CLINICAL PERSPECTIVE: Acromegaly and Cancer: Not a Problem?
Shlomo Melmed
Cedars-Sinai Research Institute-University of California at Los
Angeles School of Medicine, Los Angeles, California 90048
Address all correspondence and requests for reprints to: Shlomo Melmed, M.D., Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Room 2015, Los Angeles, California 90048. E-mail: melmed{at}cshs.org
Acromegaly is usually caused by a GH-secreting
pituitary adenoma. Somatic growth and metabolic dysfunction occur
subsequent to unrestrained GH secretion and elevated insulin-like
growth factor (IGF)-I and IGF-binding protein (IGFBP)-3 levels
(1) (Fig 1
). Classic
clinical features of acromegaly include acral overgrowth, sweating,
headaches, menstrual disturbances, and glucose intolerance (Table 1
) (2). Well-documented
clinical risks of long-term tissue exposure to uncontrolled GH
hypersecretion include cardiac disease and hypertension, diabetes,
respiratory disorders, joint disease, and neuropathy (Table 2
) (3). The degree of risk
for malignancy in these patients is unresolved; and acromegaly,
representing an experiment of nature, could answer the question of
whether or not elevated GH and IGF levels provide a permissive growth
advantage for neoplasms, resulting in more aggressive malignant disease
and/or increased cancer-associated mortality (4).

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Figure 1. Pathogenesis of acromegaly. Unrestrained GH
secretion, elaborated by a pituitary tumor, results in elevated IGF-I
and IGFBP-3 levels, somatic growth, and metabolic dysfunction.
Paracrine IGF-I and IGFBP-3 may also influence tissue growth. Adapted
from 1 .
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Analysis of the determinants for mortality outcome in acromegaly
indicates that approximately 60% of patients succumb to cardiovascular
disease; 25% from respiratory disease; and in 15% of patients, the
cause of death is attributed to malignancy (Table 2
). Nevertheless,
absolute circulating GH values seem to constitute the most significant
single determinant of survival, regardless of the cause of death
(5, 6, 7, 8, 9, 10, 11, 12, 13, 14). Several recent compelling studies support the
critical role of GH, suggesting that GH control is associated with
reversal of adverse mortality rates, regardless of the nature of
associated comorbidity (13). Thus, suppression of GH to
less than 1 ng/mL, during an oral glucose tolerance test, and
normalization of IGF-I levels portend a favorable mortality outcome
(15).
Pathogenesis of somatic dysfunction in acromegaly
Peripheral tissue somatic growth and metabolic dysfunction are
caused by direct effects of GH on peripheral receptors, impact of
hepatic-derived circulating and paracrine IGF-I, and also the impact of
elevated circulating IGFBP-3 levels. Elevated IGF-I bioactivity and
activation of the IGF-I receptor are associated with cell
proliferation and growth advantage, whereas IGFBP3 bioactivity promotes
an apoptotic advantage (16, 17, 18, 19). Thus, excess GH, by
inducing both IGFBP3 and IGF-I levels, promotes dysregulated cell
growth balance characterized by dynamic signals for cell apoptosis
vs. cell growth advantage (Fig 2
).

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Figure 2. Balance of GH influences on cell growth
regulation. GH stimulates both IGF-I and IGFBP-3, which mediate cell
proliferation and cell removal, respectively. Adapted from 21 22 23 .
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Because IGFBP-3 levels are high in acromegaly (20) (Fig 3
) and correlate with IGF-I levels, an
imbalance of circulating IGFBP-3 level vs. IGF-I action is
manifested by the broad spectrum of clinical somatic features of the
disease and is reflective of a broad range of respective circulating
values for these two factors in patients with acromegaly. This is
especially noteworthy because, in vitro, IGFBP-3 inhibits
IGF-I-induced prostate cancer cell growth (21) (Fig 4
), and breast cancer cells are diverted
into an apoptotic phase by IGFBP-3 (22). In acromegaly,
the activated IGF-I receptor accounts for increased kidney, heart, or
acral bony tissue functional cell mass. These patients, therefore,
potentially harbor a tumor growth advantage mediated by IGF-I-activated
cell renewal and increased functional mass; whereas concomitantly,
elevated IGFBP-3 accounts for an enhanced cell removal process and
apoptosis (23). Thus, pathologically elevated GH results
in peripheral tissue exposure to both excessive growth-promoting
and growth-arresting influences.
