Adrenocortical Tumors1
Ana C. Latronico2 and
George P. Chrousos
Developmental Endocrinology Branch, National Institute of Child
Health and Human Development, National Institutes of Health, Bethesda,
Maryland 20892
Address all correspondence and requests for reprints to: Dr. George P. Chrousos, Developmental Endocrinology Branch, National Institutes of Health, Building 10, Room 10N262, 9000 Rockville Pike, Bethesda, Maryland 20892-1862.
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Introduction
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Cushings syndrome due to adrenocortical tumors
was reported at the turn of the century, almost a decade before the
description of the endocrine syndrome by Harvey Cushing. At the time,
the adrenal cortexes were known to secrete an active principle
necessary for life, the absence of which led to Addisons disease. The
crucial role of the pituitary gland in the control of adrenal secretion
was not suspected. Since then, we have learned a great deal about
adrenocortical tumors, their incidence, clinical presentation,
diagnosis, therapy, and prognosis. Some research on the cell and
molecular biology of these tumors has also been performed, mostly in
the last decade. The rapidly advancing knowledge in the biology of
other more frequent nonendocrine or endocrine tumors promises that
better understanding of adrenocortical tumorigenesis is also
forthcoming.
We have been managing patients with adrenocortical neoplasms from both
an endocrinological and an oncological perspective. There are
persistent controversies in this field, and treating advanced stage
adrenocortical malignancies has been an utter frustration. The
desperate situation of the usually young patients with these vicious
neoplasms makes the early detection of these tumors pivotal and the
discovery of new effective therapeutic modalities imperative. The
purpose of this brief review is to present the state of the art in this
field and suggest new avenues of research.
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Classification
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Adrenocortical tumors are divided into benign and malignant
groups. Either can be hormonally silent or hormone secreting. The vast
majority of adrenocortical tumors are benign and hormonally silent (1, 2). The hormone-secreting tumors can produce glucocorticoids,
androgens, mineralocorticoids, estrogens, and combinations thereof
(3, 4, 5, 6, 7, 8). Adrenocortical tumors can be sporadic or hereditary, with the
former representing the overwhelming majority.
Diffuse or nodular adrenocortical hyperplasia resulting from ACTH
hyperstimulation in ACTH-dependent Cushings syndrome and congenital
adrenal hyperplasia due to defects of cortisol biosynthetic enzymes,
and nodular hyperplasia associated with isolated primary micronodular
or massive macronodular adrenal disease or Carneys complex are
considered low grade premalignant states (4, 7).
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Incidence and epidemiology
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The frequency of small benign adrenocortical tumors gradually
increases with age, ranging between 37% in adults over 50 yr (Table 1A
) (1, 2). Usually they are discovered
incidentally, in the context of abdominal computed tomographic (CT) or
magnetic resonance imaging (MRI) scans performed for various unrelated
purposes (Table 2A
). Hormone-secreting benign adrenal
adenomas are rare; equally rare are hormonally silent or
hormone-secreting adrenocortical carcinomas.
Malignant neoplasias of the adrenal cortex account for 0.050.2% of
all cancers, with an approximate prevalence of two new cases per
million of population per yr (1, 3). Adrenal cancer occurs at all ages,
from early infancy to the seventh and eight decades of life (3, 4, 5, 6, 7, 8). A
bimodal age distribution has been reported, with the first peak
occurring before age 5 yr, and the second in the fourth to fifth decade
(3). In all published series, females clearly predominate, accounting
for 6590% of the reported cases (3, 4, 5, 6, 7, 8). Whereas some investigators
report a left-sided prevalence, others note a right-sided preponderance
(3, 7, 8). Bilaterality has been reported in 210% of the cases (3, 7).
