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Immunohistochemical analysis of 147 cases of low-grade endometrial stromal sarcoma: refining the immunohistochemical profile of LG-ESS on a large, molecularly confirmed series
Low-grade endometrial stromal sarcoma (LG-ESS) can present diagnostic challenges, due to its overlapping morphological features with other uterine mesenchymal tumors. Misdiagnosis rates remain significant, and immunohistochemical data for LG-ESS are limited to small series and inconsistent antibody panels. This study aimed to refine the IHC profile of LG-ESS by analyzing a large, molecularly confirmed series of 147 cases using a panel of 24 antibodies, including newer markers like transgelin and smoothelin. CD10 and IFITM1, key endometrial stromal markers, were expressed in 86% (92% of those extensively) and 69% (60% of those extensively) of cases, with fusion-positive tumors showing significantly higher expression. Smooth muscle markers (α-SMA, desmin, h-caldesmon, calponin, transgelin) were variably expressed, predominantly in focal or low-intensity patterns, with α-SMA reaching the highest frequency of expression (44%). However, the intensity of smooth muscle marker expression was usually very low. Smoothelin was rarely expressed. Hormone receptors were frequently positive, with PR showing a higher frequency (92% vs. 83%) and intensity than ER. Markers like S-100, HMB45, and CD117 were largely negative; all tumors were p53 wild-type, with preserved SMARCB1/SMARCA4 expression and ALK and ROS1 negativity. This work represents the largest molecularly validated IHC study on LG-ESS, providing a robust diagnostic profile for routine pathology. By addressing key diagnostic limitations and examining newer markers, our study supports a more standardized approach to diagnosing LG-ESS and underscores the value of immunohistochemical panels, particularly in fusion-negative tumors where diagnosis relies on morphological and immunohistochemical interpretation. These findings contribute critical data for improving diagnostic accuracy.
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Introduction
Low grade endometrial stromal sarcoma (LG-ESS) is a rare malignant mesenchymal tumor which morphologically resembles proliferative phase endometrial stroma and exhibits an infiltrative growth pattern [1]. Endometrial stromal sarcomas constitute up to 1% of all uterine cancers and 6–20% of all uterine sarcomas, with LG-ESS representing the second most common uterine sarcoma after leiomyosarcoma [2, 3]. While most cases affect the uterine body, primary extrauterine tumors can also occur, often associated with endometriosis, making diagnosis more challenging [4, 5].
In most cases, LG-ESS can be reliably diagnosed based solely on morphology due to its distinct appearance. However, in some cases, LG-ESS can exhibit significant morphological heterogeneity with a wide range of histological patterns, which can also be reflected in their immunohistochemical profile [6]. Some less common, variant morphologies include smooth muscle-like differentiation, fibroblastic and/or myxoid features, sex cord-like structures, pseudopapillary formations, clear cell change, skeletal muscle differentiation, adipocytic metaplasia, angiomatous pattern, and cells with rhabdoid appearance or bizarre nuclei [7‐11].
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Therefore, the differential diagnosis of LG-ESS primarily includes cellular leiomyoma (and potentially other smooth muscle tumors), inflammatory myofibroblastic tumor (IMT), and uterine tumors resembling sex cord-stromal tumors (UTROSCT) [6, 8, 9, 12‐15]. Some cases with smooth muscle differentiation exhibit a characteristic “starburst” pattern, with collagen fibers radiating throughout the tumor, while others may show dispersed collagen plaques or myxoid changes, which can mimic the regressive changes found in leiomyoma or a myxoid leiomyosarcoma [7]. The presence of epithelioid/round cell differentiation may raise suspicion for high grade endometrial stromal sarcoma (HG-ESS) or perivascular epithelioid cell tumor (PEComa). In some cases, solitary fibrous tumor (SFT), gastrointestinal stromal tumor (GIST), or adenosarcoma can also stand in the differential diagnosis. Moreover, recently described sarcomas with the KAT6B/A::KANSL1 fusion usually have overlapping features between LG-ESS/endometrial stromal nodule (ESN) and smooth muscle tumors [16‐19].
With the increasing accessibility of molecular genetic methods, especially next generation sequencing (NGS), and the expanding knowledge of recurrent genetic alterations in uterine mesenchymal neoplasms, identifying characteristic fusions has greatly enhanced diagnostic accuracy. Up to 75% of LG-ESS harbor recurrent fusions, with JAZF1::SUZ12 being the most common, followed by JAZF1::PHF1, EPC1::PHF1, and MEAF6::PHF1 [6, 8, 20]. However, that leaves almost a quarter of LG-ESS which are not currently associated with any known recurrent genetic alteration. In a routine diagnostic setting, access to NGS is still rather limited and often varies between countries, with the added question of financial availability. As such, immunohistochemistry as a method which is vastly more accessible still remains a vital tool in reaching the correct diagnosis.
