| Recent
advances in histopathology and immunohistochemistry of adrenocortical
carcinoma.
Endocr Pathol. 2006
Winter;17(4):345-54.
Discerning
malignancy in resected adrenocortical neoplasms can pose diagnostic
difficulty. Macroscopic examination is the first important step toward
diagnosis and should include accurate measurement of weight and
dimension of the specimens and description of the cut surface of the
tumors. It is also important to sample the specimens for histological
diagnosis near foci of hemorrhage and/or necrosis. Histological
scoring systems evaluating multiple parameters, especially the
criteria of Weiss, have been shown to be reliable in differential
diagnosis between adrenocortical adenoma and carcinoma. A tumor is
defined as adrenocortical carcinoma when three or more of the
following criteria are met; (1) high nuclear grade, (2) mitotic rate
six or more per 50 high power fields, (3) atypical mitosis, (4) clear
cells less than 25%, (5) a diffuse architecture pattern in more than
one-third of the tumor, (6) confluent necrosis, (7) venous invasion,
(8) sinusoidal invasion, and (9) capsular invasion. The criteria are
relatively straightforward and considered the most effective standard
for diagnosis of adrenocortical malignancy. However, great care should
be taken in applying the criteria to histological evaluation of two
relatively rare and peculiar adrenocortical tumors, adrenocortical
oncocytoma and pediatric adrenocortical neoplasms. At this juncture,
ancillary biological or molecular markers are of little practical
value in terms of differential diagnosis between adrenocortical
adenoma and carcinoma but tumors with MIB1 or Ki-67 labeling index
more than 2.5 may be considered malignant. Prognostic markers of
adrenocortical carcinoma have not been established other than complete
respectability of the tumor. There are also no surrogate markers for
predicting response to therapy with Mitotane, an adrenolytic agent. It
sometimes is important for surgical pathologists to differentiate
adrenocortical carcinoma from metastatic malignancies of other sites.
An immunohistochemical evaluation of adrenal 4 binding protein (Ad4BP)
or SF-1, a transcription factor of all steroidogenesis, can aid in
this differential diagnosis because nuclear immunoreactivity for this
transcription factor is relatively specific to steroid producing
cells.
Pigmented adrenocortical carcinoma: case report and review.Endocr
Pathol. 2006 Fall;17(3):297-304.
Darkly
pigmented adrenocortical neoplasms are rare tumors that are often
referred to as "black adenomas," indicative of both their pigmented
nature and their invariably benign clinical behavior in previously
reported cases. We herein describe an exceptional case of a malignant
pigmented adrenocortical neoplasm, with late recurrence and
metastasis. At age 53, this female patient was diagnosed with
Cushing's syndrome and underwent a laparoscopic right adrenalectomy,
revealing a 3 cm well-circumscribed, darkly pigmented adrenocortical
tumor. The tumor exhibited several atypical histologic features and
was diagnosed as an atypical pigmented adrenal cortical neoplasm of
uncertain malignant potential. Eight years later, the patient
developed clinical and biochemical evidence of recurrent Cushing's
syndrome, and imaging studies revealed the presence of several masses
in the right retroperitoneum. At subsequent exploratory laparotomy,
three separate tumor nodules exhibiting varying degrees of
pigmentation and ranging from 2.2 to 3.3 cm maximum dimension were
excised. Histologically, the tumor nodules were consistent with local
recurrence/metastasis of the patient's previously excised pigmented
adrenocortical neoplasm.
Functioning
adrenocortical carcinoma with superior vena cava and upper airway
obstructions.J
Med Assoc Thai. 2006
Sep;89(9):1511-5.
BACKGROUND:
Adrenocortical carcinoma (ACC) is one of the most aggressive endocrine
malignancies with a dismal prognosis. Typically, the tumor is large
and has regional invasion or distant metastasis at initial
presentation. OBJECTIVE: To describe an unusual case of functioning
ACC presenting with superior vena cava (SVC) and upper airway
obstruction. MATERIAL AND METHOD: A 23-year-old man with cushingoid
appearance was evaluated for a neck mass and SVC syndrome. Hormonal
assessment and neck mass biopsy including immunohistochemistry study
were performed RESULTS: Cushing's syndrome was confirmed by elevated
24-hr urinary free cortisol and no suppressible cortisol level after
standard low dose (2 mg/day) of dexamethasone suppression test.
Computerized tomography (CT) study revealed a huge left suprarenal
mass and multiple mediastinal lymph nodes compressing SVC and trachea.
