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. Author manuscript; available in PMC: 2026 Aug 6.
Published in final edited form as: Am J Surg Pathol. 2025 Oct 2;50(1):31–40. doi: 10.1097/PAS.0000000000002472

PRRX1-rearranged Fibroblastic Tumors: A Clinicopathologic and Molecular Study of 17 Cases including a Novel PRRX1::EP300 fusion

Carina A Dehner 1,2, Jorge Torres-Mora 3, Judith Jebastin Thangaiah 3, Andre Oliveira 3, Michael Michal 4,5, Faizan Malik 6, Nasir Ud Din 7,8, Usman Hassan 9, Hina Maqbool 9, Farres Obeidin 10, Mara Caragea 11, Cheng-Han Lee 11, Christian Schubart 12, Abbas Agaimy 12, Bo Grundtmann 13, Linea Melchior 14, Maj-Lis Talman 14, John Gross 15, Alison L Cheah 16, Khin Thway 17,18, Cyril Fisher 17,19, Cristina R Antonescu 20, Konstantinos Linos 20
PMCID: PMC13439680  NIHMSID: NIHMS2195228  PMID: 41036703

Abstract

With the first series of PRRX1-rearranged tumors published in 2019, the spectrum of these so-called fibroblastic tumors has been expanded. Since then, several smaller case series have been published, however, our understanding of these continues to be quite limited given their rarity. We herein studied 18 additional cases, the largest series to date. Eighteen tumors present in 9 male, 8 female and 1 non-binary patient with a median age of 35 years (range: 11–70 years) and involved the neck (5), the chest region (4), thigh (3), shoulder (1), forehead (1), lower leg (1), axilla (1) and the parapharyngeal region (1).. Clinical follow-up (9/118 tumors; 50%; median: 10 months; range: 4–40 months) showed consistent indolent behavior without local recurrences or distant metastases. On morphology, these tumors were characterized by well circumscription and distinctive peripheral crescent-shaped vessels. They were composed of uniform spindle and round cells growing in short fascicles within often densely hyalinized collagen lacking significant mitotic activity, necrosis or cytologic atypia. Immunohistochemically, about half of the tested tumors expressed focal to rarely diffuse S100 with occasional co-expression of SOX10. Interestingly, almost half of the tested cases also showed complete loss of RB expression… All but 1 tumor harbored a PRRX1::NCOA1 fusion, while 1 case harbored a novel PRRX1::EP300 fusion. We herein provide additional data on these exceptionally uncommon tumors, expand their molecular spectrum, and compare them to their close morphologic mimics to aid in accurate diagnosis and avoid confusion with potentially more aggressive neoplasms.

Keywords: PRRX1, NCOA1, NCOA2, fibroblastic tumor

INTRODUCTION

Our understanding of fibroblastic tumors continues to evolve with the advent of advanced molecular techniques. Several tumor types are now recognized as being defined by specific pathogenic gene fusions. Among these are low-grade fibroblastic tumors harboring PRRX1::NCOA1/2 fusions, first described by Lacambra et al. in 20191. Since then, 24 cases have been documented1–9. These tumors are morphologically distinct, typically exhibiting a multinodular, leaf-like architecture and composed of uniform ovoid to spindle-shaped cells set within a myxocollagenous stroma. Immunophenotypically, they show relatively nonspecific profiles. Their consistently indolent clinical course underscores the importance of distinguishing them from other histologically similar but clinically more aggressive entities, such as low-grade fibromyxoid sarcoma10–13 or YAP1::KMT2A-rearranged fibroblastic sarcoma8,14,15. In this report, we present 18 additional cases, including one with a novel PRRX1::EP300 fusion, thereby expanding the known molecular landscape of these exceedingly rare neoplasms.

