NCCN Guidelines® Insights: Uterine Neoplasms, Version 3.2021

NCCN: Continuing Education

Target Audience: This activity is designed to meet the educational needs of oncologists, nurses, pharmacists, and other healthcare professionals who manage patients with cancer.

Disclosure of Relevant Financial Relationships

The NCCN staff listed below discloses no relevant financial relationships:

Kerrin M. Rosenthal, MA; Kimberly Callan, MS; Genevieve Emberger Hartzman, MA; Erin Hesler; Kristina M. Gregory, RN, MSN, OCN; Rashmi Kumar, PhD; Karen Kanefield; and Kathy Smith.

Overview

An estimated 66,570 new cases of uterine cancer will be diagnosed in the United States in 2021, and 12,940 people will die of the disease.¹ Most uterine cancers are epithelial-derived and arise in the endometrium (endometrial carcinoma). Stromal or mesenchymal sarcomas are uncommon malignant tumors, accounting for approximately 3% of all uterine cancers.² Uterine sarcomas include low-grade and high-grade endometrial stromal sarcoma (LGESS and HGESS, respectively), undifferentiated uterine sarcoma (UUS), uterine leiomyosarcoma (ULMS) including epithelioid and myxoid variants, uterine tumor resembling ovarian sex cord tumor (UTROSCT), rhabdomyosarcoma (RMS), and perivascular epithelioid cell tumors (PEComas). According to the WHO, Müllerian adenosarcoma is a “biphasic neoplasm composed of a benign epithelial component and a malignant stromal component”³; the malignant component is typically low-grade. According to a 2012 systematic review of data from 1970 to 2011, ULMS was the most common subtype (63%) of uterine sarcoma, followed by ESS (21%) and less common subtypes such as UUS.⁴ RMS and PEComas are the rarest subtypes of uterine sarcomas.⁵

Recent advances have expanded the NCCN Uterine Neoplasms Guidelines panel’s understanding of the molecular features of these tumors, leading to the identification of genetic signatures that characterize some of the uterine sarcoma subtypes. Historically, mesenchymal tumors were primarily diagnosed using histopathologic criteria, and the results of molecular studies were not used in routine pathologic evaluation. However, given the overlap in histopathologic features of these tumors, molecular analysis (eg, identification of characteristic translocations and/mutations) may help clinicians classify difficult cases and also provide insight into future therapeutic targets.⁶ In recent years, validated and FDA-approved comprehensive genomic profiling tests have become increasingly available, and have helped to facilitate cancer diagnoses and/or selection of targeted therapies. Additional gene- and/or tumor-specific confirmatory molecular tests may also be useful for these purposes. Therefore, the panel recently expanded the Principles of Pathology and Molecular Analysis section of the Uterine Sarcoma Guidelines in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Uterine Neoplasms. In addition to the introductory page (UTSARC-A 1 of 5, above), this section now includes a table containing information on histologic and molecular findings, relevant confirmatory molecular tests, prognostic features, and other clinically useful information to help clinicians differentiate between and classify uterine sarcoma subtypes (see UTSARC-A 2 of 5 through UTSARC-A 5 of 5, pages 891–894).

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Molecular Profiling for Uterine Sarcomas

This Insights article focuses on biomarkers specific to each sarcoma subtype that may help clinicians to differentiate between them and help provide a definitive diagnosis when used alongside histopathological evaluation. Of note, this article does not include certain tumors in Table 1 (ie, Müllerian adenosarcoma, carcinosarcoma) for which the panel does not currently recommend ancillary molecular testing.