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Clinical presentation
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Patients with hormone-secreting adrenocortical neoplasms have
associated endocrine syndromes that result from the secretion of
cortisol or aldosterone and their precursors, adrenal androgens and
their precursors, and/or estrogens (Table 2
). The most common syndromes
associated with adrenocortical tumors in adults are hyperaldosteronism
and Cushings syndrome (3, 4, 8). Cushings syndrome is present in
3040% of patients with adrenocortical carcinoma (3).
Virilization occurs in 2030% of adults with functional
adrenocortical carcinoma, whereas it is the most common hormonal
syndrome in children with adrenocortical cancer (4). Virilization is
secondary to hypersecretion of adrenal androgens, including
dehydroepiandrosterone and its sulfate derivative,
5-androstenediol, and
4-androstenedione,
all of which may be converted finally to testosterone and
5
-dihydrotestosterone. The signs and symptoms in adult females
include oligoamenorrhea, hirsutism, cystic acne, excessive muscle mass,
deepening of the voice, temporal balding, increased libido, and
clitoromegaly. In young girls, heterosexual precocious puberty occurs.
The combination of Cushings syndrome and virilization is seen in
1030% of the patients with adrenocortical carcinoma (3). This
combined syndrome is usually associated with secretion of multiple
steroid precursors.
Feminization and hyperaldosteronism, as pure hormonal syndromes, are
quite rare manifestations of malignant adrenocortical neoplasms. Even
more unusual presentations of adrenal cancers include hypoglycemia,
nonglucocorticoid-related insulin resistance, and polycythemia (7).
Slightly over half of the adult patients with adrenocortical carcinoma
have no recognizable endocrine syndrome. These patients present with
either abdominal pain or fullness or with the incidental finding of an
adrenal mass on imaging studies performed for unrelated reasons. A
palpable abdominal mass is present in about half of the patients with
nonfunctional adrenocortical carcinoma at the time of diagnosis (3, 7).
Finally, in a significant proportion of the patients, metastatic
disease may cause symptoms before a primary diagnosis is established
(7). Local invasion commonly involves the kidneys and inferior vena
cava, whereas metastatic disease may be found in the retroperitoneal
lymph nodes, lungs, liver, or bone.
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Laboratory studies
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Several laboratory studies are useful in the establishment or
confirmation of excessive steroid secretion and the monitoring of
patients with adrenocortical neoplasms (Table 3
). A
single dose (1 mg), overnight dexamethasone suppression test may be
helpful as a screening test (9). Hypercortisolism is best established
by measuring the 24-h excretion of urinary free cortisol (UFC) (3, 5, 9, 10). Over 90% of patients with Cushings syndrome have UFC values
greater than 200 µg/24 h, whereas 97% of normal individuals have UFC
values less 100 µg/24 h (3, 9). Recently, UFC assays using high
performance liquid chromatography have appeared in clinical practice.
These assays measure authentic cortisol and have a lower upper limit of
normal (UFC, <50 µg/24 h).
Several plasma and urinary steroids are elevated in patients with
Cushings syndrome due to functioning adrenocortical tumors. These
include dehydroepiandrosterone and its sulfate derivative,
5-androstenediol,
4-androstenedione,
pregnenolone, 17-hydroxypregnenolone, and 11-deoxycortisol in the
plasma, and 17-hydroxysteroids, 17-ketosteroids, and the tetrahydro
metabolite of 11-deoxycortisol in the urine. Despite the fact that
steroidogenic precursors, such as 17-hydroxyprogesterone and
11-deoxycortisol, are not essential in the evaluation of
hypercortisolism, they may occasionally provide clues to the presence
of an adrenal malignancy in patients with Cushings syndrome (5).
Generally, many of the steroid biosynthesis enzymes are defective in
adrenocortical carcinomas, providing an inefficient machinery for
steroid production, and are associated with plasma level patterns of
steroid precursors typical of enzymatic blocks (5).
