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FOXL2 Mutation Status in Sex Cord-stromal Tumors Cannot be Predicted by Morphology

Wessman, Sandra ; Fuentes, Beatriz Bohorquez ; Severin-Karlsson, Josefin ; Westbom-Fremer, Sofia LU orcid ; Nistér, Monica ; Kokaraki, Georgia ; Petta, Tirzah Braz ; Haglund, Felix and Carlson, Joseph W. (2024) In International Journal of Gynecological Pathology 43(1). p.78-89
Abstract

Granulosa-cell tumors (GCTs) are the most common type of malignant ovarian sex cord-stromal tumor (SCST). The histopathologic diagnosis of these tumors can be challenging. A recurrent somatic mutation of the forkhead box L2 (FOXL2) gene has been identified in adult GCT. In this retrospective single-center study of 44 SCST, a morphologic review together with analysis of FOXL2 C134W was evaluated in relation to tumor morphology. In addition, TERT promoter mutation testing was performed. Twelve of 36 cases got an altered diagnosis based on morphology alone. The overarching architectural growth pattern in 32/44 (72.7%) tumors was diffuse/solid with several tumors showing markedly heterogeneous architecture. In correlation to FOXL2 C134W... (More)

Granulosa-cell tumors (GCTs) are the most common type of malignant ovarian sex cord-stromal tumor (SCST). The histopathologic diagnosis of these tumors can be challenging. A recurrent somatic mutation of the forkhead box L2 (FOXL2) gene has been identified in adult GCT. In this retrospective single-center study of 44 SCST, a morphologic review together with analysis of FOXL2 C134W was evaluated in relation to tumor morphology. In addition, TERT promoter mutation testing was performed. Twelve of 36 cases got an altered diagnosis based on morphology alone. The overarching architectural growth pattern in 32/44 (72.7%) tumors was diffuse/solid with several tumors showing markedly heterogeneous architecture. In correlation to FOXL2 C134W mutation status, cytoplasmic color, and nuclear shape, differed between the FOXL2 C134W positive and FOXL2 C134 W negative groups, but these differences were not significant when comparing them separately. Nineteen of 44 cases underwent TERT promoter sequencing with a positive result in 3 cases; 2 adult GCTs and 1 cellular fibroma. Three patients developed a recurrence of which 2 were FOXL2 C134W positive adult GCTs and the third was an unclassified SCST. In conclusion, the morphologic and immunohistochemical diagnosis of different SCSTs is challenging and one cannot reliably identify FOXL2 mutation-positive tumors solely by morphologic features. Therefore, broad use of molecular analysis of the FOXL2 C134W mutation is suggested for SCSTs, and further studies are needed to evaluate the clinical outcome of these tumors as well as the diagnostic and prognostic implications of TERT promoter mutations.

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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Adult granulosa cell tumors, FOXL2, Morphologic features, Sex cord-stromal tumors, TERT
in
International Journal of Gynecological Pathology
volume
43
issue
1
pages
12 pages
publisher
Lippincott Williams & Wilkins
external identifiers
  • scopus:85179780508
  • pmid:37255476
ISSN
0277-1691
DOI
10.1097/PGP.0000000000000953
language
English
LU publication?
yes
id
cc38731d-d054-4d44-ba3d-27858c41a41c
date added to LUP
2024-01-31 14:04:50
date last changed
2024-06-12 07:33:01
@article{cc38731d-d054-4d44-ba3d-27858c41a41c,
  abstract     = {{<p>Granulosa-cell tumors (GCTs) are the most common type of malignant ovarian sex cord-stromal tumor (SCST). The histopathologic diagnosis of these tumors can be challenging. A recurrent somatic mutation of the forkhead box L2 (FOXL2) gene has been identified in adult GCT. In this retrospective single-center study of 44 SCST, a morphologic review together with analysis of FOXL2 C134W was evaluated in relation to tumor morphology. In addition, TERT promoter mutation testing was performed. Twelve of 36 cases got an altered diagnosis based on morphology alone. The overarching architectural growth pattern in 32/44 (72.7%) tumors was diffuse/solid with several tumors showing markedly heterogeneous architecture. In correlation to FOXL2 C134W mutation status, cytoplasmic color, and nuclear shape, differed between the FOXL2 C134W positive and FOXL2 C134 W negative groups, but these differences were not significant when comparing them separately. Nineteen of 44 cases underwent TERT promoter sequencing with a positive result in 3 cases; 2 adult GCTs and 1 cellular fibroma. Three patients developed a recurrence of which 2 were FOXL2 C134W positive adult GCTs and the third was an unclassified SCST. In conclusion, the morphologic and immunohistochemical diagnosis of different SCSTs is challenging and one cannot reliably identify FOXL2 mutation-positive tumors solely by morphologic features. Therefore, broad use of molecular analysis of the FOXL2 C134W mutation is suggested for SCSTs, and further studies are needed to evaluate the clinical outcome of these tumors as well as the diagnostic and prognostic implications of TERT promoter mutations.</p>}},
  author       = {{Wessman, Sandra and Fuentes, Beatriz Bohorquez and Severin-Karlsson, Josefin and Westbom-Fremer, Sofia and Nistér, Monica and Kokaraki, Georgia and Petta, Tirzah Braz and Haglund, Felix and Carlson, Joseph W.}},
  issn         = {{0277-1691}},
  keywords     = {{Adult granulosa cell tumors; FOXL2; Morphologic features; Sex cord-stromal tumors; TERT}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{78--89}},
  publisher    = {{Lippincott Williams & Wilkins}},
  series       = {{International Journal of Gynecological Pathology}},
  title        = {{FOXL2 Mutation Status in Sex Cord-stromal Tumors Cannot be Predicted by Morphology}},
  url          = {{http://dx.doi.org/10.1097/PGP.0000000000000953}},
  doi          = {{10.1097/PGP.0000000000000953}},
  volume       = {{43}},
  year         = {{2024}},
}