We conducted an extensive immunohistochemical analysis on a large, molecularly examined cohort of 147 LG-ESS, all subjected to rigorous central review. Our study tested a wide panel of immunohistochemical markers including sex cord-stromal markers, smooth muscle markers, hormone receptors, and selected novel antibodies, some of which have not been assessed in LG-ESS cohorts of this size. Our goal was to define the immunohistochemical profile of the largest cohort of LG-ESS to date, thus providing a practical diagnostic guide for pathologists, especially in settings where molecular testing is unavailable.
Materials and methods
Samples
The samples represent a part of the cohort assembled under the Rare Gynecological Sarcoma (REGYS) study, which is an international project involving 23 participating institutions from 10 countries, consisting mostly of members of the Central and Eastern Gynecology Oncology Group (CEEGOG). The project included a detailed assessment of the morphological features, immunohistochemical analysis, and DNA and RNA NGS analysis. A detailed description of the project, the overall cohort assembled, and the molecular results are provided in a different study (currently under review) and are not described here. Briefly, a central review was performed on all hematoxylin and eosin (HE)-stained slides available for individual cases by two experienced gynecopathologist specialists (PD, MKB). The required number of representative slides from the co-operating institutions for each case was 2 (n = 100). In those cases which came from the archives of our department (as well as cases which were sent to us as consultations, n = 47), the evaluation was performed on all slides available from the entire biopsy/resected specimen. The morphological evaluation was combined with the results of the immunohistochemical analysis and molecular testing to reach the correct diagnosis.
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An immunohistochemical (IHC) examination with a broad panel of 24 selected antibodies was performed for each tumor. Only cases unequivocally diagnosed as LG-ESS after the central review were included in the study, resulting in a final sample set of 147 cases. Of these 147 cases, 133 had RNA NGS results available which showed that 101 cases (75.9%) harbored a recurrent fusion. The most common alteration was the JAZF1::SUZ12 fusion found in 67 cases (66.3% of all fusions), followed mainly by JAZF1::PHF1 (n = 9), MEAF6::PHF1 (n = 8), and EPC1::PHF1 (n = 4).
The study was performed on formalin-fixed, paraffin embedded (FFPE) tissue blocks. Hematoxylin and eosin-stained slides from the FFPE tissue blocks were reviewed, and tissue microarrays (TMAs) were constructed from suitable tumor areas. Two tissue cores of a 2.00 mm diameter were extracted from each FFPE tissue block using the TMA instrument TMA Master (3DHISTECH Ltd., Budapest, Hungary).
Immunohistochemical analysis
Immunohistochemistry was performed on 4 µm thick section using the TMAs. In cases where the TMA approach was not possible, particularly due to small tumor size or technical difficulties during sample processing, whole-tissue sections were used where possible. The IHC was evaluated independently by two pathologists (MKB, MF). The antibodies used for IHC examination were selected based on their diagnostic utility, with an emphasis on ruling out the other entities most commonly involved in the differential diagnosis. The whole panel was comprised of estrogen receptor (ER), progesterone receptor (PR), alfa-smooth muscle actin (α-SMA), desmin, h-caldesmon, calponin, CD10, IFITM1, transgelin, BCOR, BCORL1, NTRK, S-100, HMB45, CD117, WT1, SMARCA4 (BRG1), SMARCB1 (INI1), SMARCA2, ALK, ROS1, p53, smoothelin, and cyclin D1. The complete list of antibodies used, including their clones, dilution, and manufacturers is provided in Table 1.
Table 1
List of antibodies used for immunohistochemical analysis
Antibody
Clone
Dilution
Producer
Platform
Detection
Evaluated expression
ALK
D5F3
1:100
Cell Signaling Technology, Danvers, Massachusetts, USA
The immunohistochemical results were evaluated based on the overall percentage of positivity (0–100%). Cases were classified as negative (complete absence of staining or < 1% of positive tumor cells), 1 + (1–25% of positive tumor cells), 2 + (26–50% of positive tumor cells), or 3 + (> 50% of positive tumor cells). For the antibodies NTRK and smoothelin, the staining was evaluated independently as both nuclear and cytoplasmic, for WT1 only the nuclear staining was evaluated. The immunohistochemical results were also assessed using the H-score method previously described by others [21]. This method incorporates both the percentage of positive cells and the staining intensity (1 + for weak intensity, 2 + for moderate, and 3 + for strong). The final H-score is calculated by adding the multiplication of the different staining intensities according to the following formula: [1 x (% of cells 1 +)] + [2x (% of cells 2 +)] + [3x (% of cells 3 +)], resulting in an H-score value of 0–300. To characterize expression in terms of positive and negative cases, a cut-off value of 1% was used (positive: ≥ 1% of cells showing expression). For comparing the IHC expression within the LG-ESS cohort based on the presence of fusion, the cut-off value was modified to 5% to account for minor non-specific staining variations.
