This review summarizes the classification of
tumors of the adrenal medulla and extra-adrenal paraganglia as outlined in the 5th series of the WHO Classification of Endocrine and
Neuroendocrine Tumors. The non-epithelial neuroendocrine
neoplasms (NENs) known as
paragangliomas produce predominantly
catecholamines and secrete them into the bloodstream like
hormones, and they represent a group of NENs that have exceptionally high
genetic predisposition. This classification discusses the embryologic derivation of the cells that give rise to these lesions and the historical evolution of the terminology used to classify their
tumors;
paragangliomas can be sympathetic or parasympathetic and the term
pheochromocytoma is used specifically for intra-adrenal
paragangliomas that represent the classical sympathetic form. In addition to the general neuroendocrine cell
biomarkers INSM1,
synaptophysin, and
chromogranins, these
tumors are typically negative for
keratins and instead have highly specific
biomarkers, including the
GATA3 transcription factor and
enzymes involved in
catecholamine biosynthesis:
tyrosine hydroxylase that converts
L-tyrosine to
L-DOPA as the rate-limiting step in
catecholamine biosynthesis,
dopamine beta-hydroxylase that is present in cells expressing
norepinephrine, and
phenylethanolamine N-methyltransferase, which converts
norepinephrine to
epinephrine and therefore can be used to distinguish
tumors that make
epinephrine. In addition to these important tools that can be used to confirm the diagnosis of a
paraganglioma, new tools are recommended to determine
genetic predisposition syndromes; in addition to the identification of precursor lesions, molecular immunohistochemistry can serve to identify associations with SDHx, VHL, FH, MAX, and MEN1 mutations, as well as pseudohypoxia-related pathogenesis.
Paragangliomas have a well-formed network of sustentacular cells that express SOX10 and S100, but this is not a distinctive feature, as other epithelial NENs also have sustentacular cells. Indeed, it is the presence of such cells and the association with
ganglion cells that led to a misinterpretation of several unusual lesions as
paragangliomas; in the 2022 WHO classification, the
tumor formerly known as cauda equina
paraganglioma is now classified as cauda equina
neuroendocrine tumor and the lesion known as
gangliocytic paraganglioma has been renamed composite
gangliocytoma/
neuroma and
neuroendocrine tumor (CoGNET). Since the 4th edition of the WHO,
paragangliomas have no longer been classified as benign and malignant, as any lesion can have metastatic potential and there are no clear-cut features that can predict metastatic behavior. Moreover, some
tumors are lethal without metastatic spread, by nature of local invasion involving critical structures. Nevertheless, there are features that can be used to identify more aggressive lesions; the WHO does not endorse the various scoring systems that are reviewed but also does not discourage their use. The identification of
metastases is also complex, particularly in patients with germline predisposition syndromes, since multiple lesions may represent multifocal primary
tumors rather than metastatic spread; the identification of
paragangliomas in unusual locations such as lung or liver is not diagnostic of
metastasis, since these may be primary sites. The value of sustentacular cells and Ki67 labeling as prognostic features is also discussed in this new classification. A staging system for
pheochromocytoma and extra-adrenal sympathetic PGLs, introduced in the 8th Edition AJCC
Cancer Staging Manual, is now included. This paper also provides a summary of the criteria for the diagnosis of a composite
paragangliomas and summarizes the classification of neuroblastic
tumors. This review adopts a practical question-answer framework to provide members of the multidisciplinary endocrine oncology team with a most up-to-date approach to
tumors of the adrenal medulla and extra-adrenal paraganglia.