The Spectrum of Fusions Occurring in Non–Smooth Muscle Mesenchymal Uterine Tumors: A Review of the Current Knowledge

An extensive review of the literature on the subject of non–smooth muscle uterine tumors was performed. The data were obtained through a database search using a combination of the Medical Subject Headings terms uterus, uterine, endometrial, endometrium, sarcoma, endometrial stromal nodule, inflammatory myofibroblastic tumor, NTRK, perivascular epithelioid cell tumor, PEComa, alveolar soft part sarcoma, UTROSCT, GLI1, Ewing sarcoma, DSRCT, synovial sarcoma, and uterine tumor resembling ovarian sex cord tumor. The data were mined from the PubMed/MEDLINE database covering the time period from January 1988 to June 2023. After the first search the duplicates, articles related to smooth muscle tumors, and articles evidently not relevant to the topic were excluded based on the title and review of the abstract. Next, a group of 949 articles were selected for further evaluation, and these were screened based on the abstract or full text in order to select articles relevant to our study. The selection criteria included any description of molecular findings related to rearrangements and fusions of any gene. In total, 156 studies were selected, and these became the basis for this review. The data extracted from these studies were analyzed with a focus on the following parameters: the number of cases; the type of rearrangement, fusion, or other molecular change present; and the histologic type of tumor.

LG-ESS is characterized by small uniform tumor cells with regular nuclei and scant cytoplasm resembling the stroma of proliferative phase endometrium.¹⁷  The characteristic feature is tonguelike growth into the myometrium, which differentiates LG-ESS (Figure 1, A) from the endometrial stromal nodule (ESN).¹⁸  By definition, ESNs should be sharply demarcated, with fewer than 3 irregular proliferations into the myometrium less than 3 mm in the greatest dimension.¹⁸  Common variant features of LG-ESS include smooth muscle, fibroblastic, and sex cord–like differentiation.¹⁹  Immunohistochemically, most LG-ESSs are positive for CD10.²⁰  However, the specificity of CD10 is relatively low, and several smooth muscle tumors, including cellular leiomyoma and LMS, are CD10 positive.²¹  Another marker expressed in LG-ESS is IFITM1, the sensitivity of which seems to be similar to CD10, but the specificity of which is higher.²²  Expression of smooth muscle markers is variable in LG-ESS.²³  Some markers, such as smooth muscle actin and calponin, are commonly positive. Positivity for desmin may be present as well but is less common and usually only focal.²⁴  Expression of caldesmon, smooth muscle myosin, or transgelin is only rarely found.^25,26 

LG-ESSs are tumors characterized by nonrandom recurrent translocations encompassing several genes. The first-described recurrent molecular aberration characteristic for ESS was JAZF1::SUZ12.^27–30  Since then, several other translocations occurring in LG-ESS have been described, affecting mostly those genes associated with chromatin remodeling complexes involved in transcription regulation.³¹  In the literature, 187 tumors harbored a fusion characteristic for ESN and/or LG-ESS, including fusions of JAZF1 (with SUZ12, PHF1, CDKN1A, SYNGAP1), and PHF1 (with JAZF1, BRD8, EPC1, EPC2, ING3, MEAF6, MBTD1).^{12–15,32–55}  Other rare fusions in these tumors included MBTD1::CXorf67 and MEAF6::SUZ12.^56–58  Of these 187 tumors, 24 were classified as ESN, 126 as LG-ESS, 15 as endometrial stromal sarcoma not otherwise specified (ESS NOS), 4 as HG-ESS, and 14 as tumors with both a low-grade (LG) and an HG component, and 4 cases showed hybrid microscopic features between LG-ESS and perivascular epithelioid cell tumor (PEComa). The data are summarized in Table 1. Another 5 tumors harboring rare fusions (EPC1::SUZ12, EPC1::EED, EPC1::EZH2) were classified as tumors with both an LG and an HG component (n = 4) or HG-ESS (n = 1).^50,51  Two ESNs with rare fusions including YWHAE::NUTM2 and MEAF6::PHF1 have been described.^59,60  However, studies focusing on ESN are limited, and the spectrum of aberrations occurring in ESN is not clear. Because of this, molecular testing may not be suitable for assessing the biological nature for the purposes of distinguishing between LG-ESS and ESN.