Statistical analyses
All statistical analyses were conducted using R software, version 4.3.3 (2024–02–29). Standard descriptive statistics were applied to summarize the dataset: Categorical variables were reported as frequencies and percentages, and continuous variables were described using means with standard deviation (SD) or medians with interquartile range. Correlations between the expression of IHC markers (categorized as positive vs. negative) and fusion status (presence vs. absence of fusion) were assessed using Pearson’s chi-squared test or Fisher´s Exact test based on expected values. All tests were two-sided, and a p value < 0.05 was considered statistically significant.
Results
A detailed overview of the IHC results is provided in Table 2. The IHC testing for all antibodies was not possible in all of the cases due to limited material. Representative images of selected IHC markers are provided in Figs. 1, 2, 3, and 4. The cohort consisted of 122 cases (83%) of LG-ESS with the usual morphological pattern, 5 cases (3%) with pure fibroblastic pattern, and a single case each (0.6%) displaying predominant smooth muscle-like morphology or a glandular pattern. Fourteen tumors showed a mixed pattern—most commonly usual + fibroblastic (n = 7.5%) and usual + smooth muscle-like (n = 2.1%), while 6 cases (4%) showed a sex cord-stromal component of variable extent. Two cases (1%) were made up of a mixture of fibroblastic and myxoid patterns, and one case displayed a combination of usual, fibroblastic, and myxoid morphology.
Table 2
Detailed overview of IHC expression of the antibodies most commonly used in the differential diagnosis of LG-ESS
IHC marker
Negative (0–1%)
n (%)
Positive (≥ 1%)
n (%)
Positivity 1 + (1–25%)
n (%)
Positivity 2 + (26–50%)
n (%)
Positivity 3 + (> 50%)
n (%)
H-score mean (SD)
H-score median (range)
ER (n = 143)
25 (17%)
118 (83%)
6 (5%)
8 (7%)
104 (88%)
118 (87.3)
100 (0–300)
PR (n = 144)
11 (8%)
133 (92%)
8 (6%)
5 (4%)
120 (90%)
201 (106.5)
223 (0–300)
α-SMA (n = 142)
80 (56%)
62 (44%)
20 (32%)
7 (11%)
35 (56%)
46 (75.4)
0 (0–300)
Desmin (n = 141)
106 (75%)
35 (25%)
15 (43%)
6 (17%)
14 (40%)
24 (66.8)
0 (0–300)
H-caldesmon (n = 141)
121 (86%)
20 (14%)
12 (60%)
3 (15%)
5 (25%)
7 (28.0)
0 (0–200)
Calponin (n = 143)
94 (66%)
49 (34%)
22 (45%)
4 (8%)
23 (47%)
31 (72.7)
0 (0–300)
CD10 (n = 141)
20 (14%)
121 (86%)
6 (5%)
4 (3%)
111 (92%)
171 (110.9)
196 (0–300)
IFITM1 (n = 143)
45 (31%)
98 (69%)
28 (29%)
11 (11%)
59 (60%)
65 (77.2)
20 (0–300)
Transgelin (n = 141)
110 (78%)
31 (22%)
13 (42%)
6 (19%)
12 (39%)
16 (49.7)
0 (0–300)
BCOR (n = 142)
135 (95%)
7 (5%)
2 (29%)
1 (14%)
4 (57%)
3 (19.3)
0 (0–170)
BCORL1 (n = 141)
107 (76%)
34 (24%)
31 (91%)
2 (6%)
1 (3%)
2 (7.9)
0 (0–70)
NTRK nuclear (n = 145)
137 (94%)
8 (6%)
5 (63%)
3 (38%)
0 (0%)
2 (11.9)
0 (0–100)
NTRK cytopl. (n = 145)
141 (97%)
4 (3%)
2 (50%)
1 (25%)
1 (25%)
1 (8.8)
0 (0–100)
S-100 (n = 143)
143 (100%)
0 (0%)
0 (-)
0 (-)
0 (-)
0 (-)
0 (-)
HMB45 (n = 143)
140 (98%)
3 (2%)
3 (100%)
0 (0%)
0 (0%)
0 (1.8)
0 (0–20)
CD117 (n = 146)
145 (99%)
1 (1%)
1 (100%)
0 (0%)
0 (0%)
0 (1.7)
0 (0–20)
WT1 (n = 140)
84 (60%)
56 (40%)
18 (32%)
4 (7%)
34 (61%)
25 (43.3)
0 (0–200)
Smoothelin nuclear (n = 142)
141 (99%)
1 (1%)
1 (100%)
0 (0%)
0 (0%)
0 (0.1)
0 (0–1)
Smoothelin cytopl. (n = 142)
141 (99%)
1 (1%)
1 (100%)
0 (0%)
0 (0%)
0 (0.1)
0 (0–1)
Cyclin D1 (n = 141)
62 (44%)
79 (56%)
39 (49%)
26 (33%)
14 (18%)
25 (48.6)
2 (0–300)
SD standard deviation, cytopl. cytoplasmic. The number of analyzed cases for each stain differs due to the amount of available tissue. Percentages are rounded up/down. Percentages of 1 + /2 + /3 + positivity are counted only from the positive cases
Fig. 1