LGESS and HGESS

Following smooth muscle neoplasms, endometrial stromal tumors are second most common mesenchymal tumors of the uterus. The most recent WHO classification schema for endometrial stromal tumors is as follows: endometrial stromal nodule (a benign entity), LGESS, HGESS, and UUS (see next subsection).³ LGESSs are composed of small fusiform cells resembling endometrial stromal cells in the proliferative phase.^5,7 LGESS have distinct fingerlike patterns of myometrial invasion, and lymphovascular space invasion is usually present. LGESS displays a heterogenous mix of morphologic and genetic features, with many harboring JAZF1, PHF1, or EPC1 gene fusions and presenting as earlier-stage tumors.^6,8–11 The panel notes that diagnosis of LGESS can be confirmed by identifying any LGESS-associated gene fusion by using fluorescence in situ hybridization (FISH) and/or targeted RNA sequencing, though the lack of rearrangement or fusion does not exclude the diagnosis. It is worth noting that in rare instances, LGESS can transform into HGESS (either at the time of primary diagnosis or recurrence), which will require histopathological and molecular (eg, JAZF1 or PHF1 translocation) confirmation.¹²

Recently, a more aggressively behaving ESS with distinctive morphology (eg, uniform epithelioid cells with eosinophilic cytoplasm, angulated high grade nuclei, and vesicular chromatin) and a unique genetic rearrangement, YWHAE-FAM22A/B (also known as YWHAE-NUTM2A/B), was identified. This subtype is now known as HGESS.¹³ More recently, another distinct subtype of HGESS harboring BCOR alterations was described, either in the form of a ZC3H7B-BCOR fusion^14,15 or an internal tandem duplication (ITD).¹⁶ Both ZC3H7B-BCOR fusion-positive and BCOR ITD HGESS have spindle and/or round cells embedded in myxoid matrix, and demonstrate strong and diffuse positivity for cyclin D1 and variable positivity for CD10, estrogen receptor (ER), and progesterone receptor (PR).^15,16 Immunohistochemistry (IHC) testing for CD10, cyclin D1, and BCOR and, in some cases, molecular analysis of BCOR alterations, may help differentiate between BCOR-altered HGESS and myxoid uterine leiomyosarcoma (myxoid ULMS) due to overlapping morphologic features. It is currently unclear whether specific types of HGESS (ie, YWHAE-altered or BCOR-altered) differ in prognosis and/or response to chemotherapy.

These findings provided additional support for subdividing ESS into distinct low-grade and high-grade categories based on distinct histopathology, clinical behavior, and patient outcomes. In light of this new information, WHO released an updated (4th) edition of the WHO Classification of Tumors of Female Reproductive Organs in 2014.¹⁷ WHO subsequently published a 5th edition on Female Genital Tumors in 2020,³ which also recognizes BCOR-altered sarcomas as a distinct subtype of HGESS.

Undifferentiated Uterine Sarcoma

UUSs are a group of high-grade/aggressive sarcomas characterized by infiltrative sheets of epithelioid and/or spindle cells that may be uniform or pleomorphic. As a class, it is a heterogenous group of high-grade mesenchymal neoplasms of the uterus that fail to meet the diagnostic threshold for other characterized uterine mesenchymal neoplasms. As such, UUS is usually reserved as a diagnosis of exclusion, after other defined uterine mesenchymal neoplasms have been excluded using a multiprong approach that often requires a combination of extensive IHC panel and next-generation sequencing molecular analysis. For example, HGESS is often misdiagnosed as UUS due to a shared lack of smooth muscle differentiation.^18,19 The panel notes that molecular testing for BCOR alterations, which can occur in HGESS as noted above, is useful to exclude an HGESS diagnosis before rendering a diagnosis of UUS.

A subset of UUSs called SMARCA4-deficient uterine sarcomas (SDUSs) have distinctive morphology (eg, phyllodiform architecture) along with biallelic inactivation of SMARCA4 that results in loss of SMARCA4/BRG1 expression. These tumors occur in younger women and may be associated with very aggressive clinical behavior.^20,21 The panel recommends analysis of SMARCA4/BRG1 by IHC and/or SMARCA4 by DNA sequencing to confirm a diagnosis of SDUS with otherwise appropriate morphologic and immunophenotypic features. However, loss of SMARCA4/BRG1 alone does not constitute a diagnosis of SDUS, and other aggressive malignancies such as undifferentiated endometrial carcinoma may show loss of expression of this protein.^22,23

Uterine Leiomyosarcoma

ULMSs are usually of the spindle cell (conventional) type, but less common variants with myxoid^24,25 or epithelioid²⁶ morphology also exist. Although morphology differs between subtypes, all express varying degrees of the smooth muscle markers, including desmin, smooth muscle actin (SMA), and caldesmon. The panel recommends an IHC panel including desmin and SMA to support a ULMS diagnosis, particularly if myxoid or epithelioid ULMS is suspected.