MATERIALS AND METHODS

Study Cohort

Following ethics approval by the institutional review boards of the participating institutions, 18 cases of low-grade fibroblastic neoplasms harboring PRRX1 fusions were retrieved from the departmental archives and included upon re-review of Hematoxylin-and eosin-stained slides and immunohistochemical stains. Clinical data, such as age, gender, anatomic location, treatment, and follow-up, were retrieved from pathology reports and clinical records. Hematoxylin-and eosin-stained slides and immunohistochemical stains from all specimens were reviewed by 2 of the authors (K.L., C.A.D.).

Molecular Fusion Sequencing

Detailed description of amplicon-based targeted RNA next-generation sequencing (NGS) assay using the Archer Fusion Plex standard protocol, were described previously16. In brief, RNA was extracted from formalin-fixed paraffin-embedded tumor materials, followed by cDNA synthesis. Archer FusionPlex was performed in 15 cases. cDNA libraries were prepared using the Archer FusionPlex standard protocol. Fusion unidirectional GSPs have been designed to target specific exons in 123 genes known to be involved in chromosomal rearrangements based on current literature. The final targeted amplicons were ready for 2 150-bp sequencing on an Illumina MiSeq sequencer. FASTQ files were automatically generated using the MiSeq reporter software (version 2.6.2.3) and analyzed using the Archer analysis software (version 5.0.4). Each fusion call was supported by a minimum of 5 unique reads and a minimum of 3 reads with unique start sites. Sarcoma Targeted Gene Fusion/Rearrangement Panel (SARCP) was performed on 4 cases (cases 7,8,12 and 13), 9 cases (cases 1–5, 9–10,16–17) were sequenced with the TruSight RNA panel identical to the previously described protocol, 1 case (case 11) underwent testing at Northwestern University, 1 case (case 14) underwent testing at St. Jude Children’s Research hospital and 1 case (case 18) underwent testing at Monash Health in Melbourne, Australia. Two cases (cases 6 and 15) underwent testing at Alberta Precision Laboratory (Calgary, Canada).

RESULTS

Clinical Findings

Table 1 summarizes the clinicopathologic and molecular genetic features of the studied cases. Fifteen tumors occurred in 9 male, 8 female and 1 non-binary patients with a median age of 34 years of age (range: 11 – 70 years of age). The tumors presented as single well-defined lesions with a median tumor size of 6.7 cm (range: 2.0–8.6 cm) and involved the superficial soft tissues of the neck (5 cases), chest (4 cases), thigh (3 cases), and 1 case each on the back, shoulder, lower leg, axilla, forehead and parapharyngeal region. All tumors underwent surgical resection without neoadjuvant or adjuvant treatment. Follow-up information was available for only 9 of the 18 cases, likely reflecting the uniformly benign clinical behavior of these tumors. All 9 patients showed no evidence of disease at a median follow-up of 10 months (range: 4–40 months), despite positive margins in 6 of 9 tumors.

Table 1:

