Download Adrenal Carcinoma - LNMI - cleare

Adrenal Carcinoma.doc
(92 KB) Pobierz
Adrenal Carcinoma
Author: Bagi RP Jana, MD; Chief Editor: Jules E Harris, MD
Background
Adrenocortical cancers (ACs) are uncommon malignancies that can have
protean clinical manifestations. Adrenocortical masses are common;
autopsy studies show that approximately 5-15% of the general adult
population may have adrenal incidentalomas. Adrenal incidentalomas
are biochemically and clinically asymptomatic adrenal masses found
incidentally as a result of unrelated imaging investigations such as
abdominal CT or MRI scans. Findings from abdominal CT scans suggest
that the prevalence rate is 1-5%. Only a small number of adrenal tumors
are functional and an even smaller number are malignant.
Regardless of size, approximately 1 per 1500 adrenal tumors is
malignant. The evaluation of these incidentalomas, therefore, focuses on
(1) identifying functional masses and treating them appropriately
(including surgical removal); (2) identifying adrenal carcinomas early,
with the intent of attempting complete surgical extirpation; and (3)
reassuring the patients whose masses are neither functional nor
malignant and arranging for their subsequent follow-up.
Although the means of identifying ACs from this subpopulation still are
controversial, virtually all authorities agree about removing all
nonfunctional adrenal tumors larger than or equal to 6 cm because of the
significant potential cancer risk. Authorities also generally agree that
nonfunctional adrenal tumors (≤ 3 cm) have a very low probability of
being adrenal cancer; therefore, they can be observed safely.
The management strategy for adrenal masses larger than 3 cm and less
than 6 cm is disputed. Some authorities suggest lowering the threshold
for surgical removal of nonfunctional masses from 6 cm to 4-5 cm.
Others individualize the follow-up of these patients depending on their
clinical status, CT scan characteristics, and age. Particularly important is
the fact that these criteria do not apply to children, who generally have
smaller ACs. A review of the available data suggests that the incidence
rate of malignancy is small (< 0.03%) in all adrenal incidentalomas that
are 1.5-6 cm. However, this rate increases considerably with tumors
larger than 6 cm (up to 15%). The smallest identified AC associated with
metastasis reported in the literature was 3 cm in diameter.
Classifying adrenal tumors
Adrenal tumors are classified in several ways. One of the popular means,
which has great clinical relevance, is to subclassify them as functional or
nonfunctional, depending on the elaboration of adrenocortical hormones
(glucocorticoids, mineralocorticoids, androgens, estrogens, rarely a host
of possible peptides). Nonfunctional variants of AC were previously
reported to be far less common than the functional types; older reports
suggest that approximately 50-80% of ACs are functional, and patients
mainly present with Cushing syndrome. More recent reports suggest that
nonfunctional ACs may be more common than previously suggested.
While AC accounts for only approximately 5-10% of cases of Cushing
syndrome, approximately 40% of patients with both Cushing syndrome
and an adrenal mass also have a malignant tumor. Virtually all
feminizing adrenal tumors in men are malignant.
Another method is to subdivide ACs into sporadic and syndromic
variants. The syndromic variants occur with multiple cancer
predisposition syndromes, including Gardner syndrome, BeckwithWiedemann syndrome (associated with hemihypertrophy), multiple
endocrine neoplasia type 1, the SBLA syndrome (sarcoma, breast, lung,
and adrenal carcinoma and other tumors within several kindreds, which
have not been clearly associated with localization to a single gene), and
Li-Fraumeni syndrome. Other classification methods are dependent on
the cellular origin of the neoplasm. Included here are primary
adrenocortical carcinomas, primary adrenal lymphomas, soft-tissue
sarcomas of the adrenal, malignant pheochromocytomas, and secondary
metastatic adrenal tumors (common primaries are the breast, kidney,
lung, ovary, melanoma, leukemia, lymphoma). Only the adrenocortical
carcinomas typically are included in discussions of adrenal cancers, and
this monograph will be restricted to those.
Authorities also report rare composite adrenal tumors, which are
different histologic variant tumors of the same embryologic origin (eg,
coexisting neuroblastoma and malignant pheochromocytoma) and mixed
adrenal tumors (typically mixtures of pheochromocytoma, spindle cell
sarcomas, and adrenocortical carcinomas). These complex tumors
sometimes are called neuroendocrine carcinomas. Recognition of
primary adrenal lymphomas, as distinct from AC, is important not only
because these are rare (< 100 well-documented cases in the medical
literature), but also because they may be associated with a better
prognosis than AC because of the potential roles for standard lymphoma
treatment using multiagent chemotherapy and radiotherapy.
