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Original Articles

Sclerosing Epithelioid Fibrosarcoma

A Distinct Sarcoma With Aggressive Features

Warmke, Laura M. MD; Meis, Jeanne M. MD

Author Information
The American Journal of Surgical Pathology: March 2021 - Volume 45 - Issue 3 - p 317-328
doi: 10.1097/PAS.0000000000001559
  • Open

Abstract

Sclerosing epithelioid fibrosarcoma (SEF) is a rare and distinctive deep-seated variant of fibrosarcoma typically occurring in adults. It was initially described in 19951 and its existence subsequently confirmed by others.2–5 The classic histologic features of SEF include nests and cords of uniform small epithelioid cells embedded in a densely sclerotic matrix. Ultrastructural studies have proven its fibroblastic nature replete with a dense collagenous matrix indistinguishable from osteoid.1,6 Minor fibroma or low grade fibromyxoid sarcoma (LGFMS)-like zones, cysts and calcification may be seen in SEF, although they are typically minimal. Recent studies have emphasized the morphologic, immunohistochemical and molecular overlap between SEF and LGFMS,2,7 leading them to conclude these are closely inter-related tumors.

LGFMS, first recognized as a distinct entity by Evans,8 is characterized by bland, whorled fibrous areas with myxoid zones and thin-walled blood vessels. Tumors previously described as “hyalinizing spindle cell tumor with giant rosettes (HSCTGR)” have been shown to be within the morphologic spectrum of LGFMS.9,10 Although the classic histologic picture of LGFMS is distinct, a subset of cases has been shown to have morphologic areas resembling SEF (so-called “hybrid” cases),11–13 and several cases of LGFMS have progressed to a predominant SEF-like morphology in local recurrences and metastases.5

Immunohistochemically, MUC4, a high-molecular weight transmembrane glycoprotein,14 is a sensitive marker demonstrating strong cytoplasmic expression in both LGFMS (99% to 100%) and SEF (at least 78%).15,16 On a molecular level, LGFMS has traditionally demonstrated either the t(7;16) (q32-34;p11) translocation, resulting in FUS-CREB3L2 fusion (96%) or the t(11;16) (p11;p11) translocation resulting in FUS-CREB3L1 fusion (4%).17 In contrast, the most common molecular alteration in SEF is EWSR1-CREB3L1.5,11 Although rearrangements with EWSR1 and CREB3L1 are more common in SEF and rearrangements with FUS and CREB3L2 more common in LGFMS, as with several distinctive sarcomas, molecular heterogeneity exists. Cases of SEF (without recognizable LGFMS-like areas) have shown FUS gene rearrangement by fluorescence in situ hybridization (FISH)4,12; rare cases of SEF have shown EWSR1-CREB3L2 and FUS-CREB3L2 fusions18,19; and at least 2 cases of classic LGFMS, including 1 HSCTGR, have shown EWSR1-CREB3L1 translocation.20 The described molecular alterations have further been expanded to include recurrent YAP1 and KMT2A gene rearrangements in a subset of MUC4-negative SEF.21

Considering the immunohistochemical and molecular overlap of these tumors, the purpose of our study is to re-examine the histologic, clinical, and molecular features of SEF seen at a single institution after its initial description 25 years ago and to reassess whether or not it is truly unique from LGFMS. To this end, we chose to compare the survival of patients with SEF to the survival of a previously published series of patients with LGFMS from the same institution to minimize intrinsic biases in diagnosis, referral, and treatment patterns.

MATERIALS AND METHODS

The histologic slides of cases diagnosed as SEF or potential SEF were retrieved from the files of The University of Texas MD Anderson Cancer Center (MDACC) from January 1998 to March 2020 (81 cases). In all cases, the hematoxylin and eosin-stained slides and immunohistochemical studies performed at the time of diagnosis were reviewed by both authors. Fifty-one cases remained classified as SEF after histologic review. No cases of hybrid SEF-LGFMS were identified or included in this study. All available subsequent biopsies and resection specimens for each case were reviewed. Clinical follow-up information was obtained from electronic medical record review or from the pathologist at the referring institution. Follow-up duration was calculated from the date of first histologic diagnosis.

