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Staging and prognostic factors in uterine adenosarcoma

TL;DR — FIGO 2009 gives adenosarcoma its own stage I substaging: IA = tumour limited to endometrium/endocervix with no myometrial invasion; IB = ≤50% myometrial invasion; IC = >50% (Prat 2009, PMID 19135669). That is different from leiomyosarcoma/ESS, which use tumour size. The distinction exists because myometrial invasion, not size, was the recurrence-associated feature in the classic series (Clement 1990, PMID 2156771; Zaloudek 1981, PMID 6263458). Beyond stage, the variables that survive multivariable analysis in institutional series are sarcomatous overgrowth, LVSI, myometrial invasion, age, resection status and FIGO stage (Carroll 2014, PMID 25449308; Nathenson 2018, PMID 30044322). Nodal metastasis is uncommon (2.9% in SEER) but, when present, carries an adjusted CSS hazard similar to ESS and LMS (Machida 2017, PMID 28109626). Registry models that ignore SO and LVSI still discriminate (c-index 0.774, Qu 2020, PMID 33680946) and cannot be used to counsel a patient whose path report has those fields.

FIGO 2009 adenosarcoma staging

Prat’s 2009 FIGO communication established separate staging for uterine sarcomas, with adenosarcoma substaged on depth of myometrial invasion rather than size (Prat 2009, PMID 19135669). NCI PDQ restates the adenosarcoma-specific table (NCI PDQ — "Uterine Sarcoma Treatment", https://www.cancer.gov/types/uterine/patient/uterine-sarcoma-treatment-pdq, accessed 2026-09-01):

Stage Adenosarcoma
I Limited to uterus
IA Limited to endometrium and/or endocervix, no myometrial invasion
IB Invades ≤ half the myometrium
IC Invades > half the myometrium
II Extends beyond uterus, within pelvis
IIA Adnexal involvement
IIB Other pelvic tissues
III Infiltrates abdominal tissues
IIIA One site
IIIB >1 site
IIIC Pelvic and/or para-aortic nodes
IVA Bladder and/or rectum
IVB Distant metastasis

LMS and ESS stage I uses ≤5 cm vs >5 cm, not invasion depth (Prat 2009, PMID 19135669; D'Angelo 2010, PMID 19853898). Carcinosarcomas are staged as endometrial carcinomas (D'Angelo 2010, PMID 19853898). Mixing these systems in a registry extract is a documented source of noise (Seagle 2016, PMID 27771166 used AJCC; Machida 2017, PMID 28109626 used SEER historic stage).

Myometrial invasion was present in 15 of Clement’s 100 cases and was deep in only four; it was the only feature associated with increased recurrence risk in that series (Clement 1990, PMID 2156771). Gallardo: 14/30 uterine tumours (47%) invaded myometrium — minimal in 5, one-third thickness in 7, >50% in 2 (Gallardo 2009, PMID 18941402). Arend SEER: survival 63–69% when tumour invaded the uterine wall, <50% with extra-uterine disease; stage I 5-year 79% (75–84%), stage III 48% (29–65%) (Arend 2010, PMID 20688363).

Prognostic factors that survive multivariable analysis

Two institutional series have enough events for Cox models with sarcoma-pathologist review.

Carroll 2014, n=74, MD Anderson 1982–2011. Multivariate: SO and LVSI predicted worse PFS and OS. SO: PFS HR 2.58 (1.37–4.84), OS HR 2.45 (1.26–4.76). Stage I recurrence 77% (17/22) with SO vs 22% (8/37) without (Carroll 2014, PMID 25449308).

Nathenson 2018, n=165, MD Anderson 1982–2014. Median OS 8.5 years, DFS 4.7 years for all patients. Pathologic characteristics associated with OS/DFS/LRFS on univariate analysis: SO, myometrial invasion, LVSI, tumour size, mitotic count, ER, PR, FIGO stage, age, resection status. On Cox analysis, only SO, myometrial invasion, LVSI, age, resection status and FIGO stage remained. Median OS: SO 5.2 vs 14.5 years (p<0.0001); myometrial invasion 5.8 years vs not reached (p=0.0005); LVSI 1.0 vs 8.9 years (p=0.0021) (Nathenson 2018, PMID 30044322).