Pathophysiology
While some reports suggest an increased predilection for the left adrenal,
most reports suggest no side preference. The exact etiopathogenesis of
sporadic AC is unclear, but analysis of syndromic variants of the
condition gives some insight.
The role of tumor suppressor gene mutations is suggested by their
association with Li-Fraumeni syndrome, which is characterized by
inactivating germline mutations of the TP53 gene (a vital tumor
suppressor gene or antioncogene) on chromosome 17. This syndrome
also is associated with a predisposition to other malignancies, including
breast carcinoma, leukemias, osteosarcomas, and soft-tissue sarcomas. A
few reports describe an association between AC and familial
adenomatous polyposis, which also is due to a germline inactivating
mutation of a tumor suppressor gene (in this case, the adenomatous
polyposis coli gene, APC). However, such mutations have not been
found in sporadic APC cases. Others studies report the following:
Suggestions have been made that adrenal hyperplasia predisposes
patients to develop AC. A few cases of congenital adrenal hyperplasia
are associated with functional adrenocortical adenomas but not
carcinoma.
A few cases of AC are associated with primary hyperaldosteronism, in
which the adrenal tissue has portions showing adrenocortical
hyperplasia.
A definitive proof for a hyperplasia-to-adenoma-to-carcinoma sequence,
which occurs with colonic neoplasms, is lacking, although a multistep
tumor progression model has been suggested as a possible etiologic
basis for sporadic AC.
Among the putative pathogenetic mechanisms that may function in
concert are alterations in intercellular communication, paracrine and
autocrine effects of various growth factors, cytokines elaborated by the
tumor cells, and promiscuous expression of various ligand receptors on
the cell membranes of the cells that cause them to be in a state of
perpetual hyperstimulation. This is presumed to lead to clonal adrenal
cellular hyperplasia, autonomous proliferation, tumor formation, and
hormone elaboration.
Epidemiology
Frequency
International
AC tumors are uncommon. The incidence is approximately 0.6-1.67
cases per million persons per year. Some reports suggest an inordinately
high frequency (up to 10-fold higher) of cases among children in
southern Brazil, for unknown reasons. Overall, AC accounts for 0.020.2% of all cancer-related deaths; therefore, it is relatively rare.
Race
AC has no specific racial predilection.
Sex
The female-to-male ratio is approximately 2.5-3:1. Male patients tend to
be older and have a worse overall prognosis than female patients.
Female patients are more likely than male patients to have an associated
endocrine syndrome. Nonfunctional ACs are distributed equally between
the sexes.
Age
AC occurs in 2 major peaks: in the first decade of life and again in the
fourth to fifth decades. Approximately 75% of the children with AC are
younger than 5 years. Functional tumors also are more common in
children, while nonfunctional tumors are more common in adults.
History
Unfortunately, most patients with AC present with advanced disease that
is characterized by multiple abdominal or extra-abdominal metastatic
masses (stage IV disease); therefore, distinguishing potential AC from
adrenal incidentalomas is crucial (and controversial).
Nonfunctional variants: These hormonally silent tumors account for
approximately 40% of patients with AC. These tend to be more common
in older patients and appear to progress more rapidly than functional
tumors.
These typically present with fever, weight loss, abdominal pain and
tenderness, back pain, abdominal fullness, or symptoms related to
metastases.
In other cases, the mass is found incidentally, during either examination
or radiologic imaging.
Endocrine syndromes: The hormonally active variants of AC constitute
approximately 60% of cases.
Approximately 30-40% of adult patients present with the typical features
of Cushing syndrome, while 20-30% present with virilization
syndromes.
In children, however, more than 80% present with virilization
syndromes while isolated Cushing syndrome is much less common at
approximately 6% of cases. Virilization (in girls) or precocious puberty
(in boys) is the most common endocrine presentation of a functional AC.
Hirsutism, facial acne, oligo/amenorrhea, and increased libido all are
possible presenting symptoms. Feminization as a presentation of AC is
quite rare. Other modes of presentation include profound weakness,
hypertension, and/or ileus from hypokalemia related to
hyperaldosteronism and hypoglycemia.
Combined endocrine systems: Some cases of adrenal insufficiency are
described in association with primary adrenal lymphomas, while other
cases are associated with hypercalcemia.