Clinicopathologic Features of the Studied Tumors

Case number Age (y)/ Sex Location/tumor size (cm) Immunohistochemistry Molecular testing Follow-up (mo)/status
Positive Negative
1 70/F Left thigh/7.5 S100 (focal), SOX10 (minimal; < 10%) RB reduced but no loss of expression PRRX1 exon 1::NCOA1 exon 15, NCOA1 exon 19 :: PRRX1 exon 2 Not available
2 40/M Forehead CD56 (focal) ALK, EMA, ERG, pan-TRK, desmin, MUC4, CD68, S100, SMA, CD34, SOX10, RB retained PRRX1 exon 1::NCOA1 exon 15, NCOA1 exon 19 :: PRRX1 exon 2 18/NED
3 30/M Left axilla None MUC4, ERG, EMA, SOX10, RB retained PRRX1 exon 1::NCOA1 exon 15, NCOA1 exon 19 :: PRRX1 exon 2 Not available
4 25/M Parapharyngeal/6.7 S100 (focal), complete RB loss ALK, EMA, MUC4, NUT, pan-TRK, STAT6, SS18, keratin AE1/AE3, desmin, SOX10 PRRX1 exon 1 :: EP300 exon 2
EP300 exon 2 :: PRRX1 exon 1,		 Not available
5 70/F Left neck/7.5 S100 (focal), CD10 SOX10, CD34, desmin, ER, PR, STAT6, MUC4, GLUT1, EMA, ALK, RB retained, low Ki67 PRRX1 exon 1 :: NCOA1 exon 13 6/NED
6 24/M Right lower leg /7.1 None S100, EMA, MUC4, SMA, desmin, SOX10, CD34, STAT6, ALK, GLUT1, PANK PRRX1 exon 1 :: NCOA1 exon 13 4/NED
7 53/F Right chest None CD34, MUC4, keratin AE1/AE3, CK8/18. p40, p63, b-catenin, S100, SOX10, desmin, ER, BCL2 PRRX1 exon 1 :: NCOA1 exon 13 Not available
8 32/F Neck S100 (focal) CD34, desmin, STAT6, MUC4, keratin AE1/AE3, D2–40, CD31, SOX10 PRRX1 exon 1 :: NCOA1 exon 13 Not available
9 41/M Chest wall/3.5 S100 (focal), SOX10 (focal), complete RB loss PRRX1 exon 1::NCOA1 exon 15, NCOA1 exon 19 :: PRRX1 exon 2 10/NED
10 24/F Neck/4.0 S100 (diffuse), SOX10 (focal), CD34 (patchy), complete RB loss STAT6, MUC4, desmin, b-catenin, keratin, actin, CD99 PRRX1 exon 1 :: NCOA1 exon15 Not available
11 28/NB Midline lower back S100 (rare cells) MUC4, EMA, SOX10, GLUT1, Claudin-1, CD34, STAT6, AE1/AE3, ERG, SMA, desmin, RB (retained) PRRX1::NCOA1 7/NED
12 35/M Left posterior shoulder/4.0 SMA (focal) MUC4, S100, desmin, CD34, STAT6 PRRX1 exon 1 :: NCOA1 exon 13; negative FISH for EWSR1 and FUS Not available
13 24/M Left thigh/8.6 SMA (focal), HHF35 keratin AE1/AE3, CD34, CD117, desmin, S100, SOX10; PRRX1 exon 1 :: NCOA1 exon 13 Not available
14 11/F Right neck soft tissue CD34, S100 (focal), complete RB loss MUC4, beta-catenin, LEF-1, desmin, pankeratin, ALK, desmin, MYOD1, STAT6, EMA, BCOR, ER, and SS18-SSX, SOX10 PRRX1 exon 1 :: NCOA1 exon 15
NCOA1 exon 19 :: PRRX1 exon 2		 10/NED
15 68/F Left upper chest S100 diffuse, SOX10 focal MUC4, EMA, CD34, desmin, actin, CKAE1/3, GLUT1, claudin 1, laminin PRRX1 exon 1 :: NCOA1 exon 13 12/NED
16 41/M Chest wall S100 (rare cells), SMA, CD31, calponin, desmin (focal), EMA, CD99, Vimentin; Ki67<5%, complete RB loss S100, CD34, STAT6, ER, CD68, PR, keratin, ALK1, b-catenin, bcl2, AR, SOX10 PRRX1 exon 1 :: NCOA1 exon 13 40/NED
17 43/M Lateral aspect of right groin p16 (multifocal), scant SMA MUC4, desmin, h-caldesmon, myogenin, SOX10, S100, ERG, CD31, CD34, STAT6, CDK4, AE1AE3, EMA, retained BRG1, low Ki67 PRRX1::NCOA1 28/NED
18 30/M Right posterior neck S100 focal MUC4, SOX10, EMA, CD34, desmin, claudin 1, STAT6; RB (retained) PRRX1 exon 1 :: NCOA1 exon 13
NCOA1 exon 13 :: PRRX1 exon 1 		Not available
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F=female; M=male; NB=non-binary; NED = no evidence of disease; mo = months

Molecular Genetic Features

Next-generation sequencing demonstrated PRRX1::NCOA1 fusions in 17 cases, while one case harbored the novel PRRX1::EP300 fusion (see Fig 1). For all cases with more detailed molecular information (see table 1), reciprocal reads into both directions were identified, similar to previously reported cases1.