Examples of CD10 and IFITM1 expression in different morphological variants of LG-ESS. All microphotographs taken at 100 × magnification. A Diffuse, strong expression of CD10 in a usual LG-ESS (no fusion detected). B Focal expression of CD10 of a variable intensity in a case with predominant smooth-muscle morphology (JAZF1::SUZ12 fusion). C Moderate to strong CD10 expression in an LG-ESS with a sex cord stromal-like morphology (JAZF1::SUZ12 fusion). D Diffuse, strong expression of CD10 in a myxoid LG-ESS (JAZF1::SUZ12 fusion). E Diffuse and strong expression of IFITM1 in LG-ESS with a usual morphology (SVIL::EPC1 fusion). F Complete IFITM1 negativity in a case with predominantly smooth muscle morphology (JAZF1::SUZ12 fusion). G Disperse IFITM1 expression of a variable intensity in an LG-ESS with sex cord stromal-like morphology. Same case as depicted in 1C (JAZF1::SUZ12 fusion). H Focal, occasional granular expression of IFITM1 in a case with myxoid features. Same case as depicted in 1D (JAZF1::SUZ12 fusion)
Examples of the expression of selected smooth muscle markers in different morphological variants of LG-ESS. A α-SMA in a usual LG-ESS, 100 × magnification (JAZF1::SUZ12 fusion). B Focal irregular expression of α-SMA in LG-ESS with predominantly smooth-muscle morphology, 200 × magnification (JAZF1::SUZ12 fusion). C Occasional rare expression of α-SMA in individual cells in a myxoid variant of LG-ESS (with positively staining vessels in the field), 100 × magnification (JAZF1::SUZ12 fusion). D Almost complete negativity of transgelin in a usual LG-ESS (with positively staining admixed myometrium), 100 × magnification (no fusion detected). E Focal expression of transgelin smooth muscle variant of LG-ESS, 200 × magnification (JAZF1::SUZ12 fusion, same case as 2B). F Transgelin in an LG-ESS with sex cord stromal-like morphology showing irregular but extensive weak to moderate expression, 100 × magnification (JAZF1::SUZ12 fusion)
Examples of the expression of selected smooth muscle markers in different morphological variants of LG-ESS, continued. A Negativity of desmin in a usual variant of LG-ESS, 100 × magnification (no fusion detected, same case as 2D). B Disperse strong expression of desmin in a myxoid variant of LG-ESS, 100 × magnification (JAZF1::SUZ12 fusion, same case as 2C). C) Focal weak to moderate expression of h-caldesmon in an LG-ESS with smooth muscle morphology, 200 × magnification (JAZF1::SUZ12 fusion). D Smoothelin in a usual LG-ESS, 200 × magnification (no fusion detected, same case as 2D and 2G)
Examples of the expression of other selected IHC markers useful in the differential diagnosis of LG-ESS. A Extensive and nearly diffuse weak to moderate expression of Cyclin D1, 100 × magnification (JAZF1::SUZ12 fusion). B Diffuse strong nuclear expression of WT1, 100 × magnification (JAZF1::SUZ12 fusion). C Disperse expression of NTRK with variable (mostly moderate) intensity, 100 × magnification (JAZF1::SUZ12 fusion). D The expression of p53 showing disperse, weak positivity of tumor cell—wild-type pattern of staining, 200 × magnification (JAZF1::SUZ12 fusion). E Diffuse expression of ER of moderate intensity, 100 × magnification (JAZF1::SUZ12 fusion). F Diffuse expression of PR, note the characteristic significantly stronger intensity of PR expression compared with ER (corresponding field from the same case as seen in 3E), 100 × magnification (JAZF1::SUZ12 fusion)
As expected, the tumors showed high levels of expression of the endometrial stromal markers CD10 and IFITM1. CD10 expression was seen in 86% of cases, with a majority of the positive cases (92%) exhibiting diffuse, extensive staining of a high intensity (median H-score 196). The other marker of endometrial stromal differentiation IFITM1 was positive in a lower number of cases (69%) with a heterogenous extent of expression, which was mostly diffuse but of varying intensity. The expression of the standard smooth muscle markers (α-SMA, desmin, h-caldesmon, calponin, and transgelin) was present to a variable degree in all of the examined tumors, with α-SMA reaching the highest frequency of positive cases (44%). The extent of expression of these markers was typically on the opposite ends of the spectrum—either only rare and focal (with positively staining areas comprising less than 25% of the tumor tissue) or extensive and diffuse (with