Endocrine syndromes associated with adrenocortical carcinoma
Cushing syndrome (30%)
Virilization and precocious puberty (22%)
Feminization (10%)
Primary hyperaldosteronism (2.5%)
Combined hormone excess (35%)
Polycythemia ( < 1%)
Hypercalcemia ( < 1%)
Hypoglycemia ( < 1%)
Adrenal insufficiency (particularly from primary adrenal lymphomas)
Non–glucocorticoid-mediated insulin resistance
Catecholamine excess due to rare instances of coexisting
pheochromocytoma
Cachexia (usually preterminal)
Physical
The findings during examination are variable and depend on which, if
any, endocrine syndrome exists.
Patients may have the distinct typical features of Cushing syndrome,
including truncal obesity, striae, severe acne, malar flushing,
supraclavicular and dorsocervical fat pads, Conn syndrome
(hypertension with weakness and ileus resulting from hypokalemia),
virilization in girls, or precocity and feminization (rarely) in boys.
In the nonfunctional tumors, the major (and often only) finding is an
abdominal mass, typically in a flank.
Classification of adrenal malignancies
Adrenocortical carcinomas
Functional
Nonfunctional
Well differentiated
Intermediate
Poorly differentiated to anaplastic
Metastatic adrenal tumors - Most common potential primaries include
the following:
Lung
Breast
Melanoma
Renal cell carcinoma
Extra-adrenal lymphoma…
Causes
While the mutation-induced inactivation of tumor suppressor genes
appears to be a plausible mechanism for AC development, other
potential mechanisms, including activation of various protooncogenes
(eg, ras, PKC), inhibition of apoptosis, or changes in various
adrenocortical tissue-specific factors (eg, the steroidogenic acute
regulatory protein [StaR]) are possible. Potential mechanisms for
adrenocortical tumorigenesis are as follows:
Activation of various protooncogenes -Ras, PKC, C myc, C fos, G
proteins, G protein-coupled receptors (eg, for vasoactive intestinal
peptide [VIP], gastric-inhibitory peptide [GIP], luteinizing hormone
[LH], and catecholamines)
Inactivation of tumor suppressor genes (antioncogenes) -TP53, TP57,
TP16, H19, retinoblastoma gene, APC gene, various DNA repair
enzyme genes
Inhibition of senescence and/or apoptosis - Mutations involving
telomerase and/or BCL-2 genes
Changes in adrenocortical tissue-specific factors - Mutations involving
the genes for StaR, SF-1 (steroidogenic factor), and Dax-1 transcription
factor
Aberrant expression of receptors to normal adrenocortical trophic agents
and ligands - Adrenocorticotropic hormone, angiotensin 2,
catecholamines, and endorphins
Ectopic expression of receptors on adrenocortical cells to atypical
trophic factors and ligands - Cytokines, growth factors, and
neurotransmitters
Laboratory Studies
Include screening tests that can exclude excess hormone production
when evaluating all primary adrenal masses.
The best screening tests for Cushing syndrome are the standard 1-mg
dexamethasone suppression test and the 24-hour urinary cortisol
excretion test. The recent recognition of the relatively high prevalence of
subclinical Cushing syndrome in adrenal incidentalomas (some reports
suggest a prevalence as high as 5-8%) that may otherwise appear
hormonally silent informs the policy of some experts to perform more
in-depth testing of the HPA axis in patients with identified adrenal
masses. Such testing would include the screening tests mentioned as
well as diurnal rhythm evaluation with 8 am and midnight serum or
salivary cortisol estimations, corticotropin-releasing hormone (CRH)
stimulation test, serum adrenocorticotropic hormone (ACTH)
estimations (generally found to be low), and serum
dehydroepiandrosterone (DHEAS) levels (also generally found to be
suppressed). Alternatively, 24-hour urinary cortisol and its metabolites
can be measured.
Screen for hyperaldosteronism by using simultaneous aldosterone and
renin levels to compute aldosterone-to-renin ratios.
Screen for virilization syndromes using serum adrenal androgens
(androstenedione, dehydroepiandrosterone, dehydroepiandrosterone
sulfate), serum testosterone, and 24-hour urinary 17 ketosteroids.
Plasma estradiol and/or estrone tests can help screen for feminization
syndromes.
The evaluation of adrenal masses also must include screening for
possible pheochromocytoma, including, at a minimum, a 24-hour
urinary estimation of catecholamines (epinephrine, norepinephrine,
dopamine) and metabolites (particularly metanephrines and
normetanephrines). In addition, plasma metanephrines and
catecholamines can be assayed.
