Skip to main content
Latest news
Browse specialties
Breast cancer Genitourinary cancers Lung & thoracic cancers
In focus
Next-generation sequencing: Emerging biomarkers in thyroid and NSCLCs ctDNA and bladder cancer: Current understanding and beyond ROS1 fusion-positive NSCLC NSCLC driver mutations: Discussing the importance of RET, ALK and ROS1 alterations in NSCLC Early-stage NSCLC management: Surgery, targeted treatment and immunotherapy ALK fusion-positive NSCLC: International approaches to management RET fusion-positive NSCLC: Informing on the use of pralsetinib for patients with RET fusion-positive, advanced NSCLC COVID-19 & cancer
Conferences
SABCS 2022 ESMO 2022 2022 ASCO Annual Meeting
About us
Medicine Matters Oncology
EXTENDED SEARCH
Top

12-01-2018 | Uterine cancer | Article

Genome profiling is an efficient tool to avoid the STUMP classification of uterine smooth muscle lesions: a comprehensive array-genomic hybridization analysis of 77 tumors

Authors: Sabrina Croce, Agnès Ducoulombier, Agnès Ribeiro, Tom Lesluyes, Jean-Christophe Noel, Frédéric Amant, Louis Guillou, Eberhard Stoeckle, Mojgan Mojgan Devouassoux-Shisheboran,, Nicolas Penel, Anne Floquet, Laurent Arnoud, Frédéric Guyon, Florence Mishellany, Camille Chakiba, Tine Cuppens, Michal Zikan, Agnès Leroux, Eric Frouin, Isabelle Farre, Catherine Genestie, Isabelle Valo, Gaëtan MacGrogan, Frédéric Chibon

Login to get access

Abstract

The diagnosis of a uterine smooth muscle lesion is, in the majority of cases, straightforward. However, in a small number of cases, the morphological criteria used in such lesions cannot differentiate with certainty a benign from a malignant lesion and a diagnosis of smooth muscle tumor with uncertain malignant potential (STUMP) is made. Uterine leiomyosarcomas are often easy to diagnose but it is difficult or even impossible to identify a prognostic factor at the moment of the diagnosis with the exception of the stage. We hypothesize, for uterine smooth muscle lesions, that there is a gradient of genomic complexity that correlates to outcome. We first tested this hypothesis on STUMP lesions in a previous study and demonstrated that this 'gray category' could be split according to genomic index into two groups. A benign group, with a low to moderate alteration rate without recurrence and a malignant group, with a highly rearranged profile akin to uterine leiomyosarcomas. Here, we analyzed a large series of 77 uterine smooth muscle lesions (from 76 patients) morphologically classified as 19 leiomyomas, 14 STUMP and 44 leiomyosarcomas with clinicopathological and genomic correlations. We confirmed that genomic index with a cut-off=10 is a predictor of recurrence (P<0.0001) and with a cut-off=35 is a marker for poor overall survival (P=0.035). For the tumors confined to the uterus, stage as a prognostic factor was not useful in survival prediction. At stage I, among the tumors reclassified as molecular leiomyosarcomas (ie, genomic index ≥10), the poor prognostic markers were: 5p gain (overall survival P=0.0008), genomic index at cut-off=35 (overall survival P=0.0193), 13p loss including RB1(overall survival P=0.0096) and 17p gain including MYOCD gain (overall survival P=0.0425). Based on these findings (and the feasibility of genomic profiling by array-comparative genomic hybridization), genomic index, 5p and 17p gains prognostic value could be evaluated in future prospective chemotherapy trials.

