Immunohistochemical distinction of paragangliomas from epithelial neuroendocrine tumors—gangliocytic duodenal and cauda equina paragangliomas align with epithelial neuroendocrine tumors

Mamilla, Divya; Manukyan, Irena; Fetsch, Patricia; Pacák, Karel; Miettinen, Markku

doi:10.1016/j.humpath.2020.07.010

Cited by 30 publications

(24 citation statements)

References 28 publications

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“…In contrast, GATA3 was not expressed in any of the 31 CEPs analyzed of our own cohort. In line with our own findings, Mamilla et al [14] recently reported absence of GATA3 expression in three CEPs as well as strong cytokeratin expression. Compared to previous studies showing cytokeratin expression in some CEPs [11,17,21], all CEPs in our series strongly expressed cytokeratin.…”

Section: Discussionsupporting

confidence: 93%

Molecular characterization of CNS paragangliomas identifies cauda equina paragangliomas as a distinct tumor entity

et al. 2020

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Paragangliomas/pheochromocytomas are rare neuroendocrine tumors that arise from the adrenal gland or ganglia at various sites throughout the body. They display a remarkable diversity of driver alterations and are associated with germline mutations in up to 40% of the cases. Comprehensive molecular profiling of abdomino-thoracic paragangliomas revealed four molecularly defined and clinically relevant subtypes. Paragangliomas of the cauda equina region are considered to belong to one of the defined molecular subtypes, but a systematic molecular analysis has not yet been performed. In this study, we analyzed genome-wide DNA methylation profiles of 57 cauda equina paragangliomas and show that these tumors are epigenetically distinct from non-spinal paragangliomas and other tumors. In contrast to paragangliomas of other sites, chromosomal imbalances are widely lacking in cauda equina paragangliomas. Furthermore, RNA and DNA exome sequencing revealed that frequent genetic alterations found in non-spinal paragangliomas—including the prognostically relevant SDH mutations—are absent in cauda equina paragangliomas. Histologically, cauda equina paragangliomas show frequently gangliocytic differentiation and strong immunoreactivity to pan-cytokeratin and cytokeratin 18, which is not common in paragangliomas of other sites. None of our cases had a familial paraganglioma syndrome. Tumors rarely recurred (9%) or presented with multiple lesions within the spinal compartment (7%), but did not metastasize outside the CNS. In summary, we show that cauda equina paragangliomas represent a distinct, sporadic tumor entity defined by a unique clinical and morpho-molecular profile.

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Section: Discussionsupporting

confidence: 93%

Molecular characterization of CNS paragangliomas identifies cauda equina paragangliomas as a distinct tumor entity

et al. 2020

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“…The tumor cell nuclei display a vesicular chromatin and visible nucleoli, and the cytoplasm is often granular and intensely basophilic. The tumors invariably express neuroendocrine markers such as chromogranin A, synaptophysin, ISLET1, and INSM1 ( 54 ) and are most often keratin-negative and GATA3-positive, with few exceptions ( 55 ). From a differential diagnosis perspective, when the surgical pathologist assesses core needle biopsies from apparent metastatic deposits, the combination of tumoral positivity for neuroendocrine markers and GATA3 with negative keratin stains strongly argues in favor of metastatic PPGL and basically excludes most well-differentiated neuroendocrine tumors of the gastrointestinal tract.…”