Imaging Studies
CT scans and MRI
Adrenal CT scans and MRI are the imaging studies of choice. The
typical case is characterized by a large unilateral adrenal mass with
irregular edges. The presence of contiguous adenopathy serves as
corroborating evidence. While the issue of exactly what cutoff
dimension size of adrenal masses should elicit a decision for surgical
removal irrespective of hormonal functionality, clearly larger tumors
have a greater chance of being carcinomatous. The National Italian
Study Group review of adrenal incidentalomas demonstrated that 90% of
AC cases had diameters of 4 cm or larger on radiologic imaging. This
study, based on a cohort of 887 patients, showed that using the 4 cm
cutoff resulted in a 90% sensitivity but a poor specificity.
Targeted CT scans of the adrenal using 3- to 5-mm sections offer the
best resolution and are particularly useful in detecting tumors that are 1
cm or smaller.
Intravenous contrast generally is not necessary for localization of
adrenal masses but is useful for demonstrating vascularity and clarifying
sites of metastases. Some reports have also shown that adrenal adenomas
compared with ACs have a much earlier washout of contrast
enhancement and that this may be of diagnostic utility. The contrast
washout at 5 minutes postinjection is approximately 50% versus 8% in
adenomas versus nonadenomas, and at 15 minutes, the contrast washout
is approximately 70% versus 20%.
Accumulating evidence suggests that low attenuation values on
unenhanced CT scans can distinguish benign adrenal adenomas from AC
or metastatic adrenal deposits that have attenuation values generally
greater than 20 Hounsfield units (HU). Authorities suggest that
adenomas have HU values of 10 or less. However, many caveats
significantly limit the clinical utility of this. Authorities also suggest
using norms for HU values in intravenous contrast studies to assist in
distinguishing adrenal adenomas from AC. The sensitivity and
specificity for the 10 and 20 HU cutoffs in distinguishing adenomas
from nonadenomas, including AC and pheochromocytoma, were 40.5%
and 100% for adenomas and 58.2% and 96.9% for nonadenomas. These
numbers suggest that, while limited as a screening instrument, the HU
score has considerable utility in making definitive diagnoses when the
scores are either less than 10 HU or greater than 20 HU.
The MRI, in particular, shows significant utility in distinguishing
adrenocortical carcinoma from nonfunctional adenomas and
pheochromocytomas. The malignant lesions tend to be intermediate-tohigh density on T2 imaging, while the nonfunctional adenomas are low
intensity, and pheochromocytomas have a very high signal intensity. On
gadolinium–diethylenetriamine pentaacetic acid (DTPA) contrastenhanced MRIs, adenomas generally demonstrate mild enhancement
with rapid contrast washout, while ACs show rapid and intense
enhancement with sluggish washout. The relatively higher fat content of
adrenal adenomas compared with ACs has also been used in the new
chemical shift imaging (CSI) MRI protocols to further enhance the
distinguishing capacity of these studies.
Ultrasonography
This test has less sensitivity in detecting adrenal tumors and is highly
user-dependent in its interpretation and quality of results.
It has particular utility, however, in the follow-up of previously detected
incidentalomas.
Iodocholesterol scans rarely are indicated in suspected cases of AC, and
the findings generally are negative in this setting, unlike in steroidsecreting adrenal adenomas.
Arteriography and venography currently have very little, if any, place in
the diagnostic evaluation of adrenal masses suspected to be AC.
The following are the major imaging features that serve as red flags for a
possible AC on adrenal imaging:
Irregular shape
Large size (larger than 4 cm in diameter)
Intralesional calcification
Tumor heterogeneity on both plain and contrast enhancement, which
may indicate intralesional hemorrhage, necrosis, or both
(Inhomogeneous density estimates by CT in various parts of the tumor
on both plain and contrast-enhanced images may also indicate
intralesional hemorrhage.)
Unilateral location
High CT attenuation values (especially with >20 HU)
Evidence of tumor invasion of local structures or extension into major
vessels
Other Tests
Because the histologic analysis of these masses may be unreliable, fine
and/or core tissue needle aspiration biopsies (percutaneous route)
generally are not recommended except for possible metastatic deposits.
Fine-needle aspiration and core tissue biopsy
The fine-needle and/or percutaneous core biopsies may be CT-guided or
ultrasound-guided. Presently, the only setting where this is justified is in
the evaluation of patients with a known malignancy, in order to exclude
adrenal metastases.
