Skip to content

Pathology and diagnosis of uterine adenosarcoma

TL;DR — Diagnosis is morphological: a biphasic tumour with benign (or atypical) epithelium and a malignant stroma that typically cuffs glands and forms leaf-like projections (Clement 1974, PMID 4371193; Pinto 2016, PMID 26927725). The criteria that separate adenosarcoma from adenofibroma — stromal mitoses, cellularity, atypia — have not been validated against outcome in a prospective series, and Gallardo and Prat argued that some “adenofibromas” are well-differentiated adenosarcomas (Zaloudek 1981, PMID 6263458; Gallardo 2009, PMID 18941402). Polyps that overlap with adenosarcoma but fall short of the diagnosis followed a benign course in two retrospective series (Howitt 2015, PMID 25118811; Chapel 2022, PMID 34675347). Howitt found no specific diagnostic molecular or IHC tool (PMID 25231023), and the PubMed search rerun 2026-09-01 found no prospectively validated assay. Most of the diagnostic literature is clinicopathologic series and expert review, not diagnostic-accuracy studies.

Architecture

The defining pattern is a phyllodiform (leaf-like) growth of stroma lined by epithelium, with periglandular stromal cuffing of increased cellularity and/or intraglandular polypoid projections (Clement 1990, PMID 2156771; Pinto 2016, PMID 26927725). The epithelium is endometrioid in most cases, often with squamous or mucinous metaplasia, and may show mild to moderate atypia without qualifying as carcinoma (Pinto 2016, PMID 26927725). The stroma is typically a low-grade spindle-cell sarcoma, homologous in 78% of Clement’s 100 cases and heterologous in the remainder (Clement 1990, PMID 2156771). Extensive stromal fibrosis can give a deceptively bland appearance (Clement 1990, PMID 2156771).

Grossly the tumour is a polypoid mass filling the endometrial cavity; less often it is confined to the endocervix or myometrium (Clement 1990, PMID 2156771). Mean size in Gallardo’s 55-case series was 6.5 cm (range 1–20) (Gallardo 2009, PMID 18941402).

Sex cord-like elements occur: Clement described eight such cases (Clement 1989, PMID 2543209), and Gallardo found them in 7/55 (13%) (Gallardo 2009, PMID 18941402). Heterologous elements (rhabdomyosarcoma, cartilage, fat) were present in 13/55 (24%) in that series (Gallardo 2009, PMID 18941402) and in the remainder of Clement’s 100 after the 78% homologous fraction (Clement 1990, PMID 2156771). Rhabdomyoblastic differentiation is treated as an adverse feature in reviews, without a multivariable estimate isolated from sarcomatous overgrowth (Nathenson 2016, PMID 27718181).

Mitotic thresholds and the adenofibroma problem

Zaloudek and Norris, in 10 adenofibromas and 25 adenosarcomas, proposed that adenosarcoma had four or more stromal mitoses per 100 high-power fields in the most active areas, adenofibroma fewer than four; myometrial invasion, heterologous malignant mesenchyme, and marked stromal atypia occurred only in adenosarcoma (Zaloudek 1981, PMID 6263458). Clement and Scully’s 100-case series used, alone or in combination, two or more stromal mitoses per 10 HPF, marked stromal cellularity, and significant stromal atypia (Clement 1990, PMID 2156771). Those two thresholds differ by both cut-point and denominator and must not be compared as though they used the same field count.

Gallardo and Prat’s 55 adenosarcomas included two patients with typical low-grade morphology (mild atypia, ≤2 mitoses/10 HPF) who were initially called adenofibroma and later died of tumour (Gallardo 2009, PMID 18941402). Their IHC comparison found adenosarcoma with sarcomatous overgrowth to show strong Ki-67 and p53 and loss of CD10 and progesterone receptor, while typical adenosarcoma without overgrowth stained like adenofibroma, endometrial polyps and endometriosis (Gallardo 2009, PMID 18941402). They concluded that some tumours classified as adenofibroma on mitotic count are well-differentiated adenosarcomas. McCluggage’s WHO-framed review restates the same unresolved line (McCluggage 2016, PMID 26715175). No subsequent diagnostic-accuracy study has arbitrated the threshold against independent outcome.

The differential that causes error

Entity Discriminant Source
Adenofibroma Lower stromal mitoses/cellularity/atypia; existence as a distinct tumour is disputed Zaloudek 1981, PMID 6263458; Gallardo 2009, PMID 18941402
Carcinosarcoma Malignant epithelium (not just stroma); currently classified as metaplastic carcinoma McCluggage 2016, PMID 26715175; D'Angelo 2011, PMID 21742560
Endometrial polyp Lacks periglandular cuffing, stromal atypia and the phyllodiform pattern Howitt 2015, PMID 25118811
Atypical polypoid adenomyoma Prominent smooth muscle; usually lower-segment McCluggage 2016, PMID 26715175
Embryonal rhabdomyosarcoma Especially cervix in young patients; DICER1 near-ubiquitous in uterine ERMS, present in only ~20–26% of adenosarcomas de Kock 2020, PMID 31900434; Apellaniz-Ruiz 2021, PMID 33135284
Endometrial stromal sarcoma with glands Extensive endometrioid glandular differentiation can mimic adenosarcoma Clement 1992, PMID 1399225
Adenomyomatous polyp Clinicopathologic overlap with adenosarcoma on IHC Strickland 2019, PMID 30339971

Polyps with features overlapping adenosarcoma — abnormal architecture, periglandular stroma, stromal atypia, mitoses >2/10 HPF — were followed in 29 cases by Howitt: 27/28 with follow-up were alive without disease; one died of pancreatic adenocarcinoma (Howitt 2015, PMID 25118811). Chapel’s 63 polyps from 58 women had residual/recurrent atypical polyp in 4/36 with follow-up tissue, and no patient developed adenosarcoma over median follow-up of 150 months (Chapel 2022, PMID 34675347). Those lesions share copy-number events with early adenosarcoma (12q13–15 gain in 24%, 6q25.1 gain in 45%) but lack the alterations of clinically aggressive adenosarcoma (Chapel 2022, PMID 34675347). Conservative management with close follow-up is the authors’ proposal, not a tested protocol.

