DICER1 and FOXL2 Mutation Status Correlates with Clinicopathologic Features in Ovarian Sertoli-Leydig Cell Tumors

Anthony Karnezis, Yemin Wang, Jacqueline Keul, Basile Tessier-Cloutier, Jamie Magrill, Stefan Kommoss, Janine Senz, Winnie Yang, Lily Proctor, Dietmar Schmidt, Philip B. Clement, C. Blake Gilks, David G. Huntsman, Friedrich Kommoss

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Abstract

Sertoli-Leydig cell tumors (SLCTs) are rare ovarian sex cord-stromal neoplasms. The only known recurrent genetic abnormality is DICER1 mutation, with rare mutations reported in FOXL2. We set out to establish a molecular classifier using DICER1 and FOXL2 somatic mutation status and clinicopathologic features in 42 SLCTs. Five tumors (12%) were well differentiated, 31 (74%) moderately differentiated, and 6 (14%) poorly differentiated. Eight (19%) had heterologous elements, and 2 (5%) showed retiform differentiation; all 10 were moderately differentiated. DICER1 RNase IIIb domain mutations were identified in 18/41 (44%; 17 moderately, 1 poorly differentiated), including all cases with retiform or heterologous elements. FOXL2 c.402C<G (p.C134W) mutation was identified in 8/42 (19%) tumors (5 moderately, 3 poorly differentiated). DICER1 and FOXL2 mutations were mutually exclusive. Median age for the cohort was 47 years (range, 15 to 90 y). Patients with DICER1 mutations were younger (median, 24.5 y; range, 15 to 62 y) than patients with FOXL2 mutation (median, 79.5 y; range, 51 to 90 y) (P>0.0001). Nine of 10 tumors with retiform or heterologous elements occurred in premenopausal patients (median, 26.5 y; range, 15 to 57 y). Patients with tumors that were wild type for DICER1 and FOXL2 (15/42, 37%) had an intermediate age (median, 51 y; range, 17 to 74 y). All tumors were FOXL2 positive by immunohistochemistry. Patients with FOXL2 mutation trended toward presenting more often with abnormal bleeding (P=0.13); DICER1-mutant patients trended toward having more androgenic symptoms (P=0.22). Our data suggest at least 3 molecular subtypes of SLCT with distinct clinicopathologic features: DICER1 mutant (younger, more androgenic symptoms, moderately/poorly differentiated, retiform or heterologous elements), FOXL2 mutant (postmenopausal, abnormal bleeding, moderately/poorly differentiated, no retiform or heterologous elements), and DICER1/FOXL2 wild type (intermediate age, no retiform or heterologous elements, including all well-differentiated tumors).

Original languageEnglish (US)
JournalAmerican Journal of Surgical Pathology
DOIs
StatePublished - Jan 1 2019

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Sertoli-Leydig Cell Tumor
Mutation
Neoplasms
Hemorrhage
Ribonucleases
Immunohistochemistry

Keywords

  • DICER1
  • FOXL2
  • heterologous elements
  • molecular classifier
  • retiform pattern
  • Sertoli-Leydig cell tumor

ASJC Scopus subject areas

  • Anatomy
  • Surgery
  • Pathology and Forensic Medicine

Cite this

DICER1 and FOXL2 Mutation Status Correlates with Clinicopathologic Features in Ovarian Sertoli-Leydig Cell Tumors. / Karnezis, Anthony; Wang, Yemin; Keul, Jacqueline; Tessier-Cloutier, Basile; Magrill, Jamie; Kommoss, Stefan; Senz, Janine; Yang, Winnie; Proctor, Lily; Schmidt, Dietmar; Clement, Philip B.; Gilks, C. Blake; Huntsman, David G.; Kommoss, Friedrich.

In: American Journal of Surgical Pathology, 01.01.2019.