A low plasma ACTH level associated with elevated concurrent plasma
cortisol concentrations is indicative of autonomous activity of the
adrenal glands (9). There are several dynamic endocrine tests for the
differential diagnosis of adrenal Cushings syndrome from the
ACTH-dependent forms of the condition (9). These include the classic
high dose dexamethasone suppression test and the ovine CRH stimulation
test. Typically, both tests are associated with the lack of
responsiveness of cortisol secretion to dexamethasone and CRH.
The clinical diagnosis of adrenally induced virilization may be
confirmed by measurements of plasma adrenal androgens and testosterone
and 24-h urinary excretion of 17-ketosteroids. Feminization or
hyperaldosteronism can be confirmed by measurements of elevated plasma
estradiol and/or estrone or of aldosterone, 11-deoxycorticosterone,
and/or corticosterone, respectively.
All patients, particularly those with nonfunctional adrenal masses,
should also be screened for pheochromocytoma even in the absence of
sustained hypertension.
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Imaging procedures
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The diagnosis of adrenal neoplasms depends on the identification
of an adrenal mass on CT and/or MRI. Both normal and abnormal adrenal
glands are easily visible on CT because of the adipose tissue that
surrounds these glands in the retroperitoneum (11). The presence of a
large unilateral adrenal mass with irregular borders is virtually
diagnostic of adrenal cancer (7). CT provides information about size,
homogeneity, presence of calcifications, areas of necrosis, and extent
of local invasion, thus also being helpful in making decisions about
the resectability of the lesion. Tumors as small as 0.5 cm have been
detected by CT, although the relative lack of retroperitoneal fat in
children might decrease the sensitivity of the test in this age group
(11).
Whether MRI will prove to be superior to CT scanning in diagnosing and
differentiating adrenal masses remains to be seen. MRI provides
information about the invasion of an adrenocortical carcinoma into
blood vessels, particularly the inferior vena cava and the adrenal and
renal veins, in which tumor thrombi may be identified occasionally.
Studies have reported that MRI can distinguish with a fair degree of
accuracy among primary malignant adrenocortical tumors, nonfunctioning
adenomas, and pheochromocytomas by comparing the ratio of the signal
intensity of each type of adrenal mass to that of liver (11). Thus,
primary malignant adrenocortical lesions have an intermediate to high
signal intensity on T2-weighted images. Nonfunctional adenomas have low
signal intensity, whereas pheochromocytomas have an extremely high
signal intensity.
Other imaging modalities, such as iodocholesterol scanning, venography,
and arteriography, are rarely indicated (3, 7, 11). The
[125I]iodocholesterol scan is usually negative in
malignant adrenocortical neoplasms and positive in steroid-secreting
adenomas. [125I]Iodocholesterol uptake may help define
whether there is unilateral or bilateral autonomous steroidosynthetic
tissue when adrenal masses are seen bilaterally on CT or MRI imaging.
Also, it may help with the localization of adrenal rests or adrenal
remnants after adrenalectomy. On occasion, selective arteriography may
help distinguish between adrenal masses and upper pole renal tumors.
Inferior vena cava venography may be indicated if CT or MRI findings
suggest the presence of a tumor thrombus in this vessel. In general,
these invasive techniques are reserved for the rare instance in which
CT or MRI cannot supply the information needed.
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Pathology, staging, and prognosis
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Histologically, adrenocortical tumors consist of lipid-depleted
cells with granular cytoplasm and large multiple nuclei and nucleoli
(7). Tumor cells have varying mitotic activity. The differentiation of
benign from malignant adrenocortical neoplasms solely on the basis of
histological findings is difficult, if not impossible (3, 5, 6, 12).
Thus, several reports demonstrated that patients whose operatively
excised tumors exhibited histologically benign features and
subsequently developed local recurrences or distant metastases, whereas
others, whose tumors had a microscopic appearance typical of
malignancy, lived tumor-free for many years.
Several macroscopic and microscopic criteria are collectively used to
define the malignancy of an adrenocortical tumor and to predict its
behavior (12). Macroscopically, a wet weight of more than 500 g, a
grossly lobulated cut surface, the presence of necrotic areas and/or
calcifications, and intratumor hemorrhages predict malignancy.