Immunohistochemical Analysis

All immunohistochemical stains had been previously performed during clinical workup on 4-µm-thick formalin-fixed, paraffin-embedded tissue sections using the streptavidin-biotinylated horseradish peroxidase complex method in a Leica Bond III AutoStainer (Buffalo Grove, IL). The primary antibodies used included vimentin (V9, 1:900; DAKO, Santa Clara, CA), MUC4 (1G8, 1:500; Santa Cruz, Dallas, TX), EMA (GP1.4, 1:600; Leica, Buffalo Grove, IL), CAM5.2 (1:50; BD Bioscience, San Jose, CA), CD99 (12E7, RTU; DAKO), bcl-2 (BCL-2/100/D5, 1:200; Leica), cytokeratin cocktail (AE1/AE3, CAM5.2, MNF116, CK8/18; 1:50, 1:50, 1:50, 1:25; DAKO; BD Bioscience; DAKO; Invitrogen, Carlsbad, CA), CD45 (2B11+PD7/26, 1:300; DAKO), CD20 (L-26, 1:1,400; DAKO), CD3 (Leu-4, 1:100; DAKO), CD34 (QBEND/10, RTU; Leica), S-100 protein (EP32, RTU; Leica), SMA (1A4, 1:80,000; Sigma-Aldrich, St. Louis, MO), desmin (D33, 1:200; DAKO), and SATB2 (CL0276,1:50; Sigma Prestige, St. Louis, MO). Appropriate positive and negative controls were included in each staining run.

Fluorescence In Situ Hybridization

FISH analysis for EWSR1 and FUS genes were carried out in selected cases using EWSR1 (22q12) and FUS (16p11) LSI dual color break-apart DNA probes (Abbott Molecular, Des Plaines, IL) according to the manufacturer’s instructions.

Reverse Transcription Polymerase Chain Reaction and Sequence Analysis

Total RNA extracted from tumor specimens was used to generate targeted-enriched RNA libraries followed by sequencing on the Illumina MiSeq platform. FASTQ files generated by bcl2fastq2 v2.17 are used for read alignment with gene fusion identification and annotation using Archer Analysis pipeline v.5.1. The following fusion-centric metrics define thresholds required for a successful fusion call: ≥3 unique reads supporting the fusion, a fusion allele fraction ≥10% and total coverage by the gene-specific primer (GSP2) used to call fusion of >20 total unique reads (wildtype+fusion supporting reads). In cases 43, 48, and 50, next-generation sequencing was performed using 200 ng of genomic DNA extracted from formalin-fixed, paraffin-embedded tissue sections as previously described.22

Statistical Analysis

Univariate Cox models were used to measure the effects of potential risk factors on overall survival (OS) and metastasis free survival. When the Cox model could not be fitted due to the limited data, the log-rank test was used to evaluate survival differences between different subgroups. The Kaplan-Meier method and log-rank test were used to estimate and compare the OS between SEF patients and LGFMS patients from a prior study from the same institution.11 All statistical analyses were performed using R version 3.6.2.

RESULTS

Detailed information pertaining to the 51 patients is presented in Table 1.

