Cyclin D1 as a diagnostic immunomarker for endometrial stromal sarcoma with YWHAE-FAM22 rearrangement

Abstract

Endometrial stromal sarcoma (ESS) characterized by YWHAE-FAM22 genetic fusion is histologically higher grade and clinically more aggressive than ESS with JAZF1-SUZ12 or equivalent genetic rearrangements, hence it is clinically important to recognize this subset of ESS. To identify diagnostic immunomarkers for this biologically defined ESS subset, we compared gene expression profiles between YWHAE-FAM22 ESS and JAZF1-rearranged ESS. These studies showed consistent upregulation of cyclin D1 in YWHAE-FAM22 ESS compared with JAZF1-SUZ12 ESS. Immunohistochemically, the high-grade round cell component of all 12 YWHAE-FAM22 ESS demonstrated diffuse (≥70%) moderate to strong nuclear cyclin D1 staining, and this diffuse positivity was not seen in 34 ESSs with JAZF1 and equivalent genetic rearrangements or in 21 low-grade ESS with no demonstrable genetic rearrangements. In a series of 243 non-ESS pure uterine mesenchymal and mixed epithelial-mesenchymal tumors, only 2 of 8 undifferentiated endometrial sarcomas with nuclear uniformity and 1 of 80 uterine leiomyosarcomas demonstrate diffuse cyclin D1 immunoreactivity. Both cyclin D1-positive undifferentiated endometrial sarcomas showed diffuse strong CD10 staining, which is consistently absent in the high-grade round cell component of YWHAE-FAM22 ESS. The low-grade spindle cell component of YWHAE-FAM22 ESS showed a spatially heterogenous cyclin D1 staining pattern that was weaker and less diffuse overall. Our findings indicate that cyclin D1 is a sensitive and specific diagnostic immunomarker for YWHAE-FAM22 ESS. When evaluating high-grade uterine sarcomas, cyclin D1 can be included in the immunohistochemical panel as an indicator of YWHAE-FAM22 ESS.

Figure 1

Cyclin D1 immunostaining in high-grade round cell component of YWHAE-FAM22 ESS. The representative H&E and immunostaining images illustrate the diffuse strong nuclear cyclin D1 staining at low (A-D) and high (E-F) magnifications in the high-grade round cell component of an YWHAE-FAM22 ESS.

Figure 2

Cyclin D1 immunostaining in the low-grade spindle cell component of YWHAE-FAM22 ESS. The low-grade spindle cell component of YWHAE-FAM22 ESS (bottom right) displays weaker cyclin D1 immunostaining compared to the high-grade round cell component (A-C). The staining in the low-grade spindle cell component is variable, ranging from very focal and weak (C) to diffuse weak to moderate staining intensity (D) in the same tumor.

Figure 3

Cyclin D1 immunostaining in JAZF1 ESS. Panels A and B depict the H&E and cyclin D1 immunostaining of a primary uterine JAZF1 ESS. Panel C and D depict the H&E and cyclin D1 immunostaining of a pulmonary metastasis of a JAZF1 ESS. Panels E and E depict cyclin D1 immunostaining in two different uterine JAZF1 ESS.

Figure 4

Scatter plot of the extent of cyclin D1 immunostaining (% moderate to strong nuclear staining) in a series of gynecologic mesenchymal and mixed epithelial and mesenchymal tumors (n = 310). ESS: endometrial stromal sarcoma; UES-U: undifferentiated endometrial sarcoma with nuclear uniformity; UES-P: undifferentiated endometrial sarcoma with nuclear pleomorphism; LMS: leiomyosarcoma; Ut: uterine; endo: endometriosis; ESN: endometrial stromal nodule; UTROSCT: uterine tumor resembling ovarian sex-cord tumor.

Figure 5

Representative images of cyclin D1 immunostaining in other uterine tumor. Absent or very focal cyclin D1 immunostaining is seen in the mesenchymal component of an adenosarcoma (A) and a carcinosarcoma (B). Panel C depicts a UES-U with diffuse cyclin D1 immunostaining (one of the two cyclin D1 positive UES-U). Panel D and E show the typically weak and focal staining in a UES-P and a uterine leiomyosarcoma respectively. Panel F depicts the single case of uterine leiomyosarcoma with diffuse cyclin D1 staining; this case contains substantial histiocytic and lymphocytic infiltrates.

Figure 6

Diagnostic algorithm for work-up of suspected YWHAE-FAM22 ESS among uterine mesenchymal tumors. * with myopermeative growth pattern; ** the other differential includes sarcoma-predominant carcinosarcoma, adenosarcoma with HG sarcomatous overgrowth, rhabdomyosarcoma; † the other differential includes that were discussed in the text of the discussion.