Tumors with KAT6A/B::KANSL1 fusion resembling LG-ESS, some of them with sex cord–like features, have recently been described.^16,61  These tumors are composed of small to medium-sized monomorphic spindle and round cells with a small amount of cytoplasm, arranged in diffuse sheets (Figure 1, B). Spirallike arterioles are present and myxoid stromal change is a common feature. Despite having some overlapping morphologic features with LG-ESS, these tumors are commonly well circumscribed and lack the tonguelike permeative pattern typical for LG-ESS. Immunohistochemical profile of these tumors is nonspecific. Most cases express CD10, estrogen receptor, and progesterone receptor. Expression of smooth muscle actin is common, and other smooth muscle markers, such as caldesmon and desmin, can be positive in a minority of cases. It has been suggested that despite their rather bland morphology, including commonly present well-defined borders, these tumors have the potential for aggressive behavior and could represent a distinct entity. However, the fusions detected in these tumors do not seem to be specific, as they have also been described in 1 case of uterine leiomyoma and 1 case of uterine LMS.^62,63 

HG-ESS is a heterogeneous group of tumors that are associated with more aggressive clinical behavior than LG-ESS. The currently recognized HG-ESSs with recurrent molecular aberrations include tumors with alterations of YWHAE, BCOR, and BCORL1.

YWHAE-altered HG-ESSs with YWHAE::NUTM2A/B gene fusion were first described in 2012.^4,64–66  These tumors typically exhibit an HG but not pleomorphic round cell component that can be associated with a variable LG fibrous or fibromyxoid component (Figure 1, C). Mitotic activity is brisk. The foci of the HG component can be subtle, and rarely these tumors can have pure LG morphology.^59,67  As in LG-ESS, a tonguelike type of infiltrative growth is present. Tumors with pure LG morphology resembling LG-ESS seem to be aggressive and may recur as morphologically typical HG-ESS.⁵⁹  However, the immunohistochemical profile of these tumors with pure LG morphology is different from that of LG-ESS, mainly by cyclin D1 positivity and the negativity (or only focal weak positivity) of CD10. Of the 19 tumors with YWHAE rearrangement described in the literature, 8 were classified as HG-ESS, 5 as ESS NOS, 5 as LG-ESS, 1 as ESN (but with diffuse cyclin D1 expression and a comment on limited evidence of biological significance), and 1 as UUS.^*

HG-ESSs with BCOR gene fusion can harbor ZC3HB7::BCOR or variant fusion of BCOR with another gene.^5,51,72–74  These tumors are histologically characterized by a pushing or tonguelike invasion pattern and consist of spindle cells with mostly mild or moderate nuclear atypia (Figure 1, D). In most cases, a variable amount of myxoid stroma is present, and these tumors can show morphologic overlap with myxoid LMSs.⁵  Rarely, tumors with epithelioid or small round cells can occur. Moreover, tumors with unusual features including signet ring–like cells have been described.^75,76  Immunohistochemically, these tumors are characterized by expression of CD10, strong expression of cyclin D1 in most cases, and expression of BCOR, which occurs approximately in 50% of cases. Some tumors can express estrogen and progesterone receptors. Expression of smooth muscle markers is usually limited. Despite the bland cytologic features in some cases, the tumors are reported to behave aggressively.^72,74,77  According to the literature data, tumors with variant alterations of BCOR (other than ZC3H7B::BCOR) behave as conventional HG-ESS.⁷⁸  Of the 76 uterine tumors with BCOR fusion reported in the literature, 72 were classified as HG-ESS, 1 as LG-ESS, and 3 as ESS NOS.^†

Concerning the BCORL1-altered tumors, the first-described alteration was a JAZF1::BCORL1 fusion in a tumor with features of LG-ESS.⁶  After that, 5 tumors harboring BCORL1 fusions, including 3 cases with JAZF1::BCORL1 fusion, 1 case with EP300::BCORL1 fusion, and 1 case with BCORL1 rearrangement without a fusion partner, have been described in a series of 12 cases as tumors having similar features to BCOR-altered tumors.⁸³  Microscopically, these tumors consisted of spindle cells with at least focal myxoid stroma, admixed with variable amounts of hypocellular LG fibromyxoid areas and/or epithelioid cells with higher-grade features (Figure 2, A). Another study⁸¹  described 5 cases with BCORL1 fusion, including 4 cases with BCORL1::JAZF1 and 1 case with BCORL1::EPC1 fusion. However, BCORL1 fusions are not specific for HG-ESS, as a recent study⁸⁴  described a benign uterine tumor with equivocal features with a JAZF1::BCORL1 fusion. Another study⁸⁵  described a case of a JAZF1::BCORL1-rearranged tumor with LG features, showing unusual morphology with overlapping features with uterine tumor resembling ovarian sex cord tumor (UTROSCT). In summary, of the 12 tumors with BCORL1 alteration reported in the literature, 9 were classified as HG-ESS, 1 as LG-ESS, 1 as benign tumor with overlapping features between ESN and leiomyoma, and 1 as LG tumor with morphology similar to that of a UTROSCT.^6,81,83–85 