Figure 1: Morphologic features and fusion diagrams of case with novel PRRX1::EP300 fusion.

Figure 1:

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(A) Low power photograph shows bulging of the tumor nodules into large vascular spaces. (B) On intermediate power, the tumor shows bland spindled to ovoid cells within a fibrotic and hyalinized stroma. (C-D) Fusion schematics to demonstrate the novel fusion with reciprocal reads involving PRRX1 and EP300.

Histopathologic Features

The histologic appearance of the tumors was relatively uniform and consistent with previously reported cases1–9. At low magnification, the tumors were well-circumscribed and multinodular, often exhibiting a distinctive leaf-like architecture. This was typically accompanied by peripheral, dilated, gaping, or crescent-shaped thin-walled vessels (Figure 2). A frequent feature was the protrusion of tumor nodules into adjacent vascular spaces (Figure 2B).

Figure 2. Classic Low-Power Morphologic Features of PRRX1-Rearranged Tumors.

Figure 2.

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(A) Tumors exhibit a characteristic multinodular architecture. (B) Protrusion of tumor nodules into large vascular spaces is a common finding. (C) A classic leaf-like growth pattern is frequently observed. (D) Infiltrative growth around adnexal structures may be present. (E-F) Thickened, hyalinized vessel walls and centrally located, gaping vessels are typical features.

Tumors demonstrated variable cellularity, composed of cords and clusters of bland ovoid cells with scant cytoplasm and inconspicuous nucleoli, embedded within bundles of rope-like collagen fibers, reminiscent of those observed in spindle cell lipoma (SCL) (Figure 3). In contrast to SCL, these tumors lacked overt adipocytic differentiation, and only occasionally entrapped adipocytes were noted. In some areas, collagen fibers exhibited hyalinization with a rigid, sclerotic quality akin to that seen in sclerosing epithelioid fibrosarcoma (SEF, Figures 4F, G). The stroma ranged from loose myxoid to myxocollagenous, with focal to prominent zones of hyalinization (Figures 4A, B). Occasional pseudo–rosette-like structures were identified (Figure 4D).

Figure 3. Cytomorphologic Characteristics of PRRX1-Rearranged Tumors.

Figure 3.

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(A) Tumor cells are predominantly ovoid to spindled, often arranged in a disorganized fashion. (B) Mild to moderate degenerative-type atypia may be present, without associated mitotic activity or necrosis. (C) Some tumors exhibit a perineurioma-like appearance, with elongated cells featuring dendritic-type processes Abundant myxoid stroma is seen. (D) Scattered mast cells are frequently observed within the stroma.

Figure 4. Morphologic Spectrum of PRRX1-Rearranged Tumors.

Figure 4.

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(A) Alternating zones of dense hyalinized collagen and myxoid stroma are common. (B) Some tumors closely resemble fat-free spindle cell lipoma. (C) Others may mimic solitary fibrous tumor. (D) Giant collagenous pseudo-rosettes, similar to those seen in low-grade fibromyxoid sarcoma, may be present. (E) Intratumoral hemorrhage, as often seen in schwannomas, is a frequent finding. (F) Rare cases exhibit dense collagen deposition reminiscent of osteoid. (G) A sclerosing epithelioid fibrosarcoma–like pattern is another recognizable morphologic variant.

Scattered thick-walled, hyalinized blood vessels, reminiscent of those seen in solitary fibrous tumor (Figure 4C), were present in all cases. Intratumoral hemorrhage and numerous small, blood-filled vascular spaces were also frequently observed (Figure 4E). Proliferative activity was low (median: 1 mitosis per 10 high-power fields), and no tumor necrosis was identified in any case.