Research output: Contribution to journalArticle

Karnezis, A, Wang, Y, Keul, J, Tessier-Cloutier, B, Magrill, J, Kommoss, S, Senz, J, Yang, W, Proctor, L, Schmidt, D, Clement, PB, Gilks, CB, Huntsman, DG & Kommoss, F 2019, 'DICER1 and FOXL2 Mutation Status Correlates with Clinicopathologic Features in Ovarian Sertoli-Leydig Cell Tumors', American Journal of Surgical Pathology. https://doi.org/10.1097/PAS.0000000000001232
Karnezis, Anthony ; Wang, Yemin ; Keul, Jacqueline ; Tessier-Cloutier, Basile ; Magrill, Jamie ; Kommoss, Stefan ; Senz, Janine ; Yang, Winnie ; Proctor, Lily ; Schmidt, Dietmar ; Clement, Philip B. ; Gilks, C. Blake ; Huntsman, David G. ; Kommoss, Friedrich. / DICER1 and FOXL2 Mutation Status Correlates with Clinicopathologic Features in Ovarian Sertoli-Leydig Cell Tumors. In: American Journal of Surgical Pathology. 2019.
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abstract = "Sertoli-Leydig cell tumors (SLCTs) are rare ovarian sex cord-stromal neoplasms. The only known recurrent genetic abnormality is DICER1 mutation, with rare mutations reported in FOXL2. We set out to establish a molecular classifier using DICER1 and FOXL2 somatic mutation status and clinicopathologic features in 42 SLCTs. Five tumors (12{\%}) were well differentiated, 31 (74{\%}) moderately differentiated, and 6 (14{\%}) poorly differentiated. Eight (19{\%}) had heterologous elements, and 2 (5{\%}) showed retiform differentiation; all 10 were moderately differentiated. DICER1 RNase IIIb domain mutations were identified in 18/41 (44{\%}; 17 moderately, 1 poorly differentiated), including all cases with retiform or heterologous elements. FOXL2 c.402C<G (p.C134W) mutation was identified in 8/42 (19{\%}) tumors (5 moderately, 3 poorly differentiated). DICER1 and FOXL2 mutations were mutually exclusive. Median age for the cohort was 47 years (range, 15 to 90 y). Patients with DICER1 mutations were younger (median, 24.5 y; range, 15 to 62 y) than patients with FOXL2 mutation (median, 79.5 y; range, 51 to 90 y) (P>0.0001). Nine of 10 tumors with retiform or heterologous elements occurred in premenopausal patients (median, 26.5 y; range, 15 to 57 y). Patients with tumors that were wild type for DICER1 and FOXL2 (15/42, 37{\%}) had an intermediate age (median, 51 y; range, 17 to 74 y). All tumors were FOXL2 positive by immunohistochemistry. Patients with FOXL2 mutation trended toward presenting more often with abnormal bleeding (P=0.13); DICER1-mutant patients trended toward having more androgenic symptoms (P=0.22). Our data suggest at least 3 molecular subtypes of SLCT with distinct clinicopathologic features: DICER1 mutant (younger, more androgenic symptoms, moderately/poorly differentiated, retiform or heterologous elements), FOXL2 mutant (postmenopausal, abnormal bleeding, moderately/poorly differentiated, no retiform or heterologous elements), and DICER1/FOXL2 wild type (intermediate age, no retiform or heterologous elements, including all well-differentiated tumors).",
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T1 - DICER1 and FOXL2 Mutation Status Correlates with Clinicopathologic Features in Ovarian Sertoli-Leydig Cell Tumors

AU - Karnezis, Anthony

AU - Wang, Yemin

AU - Keul, Jacqueline

AU - Tessier-Cloutier, Basile

AU - Magrill, Jamie

AU - Kommoss, Stefan

AU - Senz, Janine

AU - Yang, Winnie

AU - Proctor, Lily

AU - Schmidt, Dietmar

AU - Clement, Philip B.

AU - Gilks, C. Blake

AU - Huntsman, David G.