TABLE 1 - Sclerosing Epithelioid Fibrosarcoma: Clinical Features of 51 Cases
Case No. Age (y)/Sex Location Size (cm) Molecular Findings Local Recurrence(s), Postresection (mo) Metastases, Postresection (mo) Follow-up (mo) Disease Status
1 50/female Thigh, right proximal 13.0 NA NA NA 50 DUC
2 48/male Retroperitoneum 14.8 NA NA (R2) Lung (0) 7 AWD
3 55/female Abdominal wall 4.6 NA U U None U
4 38/male Retroperitoneum U NA U U None U
5 25/male Chest wall, left anterior 6.0 NA NA NA 63 NED
6 45/female Thigh, right posterior 10.0 NA NA (never resected) NA 3 DOC
7 59/female Diffuse abdominal disease with ascites NA (sarcomatosis) NA NA (R2) Lung, pleura, lymph node, pericardium and ovaries (0) 7 DOD
8 45/male Paraspinal, right lower back (L4) 8.0 NA NA Lung (72), soft tissue (120) 140 AWD
9 46/male Retroperitoneum 29.0 NA NA (never resected) Lung (0) 83 DOD
10 78/male Retroperitoneum U NA U U None U
11 39/male Leg, left calf 5.0 NA NA NA 120 NED
12 66/male Paraspinal, left lower back (L3) 9.5 NA 48 Bone (57) 62 DOD
13 49/female Thyroid U NA U U None U
14 51/male Neck and C1 vertebra, left 10.0 NA 15 Lung (11) 37 DOD
15 55/female Axilla, right U NA NA Soft tissue and lung (3) 103 DOD
16 60/male Skull, right parietal 8.2 NA U U None U
17 63/male Shoulder, left anterior 10.9 FISH: Negative for SS18 gene rearrangement U U None U
18 44/male Thigh, left lateral 21.0 FISH: Negative for EWSR1 gene rearrangement NA Lung (0) 49 DOD
19 39/male Neck, right posterior 5.3 FISH: EWSR1 inconclusive, preanalytic variables NA (never resected) Lung and soft tissue (1), bone (2), brain (27) 30 DOD
20 51/female Chest wall, left posterior 7.5 FISH: Subpopulation with extra copies of EWSR1 6 Bone (1) 32 DOD
21 30/male Tibia, right proximal 9.0 FISH: Monosomy EWSR1 NA Epidural masses, thoracic and lumbar (17) 24 AWD
22 50/female Chest wall, right U (LR 4.8) FISH: Monosomy EWSR1 81 Lung (97) 99 AWD
23 39/female Thigh, right posterior 15.5 FISH: 3′ deletion EWSR1 NA Lung (139), bone (140) 150 DOD
24 31/male Kidney, left 15.0 FISH: 3′ deletion EWSR1 29 Abdomen (29) 41 AWD
25 52/male Thigh, left 4.0 FISH: 3′ deletion EWSR1 NA Lung (34), soft tissue (48) 80 DOD
26 62/female Abdomen, right anterior with ascites NA FISH: 3′ deletion EWSR1 11 (sarcomatosis) Lung, bone and peritoneum (11) 15 AWD
27 68/male Knee, right posterior 10.0 FISH: EWSR1 gene rearrangement NA Lung and pleura (21) 84 DOD
28 66/female Abdomen, right lower quadrant 4.0 FISH: EWSR1 gene rearrangement NA NA 35 NED
29 59/female Groin, right 7.5 FISH: EWSR1 gene rearrangement NA Lung (13) 29 AWD
30 45/male Mandible, right 5.3 FISH: EWSR1 gene rearrangement NA Bone and lymph node (10) 81 AWD
31 45/male Chest wall, right paraspinal (T9-T11) Two masses: 9.8 and 6.4 FISH: EWSR1 gene rearrangement LR1 (57), LR2 (109) NA 110 AWD
32 19/male Forehead, right U (LR 3.6) FISH: EWSR1 gene rearrangement 20 Lungs and liver (43), bone (57), brain (68) 73 AWD
33 58/female Abdomen, left rectus 8.3 FISH: EWSR1 gene rearrangement NA (residual disease) U 70 DOD
34 25/female Pelvic sidewall, left 13.5 FISH: EWSR1 gene rearrangement 23 Bone (23) 69 DOD
35 28/female Groin, right 8.0 FISH: EWSR1 gene rearrangement NA (never resected) Lung and bone (0) 5 DOD
36 40/female Chest wall/breast, right 4.5 FISH: EWSR1 gene rearrangement NA Bone, liver and soft tissue (0) 19 DOD
37 53/female Thigh, left proximal and lateral 3.2 FISH: Negative for FUS gene rearrangement NA NA 75 NED
38 59/male Flank, right 6.5 FISH: FUS gene rearrangement NA Lung (13) 13 AWD
39 44/male Knee, left posterior 8.4 FISH: FUS gene rearrangement NA Soft tissue (9), shoulder (33), brain (113) 128 AWD
40 35/female Paraspinal, left lumbosacral/gluteal 6.7 FISH: FUS gene rearrangement 32 Soft tissue (78) 92 AWD
41 49/male Thigh, right medial U RT-PCR: Negative for FUS-CREB3L1/2 NA Soft tissue (84), lung (156), T4-T5 paraspinal (180) 216 DOD
42 54/male Stomach, lesser curvature NA (diffuse thickening) RT-PCR: EWSR1-CREB3L1; FISH: 3′ deletion EWSR1 NA (never resected) Liver (2), bone (3) 6 AWD
43 43/male Diffuse abdominal disease with ascites NA (sarcomatosis) RT-PCR: EWSR1-CREB3L1; FISH: Negative for FUS gene rearrangement 3 Lung, pericardium, bone and abdomen/pelvis (9) 16 DOD
44 27/male Chest wall, left anterior 6.2 RT-PCR: EWSR1-CREB3L1; FISH: EWSR1 gene rearrangement NA NA 18 NED
45 43/female Paranasal sinuses, orbit and frontal bone, left 5.0 RT-PCR: EWSR1-CREB3L1; FISH: Negative for EWSR1 gene rearrangement NA (incomplete resection) Bone, lungs, lymph nodes and pancreas (1) 22 DOD
46 17/male Retroperitoneum 22.8 RT-PCR: EWSR1-CREB3L1; FISH: EWSR1 gene rearrangement NA (unresectable) Lung, pancreas, bone, and abdomen/pelvis (0) 40 DOD
47 4/male Kidney, left superior 14.9 RT-PCR: EWSR1-CREB3L1; FISH: 3′ deletion EWSR1 NA Lung and bone (0) 11 AWD
48 24/female Thigh, left lateral 5.6 RT-PCR: EWSR1-CREB3L1 NA Lung (<1), liver and bone (24) 25 AWD
49 22/male Pelvic bone, left 16.2 RT-PCR: EWSR1-CREB3L2; FISH: EWSR1 gene rearrangement NA Lung (138) 181 AWD
50 26/male Thigh, left lateral 13.3 RT-PCR: YAP1-KMT2A NA (never resected) Lung (<1) 10 AWD
51 9/female Retroperitoneum 7.0 RT-PCR: YAP1-KMT2A; FISH: Negative EWSR1 gene rearrangement 178 Lung and liver (192), brain, bone and soft tissue (243) 264 AWD
AWD indicates alive with disease; DOC, died of other causes; DOD, dead of disease; DUC, died unknown causes; FISH, fluorescence in situ hybridization; LR, local recurrence; NA, not applicable; NED, no evidence of disease; R2, gross residual disease; RT-PCR, reverse transcription-polymerase chain reaction; U, unknown.