more than 50% of the tumor showing expression). However, the intensity of the smooth muscle marker expression was usually very low, with the highest average H-score of 46 (observed for α-SMA) and the median H-score 0 for all examined markers. Smoothelin showed expression in only two cases of LG-ESS, which was only focal and of a weak intensity. Hormone receptors were expressed in a high proportion of the tumors, with PR reaching a slightly higher frequency (92% vs. 83%) and also intensity of staining, compared with ER. Regarding the antibodies useful in differential diagnosis such as S-100, HMB45, and CD117, these showed almost complete negativity.
Of those markers not included in Table 2, all cases were p53 wild type, and ALK and ROS1 negative. The expression of SMARCB1 (INI1) and SMARCA4 (BRG1) was preserved, while seven cases showed an isolated loss of SMARCA2 (BRM). As the molecular profile of these tumors was known, none of them harbored BRM alterations.
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The differences in expression of all the studied markers between the tumors with a confirmed fusion (n = 101) and those without a recurrent fusion (n = 32) were also analyzed (Supplementary Table 1). The results showed that only the endometrial stromal markers CD10 and IFITM1 differed significantly between the fusion positive and negative groups, with fusion positive tumors showing a more frequent positive expression of both CD10 (p < 0.001) and IFITM1 (p = 0.007).
Due to the imbalanced number of cases showing variant morphologies compared with the usual pattern, it was not possible to statistically analyze the differences in expression between these groups. Tumors with at least a component of fibroblastic morphology (n = 13) showed the expression of α-SMA, desmin, h-caldesmon, calponin, and transgelin in 5/13 (38%), 4/13 (31%), 3/13 (23%), 5/10 (50%), and 3/13 (23%) cases respectively. CD10 was positive in 11/13 (85%) cases and IFITM1 in 7/13 (54%) cases. Tumors with a sex cord-stromal component (n = 7) showed the expression of α-SMA, desmin, h-caldesmon, calponin, and transgelin in 5/7 (71%), 3/7 (43%), 2/7 (29%), 3/7 (43%), and 2/7 (29%) cases, respectively, while CD10 was positive in 6/7 (86%) cases and IFITM1 in 5/7 (71%) cases. The three tumors with smooth muscle morphology were all negative in desmin and h-caldesmon, and the expression of α-SMA, calponin, and transgelin was seen in 2/3 cases. All cases were CD10 positive, with IFITM1 expression in 2/3 cases.
Discussion
Low grade endometrial stromal sarcoma presents a diagnostic challenge due to its significant morphological overlap with other spindle cell mesenchymal tumors of the uterus. Recent studies re-evaluating the pathological diagnoses of uterine mesenchymal tumors have reported that LG-ESS can be misdiagnosed in up to 20% of cases [22]. Current knowledge about the immunohistochemical profile of LG-ESS is derived from studies with a relatively low number of examined cases, with the largest immunohistochemically analyzed series including fewer than 50 cases [23]. Much of the published data comes from single-case studies and small antibody panels, limiting the availability of robust data. Additionally, LG-ESS is burdened with a relatively high interobserver variability, as some cases can only be reliably diagnosed using molecular testing. This introduces bias into older data, particularly due to evolving terminology and definitions, as some older studies only use the term “endometrial stromal sarcoma,” which makes the comparison of these results problematic. Given these limitations, our aim was to provide reliable data from a carefully selected, molecularly examined series of LG-ESS, the largest series described in the literature for IHC profiling to date. Reliable data on the immunoprofile of LG-ESS are especially critical in routine practice, particularly for cases with equivocal features or cases where only limited tumor tissue is available (e.g., small diagnostic biopsies or tru-cut biopsies).