Histopathological findings of the neck mass were compatible with
metastatic ACC. CONCLUSION: The present report describes a functioning
ACC patient with an unusual metastatic site causing SVC and upper
airway obstruction. His hospital course was progressively worsened due
to peptic perforation and decompensated respiratory failure, which led
him to expire.
Clinical review:
Adrenocortical carcinoma: clinical update.
J Clin Endocrinol Metab. 2006
Jun;91(6):2027-37.
CONTEXT:
Adrenocortical carcinoma (ACC) is a rare and heterogeneous malignancy
with incompletely understood pathogenesis and poor prognosis. Patients
present with hormone excess (e.g. virilization, Cushing's syndrome) or
a local mass effect (median tumor size at diagnosis > 10 cm). This
paper reviews current diagnostic and therapeutic strategies in ACC.
EVIDENCE ACQUISITION: Original articles and reviews were identified
using a PubMed search strategy (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi)
covering the time period up until November 2005. The following search
terms were used in varying combinations: adrenal, adrenocortical,
cancer, carcinoma, tumor, diagnosis, imaging, treatment, radiotherapy,
mitotane, cytotoxic, surgery. EVIDENCE SYNTHESIS: Tumors typically
appear inhomogeneous in both computerized tomography and magnetic
resonance imaging with necroses and irregular borders and differ from
benign adenomas by their low fat content. Hormonal analysis reveals
evidence of steroid hormone secretion by the tumor in the majority of
cases, even in seemingly hormonally inactive lesions. Histopathology
is crucial for the diagnosis of malignancy and may also provide
important prognostic information. In stages I-III open surgery by an
expert surgeon aiming at an R0 resection is the treatment of choice.
Local recurrence is frequent, particularly after violation of the
tumor capsule. Surgery also plays a role in local tumor recurrence and
metastatic disease. In patients not amenable to surgery, mitotane
(alone or in combination with cytotoxic drugs) remains the treatment
of choice. Monitoring of drug levels (therapeutic range 14-20
mg/liter) is mandatory for optimum results. In advanced disease, the
most promising therapeutic options (etoposide, doxorubicin, cisplatin
plus mitotane, and streptozotocin plus mitotane) are currently being
compared in an international phase III trial (www.firm-act.org).
Adjuvant treatment options after complete tumor removal (e.g. mitotane,
radiotherapy) are urgently needed because postoperative disease-free
survival at 5 yr is only around 30%, but options have still not been
convincingly established. National registries, international
cooperations, and trials provide important new structures for patients
but also for researchers aiming at systematic and continuous progress
in ACC. However, future advances in the management of ACC will mainly
depend on a better understanding of the molecular pathogenesis
facilitating the use of modern cancer treatments (e.g. tyrosine kinase
inhibitors).
Fine-needle aspiration of adrenal cortical carcinoma: cytologic
spectrum and diagnostic challenges.
Am J Clin Pathol.
2006 Sep;126(3):389-98.
We reviewed
the cytologic features of 20 adrenal cortical carcinomas (ACCs; 9
primary and 11 metastatic) from 19 patients and highlighted diagnostic
pitfalls. The mean size of primary ACCs was 11.9 cm, and that of
metastatic ACCs was 3.0 cm. The metastatic sites were liver, lung,
lymph node, soft tissue, and bone. Primary and metastatic ACCs were
cytologically similar and showed a wide range of features varying from
well-differentiated tumor resembling a benign cortical lesion or
low-grade neuroendocrine tumor to poorly differentiated pleomorphic
tumor mimicking poorly differentiated carcinoma, melanoma, or
high-grade sarcoma. The common cytologic features were
hypercellularity (70% of cases), necrotic debris in the background
(70%), moderate to marked nuclear pleomorphism (80%), mitotic figures
(90%), and prominent nucleoli (60%). Twenty percent of cases exhibited
all 5 features; 40% exhibited 4 features, and 40% exhibited 3
features. Necrosis and/or mitosis were found in all cases, even in
tumors with bland cytologic features. Cytologic, immunophenotypic, and
ultrastructural findings should be correlated with clinical and
radiologic information for achieving a proper cytologic diagnosis.
Extent of disease at
presentation and outcome for adrenocortical carcinoma: have we made
progress?World J Surg.
