Abstract
Sclerosing epithelioid fibrosarcoma (SEF) was originally described as a peculiar variant of fibrosarcoma in 1995. Subsequent studies showed that conventional SEF was associated with both immunohistochemical expression of MUC4 and EWSR1/FUS gene rearrangements with CREB3L1 as the predominant fusion partner. Since then, a distinct group of fibrous tumors characterized by YAP1::KMT2A and KMT2A::YAP1 gene rearrangements and SEF-like morphology has been described. These YAP1::KMT2A-rearranged sarcomas were further shown to lack both immunohistochemical expression of MUC4 and canonical EWSR1/FUS gene rearrangements. To better understand whether the YAP1::KMT2A-rearranged sarcomas represent a subset of MUC4-negative SEF or a distinct entity, we studied 22 cases of YAP1::KMT2A-rearranged sarcomas, the largest series to date, and performed a literature review of all previously reported next-generation sequencing (NGS)-confirmed cases. These sarcomas often arose in young adults with a median age of 38 years and a male to female (M:F) ratio of 1.4:1. They predominantly involved somatic soft tissue; however, we report the first case of a tumor that primarily developed inside bone. Immunohistochemical studies showed that the tumors often demonstrated expression of YAP1 and EMA, while all tested cases were negative for MUC4. NGS confirmed the presence of YAP1::KMT2A gene fusions in all cases, some of which initially had false negative results with targeted FISH and solid tumor panel testing. Clinical follow-up information was available in 14 patients with a median follow-up of 25 months (range 1 to 170 months). Local recurrence occurred in three patients (21%) and metastasis developed in seven patients (50%). DNA methylation analysis further showed that YAP1::KMT2A-rearranged sarcomas formed a distinct cluster, which was clearly separate from both conventional SEF and low-grade fibromyxoid sarcoma (LGFMS). These results suggest that YAP1::KMT2A-rearranged sarcomas likely represent a unique sarcoma subtype with propensity for aggressive behavior.
Keywords: YAP1, KMT2A, Sclerosing epithelioid fibrosarcoma, Sarcoma, Methylation, MUC4
Introduction
Sclerosing epithelioid fibrosarcoma (SEF) was originally described as a unique entity and peculiar variant of fibrosarcoma in 1995 based on morphologic criteria [1]. Ultrastructural studies helped to verify fibroblastic differentiation [2], and most cases of conventional SEF were subsequently found to have both immunohistochemical expression of MUC4, a high molecular weight transmembrane glycoprotein, as well as EWSR1/FUS gene rearrangements with CREB3L1 as the predominant fusion partner. Since then, a distinct group of fibroblastic tumors with SEF-like morphology but YAP1::KMT2A and KMT2A::YAP1 gene rearrangements has been described, and these cases have shown consistent absence of MUC4 expression. Although originally interpreted as a subtype of SEF, gene expression data revealed that YAP1::KMT2A-rearranged sarcomas cluster separately from conventional SEF [3]. As more of these sarcomas are identified, more evidence is needed to clarify if they represent a variant of MUC4-negative SEF or a distinct entity. To further investigate this relationship, we collected 22 cases of molecularly confirmed YAP1::KMT2A-rearranged sarcomas, the largest series to date, studied their histology and immunophenotype, and performed DNA methylation analysis in direct comparison to conventional cases of both SEF and low-grade fibromyxoid sarcoma (LGFMS).
Materials and methods
Case selection
This study was approved by the Institutional Review Boards of the participating institutions. All cases were identified either through routine clinical practice or through expert subspecialty consultation by the authors. Clinicopathologic features of all 22 cases with available resection specimens were assessed.
Immunohistochemistry
Immunohistochemical stains were performed on available 4-μm formalin-fixed paraffin-embedded (FFPE) tissue sections for each case using standard techniques. Due to the consultative nature of the cases, immunohistochemistry techniques and panels varied among contributing institutions. The details of the staining protocols and antibody sources are available upon request.
Next-generation sequencing (NGS)
Due to the consultative nature of the cases, NGS techniques and panels varied among contributing institutions. The details of the NGS protocols and panels are available upon request.
DNA methylation profiling and copy number variant (CNV) analysis
Eleven cases of YAP1::KMT2A-rearranged sarcoma (cases 1–5, 15–19, and 22) successfully underwent DNA methylation profiling using the Infinium Human-Methylation EPIC array platform as previously described [4]. Probes associated with known SNPs, non-CpGs, and sex chromosomes were not considered for evaluation. Moreover, samples with a mean detection p > 0.01 were discarded. Uniform manifold approximation and projection (UMAP) was performed on the results of a principal component analysis (30 PCs) calculated on the top 10,000 most variable CpGs via the singular value decomposition of the beta methylation matrix. The R-package used for generating the graph can be found at (http://github.com/jlmelville/uwot). For comparison, publicly available datasets (GSE110697, GSE112308, GSE140686, and EGAS00001007042) of 41 dermatofibrosarcoma protuberans (DFSP), 18 desmoid-type fibromatosis (DTFM), 11 low-grade fibromyxoid sarcoma (LGFMS), 14 infantile fibrosarcoma (IFS), 30 malignant peripheral nerve sheath tumor (MPNST), 13 nodular fasciitis (NODF), 54 high-grade osteosarcoma (OS), 16 sclerosing epithelioid fibrosarcoma (SEF), 30 solitary fibrous tumor (SFT), and 60 undifferentiated soft tissue sarcoma (USARC) were used.