Section: Diagnosismentioning

confidence: 99%

Metastatic Pheochromocytomas and Abdominal Paragangliomas

Granberg

Juhlin

Falhammar

2021

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context Pheochromocytomas and paragangliomas (PPGLs) are believed to harbor malignant potential; about 10% to 15% of pheochromocytomas and up to 50% of abdominal paragangliomas will exhibit metastatic behavior. Evidence Acquisition Extensive searches in the PubMed database with various combinations of the key words pheochromocytoma, paraganglioma, metastatic, malignant, diagnosis, pathology, genetic, and treatment were the basis for the present review. Data Synthesis To pinpoint metastatic potential in PPGLs is difficult, but nevertheless crucial for the individual patient to receive tailor-made follow-up and adjuvant treatment following primary surgery. A combination of histological workup and molecular predictive markers can possibly aid the clinicians in this aspect. Most patients with PPGLs have localized disease and may be cured by surgery. Plasma metanephrines are the main biochemical tests. Genetic testing is important, both for counseling and prognostic estimation. Apart from computed tomography and magnetic resonance imaging, molecular imaging using 68Ga-DOTATOC/DOTATATE should be performed. 123I-MIBG scintigraphy may be performed to determine whether 131I-MIBG therapy is a possible option. As first-line treatment in patients with metastatic disease, 177Lu-DOTATATE or 131I-MIBG is recommended, depending on which shows best expression. In patients with very low proliferative activity, watch-and-wait or primary treatment with long-acting somatostatin analogues may be considered. As second-line treatment, or first-line in patients with high proliferative rate, chemotherapy with temozolomide or cyclophosphamide + vincristine + dacarbazine is the therapy of choice. Other therapies, including sunitinib, cabozantinib, everolimus, and PD-1/PDL-1 inhibitors, have shown modest effect. Conclusions Metastatic PPGLs need individualized management and should always be discussed in specialized and interdisciplinary tumor boards. Further studies and newer treatment modalities are urgently needed.

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“…The chief cells are strongly positive for neuroendocrine markers of both first (chromogranin A, synaptophysin) and second generation (ISL1, INSM1), and additional stains that may help distinguish PPGL include GATA3, tyrosine hydroxylase and dopamine beta-hydroxylase (Fig. 1) [1,[14][15][16][17][18]. Keratin expression is almost always absent, except for rare subtypes such as duodenal gangliocytic paragangliomas and cauda equina paragangliomas [14].…”

Section: Diagnosticsmentioning

confidence: 99%

“…1) [1,[14][15][16][17][18]. Keratin expression is almost always absent, except for rare subtypes such as duodenal gangliocytic paragangliomas and cauda equina paragangliomas [14]. When assessing these lesions, the pathologist needs to consider many different aspects, including clinical information, primary tumor site, histology, the extent of invasion, the presence of vascular invasion, as well as the novel TNM staging system as dictated by the 8th edition of the American Joint Committee on Cancer (AJCC) Staging Manual [19,20].…”

Section: Diagnosticsmentioning

confidence: 99%

Challenges in Paragangliomas and Pheochromocytomas: from Histology to Molecular Immunohistochemistry

Juhlin

2021

Endocr Pathol

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Abdominal paragangliomas and pheochromocytomas (PPGLs) are rare neuroendocrine tumors of the infradiaphragmatic paraganglia and adrenal medulla, respectively. Although few pathologists outside of endocrine tertiary centers will ever diagnose such a lesion, the tumors are well known through the medical community—possible due to a combination of the sheer rarity, their often-spectacular presentation due to excess catecholamine secretion as well as their unrivaled coupling to constitutional susceptibility gene mutations and hereditary syndromes. All PPGLs are thought to harbor malignant potential, and therefore pose several challenges to the practicing pathologist. Specifically, a responsible diagnostician should recognize both the capacity and limitations of histological, immunohistochemical, and molecular algorithms to pinpoint high risk for future metastatic disease. This focused review aims to provide the surgical pathologist with a condensed update regarding the current strategies available in order to deliver an accurate prognostication of these enigmatic lesions.

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Immunohistochemical distinction of paragangliomas from epithelial neuroendocrine tumors—gangliocytic duodenal and cauda equina paragangliomas align with epithelial neuroendocrine tumors

Cited by 30 publications

References 28 publications

Molecular characterization of CNS paragangliomas identifies cauda equina paragangliomas as a distinct tumor entity

Molecular characterization of CNS paragangliomas identifies cauda equina paragangliomas as a distinct tumor entity

Metastatic Pheochromocytomas and Abdominal Paragangliomas

Challenges in Paragangliomas and Pheochromocytomas: from Histology to Molecular Immunohistochemistry

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