2006 May;30(5):872-8.
BACKGROUND:
Adrenocortical carcinoma (ACC), a rare and aggressive malignancy,
accounts for up to 14% of adrenal incidentalomas. The only chance of
cure for ACC is diagnosis at an early stage; therefore, a main
indication for adrenalectomy in patients with adrenal incidentaloma
has been the potential risk of ACC. Recent studies suggest that this
has led to earlier stage of ACC at diagnosis, more curative
operations, and better survival. METHODS: We analyzed data on ACC from
The National Cancer Institute's Surveillance, Epidemiology, and End
Results (SEER) database. Four equal time quartiles (1973-1979,
1980-1986, 1987-1993, and 1994-2000) were compared for changes in
demographics, pathology, treatment, and cause-specific mortality.
RESULTS: The average age was 51.2 years (range: 1-97), and 45.9% of
patients were men. The average tumor size was 12 cm (range: 2-36 cm),
and only 4.2% were < or = 6 cm. Most (88%) patients had surgical
resection of their tumor, and external beam radiotherapy was used in
only 12% of patients. Between the time quartiles compared (as well as
annually), there was no significant difference at presentation in age
at diagnosis, sex, race/ethnicity, tumor size, tumor grade, the
frequency of distant metastasis, and overall TNM stage. Low tumor
grade, lower stage of ACC, later time quartile, and surgical resection
were associated with a lower cause-specific mortality by univariate
analysis (P < or = 0.002) and by multivariate analysis (P < or =
0.031). CONCLUSIONS: Although adrenal incidentalomas have become a
common indication for adrenalectomy, this has not resulted in patients
with ACC being diagnosed earlier or treated at a lower stage of
disease at the national level. The most important predictors of
survival in these patients are tumor grade, tumor stage, and surgical
resection.
Risk assessment in
457 adrenal cortical carcinomas: how much does tumor size predict the
likelihood of malignancy?J
Am Coll Surg. 2006 Mar;202(3):
423-30.
BACKGROUND:
Laparoscopic adrenalectomy for tumors > 6 cm is controversial because
of the risk of malignancy, but data to support this position are
mostly from small series. The recent NIH consensus conference did not
make a definitive recommendation about management of 4- to 6-cm
nonfunctioning incidentalomas. STUDY DESIGN: Adrenocortical carcinomas
(ACC) recorded in the Surveillance, Epidemiology, and End Results
(SEER) database (1988 to 2000) were compared with benign functional or
nonfunctional adrenal cortical adenomas (excluding aldosteronomas)
operated on at our institution between January 1, 1993, and July 1,
2003. Data were compared using t-tests, chi-square tests, likelihood
ratios, and receiver operating characteristic (ROC) curves. RESULTS:
We identified 457 patients with ACC and 47 patients with adrenal
cortical adenomas; 376 and 44 neoplasms, respectively, had tumor size
data available. Tumor size was larger in ACC (12.0 +/- 5.6 versus 4.2
+/- 1.9 cm, mean +/- SD, p < 0.05). For ACC presenting with local
disease, the sensitivity, specificity, and likelihood ratios of tumor
size to predict malignancy were 96%, 52%, and 2.0, respectively, for
tumors > or = 4 cm; 90%, 80%, and 4.4 for tumors > or = 6 cm; 77%,
95%, and 16.9 for tumors > or = 8 cm; and 55%, 98%, and 24.4 for
tumors > or = 10 cm. Assuming a pretest probability of malignancy of
5%, the likelihood ratios derived from this study yield a posttest
probability of 10%, 19%, and 47% for cancer in adrenal cortical tumors
> or = 4 cm, > or = 6 cm, and > or = 8 cm, respectively. CONCLUSIONS:
These data suggest that size is useful for predicting malignancy, and
that at a size threshold of > or = 4 cm, the likelihood of malignancy
doubles (to 10%) and it is more than ninefold higher for tumors > or =
8 cm (47%).
Matrix
metalloproteinase type 2 expression in malignant adrenocortical
tumors: Diagnostic and prognostic significance in a series of 50
adrenocortical carcinomas.Mod
Pathol. 2006 Dec;19(12):1563-9.
The
differential diagnosis of adrenocortical carcinoma from adrenocortical
adenoma is based on different pathological parameters, usually
incorporated in scoring systems, which unfortunately lack a 100%
sensitivity and specificity. Little is known on the molecular
mechanisms leading to the malignant phenotype in adrenocortical
tumors. Among other molecules, metalloproteinases were demonstrated to
be implicated in malignant progression and metastatization of solid
tumors, including endocrine ones. Therefore, we aimed to investigate
metalloproteinases and their inhibitors expression in a series of 50
adrenocortical carcinomas and 50 control adrenocortical adenomas,
diagnosed according to the Weiss histological criteria.