Copy number variations (CNVs) were inferred from the Infinium Human-Methylation EPIC array platform using the R-package “conumee.” The settings for the copy number variation inference were as follows: a minimum number of probes per bin equal to 25; minimum bin size equal to 50,000 bp.
Results
Clinicopathologic features pertaining to the 22 patients in our series are presented in Table 1.
Table 1.
YAP1::KMT2A-rearranged sarcomas: clinicopathologic features of 22 new cases with literature review
| Case no | Age (y)/sex | Location | Size (cm) | IHC (+) | IHC (−) | Molecular findings | Treatment | Local recurrence(s), postresection (mo) | Metastases, postresection (mo) | Disease status (mo) | Secondary genomic alterations and CNV | Reference |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 49/F | Foot, right forefoot | 3.3 (LR 5.2) | EMA, YAP1 (N terminus) | MUC4, CK AE1/AE3, INI-1 (retained), desmin, S100 protein, SMA, betacatenin, CD34, GLUT1 | YAP1(ex4)::KMT2A(ex4) and KMT2A(ex6)::YAP1(ex7) | Multiple foot surgeries (11 per patient), including right mid-foot amputation | Multiple (latest, 158) | N/A | ANED (170) | Numerous CNV, FLT4 amplification, TMB: 4 mut/Mb | Current series |
| 2 | 27/M | Back, paraspinal T3 to T7/8 | 10.9 | EMA, CD99 (cytoplasmic), CD68 (focal) | MUC4, SMA, desmin, S100 protein, claudin 1, GLUT1, SS18-SSX, CD34, STAT6, ALK, C-Kit, HMB45, myogenin, CK, betacatenin | YAP1(ex6)::KMT2A(ex4) and KMT2A(ex6)::YAP1(ex9) | Preoperative RT, wide local excision | N/A | N/A | ANED (1) | Rare CNV | Current series |
| 3 | 16/M | Thigh, left | 8.5 | CD99 (diffuse, membranous), cyclin D1 (focal, weak) | CK cocktail, EMA, S100 protein, SOX10, desmin, myogenin, synaptophysin, CD43, CD45, TdT, CD3, CD20, CD163, CD68, CD34, lysozyme, MPO, CD117, ERG, WT1, TLE1, BCL6, SATB2, INI-1 (retained) | FISH FUS and EWSR1: negative; NGS: YAP1(ex4)::KMT2A(ex6) and KMT2A(ex6)::YAP1(ex7) | Neoadjuvant chemotherapy, radical resection, adjuvant chemotherapy, whole lung irradiation, CAR-T therapy, lung wedge resections | N/A | Lung (0), posterior mediastinum (13), widespread pleural disease (14) | DOD (26) | Numerous CNV, VUS: TAP2 p.L234Q | Current series |
| 4 | 42/M | Thigh, subcutaneous | 3.0 | Vimentin, cyclin D1, YAP1 (N terminus), SMA, calponin | EMA, CD34, MUC4, CK AE1/AE3, S100 protein, NF, NKX3.1, ERG, CK5, desmin, CD31, STAT6, caldesmon, TLE1, betacatenin | FISH EWSR1: negative; NGS: YAP1(ex4)::KMT2A(ex5) | Resection with positive margins | N/A | N/A | N/A | Flat CNV, APC p.I1307K | Current series |
| 5 | 55/F | Posterior mediastinum displacing great vessels and heart | 7.1 | N/A | N/A | YAP1::KMT2A and KMT2A::YAP1 | Debulking, chemotherapy, and radiation without response, hospice care | N/A | N/A | N/A | Numerous CNV, losses in SMARCB1, CHEK2, NF2, PTEN, SUFU | Current series |
| 6 | 24/M | Abdominal wall, subcutaneous | 0.7 | YAP1 (C terminus), CD34 | EMA, SOX10, SMA, desmin, GLUT1 | YAP1(ex4)::KMT2A(ex5) and YAP1(ex3)::KMT2A(ex5) | Excision, fragmented | N/A | N/A | N/A | N/A | Current series |
| 7 | 64/M | Thigh | 6.0 | YAP1 (C terminus), EMA, MDM2 (focal), CD99 (focal), GLUT1 | CK AE1/AE3, S100 protein, CD34, SMA, desmin, caldesmon, MUC4, STAT6, ERG, ETV4, SS18-SSX | YAP1(ex6)::KMT2A(ex4) and YAP1(ex4)::KMT2A(ex4) | Resection, adjuvant radiotherapy | N/A | Lung (98) | AWD (98) | N/A | Current series |
| 8 | 74/M | Chest wall, infraclavicular region, subcutaneous | N/A | EMA (focal), S100 protein (focal), CD34 (focal) | CK AE1/AE3, SOX10, pan-TRK, CD31, ERG, desmin, GLUT1 | YAP1(ex4)::KMT2A(ex5) | Excision with a focally positive margin | N/A | N/A | N/A | N/A | Current series |
| 9 | 18/M | Elbow | 4.2 | N/A | MUC4 | YAP1 (ex5)::KMT2A (ex4) | Resection | LR (30) | N/A | AWD (30) | N/A | Current series |
| 10 | 22/M | Foot | 4.5 | N/A | N/A | YAP1(ex5)::KMT2A(ex4) | Resection, re-excision of local recurrence | LR (26) | N/A | AWD (26) | N/A | Current series |