Age and Sex Distribution

Thirty patients were male and 21 were female. The age distribution is shown in Figure 1; the patients had a median age at first histologic diagnosis of 45 years (range: 4 to 78 y).

FIGURE 1
FIGURE 1:
Among 51 patients with SEF, the median age at first histologic diagnosis was 45 years (range: 4 to 78 y). The median age is higher than that typically seen in LGFMS with a previously published study showing a median age of 29 years (range: 6 to 52 y).11 Both series showed a slight male predominance: 59% (30/51) in SEF and 58% (19/33) in LGFMS.

Tumor Location

The most common primary sites included lower extremity (12), abdomen and visceral organs (9), chest wall/back/paraspinal region (9), retroperitoneum (6), bone (6), head and neck (3), inguinal/groin area (2), upper extremity (1), pelvis/pelvic sidewall (1), flank (1) and axilla (1). The anatomic distribution of the primary tumor sites is presented in Table 2 with selected radiologic imaging presented in Figure 2.

TABLE 2 - SEF and LGFMS: Anatomic Distribution of Primary and Metastatic Sites
Primary Site SEF (n=45), n (%) LGFMS (n=33), n (%) Metastatic Site SEF (n=45), n (%) LGFMS (n=33), n (%)
Lower extremity 12 (27) 6 (18) Lung 26 (58) 15 (45)
Abdomen and visceral organs 9 (20) 5 (15) Bone 17 (38) 2 (6)
Chest wall/back/paraspinal 9 (20) 3 (9) Soft tissue 10 (22) 3 (9)
Retroperitoneum 6 (13) 1 (3) Liver 5 (11) 1 (3)
Bone 6 (13) 0 Brain 4 (9) 0
Head and neck 3 (7) 2 (6) Pleura 3 (7) 2 (6)
Inguinal/groin 2 (4) 4 (12) Lymph node 3 (7) 0
Upper extremity 1 (2) 7 (21) Pericardium 2 (4) 1 (3)
Pelvis/pelvic sidewall 1 (2) 1 (3) Abdomen 2 (4) 0
Flank 1 (2) 0 Pancreas 2 (4) 0
Axilla 1 (2) 1 (3) Ovary 2 (4) 0
Buttock/perineum 0 3 (9) Heart 0 1 (3)
Forty-five cases of SEF had clinical follow-up information. The anatomic distribution of both the primary and metastatic sites was compared with a large series of LGFMS from the same institution. The comparison shows that SEF has a higher propensity for deep soft tissue, periosteal and bone involvement with a higher rate of bone metastasis.

FIGURE 2
FIGURE 2:
SEF has a wide anatomic distribution. Case 32 is a young man who initially presented with a forehead mass that later progressed to widespread metastatic disease with brain involvement as shown in coronal T1-weighted magnetic resonance imaging (A). Selected computed tomography scans illustrate the anatomic distribution with lesions arising in the soft tissue of the neck (B, case 19), retroperitoneum (C, case 9), groin (D, case 29) and anterior chest wall (E, case 44).

Preoperative Duration

The preoperative duration of the tumor varied from <1 month to 12 years in confirmed cases. Two patients reportedly presented with lesions since a very young age, one with a forehead mass since age 4 (case 32) and another with a chest wall mass since age 6 (case 44). Case 39 was clinically noted to have multiple “soft tissue lipomas” since his 20’s including a posterior knee mass which began to rapidly enlarge at age 44. Case 11 had a calf mass that was present for 5 to 6 years and became more prominent after significant weight loss. Case 35 had back pain for 8 months during pregnancy and was found to have a large groin mass during C-section; case 23 noticed a thigh mass 2 years prior which grew significantly during pregnancy. Last, case 29 had a right inguinal mass resected 26 years prior, which was diagnosed as a benign fibrous histiocytoma by a referring institution (slides unavailable for review).

