Immunohistochemical analysis of 147 cases of low-grade endometrial stromal sarcoma: refining the immunohistochemical profile of LG-ESS on a large, molecularly confirmed series

Abstract

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.

Keywords: Endometrial stromal markers; Immunohistochemistry; LG-ESS; Low-grade endometrial stromal sarcoma; Smoothelin.

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)

Fig. 2

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)

Fig. 3

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)

Fig. 4

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)