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Sarcomatous overgrowth in uterine adenosarcoma

TL;DR — Sarcomatous overgrowth (SO) is a pure sarcomatous component occupying ≥25% of tumour volume, defined in a 10-case series in 1989 (Clement 1989, PMID 2535774). It is the one histological variable with consistent independent support for worse progression-free and overall survival (Howitt 2015, PMID 25231023; Carroll 2014, PMID 25449308). Frequency is roughly 10–55% depending on series mix; the spread reflects case selection rather than a population prevalence range. Every survival estimate below is retrospective. No trial has reported randomisation stratified by SO or an SO-specific treatment effect; the old mixed-histology phase 3 registration NCT00162721 has unknown status and no posted results.

Definition

Clement’s 1989 series of 10 Müllerian adenosarcomas with sarcomatous overgrowth described typical adenosarcoma “overgrown by a pure sarcoma that accounted for 25% to 80% of the tumor.” In 7 of 10 the pure sarcoma was of higher grade and higher mitotic rate than the sarcomatous component of the associated adenosarcoma; in 3 the two sarcomatous components looked similar (Clement 1989, PMID 2535774). Median age was 59 (range 32–82). Six of 10 invaded myometrium, three to serosa. Seven of 10 recurred (including four with hematogenous metastases); six died of tumour at 9 months to 10 years. Three were alive without recurrence at 4–7 years. Clement’s conclusion, against the then-prevailing view of adenosarcoma as indolent, was that adenosarcoma with SO is aggressive (Clement 1989, PMID 2535774).

The ≥25% volume threshold is the definition used by subsequent series, the French GSF/TMRG guideline, and practical reviews (Karabajakian 2023, PMID 37202293; Ulrich 2018, PMID 30326467; Pinto 2016, PMID 26927725). Ulrich estimates SO in “about 10% of cases” (Ulrich 2018, PMID 30326467); that figure is lower than most surgical series and likely reflects mixed literature rather than a population incidence.

The threshold has not been validated as an ROC-optimised cut-point. A PubMed search rerun 2026-09-01 found no study modelling SO as a continuous volume fraction against outcome. High-grade stroma without meeting the 25% volume rule is treated as a related but distinct finding: Hodgson reported 9 high-grade adenosarcomas, 8 of 9 with SO, and argued that any high-grade component should be reported even without SO because of short-interval recurrence (Hodgson 2017, PMID 28834809). That is a 9-case observation.

Frequency across series

Series Design n SO frequency Notes
Clement 1989, PMID 2535774 Consecutive SO cases, not a prevalence series 10 SO — Defined the entity
Kaku 1992, PMID 1316323 GOG hysterectomy + staging laparotomy 31 17/31 (55%) 10 of 17 with SO had rhabdomyosarcoma
Gallardo 2009, PMID 18941402 Clinicopathologic 55 18/55 (33%) 4 of 5 deaths had SO; 2 deaths did not
Tanner 2013, PMID 23283300 Single-institution treatment series 31 5/19 up-front treated (26%) 2-yr PFS/OS 20% vs 100%
Carroll 2014, PMID 25449308 Single-institution, 1982–2011 74 included of 100 identified Not stated as a percentage in the abstract; SO was the primary stratifier Stage I recurrence 77% with SO vs 22% without
Tate 2018, PMID 29441675 6 institutional + 104 literature, Japan 110 assembled SO subset n=20 with known outcome Recurrence 45% (9/20), death 35% (7/20) among SO
Yuan 2019, PMID 31139558 Single-centre 12-year 49 15/49 (30.6%)
Li 2022, PMID 35005157 Single-institution gyn sites 31 Not separately quantified in abstract; SO associated with decreased RFS (p=0.04)
Morikawa 2025, PMID 39729099 MRI systematic review + 5 institutional 30 with imaging 55.2% Imaging-selected, not a prevalence series

Kaku’s 55% in a GOG staging-laparotomy cohort is the high end and may reflect referral and protocol selection (Kaku 1992, PMID 1316323). Ulrich’s ~10% is the low end (Ulrich 2018, PMID 30326467). Surgical series clustering around 25–35% are the most defensible working figures, with the explicit caveat that none is population-based.