Treatment

Among the 45 patients with clinical follow-up information, 38 underwent resection, 3 underwent re-resection for positive margins, 2 underwent debulking and 2 had supportive care for unresectable disease. Six patients later had resection of local recurrence and 6 underwent metastasectomy. Twenty-five patients underwent radiation involving both primary and metastatic sites; 26 patients received chemotherapy for primary and recurrent lesions with multiple regimens including doxorubicin (24), ifosfamide (23), docetaxel (12), gemcitabine (12), pazopanib (8), vincristine (5), cisplatin (5), cyclophosphamide (4), etoposide (3), and dacarbazine (2). One patient was initially treated with chemotherapy regimen including cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate and prednisione at a referring institution after first being diagnosed with diffuse large B-cell lymphoma (case 12). Patients with widespread disease progressed despite multiple chemotherapy regimens, and several patients underwent investigational therapy.

Tumor Size

Primary tumor size (maximum diameter) was known in 40 cases in which it ranged from 3.2 to 29.0 cm with a median of 8.2 cm. Only 1 tumor measured <3.5 cm (case 37).

Histologic Findings

Typical areas of the tumor demonstrated nests and cords of epithelioid cells with scant clear to pale eosinophilic cytoplasm, stippled chromatin and inconspicuous to small nucleoli. The cells were embedded in a dense fibrous matrix that was variable, ranging from delicate lace-like arrangements simulating osteoid to dense linear strands of collagen to sclerotic zones (Figs. 3, 4). Cellularity was variable, and nuclear pleomorphism was predominantly mild. Minor fibroma or LGFMS-like zones were present in some cases but typically comprised 10% or less of the tumor in each case. Highly cellular areas, overlapping with small cell sarcoma, were seen in several cases. Mitotic activity was generally low with most cases having ≤5 mitotic figures per 10 high-power fields. Two cases had 15 and >20 mitotic figures per 10 high-power fields (case 40 had received intraoperative radiation and case 22 had received radiation for right breast cancer 6 y previously, respectively). Tumor necrosis was noted in 20 cases, predominantly posttreatment, with a range of 5% to 95% (median 15% to 20%).

FIGURE 3
FIGURE 3:
SEF typically demonstrates nests and cords of epithelioid cells with scant clear to eosinophilic cytoplasm in a sclerotic background (A–D, cases 38, 41, 37 and 18, respectively). The nuclei have stippled chromatin with inconspicuous to small nucleoli (B and C). Nuclear atypia is usually mild; however, focal areas can show more pronounced atypia (D and E, cases 18 and 2) and hypercellularity with a small cell appearance (E and F, cases 2 and 14). The collagen deposition can range from being prominent (A, D), thereby simulating an osteosarcoma, to very delicate (C, E, and F).
FIGURE 4
FIGURE 4:
SEF frequently demonstrates variable cellularity with deceptively bland fibroma-like zones (A, case 28), classic areas (B, case 29), and fibrosarcoma-like areas (C, case 29). The architectural pattern may be occasionally nested (D, case 3) or more commonly composed of cords (E, case 44) with focal solid-appearing areas (F, case 24).

Immunohistochemistry

Immunohistochemical staining showed that cases were positive for vimentin (16/16), MUC4 (6/8), EMA (15/29), CAM5.2 (2/8), CD99 (10/13, cytoplasmic) and bcl-2 (5/7), while they were essentially negative for keratin (0/41), CD45 (0/18), CD20 (0/12), CD3 (0/7), CD34 (2/32, focal), S-100 protein (2/38, focal), SMA (2/23, focal) and desmin (0/26). One of 5 cases showed variable weak to moderate staining with SATB2; however, staining was only present in scattered cells.

Molecular Analysis

Twenty-six cases underwent FISH for EWSR1 gene rearrangement with the following results: gene rearrangement (13), 3′ deletion of EWSR1 (6), monosomy for EWSR1 (2), negative (3), inconclusive (1) and extra copies suggestive of aneuploidy (1). Seven cases were confirmed to have EWSR1-CREB3L1 fusion (including 2 cases previously shown to have 3′ EWSR1 deletion and 1 case that was initially negative for EWSR1 gene rearrangement by FISH); 1 case was confirmed to have EWSR1-CREB3L2 fusion. FISH further revealed FUS gene rearrangement in 3 cases, and 2 cases were shown to have YAP1-KMT2A fusion.