Myxoid ULMSs may appear histologically similar to BCOR-altered HGESSs or inflammatory myofibroblastic tumor. The panel recommends cyclin D1 and/or BCOR IHC to help exclude an HGESS diagnosis, as the latter is often overexpressed in HGESS. A subset (25%) of myxoid ULMSs also harbor PLAG1 fusions. Therefore, a myxoid ULMS diagnosis may be supported by positive desmin and SMA IHC along with PLAG1 rearrangement by FISH assay or RNA sequencing.^24,25

One differential diagnosis that must be considered for epithelioid ULMS is PEComa, given the observed similarities in morphology and IHC for smooth muscle markers. IHC testing for HMB45 and melan A may be performed if a diagnosis of PEComa is being considered, with HMB45 being fairly sensitive and melan A being specific for PEComa compared with ULMS. However, it is recognized that uterine mesenchymal tumors with myomelanocytic differentiation can still be challenging to classify solely by IHC. Recently, a study examining this specific group of diagnostically challenging tumors supported the use of genomic profiling to aid in their classification.²⁷

Uterine Tumor Resembling Ovarian Sex Cord Tumor

UTROSCTs are very rare tumors with sex cord-like differentiation, but without a stromal component as observed in ESSs. Most of these tumors harbor either ESR1 or GREB1 fusions.^28–30 The panel recommends an IHC panel that includes sex cord markers (eg, inhibin, calretinin, SF1, FOXL2); UTROSCTs are often positive for a broad range of biomarkers. In some cases, FISH or RNA sequencing for ESR1 or GREB1 fusions may be helpful to confirm the diagnosis. Approximately 25% of these tumors are malignant³¹; the panel notes that the presence of necrosis, high mitotic index, and GREB1 fusions may be associated with malignant behavior.

Rhabdomyosarcoma

Uterine RMSs are an aggressive, heterogeneous group of tumors that are extremely rare in adult women. Subtypes include alveolar, embryonal, and pleiomorphic³²; all express myogenic biomarkers (eg, myogenin and MyoD1).³³ Therefore, the panel notes that diffuse expression of ≥1 myogenic biomarkers by IHC can help confirm a uterine RMS diagnosis. Prognosis differs between subtypes, with embryonal RMS having the best prognosis of the 3 subtypes.³⁴ Molecular alterations also differ between subtypes. FOXO1 fusions are found in alveolar RMS, whereas PIK3CA and TP53 mutations are found in pleomorphic RMS. DICER1 mutations are present in up to 95% of embryonal RMS.^35,36 The embryonal subtype also is known to harbor FGFR4/RAS/AKT pathway mutations.³³ The panel notes that extensive sampling should be performed to exclude epithelial components and diagnoses of carcinosarcoma and adenosarcoma with heterologous rhabdomyosarcomatous differentiation.⁶ The panel recommends FISH and/or RNA sequencing for FOXO1 to help confirm cases of suspected uterine alveolar RMS.

Conclusions

Emerging evidence informs panel recommendations in the NCCN Guidelines for Uterine Neoplasms as well as all other NCCN Guidelines. Recent updates to the NCCN Uterine Neoplasms Guidelines include molecular profiling information for uterine sarcomas. This information is intended to complement histopathologic testing to improve differential diagnosis of relatively rare uterine sarcoma subtypes and provide safer, more effective care for patients with the disease. The panel notes that this information is not exhaustive, and intends to update these recommendations as more data become available.

NCCN CATEGORIES OF EVIDENCE AND CONSENSUS

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Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted.

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PLEASE NOTE

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. The NCCN Guidelines Insights highlight important changes in the NCCN Guidelines recommendations from previous versions. Colored markings in the algorithm show changes and the discussion aims to further the understanding of these changes by summarizing salient portions of the panel's discussion, including the literature reviewed.

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