Early and Precursor Lesions in Endocrine Pathology
Moderators: Thomas Giordano, Paul Komminoth, Martin Anlauf, William D. Travis
Early and Precursor Lesions of the Adrenal Gland
Thomas J. Giordano
Department of Pathology
University of Michigan Health System
Ann Arbor , MI , USA
Incipient neoplasia is one of the most challenging areas of surgical pathology. This is particularly
true for lesions of the endocrine system, including those of the adrenal gland. Much controversy exists
regarding the definitions of commonly used terms such as "within normal
limits", "diffuse and nodular hyperplasia" and "neoplasm". This is a direct consequence of the rarity of these lesions and the lack
of availability of specimens that represent the entire population spectrum. Many of these lesions are
asymptomatic and thus usually go clinically undetected until they have developed well beyond the
incipient category. For instance, it is especially difficult to derive the age and sex-appropriate
cutoffs for how many C cells constitute C cell diffuse hyperplasia due to the
lack of availability of truly normal thyroids from across the full spectrum of the population.
One of the recent trends in medicine is the increasing incidence of the adrenal
incidentaloma, i.e. a mass of the adrenal gland incidentally discovered during imaging studies for
other medical conditions such as trauma . The majority of these tumors are benign cortical adenomas, but occasionally they are either malignant (adrenal cortical carcinoma) or rarely evolve into carcinoma over time.
The patient is a 42 old female who was found to have a 2 cm adrenal mass by CT. She was otherwise in
reasonably good general health and was lost to followup. About 4 years later, she developed excessive
hair growth on her face, abdomen, and legs. She also complained of a 25 lb weight gain over the past 2
years. Ultrasound of the abdomen uncovered a left adrenal mass. Laboratory evaluation revealed an
elevated testosterone. The patient underwent left adrenal resection. The resection specimen consisted
of an adrenal yellow-tan encapsulated mass with up to 20% areas of necrosis and weighed 180 with a
maximum diameter of 6 cm. A somewhat distinct appearing 1.5 cm area was also noted grossly.
Microscopically, the bulk of the tumor consisted of a cellular neoplasm with large cells
separated by prominent yet delicate blood vessels. Tumor cells displayed abundant eosinophilic
cytoplasm, round nuclei with prominent nucleoli, occasional mitotic figures, and patchy areas of tumor
necrosis. Focally, areas of lipid-rich cells with clear cytoplasm were present. The tumor was
surrounded by a fibrous capsule, but importantly there were numerous foci of both vascular and capsular
invasion. The overall picture of the pathology of this tumor was a low-grade adrenal cortical carcinoma
with capsular and vascular invasion.
The distinct area noted grossly was an area of relatively pure lipid-rich cells without the associated
features of carcinoma described above. Thus, this nodule displayed the typical pathologic features of an
adrenal cortical adenoma.
Despite treatment, the following year the patient developed a prominent skull-based
metastasis that was proven to be metastatic adrenal cortical carcinoma by biopsy. The patient then
followed a downhill course and expired with the year of metastatic disease.
This case illustrates the rare instance in which a small adrenal cortical tumor eventually
developed into a life-ending adrenal cortical carcinoma. As is often the case, finding small adrenal
cortical carcinomas is exceedingly difficult, but given the increasing incidence of incidentaloma, cases
like these are bound to become more frequent. Even rare is finding a carcinoma with areas that resemble
adenoma, a finding that has led to the belief by some that adrenal adenomas are not precursor lesions of
carcinomas. However, it is entirely possible that another explanation exists. It is possible that the
risk of an adenoma acquiring the necessary molecular changes to evolve into a carcinoma is very low,
similar to or lower than to the risk of a colonic adenoma evolving into an adenocarcinoma. Given the
exceptionally low incidence of cortical tumors to begin with, it can then be argued that the scarcity of
small adrenal cancers is a consequence of the above factors and not a function of its biology.