Tumor Behavior and Patient Survival

Clinical follow-up information was available in 45 patients with a median follow-up of 49 months (range: 3 to 264 mo). Local recurrence occurred in 12 patients (27%) at a median 26 months (range: 3 to 178 mo). Metastases developed in 36 patients (80%) at a median 10.5 months (range: 0 to 192 mo) to lung (26), bone (17), soft tissue (10), liver (5), brain (4), pleura (3), lymph node (3), pericardium (2), abdomen (2), pancreas (2) and ovary (1). The anatomic distribution of the metastatic sites is presented in Table 2. Several patients survived for a prolonged period with extensive metastatic disease.

An OS curve for the 45 patients with SEF is shown in Figure 5 and compared with another survival curve of 33 patients with LGFMS (previously published) from the same institution. Nineteen patients with SEF were alive with disease (42%) at a median of 41 months (range: 6 to 264 mo), 19 patients were dead of disease (42%) at a median of 49 months (range: 5 to 216 mo), and 5 patients showed no evidence of disease (11%) at a median of 63 months (range: 18 to 120 mo). One patient died of heart failure secondary to trisomy 21 at 3 months (case 6), and 1 died of unknown causes at 50 months (case 1).

FIGURE 5
FIGURE 5:
OS of 45 patients with SEF in comparison to 33 patients with LGFMS.11 Both series are from the same institution and reflect the same biases intrinsic to a cancer treatment center.

Statistical Analysis

None of the following factors were found to significantly affect either metastasis free or OS: patient age, patient sex, tumor location (central vs. peripheral), tumor size, primary location in bone versus soft tissue, intra-abdominal involvement, mitotic rate, and presence versus absence of EWSR1 abnormality. However, metastasis was found to be significantly related to OS (P=0.005).

DISCUSSION

Despite occasional overlapping morphologic and molecular features, SEF is a distinct sarcoma with several unique features distinguishing it from LGFMS. Compared with LGFMS with a median age of 29 years at first histologic diagnosis,11 SEF affects an older age group with a median age of 45 years. While SEF commonly arises in middle-aged adults, this series shows that it can also present in very young patients. Although both LGFMS and SEF can also present with diffuse abdominal disease, this study shows that extensive peritoneal sarcomatosis and visceral organ involvement is more common in SEF. Similar to LGFMS, SEF is well-known to have a wide anatomic distribution, having been described in many sites including the oral/maxillofacial region,23,24 abdomen,25 cecum,26 distal pancreas,27 kidney,28 pelvis,29 ovary,30 and bone31–33; however, unlike LGFMS, it shows a marked propensity to involve periosteal and osseous sites. Furthermore, SEF has a more aggressive clinical course than LGFMS, with a local recurrence rate of 27%, metastatic rate of 80% and overall mortality rate of 47% in this study. It also metastasizes more quickly and extensively than LGFMS, which has local recurrence and metastatic rates of 58% and 45% at median intervals of 3.5 and 5 years, respectively, and a death rate of 42% at a median interval of 15 years.11 Similar to LGFMS, SEF most commonly metastasizes to the lungs; however, it is far more likely to develop widespread osseous metastases (17/45, 38%) compared to LGFMS (2/33, 6%). Increased rates of cranial and bone involvement were also observed.

Although commonly arising in middle-aged adults, this study shows that SEF can present at a younger age than previously reported. Case 24 is a young boy who presented with a SEF of the left kidney at 4 years of age (Fig. 6). Because of the patient’s young age with visceral organ involvement, his tumor was originally diagnosed as a clear cell sarcoma of the kidney at a referring institution. The diagnosis of SEF was later confirmed with EWSR1-CREB3L1 fusion. Similar to SEF, clear cell sarcoma of the kidney is characterized by uniform, small cells with fine chromatin and positivity for vimentin. This case was especially challenging as the patient initially presented with bone metastases typical of clear cell sarcoma, which is also referred to as the “bone metastasizing renal tumor of childhood.” Two additional patients in this study had clinical histories of first noticing a mass at age 4 (case 32) and age 6 (case 44); however, histologic diagnosis was only confirmed years later.

FIGURE 6
FIGURE 6:
The youngest patient (case 47) is a 4-year-old boy who first presented limping with leg pain. Radiologic imaging revealed a right distal femur lesion, which was initially thought to be osteomyelitis (A). Biopsy of the osseous lesion revealed metastatic sarcoma (B), and subsequent computed tomography scan revealed the primary tumor arising from the anterior superior left kidney (C). Before molecular analysis revealed EWSR1-CREB3L1 fusion, the kidney lesion (D) was first diagnosed as clear cell sarcoma at the referring institution.