The main IHC markers for diagnosing endometrial stromal tumors are CD10 and the more recently introduced marker IFITM1 [24, 25]. The expression of CD10 has long been established as one of the key diagnostic markers, as it is sensitive (75–100%) and has been reported in 258/294 (88%) of all cases of LG-ESS with the available IHC results to date. However, CD10 is not highly specific for LG-ESS, as a small portion of LG-ESS can be negative, especially in cases with poor fixation [26]. CD10 expression is also reported in up to 30% of smooth muscle tumors (including cellular leiomyoma), as well as in PEComa and the sarcomatous component of adenosarcoma [10, 27‐30].
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Currently, there is limited data on the expression of IFITM1 in LG-ESS. Two studies report IFITM1 expression in 83% (10/12) and 100% (16/16) of LG-ESS cases, compared with 30% (6/20) and 40% (12/30) of smooth muscle tumors [25, 31]. Both studies concluded that IFITM1 specificity (70% and 86,7%) surpasses CD10, although each study examined a relatively small series of cases. IFITM1 expression, while not entirely restricted to LG-ESS, tends to be weak and focal in smooth muscle tumors. Zhao et al. also emphasized IFITM1’s superior sensitivity and specificity over CD10, although also based on a small series [32]. Our study found IFITM1 expression in 98/143 cases (69%), mostly extensive or diffuse with variable intensity. IFITM1 seems to outperform CD10 in distinguishing LG-ESS from smooth muscle tumors; however, larger studies are still needed to confirm its utility. A useful approach would therefore include using both CD10 and IFITM1 as a part of the IHC panel. Interestingly, our study found that both CD10 and IFITM1 were significantly more commonly expressed in LG-ESS cases with a recurrent fusion, which underscores the diagnostic challenges of fusion-negative tumors given the lack of recurrent genetic alterations and potentially more equivocal IHC results.
Hormone receptors, specifically ER (ERα) and PR, are another crucial part of the diagnostic panel. The available literature indicates that ER is expressed in 84,5% of LG-ESS, with PR expression reaching 87% [15, 23, 33‐38]. Most studies report more extensive, stronger PR expression than ER, which is consistent with our findings. The expression of androgen receptor (AR) has also been described in a high percentage of LG-ESS, though the number of studies is limited [35]. While ER and PR are typically less useful for distinguishing smooth muscle neoplasms, they can aid in ruling out other non-Müllerian origin tumors, particularly for extrauterine LG-ESS.
Hormone marker expression (especially ER and PR) may also have predictive significance, with their high expression rates in LG-ESS supporting hormone therapy such as high-dose progestins, aromatase inhibitors, or GnRH analogues as a viable treatment option [39‐41]. A recent meta-analysis found that adjuvant hormone therapy can reduce recurrence risk in patients with FIGO stages I–II disease, but with no benefit concerning overall survival [42]. Another study suggested that hormone therapy can also reduce recurrence risk even in stages II–IV LG-ESS, recommending 12 months of high-dose progestin treatment post-surgery [43]. While the effectiveness of hormone therapy is debated, reporting tumor hormone status remains essential as it can help guide treatment decisions. Conflicting evidence also exists regarding ER/PR expression as a prognostic factor, requiring validation through a molecularly confirmed series [35, 43, 44].
In routine practice, one of the common diagnostic pitfalls lies in differentiating cellular leiomyoma (CL) from LG-ESS. The correct diagnosis of CL versus LG-ESS is of extreme clinical importance, given the different biological natures and behavior of these tumors. In which case, a combination of smooth muscle markers such as α-SMA, desmin, h-caldesmon, calponin, transgelin, and smoothelin, and endometrial stromal markers, such as CD10 and IFITM1, is essential. Smooth muscle markers are frequently positive in LG-ESS, especially in cases with smooth muscle differentiation [10, 12, 28, 30, 45, 46]. In contrast, endometrial stromal markers can be expressed in smooth muscle tumors, especially cellular leiomyomas. In our previous study on CL, the expression of CD10 was seen in 65% of cases, and the expression of IFITM1 in 36.5% of cases [13]. This can lead to a potential misclassification if an immunohistochemical (IHC) profile is not rigorously interpreted within the morphological context. The most expressed smooth muscle marker in LG-ESS is α-SMA (50% of cases reported in literature), closely followed by desmin (47%). While relatively common, the expression of all smooth muscle markers tends to be mostly focal and weak.
