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Large cell calcifying Sertoli cell tumour: molecular and immunohistochemical assessment of a series comprising non-metastasising and metastasising neoplasms

S. Yu, LM. Sholl, S. Siegmund, TM. Ulbright, K. Collins, M. Colecchia, M. Del Pilar Gonzalez-Peramato, K. Michalová, JB. Gordetsky, KM. Cornejo, CS. Kao, SE. Wobker, SO. Vargas, F. Maclean, MT. Idrees, WJ. Anderson, CDM. Fletcher, AM. Acosta

. 2023 ; 82 (7) : 1079-1088. [pub] 20230316

Jazyk angličtina Země Anglie, Velká Británie

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc23011265

Large cell calcifying Sertoli cell tumour (LCCSCT) is a type of testicular sex cord-stromal tumour that may occur sporadically or in the context of Carney complex and other genetic syndromes. A subset is clinically malignant, and the molecular mechanisms that drive such aggressive behaviour remain unknown. METHODS AND RESULTS: We analysed 21 samples from 20 patients with LCCSCT (12 non-metastasising and eight metastasising) using PRKAR1A immunohistochemistry (IHC) and next-generation sequencing. All tumours except two (cases 17 and 20, both metastasising) demonstrated loss of PRKAR1A expression. Among 11 cases with interpretable sequencing results, all harboured pathogenic single nucleotide variants of PRKAR1A. Evidence of loss of heterozygosity (LOH) of PRKAR1A was present in all tumours with interpretable zygosity data, but the mechanisms of LOH were different for non-metastasising and metastasising tumours. Non-metastasising tumours demonstrated only copy-neutral LOH, while metastasising tumours demonstrated a spectrum of mechanisms of LOH, including copy-loss LOH, two concurrent mutations or copy-neutral LOH. Relevant molecular findings in non-metastasising LCCSCT were limited to PRKAR1A variants. In contrast, all metastasising LCCSCTs with interpretable data harboured additional pathogenic variants, including (but not restricted to) BRCA2 mutations with evidence of LOH and bi-allelic CDKN2A/B deletions. Three patients harboured PRKAR1A variants of inferred germline origin, including one with Carney complex and two without known syndromic features. CONCLUSIONS: This study further confirms that PRKAR1A IHC is a useful diagnostic tool for both non-metastasising and metastasising tumours and suggests that molecular analyses can be helpful to identify non-metastasising tumours with malignant potential in selected patients. Importantly, these results highlight that germline assessment could be beneficial for all patients presenting with LCCSCT.

Citace poskytuje Crossref.org

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$a Large cell calcifying Sertoli cell tumour (LCCSCT) is a type of testicular sex cord-stromal tumour that may occur sporadically or in the context of Carney complex and other genetic syndromes. A subset is clinically malignant, and the molecular mechanisms that drive such aggressive behaviour remain unknown. METHODS AND RESULTS: We analysed 21 samples from 20 patients with LCCSCT (12 non-metastasising and eight metastasising) using PRKAR1A immunohistochemistry (IHC) and next-generation sequencing. All tumours except two (cases 17 and 20, both metastasising) demonstrated loss of PRKAR1A expression. Among 11 cases with interpretable sequencing results, all harboured pathogenic single nucleotide variants of PRKAR1A. Evidence of loss of heterozygosity (LOH) of PRKAR1A was present in all tumours with interpretable zygosity data, but the mechanisms of LOH were different for non-metastasising and metastasising tumours. Non-metastasising tumours demonstrated only copy-neutral LOH, while metastasising tumours demonstrated a spectrum of mechanisms of LOH, including copy-loss LOH, two concurrent mutations or copy-neutral LOH. Relevant molecular findings in non-metastasising LCCSCT were limited to PRKAR1A variants. In contrast, all metastasising LCCSCTs with interpretable data harboured additional pathogenic variants, including (but not restricted to) BRCA2 mutations with evidence of LOH and bi-allelic CDKN2A/B deletions. Three patients harboured PRKAR1A variants of inferred germline origin, including one with Carney complex and two without known syndromic features. CONCLUSIONS: This study further confirms that PRKAR1A IHC is a useful diagnostic tool for both non-metastasising and metastasising tumours and suggests that molecular analyses can be helpful to identify non-metastasising tumours with malignant potential in selected patients. Importantly, these results highlight that germline assessment could be beneficial for all patients presenting with LCCSCT.
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$a Sholl, Lynette M $u Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA $1 https://orcid.org/0000000295329735
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$a Siegmund, Stephanie $u Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
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$a Ulbright, Thomas M $u Department of Pathology, Indiana University School of Medicine, Indianapolis, IN, USA
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$a Collins, Katrina $u Department of Pathology, Indiana University School of Medicine, Indianapolis, IN, USA $1 https://orcid.org/0000000296036731
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$a Colecchia, Maurizio $u Department of Pathology, Vita- Salute San Raffaele University, Milan, Italy
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$a Del Pilar Gonzalez-Peramato, Maria $u Department of Pathology, La Paz University Hospital, Universidad Autónoma de Madrid, Madrid, Spain
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$a Michalová, Květoslava $u Department of Pathology, Charles University, Medical Faculty and Charles University Hospital Plzen, Czech Republic
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$a Gordetsky, Jennifer B $u Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA $1 https://orcid.org/0000000207452160
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$a Cornejo, Kristine M $u Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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$a Kao, Chia-Sui $u Department of Pathology, Stanford University, Stanford, CA, USA
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$a Wobker, Sara E $u Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA
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$a Vargas, Sara O $u Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA
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$a Maclean, Fiona $u Douglass Hanly Moir Pathology, Macquarie University, Sydney, Australia
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$a Idrees, Muhammad T $u Department of Pathology, Indiana University School of Medicine, Indianapolis, IN, USA $1 https://orcid.org/0000000166116389
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$a Anderson, William J $u Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA $1 https://orcid.org/0000000258077831
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$a Fletcher, Christopher D M $u Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
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$a Acosta, Andres M $u Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA $1 https://orcid.org/0000000301645911
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