| 11 | 31/F | Axilla | 1.8 | EMA | N/A | YAP1(ex4)::KMT2A(ex5) | Resection | N/A | N/A | ANED (15) | N/A | Current series |
| 12 | 25/F | Left upper arm | 2.2 | EMA | N/A | YAP1(ex5)::KMT2A(ex5) | Resection | N/A | N/A | N/A | N/A | Current series |
| 13 | 35/F | Buttock | N/A | N/A | N/A | YAP1(ex4)::KMT2A(ex5) | Resection | N/A | Lung and pleura (108) | AWD (108) | N/A | Current series |
| 14 | 43/F | Chest wall | 6.5 | N/A | N/A | YAP1(ex5)::KMT2A(ex4) | Resection, radiation, palliative chemotherapy | N/A | Lung (24) | AWD (24) | N/A | Current series |
| 15 | 34/F | Buttock | N/A | EMA (focal) | MUC4, pankeratin, S100 protein, SOX10, CD34, CD31, desmin, MART1, SSX, SS18-SSX, SMA, HMB45 | YAP1::KMT2A::YAP1 | N/A | N/A | N/A | N/A | Several CNV | Current series |
| 16 | 62/M | Axilla, right | 5.5 | N/A | MUC4, desmin, S100 protein, SMA, SOX10, CK AE1/AE3, CAM5.2, STAT6, HMB45, MDM2 | YAP1::KMT2A | Resection, adjuvant radiotherapy | No | No | ANED (35) | Numerous CNV, homozygous deletion CDKN2A, loss of FOXP1 | Current series |
| 17 | 31/F | Bone, arising from left superior acetabulum with soft tissue component | 13.1 | CK AE1/AE3 (rare) | CAM5.2, S100 protein, SOX10, CD34, ERG, CD31, desmin, MyoD1, STAT6, MUC4, DUC4 | YAP1::KMT2A::YAP1 | N/A | N/A | Lung (0) | N/A | Numerous CNV, losses on BRCA1, BCL2, SETD1 | Current series |
| 18 | 46/M | Shoulder, right | 9.5 | EMA, vimentin | MUC4, pankeratin, CAM5.2, calretinin, CD30, CD31, CD34, CD68, desmin, Melan-A, MITF, S100 protein, SMA, WT-1 | YAP1::KMT2A | N/A | N/A | N/A | N/A | Numerous CNV, chromothripsis chr10, losses in chr11, loss AR1D1 | Current series |
| 19 | 32/M | Back, right posterior | 13.5 | Vimentin, BCL2 | CD34, SMA, MSA, desmin, CK AE1/AE3, S100 protein, STAT6, MUC4, MDM2, EMA | YAP1(ex5)::KMT2A(ex4) | Neoadjuvant chemotherapy with adriamycin, resection, adjuvant chemotherapy | No | Lung (24) | AWD (24) | N/A | Current series |
| 20 | 47/M | Left arm, subcutaneous | 3.1 | YAP1 (N terminus), EMA (focal) | MUC4, GLUT1, S100 protein, SMA, SOX10, desmin, STAT6 | YAP1::KMT2A and KMT2A::YAP1 | Neoadjuvant radiation, wide local excision with focally positive margin, re-excision with clear margins | N/A | N/A | ANED (5) | N/A | Current series |
| 21 | 41/F | Abdominal wall, rectus abdominis | 8.0 | EMA (diffuse), CD34 (heterogeneous, weak) | STAT6, LEF1, S100 protein, pankeratin, desmin, ER, GLUT1, MUC4, SMA, betacatenin | YAP1(ex6)::KMT2A(ex4) | Marginal resection | N/A | N/A | ANED (4) | None, TMB: 0 mut/Mb | Current series |
| 22 | 75/M | Soft tissue, left sciatic foramen with extension into pelvis and gluteal muscles | 17.4 | CD99 (diffuse) | MUC4, CK AE1/AE3, desmin, SMA, S100 protein, CD34, STAT6 and CD45 | FISH KMT2A: Positive; FISH EWSR1 and FUS: negative; NGS: YAP1(ex5)::KMT2A(ex4) and KMT2A(ex6)::YAP1(ex9) | Chemotherapy (doxorubicin, trabectedin) | N/A | Lungs, bone, and soft tissue (0) | AWD (5) | Several CNV | Current series |
| Previously reported sarcomas with NGS confirmation of YAP1::KMT2A fusion | ||||||||||||
| 23 | 35/F | Chest wall | N/A | N/A | N/A | YAP1::KMT2A | N/A | N/A | N/A | N/A | N/A | [16] |
| 24 | 20/F | Thigh, right proximal | 8.5 | EMA (focal), CD34 (focal), CD31 (focal), ERG (focal), YAP1 (N terminus) | CK AE1/AE3, S100 protein, SMA, desmin, myogenin, STAT6, WT1, BCOR, NKX2.2, MUC4, YAP1 (C terminus), INI-1 (retained) | YAP1(ex5)::KMT2A(ex4) | Resection, adjuvant chemotherapy | N/A | Lungs, pleura, and thoracic vertebra (N/A) | DOD (24) | N/A | [17] |
| 25 | 45/F | Paraspinal, deep | 2.6 | N/A | N/A | YAP1(ex5)::KMT2A(ex4) and KMT2A(ex6)::YAP1(ex9) | Piecemeal excision, neoadjuvant radiation, and resection of LR | LR1 (12) | N/A | AWD (12) | N/A | [18] |
| 26 | 45/F | Thigh, subcutaneous | 3.4 | N/A | N/A | YAP1(ex4)::KMT2A(ex5) and KMT2A(ex5)::YAP1(ex9) | Resection | N/A | Soft tissue (18) | AWD (18) | N/A | [18] |
| 27 | 47/M | Lower leg, intramuscular | 2.0 | N/A | N/A | YAP1(ex5)::KMT2A(ex4) and KMT2A(ex6)::YAP1(ex9) | Resection | LR1 (120), LR2 (204), LR3 (252) | N/A | AWD (252) | N/A | [18] |