Admittedly, there is controversy in this area and much research needs to done. One of the active areas
of work in my research laboratory is the molecular biology of adrenal cortical tumors. In previously
published work , we derived a gene expression signature of benign and malignant adrenal cortical
tumors using DNA microarrays. While the tumor set was limited, there was one low-grade tumor (C13 in
figure below) by mitotic activity that closely globally resembled the benign tumors in gene expression,
but that clustered with the malignant tumors when using a selected gene set for the analysis. Clearly,
this work needs to greatly expanded, but it suggests that early or low-grade adrenal carcinomas share
gene expression patterns that are intermediate between benign adenomas and high-grade carcinoma, a
finding that lends support to a model in which adenomas can rarely evolve into carcinomas.
Other recent molecular work supports this model. Investigation of the wnt signaling pathway revealed mutations of beta-catenin in both adenomas and
carcinoma , suggesting some commonality in their pathogeneses and leading the authors to suggest that
there "may be a common pathophysiologic mechanism involving a multistep tumorigenesis process as
speculated for other types of tumors."
The patient is a 38 year-old female who is in good overall health. A family member was recently
discovered to have multiple endocrine neoplasia, type IIA. Genetic testing of the patient showed a RET
mutation. The patient underwent serum calcitonin testing which revealed elevated levels. 24 hour
urinary catecholamines were also elevated. A nuclear medicine scan with I131- iodine-131-meta-iodobenzylguanidine (MIBG) revealed bilateral adrenal uptake that
was interpreted as abnormal. The patient underwent bilateral adrenalectomy. Subsequently, the patient
underwent total thyroidectomy.
The left adrenal gland was trimmed and weighed (8 gm) and was serially sectioned and found to contain
a well circumscribed brown nodule that measured 0.8 cm in greatest dimension. The adrenal gland away
from the nodule was grossly unremarkable. The right adrenal gland was trimmed and weighed (7 gm). It
was grossly unremarkable.
Microscopically, the left adrenal gland showed a circumscribed nodule consisting of large cells
growing in nests surrounded by blood vessels. The tumor cells contained abundant granular cytoplasm.
Mitotic figures were not identified. The adjacent medullary tissue appeared to be increased in volume,
but morphometric studies were not performed. The right adrenal gland showed a similar nodule that was
0.2 cm and one area in which the medullary volume was increased relative to the cortex.
Adrenal Medullary Hyperplasia
The definition of adrenal medullary hyperplasia (AMH) is simply
defined as an increased number of medullary cells. It can be divided into nodular and diffuse forms. As is the situation with
case, it is usually associated with a genetic syndrome that predisposes to its development as well as
pheochromocytoma, such as Multiple Endocrine Neoplasia, types IIa and IIb. Also illustrated by this case
is the prominent role that genetic testing of the RET gene has assumed in the management of MEN-II
for recent reviews).
Differential Diagnosis with Pheochromocytoma
The distinction between nodular medullary hyperplasia and pheochromocytoma is completely
arbitrary. A 1 cm cutoff has been suggested  but is largely based on historical precedent than any
biologic or pathologic parameter. As is the situation with other endocrine organs in MEN (such as
parathyroid glands in MEN-1) many are beginning to believe that nodular hyperplasia actually represents
confluent growth of neoplasms rather than true hyperplasia. This is supported by clonality work done on
nodular hyperplasia that demonstrated that nodular AMH is clonal and thus likely to represent true
neoplasms . Thus, it can also be argued that all nodules of AMH should actually be regarded as
pheochromocytoma. Regardless of the definitions used by pathologists, there will be an arbitrary nature
until molecular profiling or other studies can definitely differentiate hyperplasia from neoplasia, if it
is even possible.
Diffuse AMH and Morphometric Analysis
The diagnosis of the diffuse type of AMH is quite difficult and requires careful
sectioning of the gland with particular attention to where in the adrenal gland the sections are taken.
This is true because the adrenal:medullary ratio varies in the different regions of the gland (body, hear
References and Additional Reading
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