PRRX1::NCOA1 Rearranged Fibroblastic Tumour: A New Report With a Brief Literature Review of an Uncommon Neoplasm

Abstract

The increased application of next-generation sequencing technologies in challenging spindle cell neoplasms has given rise to the discovery of a novel PRRX1::NCOA1 rearranged fibroblastic neoplasm, which is not yet included in the World Health Organization (WHO) classification of soft tissue tumours. We report on an additional example of a well-circumscribed, monomorphic, oval- to spindle-shaped cellular tumour, which had patchy reactivity for smooth muscle actin and S100 on immunohistochemistry and a PRRX1::NCOA1 fusion transcript. To date, 43 tumours have been described in the literature. We review the clinicopathologic and molecular features of reported tumours and discuss relevant differential diagnoses. Available data suggest indolent behaviour; however, a long-term follow-up is required to ascertain the risk of recurrence or malignant behaviour.

Introduction

Benign mesenchymal tumours are a heterogeneous set of neoplasms that include fibroblastic and myofibroblastic lesions with distinct morphologic and molecular characteristics. ¹ While many entities such as nodular fasciitis and fibromatosis are well researched and characterised, the increasing application of next-generation sequencing (NGS) in surgical pathology has led to the recognition of additional, previously unclassified spindle cell neoplasms defined by recurrent gene fusions.^2,3

The WHO has classified some of these molecularly defined lesions as ‘emerging entities’. One such recently described tumour is the PRRX1::NCOA1-rearranged fibroblastic tumour.^4,5 To date, 43 tumours have been reported in the literature, the first reported by Lacambra et al in 2019 but formally described by Dermawan et al in 2021.^4,5 The tumour is characterised by recurrent PRRX1::NCOA1 gene fusion. ⁶ These lesions are typically well circumscribed and composed of monomorphic ovoid to spindle cells. Immunohistochemically, they may demonstrate focal or patchy expression of smooth muscle actin and S100, while most lack expression of CD34, desmin, STAT6, MUC4, and keratins.^4–14 Although PRRX1 and NCOA1 are involved in transcriptional regulation in mesenchymal tissues, the precise oncogenic mechanism of this fusion remains unclear.^6,12

Here we report on a further example of the novel PRRX1::NCOA1 rearranged fibroblastic tumour and provide a tabulated review of the clinical, histopathological and molecular features that are currently reported in the literature. To our knowledge, this tumour represents the 44^th reported example.

Patient Presentation

Clinical Information

A 32-year-old woman presented with a non-pigmented subcutaneous lesion in her left proximal shin. The patient had undergone a bariatric procedure for weight loss and had ongoing follow up with the surgeon, where this leg lesion was initially assessed. Magnetic resonance imaging (MRI) of her left lower leg demonstrated a complex enhancing soft tissue lesion in the anteromedial aspect of the subcutaneous tissues of the mid to proximal left lower leg measuring 24.5 × 21.7 × 15.6 mm. The lesion was seen to abut the cortex of the anteromedial aspect of the tibia but showed no associated bony erosion or cortical breakthrough in the region. There were associated surrounding inflammatory changes with subcutaneous tissue fluid (Figure 1). The differentials in the context of the MRI were neurogenic tumours such as a neurofibroma or sinister pathologies such as sarcoma, which could not be excluded radiologically. The patient underwent an excision under general anaesthesia, and the lesion was seen to be adjacent to the interosseous membrane, not invading the periosteum. The lesion was orientated with marking sutures and sent for histopathological diagnosis.

Figure 1.

(Left) Sagittal view of MRI – subcutaneous nodule. (Right) Coronal view of MRI – subcutaneous nodule.

Macroscopic Details

Macroscopic examination revealed a fibrofatty nodule weighing 6 g and measuring 25 × 29 × 19 mm with sectioning revealing an 18 × 15 × 25 mm circumscribed cream nodule.

Microscopic Findings

Microscopy revealed a well circumscribed, subcutaneous spindle cell lesion composed of bland spindle cells embedded in a variably collagenous stroma. The nuclei were oval to spindle and relatively uniform. The cells were arranged in short fascicles (Figure 2). There was no nuclear atypia and no atypical mitotic figures were identified. Irregular and dilated vessels were prominent. The lesion had a fibrous background.

Figure 2.

(Left) Low Power H&E of architecture and borders. (Right) Medium Power H&E of nuclear features.

Immunohistochemistry (IHC)

The tumour cells demonstrated patchy reactivity for smooth muscle actin and S100 protein (Figure 3) and were negative for CD31, CD34, desmin, STAT6, MUC4, SOX10, epithelial membrane antigen and NTRK, myogenin, h-caldesmon, CD99 and HMB45. TLE1 showed patchy reactivity and was regarded as negative. The provisional diagnosis was a low-grade spindle cell neoplasm and was subsequently referred for RNA fusion panel testing.

Figure 3.

