Cauda equina paragangliomas express HOXB13

Bockmayr, Michael; Körner, Meik; Schweizer, Leonille; Schüller, Ulrich

doi:10.1111/nan.12713

Cited by 9 publications

(4 citation statements)

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“…2 For example, in the pituitary, they express PIT1, TPIT, or SF1, in thyroid and lung they express TTF1, in the gut they express CDX2. These and PAX8 were all negative in this series of tumors, but the expression of HOXB13 is a novel biomarker that has recently been reported in these lesions 11 and we confirm that this is a common finding in CENETs. HOXB13 is highly expressed in the tail bud of the developing embryo; in adults, it is most highly expressed in the mature prostate, where it is implicated in tumor development, 12,13 and in distal colonic mucosa.…”

Section: Discussionsupporting

confidence: 86%

“…HOXB13 is highly expressed in the tail bud of the developing embryo; in adults, it is most highly expressed in the mature prostate, where it is implicated in tumor development, 12,13 and in distal colonic mucosa. It has been localized with strong staining in myxopapillary ependymomas 11,14 that are clearly unrelated tumors. While it has not been found in PGLs at other sites, its expression in other NETs remains to be clarified.…”

Section: Discussionmentioning

confidence: 99%

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Cauda Equina Neuroendocrine Tumors

Sylvia

Mete

Schüller

et al. 2022

American Journal of Surgical Pathology

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The tumor formerly known as "cauda equina paraganglioma" was recently renamed as cauda equina neuroendocrine tumor (CENET) based on distinct biological and genetic properties. Nevertheless, it remains insufficiently understood. For this study, we retrieved CENETs (some previously reported), from the pathology files of 3 institutions; we examined their immunohistochemical profile, including common neuroendocrine tumor-associated hormones and transcription factors. We identified 24 CENETs from 7 female and 17 male adult patients, with a median age of 47 years. Six included neurofilament-positive ganglion cells. All tumors tested were positive for INSM1, synaptophysin, chromogranin A, SSTR2, and CD56 as well as at least 1 keratin (AE1/AE3, CAM5.2); CK7 and CK20 were negative. Glial fibrillary acidic protein was negative, except for peripheral nontumoral elements. S100 protein was variable but mainly expressed in scattered sustentacular cells. All but 1 tumor tested were positive for HOXB13; several stained for SATB2, and all tumors were consistently negative for GATA3. All tumors tested were negative for transcription factors found in various other epithelial neuroendocrine neoplasms including TTF1, CDX2, PIT1, TPIT, SF1, and PAX8; staining for T-brachyury was negative. Four of 5 CEN-ETs tested had at least focal tyrosine hydroxylase reactivity. Serotonin expression was detected in all 21 tumors tested; it was diffusely positive in 5 and had variable positivity in the remainder. A few tumors had scattered cells expressing gastrin, calcitonin, pancreatic polypeptide, and peptide YY, while glucagon, adrenocorticotropic hormone, and monoclonal carcinoembryonic antigen were negative. PSAP expression was found focally in 4 of 5 tumors examined. SDHB was consistently intact; ATRX was intact in 14 tumors and showed only focal loss in 3. The median Ki-67 labeling index was 4.5% (range: 1% to 15%). We conclude that CENET represents a distinct neuroendocrine neoplasm; the subset with ganglion cells qualifies for designation as composite gangliocytoma/neuroma-neuroendocrine tumor (CoGNET) as defined in the 2022 WHO classification of neuroendocrine neoplasms. In addition to INSM1, chromogranin, synaptophysin, and keratins, the most characteristic finding is nuclear HOXB13 expression; a subset also express SATB2. Serotonin is the most common hormone expressed. The cytogenesis and pathogenesis of these lesions remains unclear.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Cauda Equina Neuroendocrine Tumors

Sylvia

Mete

Schüller

et al. 2022

American Journal of Surgical Pathology

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“…Based on these features, they were classified as paragangliomas; however more recently, they were found to express cytokeratins [152]. While some authors interpreted keratin expression to represent divergent ependymal differentiation by paragangliomas, it then became clear that these tumors do not express the characteristic paraganglioma transcription factor GATA3; instead, they express HOXB13, a transcription factor that is developmentally expressed in the spinal cord [153]. Moreover, these unique tumors are not found in patients with SDHx gene mutations [154] and they do not show loss of SDHB by immunohistochemistry [35].…”