Microscopically, architectural disarray, frequent mitoses, marked
cellular pleomorphism, nuclear atypia and hyperchromasia, as well as
invasion of the capsule suggest malignancy.
Abnormal DNA contents have been detected in adrenocortical carcinomas
by flow cytometric DNA analysis (13, 14). Aneuploidy occurs in
neoplastic subpopulations through genetic instability and mitotic
irregularities. Bowlby et al. reported that 83% of the
carcinomas showed aneuploidy, suggesting that flow cytometric analysis
may prove to be a complement to the conventional histopathological
methods and a valuable tool in predicting the prognosis of patients
with adrenocortical tumors (13).
The staging system for adrenocortical carcinomas depends upon tumor
size, nodal involvement, invasion of adjacent organs, and presence of
distant metastases (Table 4
) (15). Staging is helpful in
defining prognosis and therapy. Only patients with stage I and II
disease are curable with surgery. Unfortunately, the great majority of
the patients have either stage III or IV disease at the time of
diagnosis. Despite complete resection, virtually 100% of patients with
stage III disease have recurrent and metastatic disease within 5 yr of
tumor resection. Moreover, the 5-yr survival for stage III adrenal
carcinoma is generally less than 30%. The most frequent sites of
metastases are lymph nodes (2546%), lungs (47%97%), liver
(53%68%), abdomen (3343%), and bones (1133%). Metastases have
been reported in ovary, spleen, pleura, thyroid, pharynx, tonsils,
mediastinum, myocardium, brain, spinal cord, skin, and sc tissue (4, 7). Despite aggressive surgical therapy, the mean 5-yr survival of
patients with stage IV disease is 1525%.
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Molecular studies of adrenocortical tumorigenesis
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Except in life periods characterized by rapid growth, the accrual
of a certain type of cells in a tissue is equal to the withdrawal of
the same type and number of cells. New cell accrual is stimulated by
genes that activate the cell cycle (protooncogenes) and inhibited by
others that suppress it (tumor suppressor genes). Cell withdrawal, on
the other hand, takes place by programmed cell death (apoptosis),
differentiation to a different type of cell, or natural senescence.
Tumorigenesis occurs when the equation between cell accrual and
withdrawal is disturbed by defects in one or more of the multiple
checkpoints in the life of a cell that ensure control of the cellular
composition of a tissue. In 1914, Boveri predicted the importance of
genetic alterations of somatic cells in the development of cancer.
Indeed, within the last 20 yr, molecular and cell biology studies have
revealed that activation of protooncogenes and/or loss of function of
tumor suppressor genes represent key mechanisms in the formation of
many animal and human cancers. At this time, more than 50 oncogenes and
12 tumor suppressor genes have been identified in the human genome;
however, only a small proportion of these have been actually implicated
in the development of specific human neoplasms.
Recently, the clonal composition of adrenocortical tumors was
determined using X-chromosome inactivation analysis (16, 17). Like most
tumors, adrenal adenomas and carcinomas were most often monoclonal,
whereas ACTH-induced diffuse and macronodular hyperplasias were
polyclonal (16). These findings support the fundamental contemporary
assumption that tumors arise as monoclonal expansions of a single cell,
which become tumorous in response to a series of multistep genetic
aberrations involving overexpression of protooncogenes and/or
inactivation of tumor suppressor genes as well as alterations of the
proteins involved in the normal progression of senescence, induction of
apoptosis, and differentiation. The rate of DNA defects developed and
passed on with each replication, also called rate of genomic
instability, is proportional to the rate of development of clones with
survival advantages and, therefore, is proportional to the potential of
a tumor to grow and prevail over the host. The ability of the cell to
rapidly repair DNA aberrations is crucial for the prevention of clonal
expansion and tumorigenesis. Defects in proteins responsible for DNA
repair also participate in tumorigenesis.