| 28 | 42/M | Thigh, subcutaneous | 2.5 | N/A | N/A | YAP1(ex5)::KMT2A(ex4) | N/A | N/A | N/A | N/A | N/A | [18] |
| 29 | 22/M | Neck/paraspinal, deep | 8.0 | N/A | N/A | KMT2A(ex6)::YAP1(ex9) | Unresectable, chemotherapy | N/A | N/A | AWD (12) | N/A | [18] |
| 30 | 91/F | Finger, subcutaneous | 2.5 | EMA | MUC4 | YAP1(ex6)::KMT2A(ex5) and KMT2A(ex6)::YAP1(ex9) | Marginal resection | N/A | N/A | DUOC (80) | N/A | [3] |
| 31 | 11/M | Supraclavicular fossa, subcutaneous | 5.0 | EMA | MUC4 | FISH KMT2A: negative; NGS: YAP1(ex5)::KMT2A(ex4) and KMT2A(ex6)::YAP1(ex9) | Marginal resection, resection of local recurrence | LR1 (111) | N/A | ANED (321) | N/A | [3] |
| 32 | 16/F | Heel/ankle, deep | 3.0 | EMA | MUC4 | FISH KMT2A: Positive; NGS: YAP1(ex3)::KMT2A(ex5) and KMT2A(ex6)::YAP1(ex8) | Marginal resection, radiation, amputation after 4th LR | LR1 (7), LR2 (13), LR3 (77), LR4 (149) | N/A | ANED (184) | N/A | [3] |
| 33 | 53/M | Foot, deep | 8.2 | EMA | MUC4 | FISH KMT2A: Positive; NGS: YAP1(ex5)::KMT2A(ex4) and KMT2A(ex6)::YAP1(ex9) | Amputation, chemotherapy | N/A | Inguinal and iliac lymph nodes, lungs (4) | DOD (23) | N/A | [3] |
| 34 | 69/M | Chest wall, deep | 6.5 | EMA | MUC4 | KMT2A(ex6)::YAP1(ex9) | Marginal resection | N/A | N/A | ANED (11) | N/A | [3] |
| 35 | 51/F | Thigh, subcutaneous | 4.0 | EMA | MUC4 | YAP1(ex4)::KMT2A(ex5) and KMT2A(ex6)::YAP1(ex9) | Marginal resection | N/A | N/A | N/A | N/A | [3] |
| 36 | 34/F | Thigh, subcutaneous | 3.0 | EMA | MUC4 | YAP1(ex4)::KMT2A(ex5) and KMT2A(ex6)::YAP1(ex9) | Marginal resection | N/A | N/A | N/A | N/A | [3] |
| 37 | 42/F | Abdomen, left upper quadrant | 13.0 | Cyclin D1, SMA | MUC4, ERG, CD34, S100 protein, desmin, STAT6, CD45, MDM2, CDK4, ALK, ROS1 | KMT2A(ex6)::YAP1(ex9) | Palliative radiation | N/A | Peritoneal metastases (0) | DOD (7) | None | [13] |
| 38 | 35/F | N/A | N/A | N/A | N/A | YAP1(ex5)::KMT2A(ex4) and KMT2A(ex6)::YAP1(ex9) | N/A | N/A | Lung* | N/A | CDKN2A homozygous loss, STAG2 p.R953, PTEN p.D92N, PASK c.3814 + 1G > A | [13] |
| 39 | 60/F | Abdomen | N/A | N/A | N/A | YAP1(ex5)::KMT2A(ex4) and KMT2A(ex6)::YAP1(ex9) | N/A | N/A | N/A | N/A | None | [13] |
| 40 | 31/F | Retroperitoneum | N/A | N/A | N/A | YAP1(ex5)::KMT2A(ex4) and KMT2A(ex6)::YAP1(ex9) | N/A | N/A | N/A | N/A | RB1 homozygous loss | [13] |
| 41 | 66/F | Scalp | N/A | N/A | N/A | YAP1(ex5)::KMT2A(ex4) and KMT2A(ex6)::YAP1(ex9) | N/A | N/A | N/A | N/A | Homozygous loss of CDKN2A and CD58 | [13] |
| 42 | 47/M | Chest | N/A | N/A | N/A | YAP1(ex5)::KMT2A(ex4) and KMT2A(ex6)::YAP1(ex9) | N/A | N/A | N/A | N/A | CDKN2A homozygous loss | [13] |
| 43 | 63/F | Abdomen | N/A | N/A | N/A | YAP1(ex5)::KMT2A(ex4) and KMT2A(ex6)::YAP1(ex9) | N/A | N/A | N/A | N/A | Amplification of MDM2 and PMI1, CDKN2A homozygous loss | [13] |
| 44 | 33/M | Back | N/A | N/A | N/A | YAP1(ex5)::KMT2A(ex4) and KMT2A(ex6)::YAP1(ex9) | N/A | N/A | Right axilla* | N/A | None | [13] |
| 45 | 29/M | Leg, right | N/A | N/A | N/A | YAP1(ex5)::KMT2A(ex4) and KMT2A(ex6)::YAP1(ex9) | N/A | N/A | Thoracic spine* | N/A | CDKN2A homozygous loss, FLCN p.W306 | [13] |
| 46 | 32/F | Thigh, left | N/A | N/A | N/A | YAP1(ex5)::KMT2A(ex4) and KMT2A(ex6)::YAP1(ex9) | N/A | N/A | N/A | N/A | Amplification of MDM4, IKBKE, and MCL1 | [13] |
| 47 | 20/F | N/A | N/A | N/A | N/A | YAP1(ex5)::KMT2A(ex4) and KMT2A(ex6)::YAP1(ex9) | N/A | N/A | Pleura* | N/A | CDKN2A homozygous loss, ZNF703 amplification | [13] |
| 48 | 64/F | Hand, left | N/A | N/A | N/A | YAP1(ex5)::KMT2A(ex4) and KMT2A(ex6)::YAP1(ex9) | N/A | N/A | Lung* | N/A | CD36 p.V263fs*16 | [13] |
| 49 | 38/M | Hip, left | N/A | N/A | N/A | YAP1(ex5)::KMT2A(ex4) and KMT2A(ex6)::YAP1(ex9) | N/A | N/A | Pleura* | N/A | CDKN2A homozygous loss | [13] |
| 50 | 30/F | Peritoneum | N/A | N/A | N/A | YAP1(ex5)::KMT2A(ex4) and KMT2A(ex6)::YAP1(ex9) | N/A | N/A | Right shoulder* | N/A | Homozygous loss of CDKN2A and RB1, ATR duplication intron 15-exon 20 | [13] |
