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Surgical management of uterine adenosarcoma

TL;DR — Hysterectomy is the treatment with evidence of survival association; everything else is inferred. NCDB analysis of 2,205 Müllerian adenosarcomas found complete surgical resection the only treatment with well-evidenced OS benefit; positive margin independently predicted death (Seagle 2016, PMID 27771166). Bilateral salpingo-oophorectomy is standard in reviews and guidelines (Nathenson 2016, PMID 27718181; Friedlander 2014, PMID 25341585) but ovarian preservation in premenopausal stage I disease has not been shown to worsen survival in the small subsets that exist (Li 2022, PMID 35005157; Nasioudis 2017, PMID 28541635). Lymphadenectomy is not supported as routine: nodal metastasis 2.9–3.1% (Machida 2017, PMID 28109626; Seagle 2016, PMID 27771166). Fertility-sparing surgery is case-level evidence (L’Heveder 2019, PMID 31584132; Yuan 2019, PMID 31139558). Morcellation is a safety problem, not a technique (see red flags).

Hysterectomy

Clement: primary treatment known in 97 of 100, some form of hysterectomy in 93, conservative resection in 4 (Clement 1990, PMID 2156771). Gallardo: treatment known in 50 — 10 polypectomy, 1 cone, 39 hysterectomy (24 with BSO, 4 with lymphadenectomy) (Gallardo 2009, PMID 18941402). Tanner: all 19 up-front-treated patients had hysterectomy, 84% BSO (Tanner 2013, PMID 23283300). Li: surgical management “primarily consisted of total hysterectomy ± bilateral adnexectomy ± lymph node dissection” (Li 2022, PMID 35005157).

Seagle: among 2,205 NCDB adenosarcomas of uterus, cervix or ovary, complete resection was the treatment associated with OS; positive margin independently predicted decreased OS; surgical procedure type (the specific operation) was not independently associated with OS once margin and metastasis were in the model (Seagle 2016, PMID 27771166). That is a registry argument for getting the tumour out intact, not for a particular incision.

Minimally invasive hysterectomy is not adenosarcoma-specific in this literature. The morcellation data are about occult sarcoma as a class (Raine-Bennett 2016, PMID 26646120; Multinu 2019, PMID 30447212). ESGO 2024 discourages morcellation because of dissemination risk (Ray-Coquard 2024, PMID 39322612). Intact removal is the operational rule; the evidence is analogy plus the NCDB margin finding.

Oophorectomy

Standard-of-care statements recommend TAH-BSO (Nathenson 2016, PMID 27718181; Nathenson 2018, PMID 30044322; Friedlander 2014, PMID 25341585; Ulrich 2018, PMID 30326467). The rationale is that adenosarcoma can express hormone receptors and that occult ovarian involvement is possible, not a randomised comparison.

Evidence that preservation is not disastrous in selected patients:

  • Li 2022: ovaries preserved in 6/31 (19.4%); none of those 6 recurred. The authors call ovarian preservation “a feasible management option with non-inferior outcomes for premenopausal women with early-stage disease” and immediately note that larger cohorts are needed (Li 2022, PMID 35005157). n=6.
  • Nasioudis 2017: SEER women ≤50 with stage I uterine sarcoma, hysterectomy ± oophorectomy, no radiation. 1,482 women: 800 LMS, 520 LG-ESS, 162 adenosarcoma; ovarian preservation in 418/1,482 (28.2%). No difference in OS (p=0.220) or CSS (p=0.210) overall; multivariate confirmed ovarian preservation not associated with worse mortality. The authors’ own limit: “No conclusions could be made for those with LG-ESS or AS” (Nasioudis 2017, PMID 28541635). The adenosarcoma n=162 is nested, not separately powered.

Hormone-receptor biology makes the ovarian-preservation question different from LMS. Ioffe found ER positivity in 34/54 (63%) uterine sarcomas of mixed histology and improved OS (median 36 vs 16 months, p=0.004; multivariate HR 0.32, 0.12–0.89) (Ioffe 2009, PMID 19767065). That paper is not adenosarcoma-specific. French and ESGO guidance reserve endocrine therapy for ER/PR-positive low-grade recurrent/metastatic disease and warn against tamoxifen (Karabajakian 2023, PMID 37202293; Ray-Coquard 2024, PMID 39322612). Leaving ovaries in a premenopausal woman with a receptor-positive tumour is a hormone-exposure decision as well as a surgical one, and it has not been isolated in adenosarcoma.