Machida 2017, SEER n=994 adenosarcoma plus literature review n=230 surgically treated. Nodal metastasis 2.9% in adenosarcoma vs 3.4% LMS vs 6.6% ESS (p<0.001). Nodal metastasis independently associated with CSS in all three (aHR 2.34 adenosarcoma, 2.43 ESS, 2.10 LMS). In the 230-case literature review, nodal metastasis had the largest aHR for PFS (4.72) compared with SO (2.88), heterologous elements (2.08) and deep myometrial invasion (1.51). Large tumour, deep invasion and SO were associated with nodal risk (Machida 2017, PMID 28109626). The literature-review half is subject to publication bias; the SEER half has no SO field.

Seagle 2016, NCDB n=2,205. Independent OS detriments: distant metastasis, positive surgical margin, older age, higher comorbidity score, adjuvant radiotherapy. Each 1 cm increase in uterine-tumour size: HR 1.06 (1.01–1.12). Primary site, node status, procedure type, chemotherapy, race, insurance, income not associated with OS. Nodal metastasis 36/1,176 (3.1%); distant metastasis 33/1,342 (2.5%) (Seagle 2016, PMID 27771166).

Yuan 2019, n=49. Multivariate: presence of a tumour stalk independently protective for recurrence (HR 0.088, p=0.005); LVSI a risk factor (HR 11.95, p=0.002) (Yuan 2019, PMID 31139558). Stalk as a protective factor is unique to this series and has not been replicated.

Li 2022, n=31. SO (p=0.04), high-grade histology (p=0.002) and greater myometrial invasion (p=0.001) associated with decreased RFS. Zero of 15 lymphadenectomies had positive nodes. Zero of 6 ovarian-preservation patients recurred (Li 2022, PMID 35005157). Small series.

Kaku 1992, GOG n=31. Recurrence 9/30 (30%); death 6/30 (20%) at mean follow-up 38.3 months. Stage III (p<0.001) and myometrial invasion (p=0.04) associated with recurrence; LVSI, SO and rhabdomyosarcoma indicated poor prognosis without significance (Kaku 1992, PMID 1316323).

How to read the Nathenson review list

Nathenson and Conley 2018 name age, SO, myometrial invasion, LVSI and nodal involvement as the most important prognostic factors, and argue that low-risk patients can be observed and high-risk patients are “candidates for aggressive therapy with adjuvant chemotherapy” (Nathenson 2018, PMID 30169984). The candidate status is a reviewer’s inference, not a trial result. The same group’s radiation analysis found no OS or LRFS benefit (Nathenson 2018, PMID 30044322).

Registry models without the important variables

Qu trained a deep survival model on 797 SEER adenosarcomas (train 519 / val 143 / test 143) using 15 variables: age, grade, positive nodes, marital status, race, tumour extension, stage, surgery, and others that SEER holds. External-test c-index 0.774, Brier 0.14, versus Cox c-index 0.726, Brier 0.17 (Qu 2020, PMID 33680946). The model cannot include SO, LVSI, heterologous elements, or hormone receptors. A c-index of 0.774 in a registry that is missing the strongest institutional predictors is a statement about coded stage and age, not a replacement for the pathology report.

Open questions

  • Does LVSI remain independent of SO in series that are not MD Anderson? Two MD Anderson papers (Carroll 2014, PMID 25449308; Nathenson 2018, PMID 30044322) and Yuan (PMID 31139558) are the multivariable support.
  • Should FIGO IA with SO be counselled as high-risk despite “early” stage? Carroll’s 77% vs 22% stage I recurrence split says yes (Carroll 2014, PMID 25449308); no guideline has created an IA-SO substage.

References

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