Immunohistochemical results were scored by semiquantitative analysis
and compared with clinicopathological parameters and outcome.
Metalloproteinase type 2 gave the most significant result, being
detected in neoplastic cells in 1/50 adrenocortical adenomas (2%) and
37/50 adrenocortical carcinomas (74%) (P < 0.001), with a focal (score
1, <20% of positive cells--two-thirds of cases) or diffuse (score 2,
>20% of positive cells--one-third of cases) pattern. In addition,
diffuse (score 2) metalloproteinase type 2 protein expression, as
compared to focal or negative immunostaining, correlated with shorter
survival (P < 0.02) and disease-free interval (P = 0.05). No
correlation was found comparing metalloproteinase type 2 expression
and any clinicopathological parameter. Our data indicate that
metalloproteinase type 2 immunohistochemical localization in tumor
cells is significantly restricted to malignant adrenocortical tumors,
with high specificity but low sensitivity. In addition, a strong
metalloproteinase type 2 expression in adrenocortical carcinoma was
for the first time recognized as an unfavorable prognostic factor.
Pathologic features
of prognostic significance for adrenocortical carcinoma after curative
resection.
Arch Surg.1999 Feb;134(2):181-5.
OBJECTIVE: To
identify the pathologic features of prognostic significance in
patients with resectable adrenocortical carcinomas. DESIGN:
Retrospective review. SETTING: Tertiary referral center. PATIENTS:
Review of the Memorial Sloan-Kettering Cancer Center prospective
adrenocortical carcinoma database from 1986 through 1996 identified 46
patients who underwent curative adrenalectomy for primary disease. All
cases were reviewed by a single pathologist and each primary tumor was
characterized by 16 separate pathologic parameters. MAIN OUTCOME
MEASURE: Overall survival rates in the patient population. RESULTS:
The 5-year overall survival rate for the entire cohort was 36% (median
survival rate, 28 months). Of the pathologic factors analyzed, tumor
size, number of mitotic figures, and the presence of intratumoral
hemorrhage were independent prognostic factors. Patients presenting
with primary tumors larger than 12 cm (n = 30) had a worse outcome
compared with those with smaller tumors (n = 16) (5-year survival
rate: 53% vs. 22%, P<.05). Mitotic count (> or =6 per 10 high-power
fields) was a negative prognostic feature (n = 15) with a 5-year
survival rate of 13% vs. 51% for 0 to 6 mitotic figures per 10
highpower fields (n = 31, P<.05). Intratumoral hemorrhage (n = 23) was
also a negative prognostic factor compared with no evidence of
intratumoral hemorrhage (n = 23) (5-year survival rate, 53% vs. 22%,
P<.05). Overall survival rates were also calculated based on the
number of pathologic risk factors. Patients with no risk factors had
an 83% 5-year survival rate, which decreased to 42% with 1 factor, 33%
with 2 factors, and 0% with all 3 risk factors. CONCLUSIONS: Tumor
size, hemorrhage, and mitotic count correlate with survival rates for
patients undergoing curative resection. Based on these pathologic
factors, adrenocortical carcinomas may be divided into low- and
high-risk groups.
Cytomorphology of
adrenocortical carcinoma and comparison with renal cell carcinoma.
Acta Cytol.1997
Mar-Apr;41(2):385-92.
OBJECTIVE: To
review the cytomorphologic features of adrenocortical carcinoma (ACC),
correlate them with histology and compare them with the
cytomorphologic features of very similar renal cell carcinoma (RCC) on
fine needle aspiration (FNA) smears. STUDY DESIGN: Cytomorphologic
features in 7 cases of ACC in FNA smears were analyzed and compared
with those in 10 cases of RCC. Five cases of ACC and five of RCC were
later confirmed on histopathology. Parameters analyzed pertained
mainly to architectural, cytoplasmic and nuclear features. RESULTS:
The presence of cells in sheets with a central, thin-walled vascular
core (endocrine vascular pattern); monomorphic cell population;
eccentric nuclei; focal dramatic anisonucleosis; and focal spindling
with crushing was a prominent feature of ACC in contrast to RCC, which
showed mainly an acinar pattern with only a focal endocrine pattern,
well-defined cytoplasmic angles and projections, and cytoplasmic
vacuolations; pleomorphism, if present, was gradual and seen uniformly
in all the cells. Univariate analysis using the chi 2 test showed the
presence of endocrine architecture; focal dramatic anisonucleosis;
crushed spindle fragments; eccentric nuclei; and absence of
cytoplasmic vacuolizations as significant differentiating features in
favor of ACC (P < .05). CONCLUSION: A cytomorphologic comparison of
ACC with RCC showed that differentiation is possible by a set of
statistically significant features that not only have diagnostic value
but, as with crushed spindle fragments, also have prognostic
significance.