| 51 | 54/M | Buttock, right | N/A | N/A | N/A | YAP1(ex3)::KMT2A(ex5) and KMT2A(ex6)::YAP1(ex5) | N/A | N/A | Lung* | N/A | None | [13] |
| 52 | 52/M | Buttock, right | N/A | N/A | N/A | YAP1(ex3)::KMT2A(ex5) and KMT2A(ex6)::YAP1(ex5) | N/A | N/A | Lung* | N/A | Amplification of MDM2 and FRS2 | [13] |
| 53 | 26/M | Thigh, left vastus lateralis | 13.3 | N/A | N/A | YAP1::KMT2A | N/A | N/A | Lung (<1) | AWD (10) | N/A | [6] |
| 54 | 9/F | Retroperitoneum | 7.0 | N/A | N/A | YAP1::KMT2A | Resection | LR1 (178) | Lung and liver (192), brain, bone, and soft tissue (243) | AWD (264) | N/A | [6] |
| 55 | 31/M | Chest wall, subcutaneous | 11.0 | Vimentin | N/A | YAP1(ex5)::KMT2A(ex4) and KMT2A(ex6)::YAP1(ex9) | N/A | N/A | Lung (15) | DOD (31) | N/A | [19] |
ANED alive with no evidence of disease, AWD alive with disease, chr chromosome, cm centimeter, CNV copy number variant, DOD died of disease, DUOC died of unknown other cause, ex exon, F female, FISH fluorescence in-situ hybridization, IHC immunohistochemistry, LR local recurrence, M male, Mb megabase, mo months, mut mutation, N/A not applicable, NGS next-generation sequencing, No. number, RT radiation therapy, TMB tumor mutational burden, VUS variant of undetermined significance, y years
Presumed metastatic site as sequenced tumor site is different from primary location
Age and sex distribution
Thirteen patients were male and nine were female with a M:F ratio of 1.4:1. The patients had a median age at first histologic diagnosis of 38 years (range 16 to 75 years).
Tumor location
Most cases involved somatic soft tissue (n = 21), including subcutaneous and deep locations, with a wide anatomic distribution, including the lower extremity (5), upper extremity (4), buttock (3), back/paraspinal region (2), abdomen (2), axilla (2), chest wall (2), and posterior mediastinum (1). A single case arose as a bone primary, presenting as a destructive mass involving the left superior acetabulum (Fig. 1).
Fig. 1.
Anatomic distribution. YAP1::KMT2A-rearranged sarcoma has a wide anatomic distribution. Case 5 is a 55-year-old man who was found to have a large posterior mediastinal mass displacing the great vessels and heart (A: CT scan, coronal view). Case 3 is a 16-year-old boy who had a left thigh mass encasing his femoral artery and vein (B: MRI, T2-weighted with contrast, axial view). Case 17 is a 31-year-old woman who was found to have a primary bone tumor arising from the left superior acetabulum with soft tissue extension (C: CT scan, coronal view)
Clinical presentation
Most patients presented with a palpable mass, which was reportedly present for variable amounts of time, ranging from 1 month to 20 years (case 8), prior to the initial diagnosis. Multiple patients reported a mass for several years duration but did not seek care until the lesion became painful (case 4, case 8). Similarly, several patients received a benign diagnosis on initial pathology; it was not until the tumor recurred that a sarcoma was suspected. Patient 1 was originally thought to have plantar fibromatosis of the right forefoot and had undergone multiple foot surgeries for recurrent disease before ultimately undergoing a right midfoot amputation for complete control with final diagnosis confirmation. Similarly, case 5 had undergone prior surgery for a “schwannoma” in another country for which pathology was unavailable for review. Case 13 had previously undergone a resection of a soft tissue gluteal mass nine years prior, which was reportedly diagnosed as a “fibrous histiocytoma.” Slides from the original resection were unavailable for review. A single patient (case 21) presented at 24 weeks gestation. Case 22 had a lesion involving the left sciatic foramen and reported several years of lower back and buttock pain, which had worsened in the past 6 months, along with difficulty urinating, constipation, and unintentional weight loss of 15 pounds despite undergoing a L4–5 laminectomy without relief.