Lymphadenectomy

Source Nodal metastasis Survival association Practice implication as stated
Seagle NCDB, PMID 27771166 36/1,176 (3.1%) Node status not independently associated with OS Complete resection, not node dissection, is the evidenced treatment
Machida SEER, PMID 28109626 2.9% of adenosarcoma Nodal metastasis aHR 2.34 for CSS Incidence low; impact when present comparable to ESS/LMS
Machida literature review, PMID 28109626 230 unique surgically treated cases Nodal metastasis aHR 4.72 for PFS (largest of the factors modelled) SO, large tumour, deep invasion associated with nodal risk
Li institutional, PMID 35005157 0/15 dissected — Small single-institution series
Gallardo, PMID 18941402 Lymphadenectomy in 4/39 hysterectomies — Not a nodal-staging series
Kaku GOG, PMID 1316323 Pelvic node metastases in 2 of the 6 patients with extrauterine spread Stage III associated with recurrence Staging laparotomy suggested for clinical stage I–II in 1992

Nathenson’s 2018 treatment-outcomes paper concludes that standard of care should remain TAH-BSO “± lymphadenectomy” and no adjuvant radiation (Nathenson 2018, PMID 30044322). The ± is the honest state of the evidence: dissection finds disease rarely; when it does, prognosis is worse; whether the dissection itself changes outcome is untested. Machida’s finding that SO, large tumour and deep invasion predict nodal risk is the closest thing to a selection rule, and it comes from a literature review of 230 cases (Machida 2017, PMID 28109626).

Kaku 1992 suggested staging laparotomy including peritoneal cytology for clinical stage I–II (Kaku 1992, PMID 1316323). That recommendation predates FIGO 2009, laparoscopy, and the NCDB/SEER nodal rates, and it has not been re-tested.

Fertility-sparing approaches

This is case-report and small-series territory. Presenting it as a cohort result would be a misrepresentation.

  • L’Heveder 2019: one woman diagnosed at 18 with a low-grade polypoid adenosarcoma declined TAH-BSO, was monitored with ultrasound/hysteroscopy/biopsy and annual MRI, had IVF, miscarriage at 16 weeks, then twins at 28 weeks, and underwent laparoscopic hysterectomy at 20 years with no recurrence (L’Heveder 2019, PMID 31584132). Single case, 20-year follow-up.
  • Yuan 2019: fertility-sparing surgery in 7 stage IA patients; when stage IA analysed separately, FSS was not significantly associated with DFS or OS. The authors condition acceptability on tumours with stalks and without high-risk factors, with counselling (Yuan 2019, PMID 31139558). n=7, one centre.
  • Piątek 2022: 11 young women with mixed uterine sarcomas including 3 adenosarcomas; 3 patients conceived (5 live births in the whole mixed cohort). “Patients with adenosarcoma may have a low chance of childbearing.” High-grade ESS was considered inappropriate for fertility-sparing (Piątek 2022, PMID 36012998). Mixed histologies; adenosarcoma n=3.

ESGO 2024 and French GSF/TMRG do not establish fertility-sparing as standard. The French guideline recommends complete surgical removal in localised disease (Karabajakian 2023, PMID 37202293). A patient who declines hysterectomy is making a decision the literature can describe but not power.

Recurrent disease

Nathenson 2017: 78 patients with recurrent or metastatic adenosarcoma. Median OS from recurrence 1.8 years. OS differed by pathology on recurrence (p=0.035). Median OS 26.3 months with surgery for first recurrence versus 15.1 months without. OS was not influenced by chemotherapy (p=0.58), palliative radiation (p=0.58) or hormonal therapy (p=0.15) (Nathenson 2017, PMID 29445312). Surgery for first recurrence is associated with longer OS in this retrospective series; whether that is selection of resectable biology or an effect of resection cannot be separated. French and ESGO guidance both recommend attempting complete resection of relapse when feasible (Karabajakian 2023, PMID 37202293; Ray-Coquard 2024, PMID 39322612). See recurrence and surveillance.