AU - Kommoss, Friedrich

PY - 2019/1/1

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N2 - Sertoli-Leydig cell tumors (SLCTs) are rare ovarian sex cord-stromal neoplasms. The only known recurrent genetic abnormality is DICER1 mutation, with rare mutations reported in FOXL2. We set out to establish a molecular classifier using DICER1 and FOXL2 somatic mutation status and clinicopathologic features in 42 SLCTs. Five tumors (12%) were well differentiated, 31 (74%) moderately differentiated, and 6 (14%) poorly differentiated. Eight (19%) had heterologous elements, and 2 (5%) showed retiform differentiation; all 10 were moderately differentiated. DICER1 RNase IIIb domain mutations were identified in 18/41 (44%; 17 moderately, 1 poorly differentiated), including all cases with retiform or heterologous elements. FOXL2 c.402C<G (p.C134W) mutation was identified in 8/42 (19%) tumors (5 moderately, 3 poorly differentiated). DICER1 and FOXL2 mutations were mutually exclusive. Median age for the cohort was 47 years (range, 15 to 90 y). Patients with DICER1 mutations were younger (median, 24.5 y; range, 15 to 62 y) than patients with FOXL2 mutation (median, 79.5 y; range, 51 to 90 y) (P>0.0001). Nine of 10 tumors with retiform or heterologous elements occurred in premenopausal patients (median, 26.5 y; range, 15 to 57 y). Patients with tumors that were wild type for DICER1 and FOXL2 (15/42, 37%) had an intermediate age (median, 51 y; range, 17 to 74 y). All tumors were FOXL2 positive by immunohistochemistry. Patients with FOXL2 mutation trended toward presenting more often with abnormal bleeding (P=0.13); DICER1-mutant patients trended toward having more androgenic symptoms (P=0.22). Our data suggest at least 3 molecular subtypes of SLCT with distinct clinicopathologic features: DICER1 mutant (younger, more androgenic symptoms, moderately/poorly differentiated, retiform or heterologous elements), FOXL2 mutant (postmenopausal, abnormal bleeding, moderately/poorly differentiated, no retiform or heterologous elements), and DICER1/FOXL2 wild type (intermediate age, no retiform or heterologous elements, including all well-differentiated tumors).

AB - Sertoli-Leydig cell tumors (SLCTs) are rare ovarian sex cord-stromal neoplasms. The only known recurrent genetic abnormality is DICER1 mutation, with rare mutations reported in FOXL2. We set out to establish a molecular classifier using DICER1 and FOXL2 somatic mutation status and clinicopathologic features in 42 SLCTs. Five tumors (12%) were well differentiated, 31 (74%) moderately differentiated, and 6 (14%) poorly differentiated. Eight (19%) had heterologous elements, and 2 (5%) showed retiform differentiation; all 10 were moderately differentiated. DICER1 RNase IIIb domain mutations were identified in 18/41 (44%; 17 moderately, 1 poorly differentiated), including all cases with retiform or heterologous elements. FOXL2 c.402C<G (p.C134W) mutation was identified in 8/42 (19%) tumors (5 moderately, 3 poorly differentiated). DICER1 and FOXL2 mutations were mutually exclusive. Median age for the cohort was 47 years (range, 15 to 90 y). Patients with DICER1 mutations were younger (median, 24.5 y; range, 15 to 62 y) than patients with FOXL2 mutation (median, 79.5 y; range, 51 to 90 y) (P>0.0001). Nine of 10 tumors with retiform or heterologous elements occurred in premenopausal patients (median, 26.5 y; range, 15 to 57 y). Patients with tumors that were wild type for DICER1 and FOXL2 (15/42, 37%) had an intermediate age (median, 51 y; range, 17 to 74 y). All tumors were FOXL2 positive by immunohistochemistry. Patients with FOXL2 mutation trended toward presenting more often with abnormal bleeding (P=0.13); DICER1-mutant patients trended toward having more androgenic symptoms (P=0.22). Our data suggest at least 3 molecular subtypes of SLCT with distinct clinicopathologic features: DICER1 mutant (younger, more androgenic symptoms, moderately/poorly differentiated, retiform or heterologous elements), FOXL2 mutant (postmenopausal, abnormal bleeding, moderately/poorly differentiated, no retiform or heterologous elements), and DICER1/FOXL2 wild type (intermediate age, no retiform or heterologous elements, including all well-differentiated tumors).

KW - DICER1

KW - FOXL2

KW - heterologous elements

KW - molecular classifier

KW - retiform pattern

KW - Sertoli-Leydig cell tumor

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