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Association with chromosomal abnormalities and genetic
syndromes
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The possibility that there is an inherited predisposition to
develop adrenocortical tumors has been previously entertained (18, 19, 20, 21, 22, 23, 24).
Adrenocortical carcinoma has been reported in siblings, and a high
incidence of diverse malignancies has been noted in families and
relatives of patients with adrenocortical carcinomas (20, 21, 22, 23). Also,
high frequencies of congenital anomalies and secondary tumors have been
demonstrated in patients with adrenal cancer (18, 20, 22, 23). There
are several recognized genetic syndromes that have been associated with
adrenocortical neoplasms, which are discussed below (Table 5
).
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Table 5. Clinical and molecular features of genetic syndromes
associated with benign and/or malignant adrenocortical neoplasms
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Patients with the Li-Fraumeni syndrome have a high incidence of
adrenocortical carcinomas (23). Germline mutations in p53, located on
chromosome 17p, were identified in families with this syndrome (23). In
addition, Yano et al. described abnormalities of chromosome
17 in adrenocortical carcinomas that were compatible with loss of
heterozygocity and defective tumor suppressor activity of p53, as was
later demonstrated in 27% of malignant adrenocortical tumors and two
adrenocortical tumor cell lines examined (21, 23). Loss of
heterozygosity at 17p was not found in adrenal adenomas, supporting a
malignant transformation inhibitory role for p53 in adrenocortical
tissue (22, 23, 24).
The Wiedemann-Beckwith syndrome, a growth disorder associated with
allelic loss of chromosome 11p15 and characterized by neonatal
macrosomia, macroglossia, and omphalocele, has an increased incidence
of Wilms tumors and adrenocortical carcinomas (18, 22). Koufos
et al. (19) suggested that a recessive oncogene located on
chromosome 11p confers predisposition to adrenal cortical tumors,
hepatoblastoma, and rhabdomyosarcoma. In agreement with this,
structural abnormalities at the 11p15 locus were described in
37% of sporadic adrenocortical tumors (22). Particularly,
uniparental disomy at the 11p15.5 locus, which includes the
H-ras-1, insulin-like growth factor II (IGF-II), insulin,
H19 and P57KIP2 genes, was observed in human adrenocortical
carcinomas (20, 22). Cicquel et al. (20) also detected very
high IGF-II messenger ribonucleic acid contents in 83% (five of the
six carcinomas) of the adrenocortical carcinomas examined. Four of
these five carcinomas showed abnormalities at locus 11p15.5, suggesting
that there is a strong relation between IGF-II overexpression and
rearrangements at the 11p15 locus in adrenocortical tumors (20, 22).
These findings suggest that structural abnormalities and/or
overexpression of the IGF-II gene may play a key role in the multistep
process of adrenocortical tumorigenesis.
The Carney complex, an autosomal dominant disorder, is
characterized by the association of primary pigmented nodular
adrenocortical disease, myxomas, particularly of the heart, and
psammomatous melanotic swannomas involving the peripheral nervous
system, spotty pigmentation and blue nevi of the skin or mucosa, and
diverse endocrine neoplasms (25, 26). Testicular Sertoli cell tumors,
GH-producing adenomas, thyroid follicular carcinomas, ovarian cysts,
and adrenocortical tumors were associated with this familiar syndrome,
whose chromosomal locus was recently mapped on 2p16, but whose
pathophysiological mechanism(s) remains unknown (25). From cytogenetic
studies, the Carney complex appears to be due to gain of function
mutations involving a protooncogene (26).
The familial and genetic nature of multiple endocrine neoplasia type 1
(MEN-1) syndrome was first pointed out by Wermer in 1954, who suggested
that an autosomal dominant gene with high penetrance controls the
trait. Recently, the gene for MEN-1 was mapped to chromosome 11q13, and
several alterations in this region have been described in affected
individuals (27). The most frequent endocrinopathies in MEN-1 are
hyperparathyroidism and pancreatic-duodenal and pituitary tumors.