Section: Question 11: What Are Spinal Middle Ear Neuroendocrine Tumor...mentioning

confidence: 99%

Overview of the 2022 WHO Classification of Neuroendocrine Neoplasms

et al. 2022

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In this review, we detail the changes and the relevant features that are applied to neuroendocrine neoplasms (NENs) in the 2022 WHO Classification of Endocrine and Neuroendocrine Tumors. Using a question-and-answer approach, we discuss the consolidation of the nomenclature that distinguishes neuronal paragangliomas from epithelial neoplasms, which are divided into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). The criteria for these distinctions based on differentiation are outlined. NETs are generally (but not always) graded as G1, G2, and G3 based on proliferation, whereas NECs are by definition high grade; the importance of Ki67 as a tool for classification and grading is emphasized. The clinical relevance of proper classification is explained, and the importance of hormonal function is examined, including eutopic and ectopic hormone production. The tools available to pathologists for accurate classification include the conventional biomarkers of neuroendocrine lineage and differentiation, INSM1, synaptophysin, chromogranins, and somatostatin receptors (SSTRs), but also include transcription factors that can identify the site of origin of a metastatic lesion of unknown primary site, as well as hormones, enzymes, and keratins that play a role in functional and structural correlation. The recognition of highly proliferative, well-differentiated NETs has resulted in the need for biomarkers that can distinguish these G3 NETs from NECs, including stains to determine expression of SSTRs and those that can indicate the unique molecular pathogenetic alterations that underlie the distinction, for example, global loss of RB and aberrant p53 in pancreatic NECs compared with loss of ATRX, DAXX, and menin in pancreatic NETs. Other differential diagnoses are discussed with recommendations for biomarkers that can assist in correct classification, including the distinctions between epithelial and non-epithelial NENs that have allowed reclassification of epithelial NETs in the spine, in the duodenum, and in the middle ear; the first two may be composite tumors with neuronal and glial elements, and as this feature is integral to the duodenal lesion, it is now classified as composite gangliocytoma/neuroma and neuroendocrine tumor (CoGNET). The many other aspects of differential diagnosis are detailed with recommendations for biomarkers that can distinguish NENs from nonneuroendocrine lesions that can mimic their morphology. The concepts of mixed neuroendocrine and non-neuroendocrine (MiNEN) and amphicrine tumors are clarified with information about how to approach such lesions in routine practice. Theranostic biomarkers that assist patient management are reviewed. Given the significant proportion of NENs that are associated with germline mutations that predispose to this disease, we explain the role of the pathologist in identifying precursor lesions and applying molecular immunohistochemistry to guide genetic testing.

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“…The tumor cells are positive for chromogranin and synaptophysin and may be positive for keratins [ 1 ]. The molecular alterations in cauda equina neuroendocrine tumors are unknown, although overexpression of HOXB13 [ 93 ] and typical methylation profile and CNV have been described [ 94 , 95 ]. Cauda equina neuroendocrine tumor is not associated with (germline) SDH subunit mutations.…”

Section: Pathology and Molecular Markersmentioning

confidence: 99%

Diagnosis and Treatment of Peripheral and Cranial Nerve Tumors with Expert Recommendations: An EUropean Network for RAre CANcers (EURACAN) Initiative

Pellerino

Verdijk

Nichelli

et al. 2023

Cancers

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The 2021 WHO classification of the CNS Tumors identifies as “Peripheral nerve sheath tumors” (PNST) some entities with specific clinical and anatomical characteristics, histological and molecular markers, imaging findings, and aggressiveness. The Task Force has reviewed the evidence of diagnostic and therapeutic interventions, which is particularly low due to the rarity, and drawn recommendations accordingly. Tumor diagnosis is primarily based on hematoxylin and eosin-stained sections and immunohistochemistry. Molecular analysis is not essential to establish the histological nature of these tumors, although genetic analyses on DNA extracted from PNST (neurofibromas/schwannomas) is required to diagnose mosaic forms of NF1 and SPS. MRI is the gold-standard to delineate the extension with respect to adjacent structures. Gross-total resection is the first choice, and can be curative in benign lesions; however, the extent of resection must be balanced with preservation of nerve functioning. Radiotherapy can be omitted in benign tumors after complete resection and in NF-related tumors, due to the theoretic risk of secondary malignancies in a tumor-suppressor syndrome. Systemic therapy should be considered in incomplete resected plexiform neurofibromas/MPNSTs. MEK inhibitor selumetinib can be used in NF1 children ≥2 years with inoperable/symptomatic plexiform neurofibromas, while anthracycline-based treatment is the first choice for unresectable/locally advanced/metastatic MPNST. Clinical trials on other MEK1-2 inhibitors alone or in combination with mTOR inhibitors are under investigation in plexiform neurofibromas and MPNST, respectively.

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Cauda equina paragangliomas express HOXB13

Abstract: HOXB13 is expressed in the tail bud of the developing embryo as well as in cauda equina paragangliomas and in myxopapillary ependymomas. In contrast, pheochromocytomas and paraganglioma in other locations as well as many other tumors occuring in spinal cord regions are negative.

Cited by 9 publications

References 5 publications

Cauda Equina Neuroendocrine Tumors

Cauda Equina Neuroendocrine Tumors

Overview of the 2022 WHO Classification of Neuroendocrine Neoplasms

Diagnosis and Treatment of Peripheral and Cranial Nerve Tumors with Expert Recommendations: An EUropean Network for RAre CANcers (EURACAN) Initiative

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