Immunohistochemical Features

The tumors showed focal or rarely diffuse S100 expression in 11 of the 17 tested cases (Figure 5), while 4 of 17 tested tumors additionally showed minimal SOX10 expression. Four of 8 tested tumors showed focal SMA, 1 of which also showed focal HHF35 expression. Two of 13 tested tumors were focally positive for CD34. All tested tumors were negative for MUC4 (14 cases), ALK (6 cases), EMA (10 cases), pan-TRK (2 cases), STAT6 (11 cases), b-catenin (3 cases), GLUT1 (4 cases) and claudin 1 (3 cases). RB expression was completely lost in 5 of 11 tested cases. Additional information is provided in table 1.

Figure 5. Immunohistochemical Profile of PRRX1-Rearranged Tumors.

Figure 5.

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(A, B) Approximately one-third of tumors exhibit patchy S100 expression while (C) rare cases show diffuse expression. (D) SOX10 was multifocally positive in a single cell pattern in a small subset of cases. (E) CD34 is typically negative but clearly outlines the prominent vascular architecture. (F) In this case, there is complete loss of RB expression, with good internal positive control (endothelial cells). Nearly half of the tested cases in our cohort demonstrated complete loss of RB expression. This finding may represent a significant diagnostic pitfall in the differential diagnosis with “fat-free” spindle cell lipoma.

DISCUSSION

Since the initial series by Lacambra et al in 20191, there have been several additional case series of PRRX1-rearranged fibroblastic tumors2–9. In total, including the 18 cases in this present study, 42 cases have been reported in the English literature (tables 1 and 2). These unusual tumors may occur at any age but have a predilection for middle aged adults (median: 39 years; range: 11–70 years) and seem to be roughly equally common in males and females (21 females, 20 males, 1 non-binary). Preferred sites of involvement include the neck/back region (31%), the shoulder (19%) and the lower extremities (22%); however, other locations such as chest/flank region (14%), head (7%) and abdominal wall (7%) may also be involved. Although only short-term clinical follow-up is available (25/42 tumors; 60%; median: 12 months; range: 1–40 months), these are thought to be indolent tumors, and the lack of more extensive follow-up may itself reflect their benign clinical behavior.

Table 2:

Previously reported cases

Case number Age (y)/ Sex Location/tumor size (cm) Immunohistochemistry Molecular testing Follow-up (mo)/status
11 55/F Thigh/4.0 Positive: S100 (patchy in 1 of 4 cases)
Negative: SOX10 (in tested cases)		 PPRX1 exon1 :: NCOA1 exon 13
NCOA1 exon 17 :: PRRX1 exon 2		 24/NED
21 33/M Neck/14.0 PPRX1 exon1 :: NCOA1 exon 13
NCOA1 exon 17 :: PRRX1 exon 2		 6–18/NED
31 43/F Neck/3.0 PPRX1 exon1 :: NCOA1 exon 13
NCOA1 exon 17 :: PRRX1 exon 2		 6–18/NED
41 21/F Groin/2.0 PPRX1 exon1 :: NCOA2 exon 15
NCOA1 exon 19 :: PRRX1 exon 2		 6–18/NED
52 40/M Knee/13.0 Positive: CD34, SMA and EMA (all focal)
Negative: MUC4, S100, desmin		 PRRX1 exon 1 :: KMT2D exon 22
KMT2D exon 34 :: PRRX1 exon 2		 Not available
63 49/M Abdominal wall/4.0 Negative: CD34, SMA, desmin, S100, keratin AE1/AE3, MUC4, STAT6 PPRX1 exon1 :: NCOA1 exon 13 2/NED
73 43/M Right axilla/5.5 Negative: CD34, SMA, desmin, S100, keratin AE1/AE3, MUC4, STAT6, ER PPRX1 exon1 :: NCOA1 exon 13 3/NED
83 34/F Right shoulder Negative: desmin, S100, MUC4, ALK D5F3, b-catenin; Rb1 retained PPRX1 exon1 :: NCOA1 exon 13 Not available
93 41/F Abdominal wall/4.0 Negative: CD34, SMA, desmin, h-caldesmon, S100, SOX10, EMA, MUC4, STAT6, ALK1, ER, PR, CD31, MDM2; Rb1 retained PPRX1 exon1 :: NCOA1 exon 13 Not available
103 76/F Abdominal wall/2.6 Negative: CD34, muscle cocktail, desmin, S100, SOX10, MUC4, STAT6, ER, PAX8 PPRX1 exon1 :: NCOA1 exon 13 1/NED
113 20/M Right lateral hip/5.0 Positive: desmin (focal)
Negative: CD34, SMA, myogenin, MyoD1, S100, HMB45, MUC4, STAT6, ALK1		 PPRX1 exon1 :: NCOA1 exon 13 1.5/NED
124 23/M Scalp/2.9 Negative: MUC4, CD34, STAT6, EMA, claudin1, S100, SOX10 PPRX1 exon1 :: NCOA1 exon 13 26/NED
134 46/M Neck/2.2 Negative: MUC4, S100, SOX10, EMA; Rb1 retained PPRX1 exon1 :: NCOA1 exon 13 7/NED
145 23/M Shoulder/2.5 Positive: non-pigmented cells: Factor XIIIA, S100 (focal)
Pigmented cells: S100, SOX10, MITF, pan-melanoma
Negative: pancytokeratin, SMA, desmin, CD34, STAT6, EMA and MUC4		 PPRX1 exon1 :: NCOA1 exon 13 Not available
156 46/F Neck/2.2 Positive: S100 (focal), SOX10 (focal) PPRX1 exon1 :: NCOA1 exon 13 4/NED
166 36/M Neck/3.4 Positive: S100 (focal), SOX10 (focal) PPRX1 exon1 :: NCOA1 exon 13 5/NED
176 65/F Chest wall/4.0 Positive: S100 (focal), SOX10 (focal) PRRX1 exon 1 :: KMT2D exon 25–27
KMT2D :: PRRX1 		12/NED
186 37/F Flank/9.5 Negative: S100, SOX10 PPRX1 exon1 :: NCOA1 exon 13 Not available
196 29/M Forehead/2.5 Negative: S100, SOX10 PPRX1 exon1 :: NCOA1 exon 13 Not available
206 56/F Back/3.0 Positive: S100 (focal), pan-TRK
Negative: SOX10		 PPRX1 exon1 :: NCOA1 exon 13 16/NED
217 26/F Thigh/4.0 Positive: S100 (focal), SOX10 PPRX1 exon1 :: NCOA1 exon 15 13/NED
228 22/F Supraclavicular/3.0 Positive: pan-TRK (single cells)
Negative: CD34, S100, SOX10, keratin, SMA, desmin, STAT6, ALK, EMA, GLUT1, MUC4		 PPRX1 exon1 :: NCOA1 exon 13 12/NED
239 50s/M Left shoulder Positive: S100 (strong), p16, ALK and pan-TRK
Negative: keratin AE1/AE3, EMA, p63, p40, CD34, ERG, SOX10, SMA, desmin, STAT6, MUC4, MDM2; INI1, BRG1 retained
Variable RB1 loss		 PPRX1 exon1 :: NCOA1 exon 13 Not available
249 40s/F Right shoulder Positive: p16
Negative: keratin AE1/AE3, EMA, p63, p40, CD34, ERG, SOX10, SMA, desmin, STAT6, S100, MUC4, MDM2, ALK, PanTRK
INI1, BRG1 retained
Variable RB1 loss		 PPRX1 exon1 :: NCOA1 exon 13 Not available
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F=female; M=male; NED = no evidence of disease; DOD = died of other disease; AWD = alive with disease; y = years; mo = months

The cardinal features of PRRX1-rearranged tumors include well circumscription and multinodularity on low power, often demonstrating distinctive crescent or leaf-like gaping vessels at the periphery. Closer examination demonstrates a population of uniform bland spindle and round cells growing in short fascicles within often densely hyalinized collagen. Abundant myxoid stroma and multifocal intratumoral hemorrhage are other frequently encountered features. Atypical features such as increased mitotic activity, necrosis or significant atypia have been uniformly absent.