However, other tumors are also seen more frequently than in the general
population, including adrenocortical and thyroid tumors, carcinoids,
lipomas, and pinealomas. In MEN-1, benign enlargement of adrenal cortex
has been found in about one third of necropsy cases. Diffuse and
nodular cortical hyperplasia, adenomas, and a single case of
adrenocortical carcinoma were described in patients with MEN-1 (27).
Loss of constitutional heterozygosity for alleles at 17p, 13q, 11p, and
11q was found in an MEN-1 adrenocortical carcinoma, whereas the benign
adrenal lesions retained heterozygosity for the MEN-1 locus at 11q13
(27).
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Protooncogenes
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Table 6
summarizes the genetic alterations found in
sporadic adrenocortical tumors. That hyperstimulation of the adrenals
by ACTH could result in adrenocortical tumors was directly suggested by
isolated case reports of carcinomas arising 336 yr after the
diagnosis of classic congenital adrenal hyperplasia (7, 22). Recently,
the ACTH receptor gene was cloned, and its chromosomal localization and
sequence were determined (28, 29). The direct sequencing of the ACTH
receptor gene did not reveal constitutively activating mutations in two
series of sporadic adrenal cortical neoplasms and two cancer cell
lines, indicating that this mechanism is not frequent in human
adrenocortical tumorigenesis (30, 31).
Activating mutations of the Gs
gene
(gsp mutations) were described in affected tissues from
patients with the McCune-Albright syndrome, and these included
hyperfunctioning adrenocortical adenomas (32). These findings
demonstrated that overactivity of the G protein signaling pathway might
occasionally lead to the development of adrenocortical tumors. On the
other hand, point mutations in Gi
2, corresponding to
codons 201 and 227 of Gs
, were identified in 3
of 11 sporadic adrenocortical neoplasms (33). Although defects in the
Gs and Gi
2 were not confirmed in a
large series of sporadic benign and malignant adrenal neoplasms, a
small proportion of adrenocortical tumors might be related to mutations
in the G protein genes (34, 35).
Protein kinase C activity is a potential marker for human malignant
diseases, such as breast and pituitary tumors, and malignant gliomas
(36). Calcium-dependent protein kinase C activity was recently
described, however, as not increased in benign or malignant
adrenocortical tumors and in diffuse and macronodular adrenal
hyperplasia compared to levels in normal adrenal tissue, suggesting
that this molecular mechanism is infrequent in adrenocortical
tumorigenesis (36).
Activation of K-, H-, and N-ras protooncogenes is important
in the pathogenesis of various human tumors (37, 38). The prevalence of
activating ras mutations in human adrenocortical tumors was
12.5% with an adenine to guanine transition at the second position of
N-ras codon 61, resulting in a substitution of the amino
acid glutamine by arginine (37). Equal prevalence was found in benign
and malignant tumors of N-ras mutations in this series (37).
However, Moul et al. failed to find any ras
mutations in 11 adrenocortical tumors (38). Combined, these findings
suggest that activating ras mutations are rare in
adrenocortical tumors.
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Tumor suppressor genes
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Mutations of the p53 tumor suppressor gene were recently
reported in sporadic adrenocortical carcinomas and adenomas (Table 6
)
(22, 23, 39, 40). Reincke et al. described p53 mutations in
exons 58 in 27% of adrenocortical carcinomas and the 2 tumor adrenal
cancer cell lines available at the time, but in none of the benign
cortisol-secreting adrenal adenomas examined (23). This study
demonstrated an excellent correlation between the p53
immunohistochemical findings and the DNA abnormalities. Furthermore,
Lin et al. (39) demonstrated a high frequency of p53 gene
mutations in 10 of 13 benign aldosteromas of Taiwanese patients. In
75% of the cases these mutations were clustered in exon 4. More
recently, Reincke et al. (40) reported the absence of point
mutations within exon 4 of the p53 tumor suppressor gene in 25
Caucasian patients from the U.S. and Europe with adrenal tumors,
including 12 aldosteromas. Ethnic and environmental factors may be
responsible for the mutational spectrum of the p53 tumor suppressor
gene in different populations with adrenocortical neoplasms.