Fine-needle aspiration or core tissue biopsy has no role in the diagnostic
workup of adrenal incidentalomas because of both the minimal
likelihood of a definitive diagnosis and the potential for tumor seeding
into the retroperitoneum.
Never perform fine-needle aspirations on any adrenal mass without first
definitively excluding a pheochromocytoma; otherwise, the procedure
may precipitate a potentially fatal crisis.
Histologic Findings
A specific histologic diagnosis may be difficult in a case that is lacking
clinical evidence of metastasis. Some of the macroscopic features that
suggest malignancy include a weight of more than 500 g, the presence of
areas of calcification or necrosis, and a grossly lobulated appearance.
In the Weiss system, which is considered the standard for determining
malignancy in adrenocortical tumors, tumors are scored from 0 to 9,
with a higher score correlating with increased malignancy.[3] As an
adjunct to the Weiss score, Soon et al studied the use of microarray gene
expression profiling to discriminate between adrenocortical adenomas
and carcinomas; they found that the combination of IGF2 and Ki-67
overexpression identified adrenocortical carcinomas with 96%
sensitivity and 100% specificity.
Cortical tumors
These typically have a yellowish-brown appearance on the cut surface.
Pathologic features suggestive of malignancy are the large size of the
primary tumor (tumor weights >100 g suggest malignancy); high mitotic
rate; atypical mitoses; high nuclear grade; large areas of necrosis; low
percentage of clear cells; diffuse cellular architecture; and evidence of
capsular, lymphatic, or vascular invasion.
Tumors may have broad fibrous bands separating them into nodules, and
they often have a variegate appearance, a zona glomerulosalike
appearance, or a fasciculata and reticularis appearance. Still, other areas
may show near-total dedifferentiation.
Most of the cells are lipid-poor compared to typical adrenocortical cells,
and they have an eosinophilic cytoplasm. Pleomorphic bizarre-looking
cells and multinucleate giant cells also may be evident. Predicting the
hormonal products of a particular tumor based on histologic appearance
is impossible.
Distinction between adrenocortical and adrenomedullary tumors
These have distinctive histologic appearances and immunohistochemical
staining patterns. While adrenomedullary tumors stain positive for
neuroendocrine markers (eg, synaptophysin, neuron-specific enolase,
chromogranin A), adrenocortical cells stain positive for D11, with very
little overlap. ACs are virtually always unilateral. One report suggests
that 2-10% of cases may be bilateral at initial diagnosis, but this finding
has not been replicated. Ectopic adrenocortical tumors are exceedingly
rare.
Staging
Staging for adrenal carcinoma, according to the International Union
Against Cancer[5] :
Tumor criteria
T1 - Tumor diameter £ 5 cm with no local invasion
T2 - Tumor diameter > 5 cm with no local invasion
T3 - Tumor of any size with local extension but not involving adjacent
organs
T4 - Tumor of any size with local invasion of adjacent organs
Lymph node criteria
N0 - No regional lymph node involvement
N1 - Positive regional nodes
Metastasis criteria
M0 - No distant metastasis
M1 - Distant metastasis
Stages
Stage 1 - T1, N0, M0
Stage 2 - T2, N0, M0
Stage 3 - T1 or T2, N1, M
T3, N0, M0
Stage 4 -T3, N1, M0
T4, any N, M0
Any T, any N, M1
Fassnacht et al argue that the International Union Against Cancer has
limited prognostic value. After reviewing 492 patients in the German
adrenocortical carcinoma registry who were diagnosed between 1986
and 2007, these researchers proposed that the prognostic value would be
improved if stage 3 disease were defined by the presence of positive
lymph nodes, infiltration of surrounding tissue, or ...
Plik z chomika:
cleare
Inne pliki z tego folderu:





04.MPG (34154 KB)
16.MPG (49228 KB)
11.MPG (51212 KB)
07.MPG (43178 KB)
10.MPG (31960 KB)
Inne foldery tego chomika:

badanie fizykalne filmiki ANG
 chirurgia
 Dokumenty
 Galeria
 lep kursy
Zgłoś jeśli naruszono regulamin







Strona główna
Aktualności
Kontakt
Dla Mediów
Dział Pomocy
Opinie
Program partnerski




Regulamin serwisu
Polityka prywatności
Ochrona praw autorskich
Platforma wydawców
Copyright © 2012 Chomikuj.pl