Immunohistochemistry

No marker is diagnostic. CD10 and WT1 are the most frequently positive stromal markers and are not specific (Nathenson 2016, PMID 27718181; Pinto 2016, PMID 26927725). Hormone receptors are often expressed in typical low-grade stroma and lost with sarcomatous overgrowth (Gallardo 2009, PMID 18941402). p53 immunohistochemistry correlates with TP53 mutation in high-grade adenosarcoma and can confirm a high-grade component (Hodgson 2017, PMID 28834809). BAP1 nuclear loss tracks BAP1 homozygous deletion and was seen in 6/24 (25%) of one sequenced cohort (Momeni Boroujeni 2022, PMID 36138078). None of these is a standalone diagnostic test.

Sampling error

Preoperative biopsy and imaging can fail to identify adenosarcoma, but their failure rates have not been measured. Tate’s Japanese series (6 institutional cases plus 104 from the literature) noted that preoperative radiological and pathological examinations “occasionally failed to help reach the correct diagnosis” (Tate 2018, PMID 29441675). Clement recorded five patients who presented repeatedly with “recurrent polyps” later recognised as adenosarcoma (Clement 1990, PMID 2156771). These observations make benign preoperative labelling a plausible route to morcellation; they do not quantify how often it occurs. See red flags and clinical presentation and imaging.

Open questions

  • Can a mitotic/cellularity/atypia rule be specified that separates adenosarcoma from adenofibroma and from atypical polyps with a known error rate? Gallardo’s two fatal “adenofibromas” and Chapel’s 150-month benign follow-up of atypical polyps describe opposite tails of the same continuum (Gallardo 2009, PMID 18941402; Chapel 2022, PMID 34675347).
  • Does DICER1 testing help in the ERMS vs adenosarcoma differential beyond the already-high pre-test probability from age and site? Absence of DICER1 mutation makes uterine ERMS unlikely (de Kock 2020, PMID 31900434); presence does not confirm ERMS.

References

  1. Clement PB, Scully RE. Müllerian adenosarcoma of the uterus. A clinicopathologic analysis of ten cases of a distinctive type of müllerian mixed tumor. Cancer. 1974;34:1138-49. PMID 4371193
  2. Clement PB, Scully RE. Mullerian adenosarcoma of the uterus: a clinicopathologic analysis of 100 cases with a review of the literature. Hum Pathol. 1990;21:363-81. PMID 2156771
  3. Clement PB. Müllerian adenosarcomas of the uterus with sex cord-like elements. A clinicopathologic analysis of eight cases. Am J Clin Pathol. 1989;91:664-72. PMID 2543209
  4. Zaloudek CJ, Norris HJ. Adenofibroma and adenosarcoma of the uterus: a clinicopathologic study of 35 cases. Cancer. 1981;48:354-66. PMID 6263458
  5. 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
  6. McCluggage WG. A practical approach to the diagnosis of mixed epithelial and mesenchymal tumours of the uterus. Mod Pathol. 2016;29 Suppl 1:S78-91. PMID 26715175
  7. Pinto A, Howitt B. Uterine Adenosarcoma. Arch Pathol Lab Med. 2016;140:286-90. PMID 26927725
  8. D'Angelo E, Prat J. Pathology of mixed Müllerian tumours. Best Pract Res Clin Obstet Gynaecol. 2011;25:705-18. PMID 21742560
  9. Howitt BE, et al. Uterine polyps with features overlapping with those of Müllerian adenosarcoma: a clinicopathologic analysis of 29 cases emphasizing their likely benign nature. Am J Surg Pathol. 2015;39:116-26. PMID 25118811
  10. Chapel DB, et al. Atypical uterine polyps show morphologic and molecular overlap with mullerian adenosarcoma but follow a benign clinical course. Mod Pathol. 2022;35:106-116. PMID 34675347
  11. Howitt BE, et al. Targeted genomic analysis of Müllerian adenosarcoma. J Pathol. 2015;235:37-49. PMID 25231023
  12. 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
  13. 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
  14. de Kock L, et al. Significantly greater prevalence of DICER1 alterations in uterine embryonal rhabdomyosarcoma compared to adenosarcoma. Mod Pathol. 2020;33:1207-1219. PMID 31900434
  15. Apellaniz-Ruiz M, McCluggage WG, Foulkes WD. DICER1-associated embryonal rhabdomyosarcoma and adenosarcoma of the gynecologic tract. Genes Chromosomes Cancer. 2021;60:217-233. PMID 33135284
  16. Clement PB, Scully RE. Endometrial stromal sarcomas of the uterus with extensive endometrioid glandular differentiation: a report of three cases. Int J Gynecol Pathol. 1992;11:163-73. PMID 1399225
  17. Strickland KC, et al. Clinicopathological and immunohistochemical features of uterine adenomyomatous polyps. Hum Pathol. 2019;84:239-245. PMID 30339971
  18. Nathenson MJ, et al. Uterine Adenosarcoma: a Review. Curr Oncol Rep. 2016;18:68. PMID 27718181
  19. Tate K, et al. Uterine adenosarcoma in Japan: Clinicopathologic features, diagnosis and management. Asia Pac J Clin Oncol. 2018;14:318-325. PMID 29441675