Tumor size
Primary tumor size (maximum diameter) was available in 19 cases. The median tumor size was 6.0 cm (range 0.7 to 17.4 cm).
Histologic findings
Low power examination of the YAP1::KMT2A-rearranged sarcomas in our cohort revealed variable growth patterns. While most cases appeared circumscribed at first glance, partially infiltrative borders were often noted (Fig. 2A, case 4; Fig. 2B, case 20). The infiltrative borders ranged from subtle to prominent with the latter resulting in diffuse involvement of the subcutaneous adipose tissue with a honeycomb-like growth pattern (Fig. 2C, case 8). Perineurioma-like and fibroma-like areas were frequently observed. The former showed bland spindled cells arranged in a whorled or loose storiform pattern (Fig. 2D, case 20). The background stroma in these areas was predominantly collagenous (Fig. 2E, case 15), and the cells exhibited elongated and tapered nuclei (Fig. 2F, case 20). The fibroma-like areas had sparse ovoid cells with euchromatic nuclei and indistinct cytoplasm deposited in a densely sclerotic background (Fig. 3A, case 4). Occasionally, a transition to more cellular and overtly malignant histology was observed in tumors with fibroma-like features (Fig. 3B, case 7; Fig. 3C, case 8). Focal areas with fascicular architecture were also noted (Fig. 3D, case 8). All tumors had at least focal areas closely resembling conventional SEF, composed of plump epithelioid cells arranged in cords and surrounded by fibrous stroma (Fig. 3E, case 7), while some had areas with back-to-back round cells with more obscured stroma (Fig. 3F, case 3). Mitotic activity was variable but often inconspicuous in the less cellular areas. A few cases had small areas of necrosis; however, cases with prominent curvilinear blood vessels and/or hyalinizing rosettes were not identified in our series.
Fig. 2.
Histologic findings. YAP1::KMT2A-rearranged sarcomas were usually somewhat circumscribed tumors with subtle to prominently infiltrative borders (A, case 4; B, case 20). The latter resulted in diffuse involvement of adipose tissue in a honeycomb-like growth pattern (C, case 8). Some tumors had bland spindle cells with a whorled or loose storiform pattern, reminiscent of perineurioma (D, case 20) with collagenous stroma (E, case 15), and elongated/tapered nuclei (F, case 20)
Fig. 3.
Additional histologic findings. A subset of tumors had hypocellular, fibroma-like areas (A, case 4), mimicking a benign tumor. Frequently, areas transitioning to increased cellularity with more evident cytologic atypia were present (B, case 7; C, case 8). Focal areas with fascicular architecture (D, case 8) and areas reminiscent of conventional SEF (E, case 7) were present. In more cellular lesions, the cells were often back-to-back, obscuring the stroma (F, case 3)
Immunohistochemical findings
All tested cases were positive for YAP1 (5/5), including antibodies directed at the N- and C-terminus. Most cases were positive for EMA (10/14). Rare to focal staining was also observed with CD34 (3/13), SMA (1/12), CK AE1/AE3 (1/13), MDM2 (1/3), GLUT1 (1/7), and S100 protein (1/14). All tested cases were negative for MUC4 (0/13), desmin (0/15), STAT6 (0/9), SOX10 (0/7), ERG (0/5), CD31 (0/5), CAM5.2 (0/3), myogenin (0/2), and claudin-1 (0/1). INI-1 demonstrated retained nuclear expression in all tested cases (2/2). All control slides stained appropriately. The immunohistochemical profile of case 1 is provided in Fig. 4.
Fig. 4.
Immunohistochemical findings. In case 1, immunohistochemical stains show that the tumor cells are positive for YAP1 N-terminus (A) and EMA (B), while they are negative for MUC4 (C) and GLUT1 (D). All control slides stained appropriately
Molecular genetic findings
All cases included in this series had NGS-confirmed YAP1::KMT2A gene fusions. Gene rearrangements involving either EWSR1 or FUS were not detected in any case.
Both YAP1::KMT2A and reciprocal KMT2A::YAP1 fusions were frequently detected. Among the 16 YAP1::KMT2A fusions with known breakpoints, the fusions involved exons 4–6 of YAP1 and exons 4–6 of KMT2A. The most common fusion was YAP1(ex5)::KMT2A(ex4) in five cases and YAP1(ex4)::KMT2A(ex5) in five cases, followed by YAP1(ex6)::KMT2A(ex4) in three cases, YAP1(ex4)::KMT2A(ex4) in one case, YAP1(ex4)::KMT2A(ex6) in one case, and YAP1(ex5)::KMT2A(ex5) in one case. Among the six KMT2A::YAP1 reciprocal fusions with known breakpoints, the fusions involved exons 3–4 and 6 of KMT2A and exons 4–5, 7, and 9 of YAP1. The most common fusion was KMT2A(ex6)::YAP1(ex9) in two cases and KMT2A(ex6)::YAP1(ex7) in two cases, followed by KMT2A(ex3)::YAP1(ex5) in one case, and KMT2A(ex4)::YAP1(ex4) in one case.