These tumors mostly arise in premenopausal women in the uterine cervix and rarely in the uterine corpus. They are characterized by spindle cells arranged in a storiform, herringbone, or haphazard pattern, and until recently had been regarded as a variant of uterine fibrosarcoma. Of the 49 uterine tumors with NTRK rearrangement described in the literature, 47 were classified as fibrosarcoma, NTRK-rearranged tumor, or tyrosine kinase–fused tumor.^7,46,86–99  Only one case was classified as ESS NOS. Moreover, a single case with ETV6::NTRK3 fusion was reported as inflammatory myofibroblastic tumor (IMT).¹⁰⁰  The data are summarized in Table 2.

Tumors with a similar morphology but different molecular aberrations, including FGFR1::TACC1, RET::SPECC1L, and PDGFB gene fusions, have been described.^{92,98,101–103}  Tumors with COL1A1::PDGFB are reported to be immunohistochemically CD34 positive and S100 protein and pan–TRK antibody negative, and to morphologically resemble dermatofibrosarcoma protuberans.^98,103,104  These tumors are characterized by spindle cells with mild or moderate atypia and common brisk mitotic activity. Their biological behavior is difficult to predict, as only 6 cases have been reported to date. However, some tumors were highly aggressive.^103,105,106  Tumors with a similar morphology to those with the tyrosine kinase fusions showing expression of S-100 protein but lacking detectable molecular recurrent aberrations have also been described. These tumors were suggested to represent malignant peripheral nerve sheath tumor, but the data are limited.⁹⁸ 

This tumor usually consists of spindle cells with mild to moderate nuclear atypia and variable amounts of inflammatory cells, mostly lymphoplasmacytic (Figure 2, B).¹⁰⁷  However, tumors with epithelioid cells and HG nuclear atypia including multinucleated and bizarre cells have also been described.¹⁰⁸  Three typical growth patterns have been reported, including myxoid, fascicular/compact, and fibrous/hyalinized.^107,109  The myxoid stroma is a common finding, and these tumors can be misdiagnosed as myxoid LMS.¹¹⁰  Some tumors can show a leiomyoma-like appearance, which can lead to a misdiagnosis as leiomyoma.^109,111  Uterine IMTs are characterized by ALK rearrangements in approximately 90% of cases.^{8,107,112–114}  The fusion partners of ALK are highly heterogeneous, most commonly including IGFBP5, THBS1, FN1, TIMP3, TNS1, and DES.^8,108,115  IMT can be associated with pregnancy, and these tumors seem to have some unique characteristics, including benign behavior and enrichment of fusions of ALK with the TIMP3 and THBS1 genes.¹¹⁶  All 70 tumors with ALK fusion described in the literature were classified as IMT.^‡

Moreover, IMTs with fusions of other genes have been described, including ROS1, RET, PDGFRB, and INSR.^{109,112,121,125–127}  Of the 19 tumors with ROS1, RET, and PDGFRB reported in the literature, 7 were classified as IMT, 10 as fibrosarcoma/tyrosine kinase–fused tumor, 1 as HG sarcoma, and 1 as ESS NOS.

The biological behavior of IMT is difficult to predict. Most of these tumors behave in a benign fashion, but aggressive behavior occurs in about 25% of cases.¹²⁸  It has been speculated whether the tumors with leiomyoma-like features and ALK fusion should be classified as leiomyoma, although they can behave in an aggressive manner.¹¹¹  An epithelioid variant of IMT characterized by RANBP2::ALK or RRBP1::ALK fusion with aggressive behavior has also been described.^129,130  However, this tumor has not yet been reported in the uterus. In a recent study,¹¹⁹  a risk-stratification model based on selected morphologic parameters has been suggested, including age above 45 years, size 5 cm or more, 4 or more mitotic figures/10 high-power fields, and infiltrative borders. Tumors with aggressive behavior in this study showed other molecular aberrations in addition to ALK fusions, contrary to the tumors with benign behavior in which ALK fusions were the sole molecular event. Another study¹³¹  showed an absence of p16 staining in 5 of 23 IMTs, 4 of which were associated with malignant behavior (the fifth case was lost to follow-up). The authors suggested that the immunohistochemical negativity of p16 and CDKN2A deletion may be a marker of aggressive behavior, but more data are needed.