Mod Pathol 2018. doi:10.1038/modpathol.2017.185

Literature
  1. Skorstad M, Kent A, Lieng M. Uterine leiomyosarcoma - incidence, treatment, and the impact of morcellation. A nationwide cohort study. Acta Obstet Gynecol Scand 2016;95:984–990.
  2. Oliva E, Carcangiu ML, Carinelli SG, et al. Mesenchymal tumours. Smooth muscle tumour of uncertain malignant potential. In: Kurman RJ CM, Herrington CS, Young RH (eds). WHO Classification of Tumours of Female Reproductive Organs, 2014, pp 135–147.
  3. Baird DD, Dunson DB, Hill MC, et al. High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence. Am J Obstet Gynecol 2003;188:100–107.
  4. Ricci S, Stone RL, Fader AN. Uterine leiomyosarcoma: epidemiology, contemporary treatment strategies and the impact of uterine morcellation. Gynecol Oncol 2017;145:208–216.
  5. Garcia C, Kubat JS, Fulton RS, et al. Clinical outcomes and prognostic markers in uterine leiomyosarcoma: a population-based cohort. Int J Gynecol Cancer 2015;25: 622–628.
  6. Bell SW, Kempson RL, Hendrickson MR. Problematic uterine smooth muscle neoplasms. A clinicopathologic study of 213 cases. Am J Surg Pathol 1994;18:535–558.
  7. Amant F, Coosemans A, Debiec-Rychter M, et al. Clinical management of uterine sarcomas. Lancet Oncol 2009;10:1188–1198.
  8. Hensley ML, Ishill N, Soslow R, et al. Adjuvant gemcitabine plus docetaxel for completely resected stages I-IV high grade uterine leiomyosarcoma: results of a prospective study. Gynecol Oncol 2009;112: 563–567.
  9. Amant F, Lorusso D, Mustea A, et al. Management strategies in advanced uterine leiomyosarcoma: focus on trabectedin. Sarcoma 2015;2015:704124.
  10. Omura GA, Blessing JA, Major F, et al. A randomized clinical trial of adjuvant adriamycin in uterine sarcomas: a Gynecologic Oncology Group Study. J Clin Oncol 1985;3:1240–1245.
  11. Reed NS, Mangioni C, Malmstrom H, et al. Phase III randomised study to evaluate the role of adjuvant pelvic radiotherapy in the treatment of uterine sarcomas stages I and II: an European Organisation for Research and Treatment of Cancer Gynaecological Cancer Group Study (protocol 55874). Eur J Cancer 2008;44:808–818.
  12. Rose PG, Boutselis JG, Sachs L. Adjuvant therapy for stage I uterine sarcoma. Am J Obstet Gynecol 1987;156: 660–662.
  13. Sorbe B, Johansson B. Prophylactic pelvic irradiation as part of primary therapy in uterine sarcomas. Int J Oncol 2008;32:1111–1117.
  14. Zivanovic O, Jacks LM, Iasonos A, et al. A nomogram to predict postresection 5-year overall survival for patients with uterine leiomyosarcoma. Cancer 2012;118:660–669.
  15. Iasonos A, Keung EZ, Zivanovic O, et al. External validation of a prognostic nomogram for overall survival in women with uterine leiomyosarcoma. Cancer 2013;119:1816–1822.
  16. Pautier P, Genestie C, Rey A, et al. Analysis of clinicopathologic prognostic factors for 157 uterine sarcomas and evaluation of a grading score validated for soft tissue sarcoma. Cancer 2000;88:1425–1431.
  17. Croce S, Ribeiro A, Brulard C, et al. Uterine smooth muscle tumor analysis by comparative genomic hybridization: a useful diagnostic tool in challenging lesions. Mod Pathol 2015;28:1001–1010.
  18. Oliva E. Practical issues in uterine pathology from banal to bewildering: the remarkable spectrum of smooth muscle neoplasia. Mod Pathol 2016;29(Suppl 1):S104–S120.
  19. Lagarde P, Perot G, Kauffmann A, et al. Mitotic checkpoints and chromosome instability are strong predictors of clinical outcome in gastrointestinal stromal tumors. Clin Cancer Res 2012;18:826–838.
