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Issue 27 || June 2024
WHAT’S NEW
IN PATHOLOGY?
arise from ectopic adrenal tissue.
Adrenal cysts
Benign, circumscribed, uid-containing
masses, which are divided into 4 subtypes:
WHAT’S NEW IN ADRENAL
GLAND PATHOLOGY:
WHO 5TH EDITION FOR
ADRENAL CORTEX
Carol N. Rizkalla, MB BCh BAO
Maria Tretiakova, MD, PhD
Department of Laboratory Medicine and Pathology,
University of Washington, Seattle, WA, USA
Corresponding Author:
Maria Tretiakova
Department of Laboratory Medicine and Pathology,
University of Washington, Seattle, WA, USA
E-mail: mariast@uw.edu
ORCID
Carol N. Rizkalla
https://orcid.org/0000-0002-7243-7784
Maria Tretiakova
https://orcid.org/0000-0002-0819-9638
Abstract
The 5th edition of WHO Classication of
Endocrine and Neuroendocrine Tumors
(2022) introduced many signicant changes
relevant to endocrine daily practice. In this
newsletter, we summarize the notable
changes to the adrenal cortex based on the
5th edition of the WHO.
NEW CHAPTERS
Adrenal ectopia
Benign adrenal tissue in an aberrant location
(Fig. 1).
Includes “adrenal rests,” which are aligned
with normal embryogenesis (e.g. kidneys
or gonads), and “adrenal cortical choristo-
ma,” which are in locations not aligned
with embryogenesis.
The vast majority are incidental ndings,
contain only adrenocortical cells, and
express SF1.
Rarely, adrenal cortical neoplasms may
°
Pseudocysts: most common (>60% of
adrenal cysts), do not have a cell lining,
occur following trauma, hemorrhage, or
infection including COVID-19 (Fig. 2).
°
Endothelial (vascular) cysts: lined by
Supported by an unrestricted grant from The University of Washington: Laboratory of Medicine & Pathology
Fig. 1. Adrenal ectopia: benign adrenocortical tissue within the spermatic cord.
Fig. 2. Adrenal pseudocyst: adrenal cyst without a discrete lining.
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endothelium, occur as a malformation or
as part of recanalization (Fig. 3).
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Epithelial cysts: lined by mesothelium,
occur as an inclusion cyst of embryologic
remnants.
°
Parasitic cysts: rare, uni/multi-loculated
cysts with a brous wall and clear con-
tents.
A broad differential ought to be considered
since cystic changes can occur in adreno-
cortical adenoma/carcinoma, pheochromo-
cytoma, hemangioma, renal cell carcinoma,
metastases, etc.
Myelolipoma
Benign asymptomatic tumor composed of
mature adipocytes and trilineage hemato-
poiesis.
Often coexist with adrenocortical nodular
disease, hyperplasia, or neoplasms (Fig. 4).
UPDATED CLASSIFICATION OF
ADRENAL CORTICAL
PROLIFERATIONS
Adrenal cortical hyperplasia
Cortical zonation is intact as this is a physi-
ologic response, rather than a clonal
proliferation.
Three types of true hyperplasia:
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Congenital adrenal hyperplasia (CAH):
caused by mutations in genes encoding
enzymes of steroid production.
°
ACTH/CRH dependent diffuse hyperpla-
sia: caused by Cushing’s disease, ectopic
secretion, chronic stress.
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Diffuse zona glomerulosa hyperplasia:
idiopathic.
Adrenal cortical nodular disease
Group of sporadic or germline nodular
clonal proliferations:
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Sporadic nodular adrenocortical disease:
- Formerly known as “nodular adrenal
cortical hyperplasia”.
- <10 mm non-functional adrenocortical
nodules.
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Bilateral micronodular adrenocortical
disease:
- Occurs more commonly in children and
young adults (<30 years old).
- <10 mm bilateral adrenocortical nod-
ules, could be pigmented.
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Bilateral macronodular adrenocortical
disease:
- More frequent in adults.
- >10 mm bilateral nodules (Fig. 5).
- Formerly known as “primary bilateral
macronodular adrenal cortical hyperpla-
Fig. 3. Adrenal vascular cyst: adrenal cyst with lymphangitic endothelial lining (D2-40 positive).
Fig. 4. Myelolipoma coexisting with adrenal cortical carcinoma (oncocytic variant).
Fig. 5. Bilateral macronodular (>1 cm) adrenocortical disease: representative gross sections.
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sia” or “ACTH-independent macronod-
ular adrenocortical hyperplasia”.
Bilateral micronodular and macronodular
forms of adrenocortical nodular disease
typically contribute to hypercortisolism
and are often associated with germline
variants in specic susceptibility genes
(PRKAR1A, PRKACA, PDE11A, PDE8B,
ARMC5, MEN1, etc).
The former designation “hyperplasia” is
discouraged as it is a physiological reaction
to elevated ACTH levels. The term should
not be used to describe multifocal nodules
resulting from clonal expansions.
Primary aldosteronism (PA)
Primary aldosteronism (Conn syndrome) is
a leading cause of secondary hypertension
characterized by aldosterone overproduc-
tion and suppression of the renin-angioten-
sin system.