The role of the GH-IGF-I axis in tumorigenesis has been
extensively studied. In vitro evidence supporting the role
of these growth factors in development of neoplasia includes
reports that GH and IGF-I readily transform lymphocytes, and also
induce cell proliferation. IGF-I receptor mass is increased in
neoplastic tissues, and the activated IGF-I receptor also mediates cell
transformation (16, 17, 24, 25, 26). Several growth factors
and inactivated tumor-suppressing genes also stimulate IGF-I
receptor synthesis (18). However, there are no reports of
enhanced spontaneous tumor formation in IGF-I-expressing transgenic
mice (27). Targeted expression of IGF-I by a human keratin
promoter was shown to result in epidermal hyperplasia and
hyperkeratosis, with enhanced sensitivity to tumor induction by
administered TPA (28).These latter
observations suggest a permissive, rather than an initiating, role for
IGF-I in tumorigenesis. In classic earlier papers by Moon and
colleagues (29), impure extracted GH was injected into
rats at very high doses (up to 3 mg/day) for up to 16 months, and these
animals developed primarily lymphoid hyperplasia and lung
lymphosarcomas. In vivo, GH induces neoplasm formation and
also c-myc expression in experimental models, and mice
overexpressing GH transgenes develop tumors over the long term
(30, 31). Several decades of earlier experience with
hypophysectomy showed the procedure to be protective or palliative for
patients with neoplasia (32). Somatostatin administration
lowers IGF-I levels and also retards transplanted tumor growth in some
animal models. Thus, several lines of in vitro and in
vivo evidence indicate a role for the GH-IGF-I axis in mediating
both physiologic and pathologic cell growth and tissue hypertrophy
(19). The impact of this cumulative experimental evidence
on risk for tumorigenesis in patients with acromegaly remains
unclear.
Epidemiology of IGF-cancer link
Recently, several retrospective epidemiologic studies have
suggested that elevated IGF-I levels may be concordant with a higher
risk of cancer in the general population, and that high IGFBP-3 levels
are concordant with a lower risk for cancer (33, 34, 35).
Breast cancer specifically has been epidemiologically linked to IGF-I
levels in premenopausal women (36). As levels of IGF-I
increase, there also seems to be an enhanced relative risk for colon
cancer development, whereas higher levels of IGFBP-3 are associated
with decreased relative risk for colon cancer. Extrapolation of these
findings to acromegaly should take into account the protective effect
of IGFBP-3, especially because both IGF-I and IGFBP-3 are elevated in
the disorder. Patients harboring GH-secreting tumors would thus fall
into the low-risk quartile of IGF-I and IGFBP3 levels, because they
usually exhibit elevations of both these factors (33).
Several caveats are important to consider in extrapolating these
epidemiologic retrospective studies to acromegaly. First, preexisting
cancer should be critically excluded in the test population at the time
of retrospective serum sampling, for subsequent IGF-I measurement.
Other potentially important cancer risk factors, including family and
genetic history, should also be considered. Nevertheless, extrapolation
of the epidemiological results, derived from the general population, to
acromegaly would, in fact, categorize an acromegaly cohort as low risk
(Fig 5
). Clinical prudence indicates that
if, in fact, a neoplasm is concomitantly present, acromegaly should be
aggressively treated, because elevated IGF-I levels could be growth
stimulators for that neoplasm; there is, however, no clear evidence
that tumor initiation is triggered by IGF-I. Although GH treatment
induces mammary hyperplasia in primates (19), observations
from pharmacovigilant studies of patients receiving GH as replacement
for pituitary damage have not reported significant increased risks for
colon, breast, or prostate cancer thus far. In fact, GH-deficient
adults receiving GH replacement, aimed to achieve high-normal IGF-I
levels, exhibited unaltered markers of colon epithelial cell
proliferation (37).

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Figure 5. Relative risk for development of colon
cancer. IGF-I and IGFBP-3 levels were measured retrospectively in
the general population. Because patients with acromegaly exhibit both
elevated IGF-I and IGFBP-3 levels, their relative risk for cancer
development seems to be low. Adapted from 33 .
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Colon polyps in acromegaly
Over the years, numerous retrospective and a few prospective
studies have suggested an increased incidence of benign and
precancerous colon polyps in patients with acromegaly
(38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51) (Table 3
). In an
attempt to understand the role of the GH-IGF-I axis in colon cell
growth, two transgenic animal models are particularly
illuminating (52, 53). These models of respective
GH or IGF-I overexpression distinguish two different murine phenotypes
of hypersomatotropism. The selectively overexpressed GH transgene is
associated with both high GH and high IGF-I levels, whereas the IGF-I
transgenic mouse has high IGF-I and low GH levels (52, 53). Although both models exhibit biochemical and clinical
features characteristic of acromegaly, no renal or hepatic changes are
apparent in the IGF-I transgenic mouse (53). These animals
do, however, exhibit increased bowel length, with highly proliferative
colonic crypt cells and decreased apoptosis, whereas no cellular bowel
changes are apparent in the GH transgenic model (52, 53, 54, 55, 56).