Discordance between FISH and NGS was observed in several cases. In case 22, a KMT2A gene rearrangement was detected by FISH; however, NGS performed with a sarcoma targeted gene fusion/rearrangement panel failed to detect any fusions. The YAP1::KMT2A fusion was later confirmed with whole exome sequencing. Similarly, case 4 initially underwent testing with a sarcoma targeted gene fusion/rearrangement panel, which was also negative. Subsequent testing with a more extensive panel detected the fusion.
DNA methylation analysis showed that all 11 cases of YAP1::KMT2A-rearranged sarcoma with available and evaluable DNA formed a distinct cluster which was clearly separate from both conventional SEF and LGFMS (Fig. 5).
Fig. 5.
DNA methylation analysis. YAP1::KMT2A-rearranged sarcomas clustered together in a pure and distinct cluster, separate from both conventional SEF and LGFMS
Clinical outcome
Clinical follow-up information was available in 14 patients with a median follow-up of 25 months (range 1 to 170 months). Local recurrences occurred in three patients (21%) at a median of 30 months (range 26 to 158 months). Case 1 had multiple local recurrences requiring re-excision and multiple surgeries. Metastases developed in seven patients (50%) with a median of 24 months (range 0 to 108 months). Sites involved by metastatic disease included the lungs (7), pleura (2), posterior mediastinum (1), bone (1), and soft tissue (1).
Seven patients were alive with disease (50%) at a median of 26 months (range 5 to 108 months), six patients were alive with no evidence of disease (43%) at a median of 10 months (range 1 to 170 months), and one patient died of disease after 26 months. The overall survival curve comparing YAP1::KMT2A-rearranged sarcomas to survival curves from previously published series of both conventional LGFMS [5] and SEF [6] is shown in Fig. 6.
Fig. 6.
Overall survival. The overall survival of patients with YAP1::KMT2A-rearranged sarcoma is shown in comparison to patients with conventional SEF [6] and LGFMS [5]. A log-rank (Mantel-Cox) test comparing the three survival curves showed that the survival curves are significantly different (p = 0.0011)
No definitive relationship between histologic features, fusion type, CNV, and secondary alterations was identified.
Discussion
KMT2A (lysine methyltransferase 2A), formerly known as MLL (mixed-lineage leukemia), is a transcriptional coactivator that methylates histone H3 lysine K4 (H3K4), thereby increasing genome accessibility and transcription [7, 8]. While gene fusions involving KMT2A were initially described in a subset (5–10%) of patients with acute leukemia and associated with poor prognosis [9], they are now known to occur in several neoplasms, including thymoma [10, 11], neuroblastoma [12], and a small subset (< 1%) of sarcomas [13]. Tumors showing KMT2A fusions with YAP1 characteristically demonstrate SEF-like morphology, while those with VIM are composed of cellular fascicles of uniform spindle cells with little resemblance to SEF [14]. Furthermore, KMT2A-rearranged sarcomas with non-YAP1 and non-VIM fusion partners display widely variant differentiation and behavior ranging from atypical lipomatous tumor to adult-type fibrosarcoma [13, 15]. While sarcomas with KMT2A rearrangements appear to represent a heterogeneous group of tumors, YAP1::KMT2A-rearranged sarcomas have emerged as a group with distinct and reproducible histologic features. Early reports of YAP1::KMT2A-rearranged sarcoma, dating back to as early as 2018, were initially classified as sclerosing fibrosarcoma, MUC4-negative SEF, and “tumor within the morphologic spectrum of LGFMS and SEF” [3, 6, 13, 16–19].
As we show in our series, there is a significant morphologic overlap between conventional SEF, hybrid LGFMS/SEF, and YAP1::KMT2A-rearranged sarcomas. However, subtle histologic differences have become apparent. YAP1::KMT2A-rearranged sarcomas lack alternating fibrous and myxoid zones, myxoid areas with a prominent vascular network, and giant collagenous rosettes. Furthermore, they are immunohistochemically negative for MUC4 and are epigenetically distinct from conventional SEF and LGFMS. These results support previous gene expression data, which revealed that YAP1::KMT2A-rearranged sarcomas cluster separately from both conventional SEF and LGFMS [3]. Taken together, these findings all support that YAP1::KMT2A-rearranged sarcomas represent a unique tumor subtype.
As emphasized in some of the earliest reported cases, YAP1::KMT2A-rearranged sarcomas tend to occur in young adults. The age distribution of all genetically confirmed cases reported to date (n = 55), included in Table 1, is shown in comparison to large previously published series of both conventional LGFMS (n = 33) [5] and SEF (n = 49) [6] in Fig. 7. All three sarcomas can affect a broad age range of patients; however, their peak incidence occurs in different decades. LGFMS has the youngest median age of 29 years (range 6 to 52 years), followed by YAP1::KMT2A-rearranged sarcoma with a median of 35 years (range 9 to 91 years), and conventional SEF with a median of 45 years (range 4 to 78 years). YAP1::KMT2A-rearranged sarcoma has an almost equal sex distribution (27 M:28 F), while both conventional LGFMS and SEF seem to have a slight male predominance (19 M:14 F and 29 M:20 F, respectively).