UTROSCT is composed of uniform cells with inconspicuous mitotic activity, which are arranged in trabeculae, nests, plexiform cords, whorls, retiform structures, and sertoliform tubules, which can have lumens (Figure 2, C). Most tumors consist of a combination of spindle and epithelioid cells.¹³²  This tumor can have overlapping morphologic features with LG-ESS, in which sex cord elements can be found.¹³²  Immunohistochemically, UTROSCT can express a wide range of markers, including epithelial, smooth muscle, hormonal receptors, and sex cord markers.¹³³  Molecular alterations occurring in UTROSCT have only recently been described. The current knowledge suggests that UTROSCTs are characterized by NCOA1-3, GREB1, and ESR1 rearrangements, which occur in approximately 80% of cases.¹³²  Eight distinct fusions characteristic for UTROSCT were found in the literature. These fusions included ESR1::NCOA3 (n = 19), ESR1::NCOA2 (n = 10), GREB1::NCOA1 (n = 10), GREB1::NCOA2 (n = 15), GTF2A1::NCOA2 (n = 2), and single cases with fusion GREB1::NR4A3, GREB1::SS18, and GREB1::CTNNB1. Moreover, 19 cases with rearrangement of NCOA1 (n = 7), NCOA2 (n = 3), and NCOA3 (n = 9) detected by the fluorescence in situ hybridization method without a known fusion partner were described. The data are summarized in Table 3. Of the 78 tumors with these fusions reported in the literature, 75 were classified as UTROSCT, 2 as ESS NOS, and 1 as HG sarcoma.^{132,134–146}  The first 5 cases of UTROSCT with identified fusions were described in 2019, including cases with GREB1::CTNNB1, ESR1::NCOA2, GREB1::NCOA2 fusions and 2 cases with ESR1::NCOA3 fusion.^136,137  Afterward another 4 cases of GREB1-rearranged tumors were reported (GREB1::NCOA2, GREB1::NR4A3, GREB1::SS18, and GREB1::NCOA1) and compared with an additional 4 cases of UTROSCT with ESR1::NCOA3 fusion.¹³⁵  The GREB1-rearranged cases showed a different morphology, with epithelioid cells with vesicular nuclei and prominent nucleoli (Figure 2, D). Only one of these cases showed the presence of a minor sex cord component. Another study¹³²  of 26 UTROSCT cases described a single case with typical sex cord differentiation and GREB1::NCOA2 fusion, which was the only case in this series behaving aggressively. One study¹⁴³  of 23 UTROSCT cases showed that tumors harboring GREB1::NCOA2 fusion recurred more frequently (4 of 7; 57%) compared with tumors with GREB1::NCOA1 fusion (2 of 5; 40%), ESR1::NCOA2 fusion (1 of 3; 33%), and ESR1::NCOA3 fusion (1 of 7; 14%). An additional 2 cases of UTROSCT with GREB1::NCOA2 fusion and aggressive behavior have been reported, 1 of which was originally classified as LG-ESS.^140,141  Moreover, a case of UUS with GREB1::NCOA2 has been described.¹⁴⁵  It has been suggested that tumors with GREB1 alterations, which in some cases show a different morphology and propensity for more aggressive behavior, may deserve a separate consideration, but the data are limited.^135–137  Nevertheless, there are also cases with GREB1 fusion that show the typical morphology of UTROSCT and a benign behavior.¹³⁴ 

In addition, 6 UTROSCTs with rhabdoid morphology and aggressive behavior have been described.^{138,139,143,144}  Four of these tumors harbored the ESR1::NCOA2 fusion, 1 showed the GTF2A1::NCOA2 fusion, and 1 showed the GREB1::NCOA2 fusion.

