9 ): 495 - 504 .
15. Maione L , Brue T , Beckers A , Delemer B , Petrossians P , BorsonChazot F , Chabre O , Fran?ois P , Bertherat J , Cortet-Rudelli C , Chanson P ; French Acromegaly Registry Group. Changes in the management and comorbidities of acromegaly over three decades: the French Acromegaly Registry . Eur J Endocrinol . 2017 ; 176 ( 5 ): 645 - 655 .
16. Wolinski K , Stangierski A , Dyrda K , Nowicka K , Pelka M , Iqbal A , Car A , Lazizi M , Bednarek N , Czarnywojtek A , Gurgul E , Ruchala M . Risk of malignant neoplasms in acromegaly: a case-control study . J Endocrinol Invest . 2017 ; 40 ( 3 ): 319 - 322 .
17. dos Santos MC , Nascimento GC , Nascimento AG , Carvalho VC , Lopes MH , Montenegro R , Montenegro R Jr, Vilar L , Albano MF , Alves AR , Parente CV , dos Santos Faria M. Thyroid cancer in patients with acromegaly: a case-control study . Pituitary . 2013 ; 16 ( 1 ): 109 - 114 .
18. Kauppinen-M a?kelin R , Sane T , V a?lim a?ki MJ , Markkanen H , Niskanen L , Ebeling T , Jaatinen P , Juonala M , Pukkala E ; Finnish Acromegaly Study Group. Increased cancer incidence in acromegaly-a nationwide survey . Clin Endocrinol (Oxf) . 2010 ; 72 ( 2 ): 278 - 279 .
19. Kurimoto M , Fukuda I , Hizuka N , Takano K. The prevalence of benign and malignant tumors in patients with acromegaly at a single institute . Endocr J . 2008 ; 55 ( 1 ): 67 - 71 .
20. Matano Y , Okada T , Suzuki A , Yoneda T , Takeda Y , Mabuchi H . Risk of colorectal neoplasm in patients with acromegaly and its relationship with serum growth hormone levels . Am J Gastroenterol . 2005 ; 100 ( 5 ): 1154 - 1160 .
21. Tita P , Ambrosio MR , Scollo C , Carta A , Gangemi P , Bondanelli M , Vigneri R , degli Uberti EC , Pezzino V . High prevalence of differentiated thyroid carcinoma in acromegaly . Clin Endocrinol (Oxf) . 2005 ; 63 ( 2 ): 161 - 167 .
22. Terzolo M , Reimondo G , Gasperi M , Cozzi R , Pivonello R , Vitale G , Scillitani A , Attanasio R , Cecconi E , Daffara F , Gaia E , Martino E , Lombardi G , Angeli A , Colao A . Colonoscopic screening and follow-up in patients with acromegaly: a multicenter study in Italy . J Clin Endocrinol Metab . 2005 ; 90 ( 1 ): 84 - 90 .
23. Baris D , Gridley G , Ron E , Weiderpass E , Mellemkjaer L , Ekbom A , Olsen JH , Baron JA , Fraumeni JF Jr. Acromegaly and cancer risk: a cohort study in Sweden and Denmark . Cancer Causes Control . 2002 ; 13 ( 5 ): 395 - 400 .
24. Higuchi Y , Saeki N , Iuchi T , Uchino Y , Tatsuno I , Uchida D , Tanaka T , Noguchi Y , Nakamura S , Yasuda T , Yamaura A , Sunami K , Oka Y , Uozumi A . Incidence of malignant tumors in patients with acromegaly . Endocr J . 2000 ; 47 ( Suppl ): S57 - S60 .
25. Renehan AG , Bhaskar P , Painter JE , O'Dwyer ST , Haboubi N , Varma J , Ball SG , Shalet SM . The prevalence and characteristics of colorectal neoplasia in acromegaly . J Clin Endocrinol Metab . 2000 ; 85 ( 9 ): 3417 - 3424 .
26. Popovic V , Damjanovic S , Micic D , Nesovic M , Djurovic M , Petakov M , Obradovic S , Zoric S , Simic M , Penezic Z , Marinkovic J ; The Pituitary Study Group. Increased incidence of neoplasia in patients with pituitary adenomas . Clin Endocrinol (Oxf) . 1998 ; 49 ( 4 ): 441 - 445 .
27. Cheung NW , Boyages SC . Increased incidence of neoplasia in females with acromegaly . Clin Endocrinol (Oxf) . 1997 ; 47 ( 3 ): 323 - 327 .
28. Colao A , Balzano A , Ferone D , Panza N , Grande G , Marzullo P , Bove A , Iodice G , Merola B , Lombardi G . Increased prevalence of colonic polyps and altered lymphocyte subset pattern in the colonic lamina propria in acromegaly . Clin Endocrinol (Oxf) . 1997 ; 47 ( 1 ): 23 - 28 .
29. Ron E , Gridley G , Hrubec Z , Page W , Arora S , Fraumeni JF Jr. Acromegaly and gastrointestinal cancer . Cancer . 1991 ; 68 ( 8 ): 1673 - 1677 .
30. Barzilay J , Heatley GJ , Cushing GW . Benign and malignant tumors in patients with acromegaly . Arch Intern Med . 1991 ; 151 ( 8 ): 1629 - 1632 .
31. Brunner JE , Johnson CC , Zafar S , Peterson EL , Brunner JF , Mellinger RC . Colon cancer and polyps in acromegaly: increased risk associated with family history of colon cancer . Clin Endocrinol (Oxf) . 1990 ; 32 ( 1 ): 65 - 71 .
32. Nabarro JD . Acromegaly. Clin Endocrinol (Oxf) . 1987 ; 26 ( 4 ): 481 - 512 .
33. Mustacchi P , Shimkin MB . Occurrence of cancer in acromegaly and in hypopituitarism . Cancer . 1957 ; 10 ( 1 ): 100 - 104 .
34. Davies L , Welch HG . Increasing incidence of thyroid cancer in the United States, 1973 - 2002 . JAMA. 2006 ; 295 ( 18 ): 2164 - 2167 .