HISTALDO Classication combines
CYP11B2 (aldosterone synthase) immuno-
histochemistry and morphologic features
to predict the risk of biochemical recur-
rence.
“Classic” histology: 5% recurrence risk
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Aldosterone-producing adrenal cortical
carcinoma (APACC)
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Aldosterone-producing adrenal cortical
Fig. 7. Adrenal cortical carcinoma (myxoid variant) with lymphovascular invasion.
Fig. 6. Functional aldosterone-producing adrenal cortical adenoma with predominantly vacuolated cells and scat-
tered pleomorphism.
adenoma (APA) (Fig. 6): solitary, > 1 cm,
CYP11B2 diffuse reactivity.
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Aldosterone-producing nodule (APN):
solitary, < 1 cm, CYP11B2 gradient
reactivity, emphasizing increased intensity
at the outer part of the nodule.
“Non-classic” histology: 42% recurrence
risk
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Aldosterone-producing micronodule
(APM): < 1 cm, may not be recognized
on H&E but is highlighted with CY-
P11B2 (gradient reactivity).
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Multifocal aldosterone-producing nodules
(APNs).
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Aldosterone-producing bilateral diffuse
hyperplasia (APDH).
Adrenal cortical adenoma
Adrenocortical neoplasm that lacks mor-
phologic features of malignancy.
Features worrisome for malignancy:
vascular invasion, tumor necrosis, atypical
mitotic gures, increased mitotic activity
(>5 mitoses per 10 mm
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), loss of reticulin
framework.
Usually unilateral and solitary; can be
nonfunctional or hormonally active.
CLASSIFICATION OF ADRENAL
CORTICAL CARCINOMAS, MAIN
SUBTYPES, ANCILLARY
STUDIES & GRADING
Adrenal cortical carcinoma
Malignant adrenocortical neoplasm; can be
nonfunctional or hormonally active.
Adrenal masses associated with virilization
or feminization are clinically highly
worrisome for malignancy.
In addition to conventional adrenal cortical
carcinoma, three morphologic subtypes
exist:
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Oncocytic: oncocytic cells in >90% of
tumor; extensive sampling is required to
better quantify the oncocytic component.
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Myxoid: prominent extracellular mucin
deposition; poor prognosis (Fig. 7).
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Sarcomatoid: resembles sarcomatoid
carcinomas of other organs; poor progno-
sis.
Vascular invasion is an important diagnos-
tic and prognostic tool in assessment of
malignancy. It is assessed at the intersec-
tion of tumor and adrenal capsule or
beyond the capsule where tumor cells are
seen invading through the vessel wall and
forming a thrombus/brin-tumor complex.
Many scoring criteria are available for diag-
nosing adrenal cortical carcinoma and risk
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Dr. Carol N. Rizkalla is a second-year AP/CP
pathology resident at the University of
Washington. She has been an author for
PathologyOutlines.com since 2022, immers-
ing herself in a variety of genitourinary topics.
Regarding her future career, she is passionate
about surgical pathology, with a specic focus
on genitourinary and gynecologic pathology.
Dr. Tretiakova has been an author for Patholo-
gyOutlines.com since 2015, part of the
editorial board since 2019, and Deputy Editor
in Chief for GU Pathology since 2021. She is
currently a Professor and Director of Genito-
urinary Fellowship and Immunohistochemis-
try Laboratories at the University of Washing-
ton where she primarily practices GU
Pathology.
Meet the Authors
Fig. 9. Adrenal cortical carcinoma with high mitotic activity (2 mitoses in a 60
×
HPF).
Fig. 8. A: Adrenal cortical carcinoma with tumor necrosis (right of image). B: Adrenal cortical carcinoma with a
disrupted reticulin framework.
A
B
stratication; their use depends on mor-
phologic subtype and patient age:
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Weiss score, modied Weiss, and Helsin-
ki multiparameter scores.
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Lin-Weiss-Bisceglia system was developed
to evaluate oncocytic adrenal cortical
neoplasms.
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Wieneke system is used for assessing pedi-
atric adrenal cortical neoplasms.
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Reticulin algorithm requires an altered
reticulin network, in association with any
one of the following: increased mitotic
rate (>5 mitoses per 50 high-power elds
[HPF]), tumor necrosis, or vascular
invasion (Fig. 8).
A simplied approach via the reticulin
algorithm has gained popularity given its
high reproducibility and applicability to
all morphologic subtypes.
Following use of the reticulin algorithm, a
carcinoma is subsequently classied as
low-grade or high-grade based on mitotic
activity (high grade if >20 mitoses/50
HPF) (Fig. 9).
Diagnostic and prognostic biomarkers:
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p53: overexpression or global loss may be
identied in high-grade areas.
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Beta-catenin: nuclear overexpression is a
poor prognostic sign.
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IGF2: used as a diagnostic tool given that
paranuclear granular expression is found
in ≈80% of adrenal cortical carcinomas.
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Ki67: recommended to specify the Ki67
labeling index for all adrenal cortical
carcinomas via manual count or automat-
ed image analysis, and to document the
methodology used. Carcinomas typically
label >5%, and the index matters in
terms of prognosis.