Thus, IGF-I is a powerful mediator of enterotrophic effects, even in
the absence of GH (55). This latter observation would
suggest that a factor other than IGFBP-3 may, in fact, protect colon
cells from proliferative signals when GH is elevated. Another variable
in these models is the bowel cell type expressing IGF-I colonic
epithelial; or mesenchymal paracrine expression may determine differing
phenotypes of cell proliferation. These suboptimal animal models of
acromegaly, differing in colonic phenotype, may elucidate the very
discrepant clinical literature describing the pathogenesis of benign
colon polyps in acromegaly.
In summarizing 12 prospective colonoscopy studies from the literature
reporting 678 patients with acromegaly, colon adenomas were detected in
24%, 21% had hyperplastic polyps, and 2.5% harbored colon carcinoma
(Table 3
). Thus, although approximately 47% of selected patients with
diagnosed acromegaly prospectively seem to harbor a colonic lesion
(38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 50, 51), up to 40% of asymptomatic unselected
males over the age of 50 yr in the general population harbor colonic
lesions (57, 58, 59). Therefore, extrapolation of this
literature for assessing risk in patients with acromegaly should be
cautious without appropriate age-, sex-, and environmentally-matched
control population groups. A recent prospective study with rigorous
autopsy and population-derived controls demonstrated no increased
prevalence of colorectal neoplasia in 115 patients with acromegaly
(50).
Total colon length and sigmoid loop length are increased, and mucosal
hypertrophy with documented prolonged colon transit times are reported
(49, 50). If, in fact, colon polyps are detected in
patients with acromegaly, about 50% are right-sided lesions,
justifying full colonoscopy for these patients. If a colon polyp is
detected and resected in a patient with acromegaly, there is also a
25% chance that it will recur within 3 yr. Regarding age-related risk
for polyps in acromegaly, the literature is diverse, and the risk of
colonic lesions is paradoxically reported as being either higher in
patients under 55 or in those over 60 yr (43, 45, 49, 60).
There is certainly a higher risk for patients with a positive family
history of colon tumors, multiple skin (61) tags, and
history of previous polyps, and increased vigilance is recommended for
these subjects. Although repeat colon polyp growth in acromegaly seems
to occur in patients with higher IGF-I levels (51), there
is, as yet, little compelling evidence supporting a strong correlation
of circulating GH or IGF-I levels and the presence of colon polyps
(50, 62), perhaps reflecting the wide spectrum of colon
cell dysfunction observed in transgenic animal models of acromegaly.
Although eight patients with newly discovered colonic adenomas
exhibited higher IGF-I levels than patients with normal or hyperplastic
polyps (51), larger studies are required to resolve this
important question.
Cancer incidence in acromegaly
Although the role of GH-IGF-I axis in mediating normal cell and
tissue growth is well documented, the question of whether patients with
acromegaly harbor an enhanced risk for developing cancer is unresolved.
Cancer does not appear in descriptions of acromegaly clinical features;
and in a comprehensive symptom and sign review of more than 800
patients reported in the literature, cancer is not listed
(2). Multiple uncontrolled reports have associated
neoplasms of the skin, gastrointestinal system, breast, thyroid,
thymus, parathyroid, brain, bone, and hematologic system with
acromegaly. In largely selective retrospective and uncontrolled case
reports or small series (3, 63, 64, 65), benign tumors have
been especially highlighted, including skin tags, colon polyps,
adenomas, thymic tumors, parathyroid adenomas, meningiomas, and
neurinomas. No enhanced association with breast or prostate cancer has
been reported (66).