MEIS1::NCOA2 fusion was described in 5 tumors without morphologic features of UTROSCT: 3 were classified as LG sarcoma and 2 as HG sarcoma.^147–151  Three of these tumors showed LG features and consisted of monomorphic spindle cells set in a myxoid or hyalinized background. Two other tumors, however, were pleomorphic and showed aggressive behavior.^147,151 

Uterine PEComa is characterized by epithelioid or spindle cell morphology and coexpression of myogenic and melanocytic markers.¹⁵²  Most PEComas are characterized by TSC1 and TSC2 mutations.¹⁵³  Moreover, in a minority of cases the rearrangement of TFE3 can be found. To date, 10 cases of PEComa with TFE3 rearrangement have been described, 8 of them detected by the fluorescence in situ hybridization method without a known fusion partner and 2 with the TFE3::SFPQ fusion.^154–161  Immunohistochemically, tumors with TFE3 rearrangement show strong and diffuse expression of TFE3. In tumors without the TFE3 rearrangement, the expression is only focal and weak or absent.^152,162,163  Moreover, in 2 studies^156,158  4 cases of PEComa with RAD51B rearrangement were found: 1 with OPHN1 gene, 2 with RRAGB/OPHN1 genes, and 1 without a detectable fusion partner. Another case in one study¹⁵⁶  showed a nonrecurrent fusion HTR4::STR3GAL1. Four cases (already mentioned above) with an overlapping morphology and molecular profile with the coexistence of TSC2 mutation and JAZF1::SUZ12 fusion have been described.⁴⁸ 

The morphology of ASPS can overlap with that of epithelioid PEComa. However, the immunohistochemical profile of ASPS is different. Both PEComa with TFE3 rearrangement and ASPS are positive for TFE3, but ASPS is negative for myogenic and melanocytic markers. To date, only 11 cases of uterine ASPS characterized by the ASPCR1::TFE3 fusion have been described.^164–168 

Three tumors with GLI1 fusion have been reported in the uterus.^46,169  Two of these tumors consisted of bland epithelioid to ovoid spindle cells in myxoid or hyalinized stroma.⁴⁶  These tumors showed PTCH1::GLI1 and ACTB::GLI1 fusions. The third case with PAMR1::GLI1 fusion consisted of pleomorphic spindle and focally epithelioid cells intermingled with an LG spindle cell component.¹⁶⁹ 

Small round blue cell tumors of the uterus with the presence of a fusion include rare cases of Ewing sarcoma/PNET, DSRCT, and sarcoma with CIC::DUX4 fusion. Uterine PNETs can be associated with EWSR1 rearrangement; however, these tumors are rare and only 21 cases have been described in the literature.^170–183  Most uterine tumors with neuroectodermal differentiation are not characterized by a recurrent molecular aberration.^184,185  Until now, DSRCT has been reported in the uterus in only 2 cases.^186,187  Both of these cases showed typical morphologic, immunohistochemical, and molecular features of DSRCT, including EWSR1::WT1 fusion. However, the EWSR1::WT1 rearrangement is not specific for these entities, and 3 tumors arising in the female genital tract (cervix, uterine corpus/ovary, and vagina) with the EWSR1::WT1 fusion but morphologic features different from DSRCT have been described.¹⁸⁸  These tumors consisted mostly of spindle cells, but in 2 cases also showed areas with epithelioid features. Two aggressive sarcomas with CIC rearrangement (one of them with CIC::DUX4 fusion) have also been described in the uterus, one of which arose in the cervix whereas the other was found in the uterine corpus.^189,190  These tumors, despite having some overlapping morphologic and immunohistochemical features with Ewing sarcoma, are characterized by greater pleomorphism, commonly patchier expression of CD99, and WT1 positivity.

Rarely, other tumor types with recurrent fusions have been described in the uterus, including 3 cases of synovial sarcoma and a single case of sclerosing epithelioid fibrosarcoma arising in the uterine cervix.^9,191–193  Moreover, 15 nonrecurrent fusions, each in only one case, were described in tumors diagnosed as HG sarcoma (n = 3), LG-ESS (n = 5), ESS NOS (n = 3), HG-ESS (n = 1), PEComa (n = 1), IMT (n = 1), and LG-ESS–PEComa (n = 1).^{46,70,156,194,195}  The data are summarized in Table 4.

Molecular classification has become an essential part of the diagnostics of uterine mesenchymal tumors. The classification and the approach to the diagnosis of these tumors is still evolving, and, with a broadening spectrum and an increasing number of molecularly characterized entities, the diagnosis is becoming more complicated. According to current knowledge, the combination of morphology, immunohistochemistry, and identification of molecular aberrations seems to be the best approach to diagnosing these tumors. However, the significance of some molecular aberrations for diagnostic purposes is not clear, and some aberrations could mislead the correct diagnosis when inappropriately interpreted.