  20. Mehine M, Kaasinen E, Makinen N, et al. Characterization of uterine leiomyomas by whole-genome sequencing. N Engl J Med 2013;369:43–53.
  21. Mehine M, Kaasinen E, Aaltonen LA. Chromothripsis in uterine leiomyomas. N Engl J Med 2013;369:2160–2161.
  22. Makinen N, Aavikko M, Heikkinen T, et al. Exome sequencing of uterine leiomyosarcomas identifies frequent mutations in TP53, ATRX, and MED12. PLoS Genet 2016;12:e1005850.
  23. Hempling RE, Piver MS, Baker TR. Impact on progression-free survival of adjuvant cyclophosphamide, vincristine, doxorubicin (adriamycin), and dacarbazine (CYVADIC) chemotherapy for stage I uterine sarcoma. A prospective trial. Am J Clin Oncol 1995;18: 282–286.
  24. El-Rifai W, Sarlomo-Rikala M, Knuutila S, et al. DNA copy number changes in development and progression in leiomyosarcomas of soft tissues. Am J Pathol 1998;153:985–990.
  25. Hu J, Khanna V, Jones M, et al. Genomic alterations in uterine leiomyosarcomas: potential markers for clinical diagnosis and prognosis. Genes Chromosomes Cancer 2001;31:117–124.
  26. Larramendy ML, Kaur S, Svarvar C, et al. Gene copy number profiling of soft-tissue leiomyosarcomas by array-comparative genomic hybridization. Cancer Genet Cytogenet 2006;169:94–101.
  27. Perot G, Derre J, Coindre JM, et al. Strong smooth muscle differentiation is dependent on myocardin gene amplification in most human retroperitoneal leiomyosarcomas. Cancer Res 2009;69:2269–2278.
  28. Agaram NP, Zhang L, LeLoarer F, et al. Targeted exome sequencing profiles genetic alterations in leiomyosarcoma. Genes Chromosomes Cancer 2016;55:124–130.
  29. Kimura Y, Morita T, Hayashi K, et al. Myocardin functions as an effective inducer of growth arrest and differentiation in human uterine leiomyosarcoma cells. Cancer Res 2010;70:501–511.
  30. Perot G, Mendiboure J, Brouste V, et al. Smooth muscle differentiation identifies two classes of poorly differentiated pleomorphic sarcomas with distinct outcome. Mod Pathol 2014;27:840–850.
  31. Nordal RR, Kristensen GB, Kaern J, et al. The prognostic significance of stage, tumor size, cellular atypia and DNA ploidy in uterine leiomyosarcoma. Acta Oncol 1995;34:797–802.
  32. Wang WL, Soslow R, Hensley M, et al. Histopathologic prognostic factors in stage I leiomyosarcoma of the uterus: a detailed analysis of 27 cases. Am J Surg Pathol 2011;35:522–529.
  33. Pelmus M, Penault-Llorca F, Guillou L, et al. Prognostic factors in early-stage leiomyosarcoma of the uterus. Int J Gynecol Cancer 2009;19:385–390.
  34. Davidson B, Kjaereng ML, Forsund M, et al. Progesterone receptor expression is an independent prognosticator in FIGO stage I uterine leiomyosarcoma. Am J Clin Pathol 2016;145:449–458.
  35. Lim D, Alvarez T, Nucci MR, et al. Interobserver variability in the interpretation of tumor cell necrosis in uterine leiomyosarcoma. Am J Surg Pathol 2013;37: 650–658.
  36. Downes KA, Hart WR. Bizarre leiomyomas of the uterus: a comprehensive pathologic study of 24 cases with long-term follow-up. Am J Surg Pathol 1997;21: 1261–1270.
  37. Croce S, Young RH, Oliva E. Uterine leiomyomas with bizarre nuclei: a clinicopathologic study of 59 cases. Am J Surg Pathol 2014;38:1330–1339.
  38. Liegl-Atzwanger B, Heitzer E, Flicker K, et al. Exploring chromosomal abnormalities and genetic changes in uterine smooth muscle tumors. Mod Pathol 2016;29: 1262–1277.
  39. Zhang Q, Ubago J, Li L, et al. Molecular analyses of 6 different types of uterine smooth muscle tumors: emphasis in atypical leiomyoma. Cancer 2014;120:3165–3177.