Although early studies indicated a largely nonspecific or null immunophenotype, more recent work by Warmke et al.3 has proposed a potentially neural or neuroectodermal-like lineage for this presumed fibroblastic tumor. In our cohort, upon careful examination a subset of cases (65%) demonstrated at least focal S100 protein expression in a dendritic-type fashion, suggesting that S100 may serve as a useful immunohistochemical marker in this morphologic context. When combining data from all 42 reported cases to date, approximately 45% have shown some degree of S100 positivity, while around 25% demonstrated additional focal SOX10 expression.

Notably, Cloutier et al.6 reported an exceptional case of a PRRX1::NCOA1-rearranged tumor with melanocytic differentiation. This case exhibited two morphologically distinct components: one with conventional histologic features of a PRRX1-fusion tumor, and a second, heavily pigmented epithelioid and dendritic cell population that showed strong and diffuse expression of melanocytic markers. The authors proposed a parallel to the phenomenon observed in pigmented dermatofibrosarcoma protuberans (Bednar tumor)17. Rare cases have also demonstrated expression of other markers, including SMA, desmin, pan-TRK (2 cases), and ALK (4 cases). While the provisional name of this entity is PRRX1-rearranged fibroblastic tumor, the precise line of differentiation remains somewhat unclear and warrants further investigation.

Most tumors seem to harbor a PRRX1::NCOA1 fusion (90%), with 2 rare cases showing fusions involving KMT2D8 and a single case with NCOA21. In these fusion events, the resulting chimeric product retains the transcriptional activator domains of NCOA1/2 or KMT2D, while their receptor-binding domains are lost and replaced by exon 1 of PRRX1 leading to transcriptional dysregulation6. It should be noted that, similar to YAP1::KMT2A sarcomas8,14,15 and soft tissue angiofibromas18, many cases, for which sequencing data were available, showed reciprocal reads in both directions (and it is possible that additional tumors may exhibit this finding). Therefore, without further functional analysis at the protein level, it is not possible to unequivocally determine the orientation(s) of the pathogenic fusion proteins (i.e., PRRX1::NCOA1/2 vs. NCOA1/2::PRRX1).

This holds true for our case with a novel PRRX1::EP300 fusion that exhibited morphologic features essentially identical to those described in previously reported cases. EP300 is a gene that encodes the adenovirus E1A-associated cellular p300 transcriptional co-activator protein and thereby functions as histone acetyltransferase regulating transcription via chromatin remodeling19. Specifically, it mediates cAMP-gene regulation by binding to the phosphorylated CREB protein20. It has been previously reported as a 5’ fusion partner in various mesenchymal tumors such as endometrial stromal sarcoma21,22, uterine leiomyosarcoma23 and 6 cases of spindle cell rhabdomyosarcoma (RMS) with predilection for the head & neck24–26.

Even though the morphologic spectrum of PRRX1-rearranged tumors is seemingly consistent, these neoplasms continue to be a diagnostic challenge given significant morphologic overlap with various other benign or low-grade myxoid spindle cell neoplasms such as the family of RB1-deficient tumors, solitary fibrous tumor, ossifying fibromyxoid tumor, schwannoma, low-grade fibromyxoid sarcoma (LGFMS) and the recently characterized sarcomas harboring YAP1::KMTA2 fusions8,14,15. While many of the differential diagnoses have been previously discussed at length, we will focus on some of the most relevant ones.