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Based on the literature, h-caldesmon has emerged as the most specific marker for distinguishing smooth muscle tumors from LG-ESS [30, 46, 47]. The published data shows the expression of h-caldesmon in 9% of LG-ESS, and in our study, h-caldesmon was also the least expressed (14%) of the traditionally examined smooth muscle markers [10, 15, 27, 30, 32, 38, 46, 48‐50]. Transgelin, an actin-binding protein of the calponin family, has similarly been noted as a highly sensitive and specific marker of smooth muscle differentiation. However, its expression in LG-ESS has been examined in just two studies, with a combined total of 32 cases [47, 51]. Our findings showed a 22% expression rate in LG-ESS, notably higher than previously published data, likely due to our larger series size. These findings highlight the need to validate the “characteristic” immunoprofile of LG-ESS to support the accurate diagnosis of challenging cases encountered in routine practice.
In our series, 14–44% of LG-ESS cases exhibited smooth muscle marker expression, underscoring the need for more specific antibodies. One such emerging marker could be smoothelin, initially identified in 1996 by van der Loop et al., which is a cytoskeletal protein primarily found in fully differentiated, contractile smooth muscle cells [52, 53]. This sets it apart from other smooth muscle markers such as calponin, α-SMA, smooth muscle myosin, and h-caldesmon, which are also present in less differentiated, proliferative smooth muscle cells. Additionally, smoothelin’s expression is notably lacking in cells that exhibit smooth muscle-like characteristics, such as myofibroblasts, myoepithelial cells, and striated muscle cells—cells that frequently express other smooth muscle proteins. Studies examining smoothelin’s utility in smooth muscle tumors of the gastrointestinal tract, uterus, and other soft tissues have indicated that cytoplasmic expression is highly sensitive and specific for benign leiomyomas [54, 55]. Notably, it has been suggested that the staining location (cytoplasmic vs. nuclear) may vary based on the biological behavior of smooth muscle tumors, as aberrant nuclear expression has been reported in a subset of leiomyosarcomas and occasionally in GIST. Our study is the first to examine smoothelin expression in LG-ESS, where we observed rare, moderate nuclear expression in one case and weak cytoplasmic expression in another. This suggests that smoothelin could be an extremely valuable marker in cases with equivocal results from the traditional smooth muscle markers. In our previous study, its expression was found in 61.5% of cellular leiomyomas, but it was commonly focal and weak, which limited its practical use [13].
A key takeaway from our findings is the awareness of smooth muscle marker expression in a subset of LG-ESS and the importance of interpreting results with caution, as they should always be evaluated together with endometrial stromal markers. When differentiating smooth muscle tumors from LG-ESS, a combined panel of high-sensitivity markers with specific markers (such as h-caldesmon, transgelin, and, potentially, smoothelin) is recommended, keeping in mind that α-SMA and desmin in particular do not serve as good discriminators between endometrial stromal and smooth muscle lineage. The staining’s extent and intensity are also essential; tumors with diffuse, strong expression of multiple smooth muscle markers should be, in a proper morphological context, classified as smooth muscle tumors, even if there is a focal expression of CD10 or IFITM1.
Of the other markers useful in differential diagnosis, cyclin D1 and BCOR are often part of the panel used for distinguishing LG-ESS from HG-ESS. Although HG-ESS typically exhibits a distinct morphology, rare cases of LG-ESS can present with epithelioid, round cell morphology which may lead to the consideration of HG-ESS. The reported rate of cyclin D1 expression in LG-ESS is generally low, reaching 28%. Our results indicate a relatively high proportion of LG-ESS with positive cyclin D1 expression (56%), though this expression was typically occasional or focal, and weak in intensity. Although a diffuse expression of cyclin D1 was seen in 14/141 (10%) cases, strong and diffuse cyclin D1 expression was present in only a single case (which showed a usual morphological pattern for LG-ESS). BCOR expression was significantly rarer (5%, 7/142) but, when present, the extent of staining ranged from occasional to nearly diffuse (albeit weak). Similarly, the expression of BCORL1, which can also be present in some cases of HG-ESS, was seen in 24% (34/141) of LG-ESS, where it was also only rare and weak. None of the cases with BCORL1 expression harbored a fusion involving the BCORL1 gene. While BCOR and BCORL1 expression likely represent non-specific staining insufficient for HG-ESS diagnosis, they could pose a diagnostic challenge in certain ambiguous cases.
One of the less common differential diagnoses of LG-ESS is GIST, especially when found in extrauterine locations. In which case, a diagnostic panel of CD117 combined with CD10, ER, and PR is most effective, as CD34 can be positive in both LG-ESS and GIST [56]. Although some reports indicate a small portion of LG-ESS exhibit CD117 expression, the staining tends to be weak and focal [57, 58]. Consistent with prior reports, only a single case from our LG-ESS showed occasional, weak expression of CD117.