Survival split

Carroll’s 74-patient MD Anderson cohort is the load-bearing multivariable analysis. On multivariate analysis, SO and LVSI predicted worse PFS and OS. Median PFS 29.4 vs 105.9 months (HR 2.58, 95% CI 1.37–4.84, p=0.003); median OS 55.4 vs 112.4 months (HR 2.45, 95% CI 1.26–4.76, p=0.008) (Carroll 2014, PMID 25449308). Among stage I, 17/22 (77%) with SO recurred versus 8/37 (22%) without (p<0.001). Adjuvant therapy in stage I with SO was associated with longer PFS (46.7 vs 29.4 months) and OS (97.3 vs 55.4 months) that did not reach significance (p=0.28, 0.18) (Carroll 2014, PMID 25449308).

Tanner’s 19 patients treated from diagnosis at MSK: 2-year PFS and OS both 20% with SO versus 100% without (median follow-up 72.9 months) (Tanner 2013, PMID 23283300). Five patients in the SO group is too few for a stable rate; the direction matches Carroll.

Nathenson’s review compiles recurrence 77% with SO versus 23% without, and 5-year OS 50–60% with SO versus 60–80% for stage I overall (Nathenson 2016, PMID 27718181). Those percentages are not from a single cohort. The 2018 Nathenson MD Anderson series (n=165) found median OS 5.2 years with SO versus 14.5 years without (p<0.0001); SO remained significant on Cox analysis with myometrial invasion, LVSI, age, resection status and FIGO stage (Nathenson 2018, PMID 30044322).

Howitt’s targeted sequencing of 20 samples from 18 subjects called SO “the only established histological variable associated with higher stage and shorter survival” (Howitt 2015, PMID 25231023). Mutation count did not differ with versus without SO (mean 9.7 vs 9.6); gene-level copy-number alterations did (mean 24.6 vs 5, p=0.0002) (Howitt 2015, PMID 25231023). SO is therefore a morphological call that tracks genomic complexity, not a higher mutation burden. See molecular and genomic features.

Kaku found rhabdomyosarcoma in 10 of 17 SO cases; rhabdomyosarcomatous differentiation, lymphatic/vascular invasion and SO all pointed toward poor prognosis without reaching significance in n=31 (Kaku 1992, PMID 1316323). Extrauterine spread (stage III) (p<0.001) and myometrial invasion (p=0.04) were the factors that did.

Hodgson’s 9 high-grade versus 9 low-grade adenosarcomas: 6/9 high-grade patients developed rapid recurrence and 1 died; no low-grade tumour recurred. TP53 pathway alterations were present in 7/9 (78%) high-grade tumours; p53 IHC correlated with mutation (Hodgson 2017, PMID 28834809). Momeni Boroujeni (n=27, enriched for high-grade) found SO more often in high-grade than low-grade tumours (12/17, 71% vs 1/10, 10%, p=0.004); heterologous elements were exclusive to high-grade cases; all deaths were from high-grade disease (Momeni Boroujeni 2022, PMID 36138078). High-grade and SO overlap heavily; they are not synonyms, and the literature does not always distinguish them.

What SO is not

SO is not a molecular diagnosis. Howitt found no mutation-count difference; the genomic correlate is copy-number complexity, MYBL1 amplification enriched in SO, and occasional TP53 or ATRX mutation (Howitt 2015, PMID 25231023). It is not a FIGO stage — a stage IA tumour can have SO, and that combination is the highest-risk “early” disease in Carroll’s stage I split (Carroll 2014, PMID 25449308). It is not an indication with trial-proven adjuvant therapy; the Carroll numerical benefit is the entire comparative evidence base and is not statistically significant (Carroll 2014, PMID 25449308). ESGO 2024 allows consideration of adjuvant chemotherapy in stage II–IV completely resected disease and after morcellation of high-grade/SO tumours, as option rather than standard (Ray-Coquard 2024, PMID 39322612).