Several retrospective reports have documented the incidence of
malignant disease in acromegaly (Table 4
). Mustacchi (67) reported
a 12-center analysis of the incidence of cancer in patients with
acromegaly. In patients ranging in age from 179 yr, and a total of
2,981 persons at risk, no observed overexpected increased cancer
prevalence was found. This very-well-documented study, concluded that
the material analyzed does not disclose the presence of a definite
influence of the pituitary on the initiation of cancer. If this
stimulus exists, it does not seem to be a very potent one
(67). Evans examined 100 consecutive death certificates of
patients with acromegaly and found no recorded increase in cancer
incidence (68). In a retrospective review of 4 million
patient charts, 1,200 patients with acromegaly were identified; 22
female subjects, and 149 patients with cancer diagnosed before the
diagnosis of acromegaly, were excluded from analysis. In the study
cohort of 1,041 males, modestly enhanced (
1.6-fold) incidence of
colon, esophageal, and stomach cancer and melanoma was detected
(69). From this large retrospective chart review, many
have concluded that, in fact, acromegaly is associated with cancer.
Careful analysis of this report, however, implies an acromegaly
prevalence of 1 in 4,000 in this highly selected hospitalized
population. This is clearly far higher than the expected prevalence of
approximately 46 per million in the general population
(6). Therefore, the ascertainment bias inherent in this
study makes it difficult to extrapolate to the nonhospitalized overall
population of patients with acromegaly (69). The Orme
study was an important contribution to the literature reporting 16,000
person years at risk in the UK (70). Cancer incidence in
patients with acromegaly was, in fact, low (0.76 Standardized
Incidence Ratio, P < 0.05), with a sharply lower
incidence of bronchial cancer (0.33 Standardized Incidence Ratio,
P < 0.05) in this group. Female breast cancer and
colon cancers were not significantly increased, and overall cancer
incidence rates were significantly lower than observed in the general
population.
With the aforementioned caveats inherent in interpreting selected
reports, reviewing retrospective published reports from 1957 through
1999, summarizing over 20,000 reported exposure years, the incidence of
cancer ranges from 0.76- up to 3.4-fold the observed overexpected ratio
(Table 4
). Prospective controlled longitudinal studies are clearly
required to resolve the significance of these observations.
Cancer mortality in acromegaly
Overall mortality in patients with acromegaly correlates with the
degree of GH control, and mortality rates from cancer also stratify
according to posttreatment GH levels (70) (Table 5
). Overall, if posttreatment GH is
controlled, both overall mortality and cancer mortality are unchanged
from the control general population (9, 70). Enhanced
mortality from cancer is thus only significant if GH levels are
uncontrolled. There are no published studies of long-term prospective
evaluation of cancer prevalence or its relationship to biochemical or
clinical disease activity in acromegaly. Other unrelated risk factors
seem far more important for cancer incidence and mortality, including
genetic predisposition, enhanced family risk, and the impact of tight
GH control on malignancy-associated mortality. Quite clearly, patients
with acromegaly now live longer, and the impact of improved overall
general mortality and reduced cardiovascular morbidity may unmask
unrelated, age-related cancer incidence previously not clinically
apparent. These unknown factors further confound our understanding of
cancer risk in acromegaly.
Nevertheless, the murky risk perspectives of cancer in acromegaly
should be compared with the striking well-documented risk of
cardiac disease and diabetes. Mortality, in patients with acromegaly
and cardiac disease at the time of diagnosis, occurs within 15 yr in
almost 100% of the cases, and only 20% of patients with diabetes and
acromegaly survive 20 yr (12). These survival curves
differ strikingly from the marginal impact of malignancy on overall
mortality derived from metaanalysis of papers published over the last
50 yr. The relative contributions to mortality in acromegaly, as
measured by elevated GH levels, hypertension, and heart disease,
clearly account for the major negative survival determinants in these
patients. Symptom duration and other factors (including cancer) account
for relatively low mortality impact (Fig 6
).

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Figure 6. Depiction of mortality determinants in
patients with acromegaly. The x-axis reflects the P
value (log) as calculated from published retrospective reports
(8 9 10 11 12 13 14 ).
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For patients with acromegaly, it seems that controlling GH levels,
hypertension, and heart disease are important for improving ultimate
mortality. Fifteen percent of deaths in acromegaly are attributable to
malignancies, which is lower than would be expected from the general
population, and confirmed by Orme (Table 2
). Uncontrolled acromegaly
may provide a growth advantage to concurrently occurring neoplasms in
these patients; and based upon experimental information, cancer in a
patient with acromegaly and uncontrolled GH levels will likely be more
aggressive, with potentially increased cancer-associated morbidity and
mortality. However, there is no clear evidence for enhanced de
novo cancer initiation in acromegaly and, as yet, no direct proven
causal relationship of acromegaly with malignant disease.
Received August 25, 2000.
Revised December 7, 2000.
Revised January 11, 2001.
Accepted January 26, 2001.
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