SEF can further present as diffuse abdominal disease with progressive peritoneal sarcomatosis. Three cases (cases 7, 26, and 43) demonstrated widespread abdominal involvement at initial presentation, and the details of case 43 have been previously published.22 Both genders were affected with an age range of 43 to 62 years, and all 3 patients presented with several months of abdominal fullness before diagnosis. Two patients died of disease between 7 and 16 months, while the third patient is currently undergoing treatment with doxorubicin-based chemotherapy. One additional patient (case 42) was found to have SEF arising in the stomach after presenting with a 2-month history of abdominal pain and upper gastrointestinal bleeding. He was originally thought to have nonsteroidal anti-inflammatory drug-induced gastric ulcers; however, imaging showed circumferential thickening of the gastric body and molecular studies later detected EWSR1-CREB3L1 fusion, confirming the diagnosis in a previously unreported site. These results indicate that SEF is more likely to involve the abdominal cavity and visceral organs than previously thought and fully capable of developing widespread sarcomatosis.

SEF has a propensity to involve bone and is well-known to occur as a primary bone tumor mimicking osteosarcoma. Six cases presented as primary bone lesions (cases 14, 16, 21, 30, 45, and 49) in our series, 5 of which were initially diagnosed as osteosarcoma at the referring institution. When involving bone, SEF can mimic osteosarcoma as its dense collagenous matrix closely simulates tumor osteoid. Focal areas of osseous metaplasia and dystrophic calcification have further been described in SEF, making radiologic correlation more difficult. Distinguishing features of osteosarcoma include more pronounced nuclear atypia, unequivocal lace-like neoplastic bone formation around individual cells with extensive matrix calcification, and strong nuclear positivity for SATB2. Potential pitfalls exist as SEF can occasionally show variable weak-to-moderate expression of SATB2,31 and rare cases of osteosarcoma can express MUC4 in scattered cells. The distinction is especially challenging when dealing with the small cell variant of osteosarcoma, which has demonstrated EWSR1-CREB3L1 fusion34 and may actually represent a primary SEF of bone. Ewing sarcoma is another primary bone tumor that can rarely show sclerotic areas morphologically resembling SEF.35 SEF may demonstrate variably weak positivity for CD99 (nonspecific cytoplasmic) in contrast to the strong membranous staining of Ewing sarcoma, which is also positive for EWSR1 gene rearrangement by FISH; determination of the EWSR1 fusion partner will distinguish between them.

In addition to arising in bone and mimicking osteosarcoma, SEF further tends to involve the periosteum with the ability to extend directly into bone. Its close morphologic similarity to aponeuroses and ability to produce osteoid-like matrix could reflect a close relationship between SEF and the Sharpey fiber–periosteal-endosteal system.36 One patient (case 32) first presented at the young age of 4 with a forehead mass, which was initially thought to be a benign cyst. Although the young age of the patient is unusual, the primary site in the subcutaneous tissue of the forehead has been previously described,6 and at least 2 patients with SEF have had metastases to the scalp.37 Several years later, the mass increased in size and was resected with an original diagnosis of malignant perineurioma/low-grade malignant peripheral nerve sheath tumor at a referring institution. Although SEF can resemble perineurioma with focal expression of EMA, FISH for EWSR1 gene rearrangement will confirm the correct diagnosis. Despite medical therapy, the patient progressed with widely metastatic disease and developed a large right frontal lesion with extensive periosteal involvement (Fig. 2A).

At the molecular level, recurrent YAP1 and KMT2A gene rearrangements have been described in a small subset of SEF.38 Although the majority of SEF cases in our series had EWSR1 rearrangements, 2 cases had confirmed YAP1-KMT2A gene fusions. The first case (case 50) is a 26-year-old male who presented with progressive thigh swelling initially thought to be bursitis. Radiologic imaging later showed a large soft tissue mass involving the left vastus lateralis muscle (Figs. 7A–C). Despite multiple chemotherapy regimens, his disease progressed with bilateral pulmonary metastases. The second case (case 51) is a 9-year-old female who first presented when her mother palpated a retroperitoneal mass, which was subsequently resected and initially thought to be a benign peripheral nerve sheath tumor at the referring institution. Over 14 years later, she developed local recurrence which was treated by radical resection with right nephrectomy and partial hepatectomy. Despite treatment with chemotherapy, she progressed with widespread disease (Figs. 7D–F).