Open questions

  • Is 25% the right cut? The definition is historical (Clement 1989, PMID 2535774). No study examining SO as a continuous volume fraction against survival was identified in the 2026-09-01 PubMed search.
  • Does high-grade stroma without SO carry the same risk as SO? Hodgson’s 9-case argument that any high-grade component should be reported is untested at scale (Hodgson 2017, PMID 28834809).
  • Would adjuvant chemotherapy in stage I SO survive a multi-institutional comparison? Carroll’s p=0.28/0.18 is compatible with benefit, harm, or noise (Carroll 2014, PMID 25449308).

References

  1. Clement PB. Müllerian adenosarcomas of the uterus with sarcomatous overgrowth. A clinicopathological analysis of 10 cases. Am J Surg Pathol. 1989;13:28-38. PMID 2535774
  2. Howitt BE, et al. Targeted genomic analysis of Müllerian adenosarcoma. J Pathol. 2015;235:37-49. PMID 25231023
  3. Carroll A, et al. Uterine adenosarcoma: an analysis on management, outcomes, and risk factors for recurrence. Gynecol Oncol. 2014;135:455-61. PMID 25449308
  4. Tanner EJ, et al. Management of uterine adenosarcomas with and without sarcomatous overgrowth. Gynecol Oncol. 2013;129:140-4. PMID 23283300
  5. Kaku T, et al. Adenosarcoma of the uterus: a Gynecologic Oncology Group clinicopathologic study of 31 cases. Int J Gynecol Pathol. 1992;11:75-88. PMID 1316323
  6. Gallardo A, Prat J. Mullerian adenosarcoma: a clinicopathologic and immunohistochemical study of 55 cases challenging the existence of adenofibroma. Am J Surg Pathol. 2009;33:278-88. PMID 18941402
  7. Nathenson MJ, et al. Uterine Adenosarcoma: a Review. Curr Oncol Rep. 2016;18:68. PMID 27718181
  8. Nathenson MJ, et al. The Importance of Lymphovascular Invasion in Uterine Adenosarcomas. Int J Gynecol Cancer. 2018;28:1297-1310. PMID 30044322
  9. Hodgson A, et al. High-grade Müllerian Adenosarcoma: Genomic and Clinicopathologic Characterization of a Distinct Neoplasm With Prevalent TP53 Pathway Alterations and Aggressive Behavior. Am J Surg Pathol. 2017;41:1513-1522. PMID 28834809
  10. Momeni Boroujeni A, et al. Mullerian adenosarcoma: clinicopathologic and molecular characterization highlighting recurrent BAP1 loss and distinctive features of high-grade tumors. Mod Pathol. 2022;35:1684-1694. PMID 36138078
  11. Yuan Z, et al. Uterine Adenosarcoma: A Retrospective 12-Year Single-Center Study. Front Oncol. 2019;9:237. PMID 31139558
  12. Li JY, et al. Clinicopathologic characteristics and oncologic outcomes in adenosarcoma of gynecologic sites. Gynecol Oncol Rep. 2022;39:100913. PMID 35005157
  13. Tate K, et al. Uterine adenosarcoma in Japan: Clinicopathologic features, diagnosis and management. Asia Pac J Clin Oncol. 2018;14:318-325. PMID 29441675
  14. Morikawa K, et al. Magnetic resonance imaging features of uterine adenosarcoma: case series and systematic review. Abdom Radiol (NY). 2025;50:3313-3326. PMID 39729099
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  17. Karabajakian A, et al. Uterin adenosarcoma: French Guidelines of the French Sarcoma Group and the Rare Gynecologic Tumor Group. Bull Cancer. 2023;110:836-843. PMID 37202293
  18. Ray-Coquard I, et al. ESGO/EURACAN/GCIG guidelines for the management of patients with uterine sarcomas. Int J Gynecol Cancer. 2024;34:1499-1521. PMID 39322612