Adrenal cortical
neoplasms. A study of 56 cases.Am
J Clin Pathol. 1996
Jan;105(1):76-86.
Fifty-six
cases of adrenal cortical neoplasm with a minimum of 5 years follow-up
are presented: 48 carcinomas and 8 adenomas. Adenomas typically had a
maximal mitotic rate of fewer than 2 mitotic figures per 10 high-power
fields (all cases), a prominent small nest growth pattern (7 cases),
predominantly clear or foamy cytoplasm (6 cases), and no tumor
necrosis (all cases), whereas carcinomas were characterized by at
least 4 mitotic figures (often many more) per 10 high-power fields in
the most active area (all cases), lack of a significant small nest
growth pattern component (45 cases--solid or trabecular growth most
common), at least a considerable proportion of cells with eosinophilic
cytoplasm (all cases), and tumor necrosis (45 cases). Carcinomas were
almost always larger than adenomas, but two adenomas (5.9 cm and 7 cm)
overlapped in size with the four smallest carcinomas (5.5 cm, 6 cm, 7
cm, and 7 cm, respectively). The patients with adenomas were older on
the average than those with carcinomas (median 58 years, range 31-71
years versus median 41 years, range 5 months-66 years). Two adenomas
and 19 carcinomas were functional. No patient with adenoma had
recurrence of tumor after excision, whereas all but nine carcinoma
patients died of tumor, after 1 to 183 months. Among carcinoma
patients, survival was significantly shorter when distant metastases
were manifest at diagnosis (P = .0003). There was a trend toward
shorter survival with higher mitotic rates and functional tumors, but
neither these nor any other parameter had a statistically significant
relationship to survival or tumor behavior when presence/absence of
metastases at diagnosis was taken into account.
Adrenocortical
carcinoma: clinical and laboratory observations. Cancer.2000 Feb
15;88(4):711-36.
BACKGROUND:
The clinical features and natural history of adrenocortical carcinoma
are highly dependent on the type of center reporting their experience.
Observations from oncology services suggest a high incidence of
nonfunctioning tumors, whereas reports from endocrine clinics
emphasize excessive corticoid and androgen production in the majority
of tumors. The incidence rate and natural history of childhood adrenal
carcinoma generally has been under emphasized. METHODS: Over the past
17 years, the authors have evaluated and treated 47 patients with
adrenocortical carcinoma referred to the University of Sao Paulo, 22
of whom were children. RESULTS: There is a bimodal age incidence of
adrenal carcinoma, with the disease peaking in the first and fourth
decades of life. Childhood adrenal carcinoma is characterized by a
high rate of incidence of virilization, marked overproduction of
androgens, and a less aggressive clinical course, and appears to be
more amenable to surgical and other therapeutic modalities. By
contrast, adrenocortical carcinoma occurring in adults presents more
commonly as a mixed Cushing and virilizing syndrome, with
overproduction of corticoids and androgens and a far more aggressive
clinical course, leading to rapid death within months or years.
Nonfunctioning adrenocortical carcinoma is less common; it generally
occurs in older adults and exhibits a rapid downhill course. Modern
day imaging methods have improved the diagnosis and staging of adrenal
carcinoma greatly. In the authors' experience, the histologic criteria
of Weiss appeared to predict tumor prognosis most accurately, whereas
immunologic markers, cytoskeletal markers, DNA ploidy, cell phase
markers, and oncogenic probes have yielded inconsistent results to
date. Surgical removal of a localized tumor remains the best hope for
long term survival. Medical therapy with mitotane and its successors
in patients with Stage III or IV (MacFarlane system as modified by
Sullivan et al.) disease appear to have added little to longevity or
quality of life. CONCLUSIONS: When diagnosed in children, adrenal
carcinoma is associated with virilism and a less aggressive natural
history; however, when it occurs in adults, the disease presents more
commonly as a mixed Cushing-virilizing syndrome and has a virulent
course. The Weiss histologic criteria appear to correlate best with
disease prognosis, but other histochemical, cell cycle, and genetic
markers have not, to date, aided in disease management.
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