The uniform, bland spindled to ovoid cells within myxocollagenous stroma, admixed with hyalinized collagen fibers and occasionally entrapped adipocytes may suggest a fat-poor variant of spindle cell lipoma (SCL) which would be further supported by the preference for the neck/upper back region and occasional rare S100 reactivity. However, the absence of diffuse CD34 helps to exclude this differential diagnosis in most cases. This stands in contrast to loss of RB expression that may rather present an important pitfall. Similar to Cordier and colleagues7 who recently reported 2 cases of PRRX1-rearranged tumor demonstrating variable RB loss by immunohistochemistry, which they subsequently confirmed by fluorescence in situ hybridization, 45% of cases of this current series showed complete loss of RB expression. The authors suggested a possibly closer relationship to Rb1-deficient entities than previously appreciated. Also, other tumors within the Rb1-deficient family such as mammary-type myofibroblastoma (MTMF) or even cellular angiofibroma (CAF), may also show significant morphologic overlap. In addition to loss of expression of RB, CAF and MTMF tend to express CD34 and estrogen receptor (ER), with MTMF also expressing desmin, all of which are usually absent in PRRX1-rearranged tumors. While beyond of the scope of this current study, additional mechanistical studies may be helpful in assessing the relationship between above mentioned tumors.

The absence of CD34 also helps to differentiate from solitary fibrous tumor, which although shares the densely hyalinized vessels with PRRX1-rearranged tumors, its cytomorphologic features are usually quite different.

The distinction between PRRX1-rearranged tumors and low-grade fibromyxoid sarcoma (LGFMS) or YAP1::KMT2A-rearranged sarcomas is particularly critical, as the latter entities may exhibit clinically aggressive behavior despite their deceptively bland histology. Key overlapping features—such as prominent stromal hyalinization, uniform bland spindle cell morphology, myxoid matrix, and the presence of giant pseudorosette-like structures—can be seen in all three entities, complicating the diagnostic process. Fortunately, MUC4 serves as a relatively sensitive and specific immunohistochemical marker for both LGFMS and sclerosing epithelioid fibrosarcoma27,28 (SEF), and its consistent absence in PRRX1-rearranged tumors helps support their distinction.

In contrast, YAP1::KMT2A-rearranged sarcomas—sometimes referred to as “MUC4-negative SEF”—pose greater diagnostic difficulty, as they typically lack a defining immunoprofile and may only show occasional EMA expression or loss of YAP1 expression8. Morphologically, a subset of YAP1::KMT2A sarcomas displays a distinctive perineurioma-like pattern with elongated, dendritic cell processes15, in contrast to the short, stubby cellular morphology typical of PRRX1-rearranged tumors. However, cases exhibiting a more fibroma-like architecture15 may closely resemble PRRX1-rearranged tumors, further complicating the distinction. Ultimately, definitive diagnosis hinges on the identification of a PRRX1 gene fusion, which remains essential for accurate classification.

In summary, we report 18 additional cases of PRRX1-rearranged tumors—representing the largest cohort to date—including one case with a novel PRRX1::EP300 gene fusion. Our findings reinforce the relatively uniform histologic appearance of these tumors, with focal S100 expression observed in a significant subset of cases, and a consistently indolent clinical course, despite the limited duration of follow-up. This study contributes to the growing but still limited body of literature, expands the known molecular landscape of these neoplasms, and underscores key morphologic and immunohistochemical features that may aid in their recognition prior to molecular confirmation.

Acknowledgements

The authors thank Silvia Cavalchini and Dr. Suzanne MacMahon for their help with the case originating from the Royal Marsden Foundation Trust, as well as Henrik Mygind for his help with the cases originating from the Copenhagen University Hospital. Lastly, we thank the talented Fredrik Skarstedt for his help with the figures of this manuscript.

FUNDING

Supported by: MSK NIH Funded Grant# P30 CA08748

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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