The retinoblastoma susceptibility gene (Rb), a tumor suppressor
gene located at chromosome 13q, has been implicated in the pathogenesis
of several tumors, including retinoblastoma and osteosarcoma (41).
Overexpression of Rb was identified in the adrenocortical carcinoma of
a patient from a family with the Li-Fraumeni syndrome, suggesting that
Rb might constitute a secondary event in the adrenal tumorigenesis of
this syndrome or might play a role in compensating for the inadequacy
of p53, a primary defect in this condition (41).
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Factors specific to the adrenal cortex
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We have summarized the potential mechanisms of adrenocortical
tumorigenesis in Table 7
. These include general
mechanisms that could be involved in tumorigenesis of any tissue. Other
potential mechanisms could be of particular importance in
adrenocortical tumorigenesis, however. These include abnormalities in
the recently described steroidogenic acute regulatory protein (42).
This protein enhances the mitochondrial conversion of cholesterol into
pregnenolone by the cholesterol side-chain cleavage enzyme, suggesting
that it is crucial for normal adrenal and gonadal steroidogenesis. More
recently, steroidogenic acute regulatory protein messenger ribonucleic
acid was expressed at high levels in normal human adrenals and
adrenocortical tumors, and it was up-regulated in parallel with
cholesterol side-chain cleavage cytochrome P450 by ACTH in adult
adrenocortical cells (43).
Another interesting protein of potential importance is steroidogenic
factor I (SF-1), a recently identified orphan nuclear receptor that is
a key regulator of the steroid hydroxylases in adrenocortical cells
(44, 45). Consistent with this role, SF-1 in adult mice is expressed in
all primary steroidogenic tissues, including the adrenal cortex,
testicular Leydig cells, and ovarian thecal and granulosa cells of the
follicle and luteinized cells of the corpus luteum (44). Targeted
disruption of the Ftz-F1 gene, which encodes SF-1, produced mice
homozygously deficient in both isoforms of this gene. Ftz-F1 null mice
had no adrenal glands and/or gonads, suggesting that this nuclear
receptor was essential for embryonic gonadal differentiation (45).
Whether abnormalities in the Ftz-F1 gene and SF-1 protein play roles in
human adrenocortical tumorigenesis remains unknown.
Recently, the DAX-1 gene, a new member of the nuclear hormone receptor
superfamily, was isolated and found to be deleted or mutated in several
patients with X-linked adrenal hypoplasia (46). The DAX-1 product acts
as a dominant negative regulator of transcription mediated by the
retinoic acid receptor (46). Whether abnormalities in the DAX-1 gene or
its product can be associated with human adrenocortical tumorigenesis
remains unknown.
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Therapy
|
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Hormone-secreting adrenocortical tumors and hormonally silent
adrenal masses with a diameter of 5 cm or more, or smaller masses with
a suspicious imaging appearance should be excised (Table 8
) (2, 3, 47). Surgical resection is also the only
therapy for adrenocortical carcinoma that unquestionably cures or
prolongs survival significantly, particularly if the disease is
detected at stages I and II (7, 8, 15). Radical excision with en
bloc resection of any local invasion offers the best chance for
cure. A wide exposure is needed, using an extended subcostal incision
or a thoracoabdominal approach (7). Patients apparently cured with
surgery require continued surveillance. Mitotane after complete
macroscopic resection in stage III and IV disease may be given to
increase the length of time between recurrences; however, this has not
been tested in a controlled study (6). An excellent review of the
treatment of adrenal cancer appeared recently (47).