Open questions

  • Does BSO change outcome in premenopausal stage I adenosarcoma without SO? Nasioudis could not conclude for this histology (PMID 28541635); Li’s n=6 is not an answer (PMID 35005157).
  • Is there a preoperative rule (SO on biopsy, size, invasion on MRI) that identifies the ~3% with nodal metastasis well enough to justify lymphadenectomy? Machida’s associations are the hypothesis (PMID 28109626).

References

  1. Seagle BL, et al. Survival of women with Mullerian adenosarcoma: A National Cancer Data Base study. Gynecol Oncol. 2016;143:636-641. PMID 27771166
  2. Clement PB, Scully RE. Mullerian adenosarcoma of the uterus: a clinicopathologic analysis of 100 cases. Hum Pathol. 1990;21:363-81. PMID 2156771
  3. Gallardo A, Prat J. Mullerian adenosarcoma: a clinicopathologic and immunohistochemical study of 55 cases. Am J Surg Pathol. 2009;33:278-88. PMID 18941402
  4. Tanner EJ, et al. Management of uterine adenosarcomas with and without sarcomatous overgrowth. Gynecol Oncol. 2013;129:140-4. PMID 23283300
  5. Li JY, et al. Clinicopathologic characteristics and oncologic outcomes in adenosarcoma of gynecologic sites. Gynecol Oncol Rep. 2022;39:100913. PMID 35005157
  6. Nathenson MJ, et al. Uterine Adenosarcoma: a Review. Curr Oncol Rep. 2016;18:68. PMID 27718181
  7. Nathenson MJ, et al. The Importance of Lymphovascular Invasion in Uterine Adenosarcomas. Int J Gynecol Cancer. 2018;28:1297-1310. PMID 30044322
  8. Nathenson MJ, et al. Treatment of Recurrent or Metastatic Uterine Adenosarcoma. Sarcoma. 2017;2017:4680273. PMID 29445312
  9. Friedlander ML, et al. GCIG consensus review for mullerian adenosarcoma of the female genital tract. Int J Gynecol Cancer. 2014;24:S78-82. PMID 25341585
  10. Ulrich UA, Denschlag D. Uterine Adenosarcoma. Oncol Res Treat. 2018;41:693-696. PMID 30326467
  11. Machida H, et al. Significance of lymph node metastasis on survival of women with uterine adenosarcoma. Gynecol Oncol. 2017;144:524-530. PMID 28109626
  12. Nasioudis D, et al. Safety of ovarian preservation in premenopausal women with stage I uterine sarcoma. J Gynecol Oncol. 2017;28:e46. PMID 28541635
  13. Ioffe YJ, et al. Hormone receptor expression in uterine sarcomas: prognostic and therapeutic roles. Gynecol Oncol. 2009;115:466-71. PMID 19767065
  14. L'Heveder A, et al. Conservative management of uterine adenosarcoma: lessons learned from 20 years of follow-up. Arch Gynecol Obstet. 2019;300:1383-1389. PMID 31584132
  15. Yuan Z, et al. Uterine Adenosarcoma: A Retrospective 12-Year Single-Center Study. Front Oncol. 2019;9:237. PMID 31139558
  16. Piątek S, et al. Fertility-Sparing Management May Be Considered in Young Women with Uterine Sarcoma. J Clin Med. 2022;11:4761. PMID 36012998
  17. 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
  18. Raine-Bennett T, et al. Occult Uterine Sarcoma and Leiomyosarcoma: Incidence of and Survival Associated With Morcellation. Obstet Gynecol. 2016;127:29-39. PMID 26646120
  19. Multinu F, et al. Incidence of sarcoma in patients undergoing hysterectomy for benign indications: a population-based study. Am J Obstet Gynecol. 2019;220:179.e1-179.e10. PMID 30447212
  20. Karabajakian A, et al. Uterin adenosarcoma: French Guidelines. Bull Cancer. 2023;110:836-843. PMID 37202293
  21. 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