FIGURE 7
FIGURE 7:
Two cases of SEF had documented YAP1-KMT2A gene fusion. The first case (case 49) is a 26-year-old male who presented with an enlarging thigh mass. Axial T2-weighted magnetic resonance imaging showed a heterogenous, lobulated and enhancing solid mass with small areas of hemorrhage and fibrosis arising in the vastus lateralis muscle (A). Biopsy of the mass showed a sclerotic sarcoma (B) with high-grade areas (C). The second case (case 50) is a 9-year-old girl who first presented with a retroperitoneal mass. Follow-up computed tomography scan showed extensive metastatic disease with a large focus involving the right lung (D). Her tumor was composed of monotonous ovoid cells with fine chromatin and small nucleoli in a background of dense collagenous stroma (E and F).

Both tumors were composed of ovoid-to-spindle cells with monotonous nuclei, fine chromatin and small nucleoli. The background stroma was densely collagenous with focal whorled architecture. Immunohistochemical staining for MUC4 was performed on one of the cases and was negative. Both cases affected young patients (<30) and demonstrated an aggressive clinical course. One patient first presented at age 9, somewhat resembling a previously described case of a 10-year-old girl who first presented with a brain tumor with secondary bone erosion.38 Similar to SEF with canonical EWSR1 gene rearrangement, a propensity for metastasis with lung, bone, and brain involvement exists.

With many histologic mimics in addition to sclerotic LGFMS, SEF remains a challenging diagnosis. Recognition of this sarcoma is especially difficult on limited biopsy material as SEF can demonstrate different morphologic patterns with varying degrees of cellularity. Less cellular fibrous areas can mimic benign lesions (eg, initial diagnosis at a referring institution of myositis ossificans in case 5 and hyalinized desmoid tumor in case 33), and cellular areas with a small cell appearance can resemble small cell sarcoma, not otherwise specified, mesenchymal chondrosarcoma (case 46) and Ewing sarcoma (cases 24 and 25). Additional histologic mimics include osteosarcoma, sclerosing variants of both rhabdomyosarcoma and lymphoma, epithelioid leiomyosarcoma (case 41) and metastatic carcinoma (eg, signet ring carcinoma and lobular breast cancer). Immunohistochemistry can help to exclude most mimics as lack of expression for keratin, leukocyte common antigen (CD45) and desmin excludes metastatic carcinoma, sclerosing lymphoma and sclerosing rhabdomyosarcoma,39 respectively.

SEF can clinically be mistaken for metastatic carcinoma when presenting with synchronous bone metastases at the time of diagnosis.33,38 Although SEF is typically negative for keratin, MUC4 is expressed in numerous carcinomas including those arising in the colon, breast, ovary, lung, and pancreas.40–44 In addition, rare cases of myoepithelial carcinomas can show focal reactivity for MUC4,16 and myoepithelial tumors are known to have EWSR1-POU5F1 and EWSR1-PBX1 gene fusions among others.45 Although FISH for EWSR1 gene rearrangement may not be helpful, the distinction can be made immunohistochemically as SEF is generally nonreactive for keratin, S-100 protein, SMA, and GFAP.

When occurring in soft tissue, the differential diagnosis includes malignant ossifying fibromyxoid tumor of soft parts (OFMT). One case, originally diagnosed as SEF at a referring institution, was excluded from the study after it was later confirmed to be an OFMT with PHF1-TFE3 fusion. OFMT is composed of small, round epithelioid cells embedded in a fibrous and myxoid stroma with cord-like and trabecular growth patterns.46 Areas identical to SEF have been described in OFMT,47 which can also have focal expression of MUC4.16 Unlike SEF, OFMT is primarily located in the subcutis, frequently demonstrates reactivity for S-100 protein, often has a rim of peripheral bone (80%) and has stromal myxoid change.

In conclusion, SEF has several features that distinguish it from LGFMS, including a propensity for bone and periosteal involvement, frequent development of diffuse abdominal disease, and a significantly more aggressive clinical course. As SEF is a fully malignant tumor with more aggressive behavior than previously recognized and typically recalcitrant to chemotherapy, recognition of this rare sarcoma with early surgical intervention, development of new treatment strategies, and close long-term follow-up is critical. With many histologic mimics, the correct diagnosis of SEF requires its consideration in the differential diagnosis of bone and soft tissue tumors with careful correlation of histomorphology, immunohistochemistry, and molecular analysis.

ACKNOWLEDGMENTS

Kim-Anh T Vu for her expertise in graphic illustration. Richard Yang, MD, PhD, Jing Ning, PhD and Maomao Ding for their expertise in biostatistics.

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Keywords:

sclerosing epithelioid fibrosarcoma; low grade fibromyxoid sarcoma; SEF; LGFMS; EWSR1

Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.