Mitotane has been used extensively in patients with
adrenocortical carcinoma; however, this drug has been generally
ineffective in prolonging overall survival in the advanced stages of
the disease (6, 47). Mitotane acts as an adrenolytic agent, possibly by
causing alterations in mitochondrial function, blocking adrenal steroid
11ß-hydroxylation, and altering the extraadrenal metabolism of
cortisol and androgens. Studies demonstrated that high oral doses (up
to 1214 g/day) of mitotane caused remission of hypercortisolism in
5060% of patients with adrenocortical carcinoma; however, 610
month-long, objective tumor responses occurred in less than 20% of
these patients (3). The side-effects of mitotane are largely dose
related. Weakness, somnolence, confusion, lethargy, and headache are
reported in half of the patients treated (3, 6). More serious
neurotoxicity, such as ataxia and dysarthria, may also occur (7).
Gastrointestinal side-effects include anorexia, nausea, and diarrhea,
which are present in most patients. Skin rash, toxic retinopathy with
papilledema, and interstitial cystitis are less commonly seen.
Several alternative chemotherapeutic regimens have been used for
the treatment of metastatic adrenocortical carcinoma (Table 8
). They
include cisplatin, etoposide, 5-fluorouracil, doxorubicin, vincristine,
gossipol, suramin, and melphalan (48, 49, 50). Gossipol, a spermatoxin
derived from crude cottonseed oil, inhibits the growth of human
adrenocortical tumors in nude mice. Oral gossipol (3070 mg/day) was
used with relative safely in out-patients with metastatic adrenal
cancer; however, a partial tumor response rate was observed in only
17% (48). This is consistent with the generally poor response of
adrenal cancer to most medical therapies.
Combining mitotane with cytotoxic chemotherapy has been associated with
limited success (47, 48, 49, 50). Various regimens have been reported,
including those using mitotane and 5-fluorouracil, cisplastin and
etoposide, and cisplatin, doxorubicin and 5-fluorouracil. Theses
studies have not shown a significant prolongation of survival, although
some isolated reports of prolonged or complete remission were published
(48, 49, 50).
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Conclusions and future directions
|
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Although the sequence of events leading to adrenal tumorigenesis
is presently unclear, the process is multistep and variable from case
to case. A multiplicity and variety of genetic abnormalities may
account for the phenotypic heterogeneity of adrenocortical tumors.
Studies targeting cellular oncogenes and tumor suppressor genes as well
as genes involved in normal senescence, apoptosis, and differentiation
might provide not only knowledge of the mechanisms of adrenocortical
tumorigenesis, but also a new generation of cancer markers that could
help identify subjects at high risk for malignancies of the adrenal
cortex. Such markers would help with the development of better
management prevention strategies for these patients.
The advances in our understanding of molecular mechanisms of
oncogenesis may also provide a better choice and administration
schedule of therapeutic agents. New compounds are likely to be
developed that take advantage of the differences between the control of
the cell cycle in normal and cancer cells to maximize therapeutic
effectiveness. Telomerase inhibitors, apoptosis inducers, genomic
instability suppressants, and inducers of adrenocortical
differentiation are among the potential classes of agents that could be
administered or directed using gene therapy methods in adrenocortical
cells to produce the long elusive cure for adrenocortical cancer. The
use of monoclonal antibodies against adrenocortical antigens or
promoters coupled to powerful toxins and expressed specifically in
adrenocortical cells is probably a worthy alternative to pursue.
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Footnotes
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1 An edited and updated transcript of the 1994 Millie Schembechler
Memorial Lecture delivered by Dr. Chrousos at the University of
Michigan (Ann Arbor, MI). 
2 On sabbatical leave from the Division of Endocrinology, Hospital
das Clínicas, University of Sao Paulo (Sao Paulo,
Brazil). 
Received January 8, 1997.
Accepted January 29, 1997.
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References
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