Another very important differential diagnosis is the entity of KAT6B/A::KANSL1 fused sarcomas, described in 2022 by Agaimy et al. [16, 16, 17, 19]. According to the current knowledge, due to the overlapping features between endometrial stromal and smooth muscle differentiation, sarcomas with the KAT6B/A::KANSL1 fusion cannot be diagnosed based only on the morphological and immunohistochemical features, and molecular testing is needed. The correct diagnosis is important in these cases as, despite their usually bland morphology, these tumors have propensity for aggressive behavior.
There are limitations to our study. The main one being the use of TMA, which brings the risk of underestimating/overestimating the IHC scoring. However, this risk was reduced by using two cores from each tumor to increase the amount of tissue, and this approach is widely used in the literature and allows for the examination of several markers on large sample collections. Additionally, a small portion of cases (n = 14) lack a known fusion status (as they could not undergo NGS RNA analysis due to insufficient amount or quality of the material), preventing molecular confirmation. Due to the low number of rare morphological variants, it was impossible to analyze the differences in expression between these and cases with conventional morphology.
Conclusion
We have performed an extensive immunohistochemical analysis of a large series of molecularly examined 147 LG-ESS, using a wide panel of 24 antibodies. This study provides a more reliable immunohistochemical profile for LG-ESS, addressing the limitations of previous, smaller studies. Our findings, while not novel for most of the antibodies examined, provide an important context and validation of knowledge accumulated from studies which were limited and often on series which lack molecular confirmation. As such, our study is the largest to evaluate the immunoprofile of LG-ESS in general, with an emphasis on markers which have only recently come into diagnostic practice (such as transgelin and smoothelin). A crucial part of our results is the confirmation of the fact that due to the overlapping IHC profiles, it is impossible to reach a correct diagnosis using singular markers, and a panel of antibodies should always be used. We are aware that in some cases with overlapping morphological and immunohistochemical features, the correct diagnosis is only possible with molecular testing. However, 21% of LG-ESS in our series did not harbor a recurrent fusion—in these cases in particular the diagnosis will hinge on the assessment of the morphology and the immunohistochemical examination. Although there are still diagnostic challenges, this study provides critical data for improving diagnostic accuracy and guiding treatment. These findings validate existing knowledge, while contributing to a more standardized approach for diagnosing LG-ESS.
Acknowledgements
The authors wish to thank Mgr. Zachary Harold Kane Kendall, B.A. (Institute for History of Medicine and Foreign Languages, First Faculty of Medicine, Charles University) for the English proofreading.
Declarations
Ethics approval
The study has been approved by the Ethics Committee of General University Hospital in Prague in compliance with the Helsinki Declaration (No. 2140/19 S-IV). The Ethics Committee waived the requirement for informed consent, as according to the Czech Law (Act. no. 373/11, and its amendment Act no. 202/17) it is not necessary to obtain informed consent in fully anonymized studies.
Competing interests
All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.
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Immunohistochemical analysis of 147 cases of low-grade endometrial stromal sarcoma: refining the immunohistochemical profile of LG-ESS on a large, molecularly confirmed series
Verfasst von
Miroslava Flídrová
Pavel Dundr
Romana Vránková
Kristýna Němejcová
David Cibula
Renata Poncová
Květoslava Michalová
Jiří Bouda
Jan Laco
Munachiso Ndukwe
Janusz Ryś
Mariusz Książek
Alberto Berjon
Ignacio Zapardiel
Ivan Franin
Antonela Njavro
Jitka Hausnerová
Petra Bretová
Vladimír Židlík
Jaroslav Klát
Zoard Tibor Krasznai
Robert Poka
Nataliya Volodko
Iryna Yezhova
Radovan Pilka
Radim Marek
Georgina Kolnikova
Milan Krkoška
Michael Halaška
Jana Drozenová
Dagmar Dolinská
Vladimír Kalist
Marcin Bobiński
Marta Ostrowska-Leśko
Magdalena Bizoń
Włodzimierz Sawicki
Maciej Stukan
Karolina Grabowska
Marcin Jędryka
Tymoteusz Poprawski
Simona Stolnicu
Mihai Emil Căpîlna
Zuzana Špůrková
Michal Zikán
Francesca Ciccarone
Giovanni Scambia
Archil Sharashenidze
Miranda Gudadze
Tetiana Piatnytska
Ihor Varchak
Michaela Kendall Bártů
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