Fig. 7.
Age distribution. Among the total of 55 cases of genetically confirmed YAP1::KMT2A-rearranged sarcoma reported to date, including our series of 22 cases and all previously reported cases, the overall median age at first diagnosis was 35 years (range 9 to 91 years). This median age is lower than that seen in a previously published series of conventional SEF with a median age of 45 years (range 4 to 78 years) [6], while it is higher than that seen in a previously published series of conventional LGFMS with a median age of 29 years (range 6 to 52 years) [5]
An important feature of YAP1::KMT2A-rearranged sarcomas is their potential to mimic benign tumors, both clinically and morphologically. Several patients had a long latency before reaching an accurate diagnosis due to delayed presentation or incorrect initial histologic interpretation. As a subset of these sarcomas contain bland hypocellular “fibroma”-like areas with dense fibrosis and thick collagen bundles, the differential may include benign entities such as fibromatosis or cellular dermatofibroma. Careful histologic examination with attention to growth pattern and cytology is helpful and will often reveal a combination of infiltrative borders, at least mild cytologic atypia, and/or transition to increased cellularity or epithelioid features. If not readily recognized on the initial resection, the inevitable malignant behavior of the tumor, often with multiple local recurrences exhibiting increased cellularity, will further help to identify the tumor as a bona fide sarcoma. This pitfall is less likely to occur in conventional SEF, where only minor ‘fibroma’-like areas are present, often comprising 10% or less of the tumor [6].
With cases demonstrating bland spindle cells with tapered nuclei in a whorled or loose storiform pattern, in combination with variable expression of CD34 and EMA, perineurioma and dermatofibrosarcoma protuberans (DFSP) also enter the differential diagnosis. While perineuriomas can involve the deep soft tissue, they more commonly arise in the subcutaneous tissue; DFSP exclusively arises above the fascia. While the infiltrative growth pattern recognized in a subset of YAP1::KMT2A sarcomas closely resembles that of DFSP, it argues against perineurioma which is typically well circumscribed. Additional immunohistochemical work-up with GLUT1 may be helpful if perineurioma is a consideration as most cases of YAP1::KMT2A-rearranged sarcoma are negative for this perineurial marker. When needed, molecular testing can easily distinguish among these mesenchymal lesions.
In this study, we report the first confirmed case of a YAP1::KMT2A-rearranged sarcoma to originate from inside bone. The primary diagnostic consideration for bone primaries would be conventional SEF, which can be excluded with MUC4 immunohistochemistry [20]. Conventional osteosarcoma could also enter the differential diagnosis as the densely sclerotic stroma of YAP1::KMT2A-rearranged sarcomas may mimic osteoid formation. In these cases, molecular testing performed on non-decalcified material would be essential to reach a correct diagnosis.
In challenging cases requiring molecular confirmation of a YAP1::KMT2A fusion, the method of testing is important. YAP1::KMT2A rearrangements can be cryptic and difficult to pick up by fluorescence in-situ hybridization (FISH) testing [18]. FISH analyses for KMT2A and/or YAP1 rearrangements can therefore yield false-negative results and sequencing is required to confirm the underlying fusion. The sensitivity of sequencing depends on the approach taken (e.g., targeted vs. whole transcriptome sequencing with full coverage of YAP1 and/or KMT2A). Case 4 and case 22 were initially screened with a targeted sarcoma panel, which had only partial coverage of the YAP1 gene and lacked KMT2A entirely. In both cases, comprehensive sequencing panels and/or whole exome sequencing was able to successfully detect the fusion. Finally, KMT2A is often not included on solid tumor/sarcoma sequencing panels; however, it is frequently found on sequencing panels for hematolymphoid neoplasms. As such, this study also highlights the potential utility of DNA methylation profiling in cases with ambiguous morphology or molecular genetic findings.
Similar to conventional SEF, YAP1::KMT2A-rearranged sarcomas are fully malignant and can follow an aggressive clinical course. Both tumors have a similar rate of local recurrence, ranging from 20 to 30% [6]. However, metastases developed in only half of the patients with YAP1::KMT2A-rearranged sarcomas, compared to a rate of 80% that has been previously reported in SEF [6]. Both sarcomas most frequently metastasize to the lungs, whereas conventional SEF shows an increased propensity to metastasize to bone. A relationship between clinical behavior and pathologic features remains unclear.
Our series, which represents the largest cohort of molecularly confirmed YAP1::KMT2A-rearranged sarcomas to date, supports that these sarcomas are a distinct entity with a unique methylation profile and aggressive behavior including a high propensity for metastasis. We also expand the clinical presentation to include primary origin inside bone. Appropriate selection of molecular testing, including DNA methylation analysis, can help to confirm the diagnosis. Increased awareness of the morphologic variability of these tumors will prevent misclassification of benign entities moving forward.
Acknowledgements
We thank the talented illustrator and graphic designer Fredrik Skarstedt for his expertise.
Funding
This study was supported by the Basel Bone Tumor Reference Centre.
Footnotes
Ethical responsibilities of authors section and compliance with ethical rules This study was approved by the ethical committees and the Institutional Review Boards of the participating institutions.
Conflict of interest The authors declare no competing interests.
Data availability
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Associated Data
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Data Availability Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.