One problematic aspect of molecular testing is the possibility of an HG transformation occurring in LG-ESS, which can be present in the primary tumor at the time of diagnosis or in the recurrent lesion.^12–15,50  This transformation has been described in tumors harboring fusions typical for LG-ESS, and reaching the correct diagnosis in these cases is possible only when focusing on the morphologic features. In one study,¹⁴  the authors described 11 cases of uterine and 1 vaginal tumor with JAZF1::SUZ12 (n = 6), JAZF1::PHF1 (n = 3), EPC1::PHF1 (n = 1), and BRD8::PHF1 (n = 1) fusions in which the HG transformation occurred, characterized by a uniform population of round to epithelioid cells with enlarged nuclei, visible nucleoli, and increased mitotic activity. Another recent study⁵⁰  described 5 cases of tumors with both an LG and an HG component harboring EPC1::EED (n = 3), EPC1::EZH2 (n = 1), and ING3::PHF1 (n = 1) fusion. The significance of these rare fusions should be assessed based on more data. The same is true for several other aberrations such as BRD8::PHF1, which have been described not only in 1 case of LG-ESS with HG transformation, but also in 3 cases of LG-ESS (1 of them with ossification) and in 1 tumor with HG morphology.^10,14,34,47  Some other tumors that can have both an LG and an HG component on a morphologic level harboring fusions of YWHAE and alterations of BCOR or BCORL1 are better regarded as HG-ESS with foci of LG morphology, rather than LG-ESS with HG transformation.^6,51,71,83 

Taken together, the current data suggest that in some cases the molecular aberrations alone are not sufficient for distinguishing between LG-ESS and HG-ESS, and it has been questioned by some authors as to whether the differentiation between LG and HG tumors can be based on the type of gene fusions and cytomorphologic features only, especially in the cases with novel fusions, the incidence and clinical significance of which are not yet well known.⁵⁰  However, the results of our review showed that of the 172 tumors harboring fusions considered characteristic for ESN/LG-ESS (after excluding 15 cases classified as ESS NOS), 87% (n = 150) were classified as ESN/LG-ESS, 8% (n = 14) as tumors with both an LG and an HG component, and 2% (n = 4) as HG-ESS, and 2% (n = 4) showed hybrid features between LG-ESS and PEComa; the latter 4 tumors also revealed a TSC2 mutation. Of the 4 tumors in the literature classified as HG-ESS, 3 with JAZF1::SUZ12 fusion were described in a 2001 study,¹³  and the description of their morphology is missing. The last case classified as HG-ESS harbored a PHF1::BRD8 fusion, but, as mentioned above, the data concerning this fusion are very limited. Because of this, we believe that the positive predictive value of well-established fusions for the diagnosis of ESN/LG-ESS is high. The most problematic issue remains the category of tumors with HG transformation, which should be correctly classified based on the morphologic features.

We are aware of the limitations of our study. First of all, we focused only on fusions and rearrangements, because (with the exception of some entities such as SMARCA4-deficient sarcoma and tumors with BCOR internal tandem duplications) rearrangements and fusions are currently the cornerstone of molecular diagnostics of uterine mesenchymal non–smooth muscle tumors. Secondly, the diagnostic criteria for non–smooth muscle uterine tumors have changed substantially during the last 2 decades, which could affect the results of our study concerning the specificity for particular entities.

In conclusion, molecular testing is currently an essential part of diagnosing mesenchymal uterine tumors. In most cases, the morphologic features in combination with the immunohistochemistry are suggestive of the diagnosis, but there are tumors in which the correct diagnosis cannot be achieved without molecular analysis. Despite the expanding knowledge about recurrent molecular aberrations, the clinical significance is unclear in some cases and the interpretation of the molecular data can be difficult, as some aberrations can also occur in benign, LG, and HG tumors. Moreover, it seems that at least some tumors with LG morphology and aberrations typical for HG sarcomas are potentially aggressive, and molecular testing in these cases is of important clinical significance. One should also be aware that at least 10% of tumors with LG-ESS (and even more with HG-ESS) morphology are without any detectable recurrent molecular aberrations. Even in these cases there are differences between the expression of genes in LG-ESS with and without the detection of known fusions, and there are still entities or molecular subgroups of ESS that remain to be discovered.⁷⁰  With the knowledge of certain limitations, molecular testing is a very important and powerful tool, which is increasingly a crucial part of diagnosing these tumors. Knowledge about the molecular aberrations is gaining significance, not only with respect to the correct classification of these tumors; they may also be of clinical value as a predictive marker of targeted treatment.

The authors wish to thank Zachary Harold Kane Kendall, BA (Institute for History of Medicine and Foreign Languages, First Faculty of Medicine, Charles University), for the English proofreading.