(Right) S100 immunohistochemistry; (left) SMA immunohistochemistry.

Next-Generation Sequencing RNA Pan-Cancer Fusion Panel and Diagnosis

Targeted NGS was performed on RNA from patient tissue. The enrichment of RNA libraries was achieved using the Illumina TruSight RNA Pan-Cancer Panel (1375 genes), followed by massively parallel sequencing performed on an Illumina NextSeq 550. The data processing including fusion calling and data alignment to the reference genome GRCh37 (hg19) was performed with the DRAGEN somatic bioinformatics pipeline via the Illumina BaseSpace Sequence Hub. The variants were annotated and analysed using the Velsera Clinical Genomics Workspace (CGW v6.13), and the results were interpreted and reported in accordance with AMP/ASCO/CAP guidelines using ISCN nomenclature.

A PRRX1::NCOA1 fusion transcript was identified, which demonstrated an in-frame fusion between exon 1 of PRRX1 and exon 13 of NCOA1, with the breakpoints being: chr1:g.170633600 and chr2:g.24949458 (Figure 4).

Figure 4.

Visual depiction of PRRX1::NCOA1 fusion transcript.

In conjunction with morphological features, the lesion was deemed to represent a PRRX1::NCOA1 rearranged fibroblastic tumour. Prognosis was deemed favourable based on limited available data with the chance of recurrence being unlikely. A period of follow-up with the patient was recommended as experience with this tumour has been limited.

Outcome/Follow-Up

There has been no report of recurrence at four months postoperatively; however, no further long-term follow-up information is available currently.

Discussion

The PRRX1::NCOA1 rearranged fibroblastic tumour represents a relatively new and uncommon entity that has come to light since the application of novel molecular diagnostic testing methods, such as NGS in the field of diagnostic surgical pathology.^2–16 This mesenchymal neoplasm has not yet been included in the WHO tumour classification of soft tissue and bone tumours due to the rare incidence. ¹ The first tumours of this nature were reported by Lacambra et al in 2019, with four examples – three with a fusion gene involving PRRX1 and NCOA1 and one with a fusion between PRRX1 and NCOA2 genes. ⁴

The initial reports described the tumours as monomorphic spindle-stellate cells with a vague fascicular pattern.^4,5 They had bland nuclei with rare mitotic activity and occasional multinucleation. ⁴ The intervening stroma was seen to be abundant and ranged from myxoid to collagenous with frequent rope like collagen bundles. ⁴ Three of the initial four tumours had prominent vasculature ranging from numerous small curvilinear vessels to ectatic and branching staghorn-like vessels. ⁴ Shortly after, Dermawan et al in 2021 reported six additional occurrences of this neoplasm and discussed their differential diagnoses. ⁵ They concluded that the ‘morphological features of PRRX1::NCOA1 rearranged fibroblastic tumours may overlap with RB1-deficient soft tissue tumours, solitary fibrous tumour and low-grade fibromyxoid sarcoma/sclerosing epithelioid fibrosarcoma’. ⁵ They suggested careful morphological and immunostaining to differentiate however, molecular studies were thought to be most differentiating. ⁵ Since this case series was published, 43 further instances of PRRX1-rearranged fibroblastic tumours have been described. This review brings the number of reported tumours up to 44 overall, with 40 being the PRRX1::NCOA1 rearranged tumour (four others were rearrangements with EP300 (Histone acetyltransferase p300), NCOA2 and KMT2D (Histone-lysine N-methyltransferase 2D)). Recently, Dehner et al described 18 further reports of this tumour type. ¹⁴ All reported tumours until now have been tabulated in Table 1 along with their clinical features and immunohistochemical profiles.

Table 1.

Tabulated Review of All Reported PRRX1-Rearranged Fibroblastic Tumours.

No.	Age	Sex	Location	Markers	Size (cm)	Fusion Partner	Ref.
1	55	F	Thigh	Desmin-, smooth muscle actin-, S100-, CD34-, epithelial membrane antigen-, keratin AE1/AE3-	4.0	NCOA1	Lacambra et al 4
2	33	M	Neck	As above	14.0	NCOA1	Lacambra et al 4
3	43	F	Neck	As above	3.0	NCOA1	Lacambra et al 4
4	21	F	Groin	As above	2.0	NCOA2	Lacambra et al 4
5	49	M	Abdominal wall	As above, MUC4-	4.0	NCOA1	Dermawan et al 5
6	43	M	Axilla	As above	5.5	NCOA1	Dermawan et al 5
7	34	F	Shoulder	As above RB1 retained	N/A	NCOA1	Dermawan et al 5
8	41	F	Abdominal wall	As above RB1 retained	4.0	NCOA1	Dermawan et al 5
9	76	F	Abdominal wall	All markers were negative	2.6	NCOA1	Dermawan et al 5
10	20	M	Hip	SOX10-, S100 N/A	5.0	NCOA1	Dermawan et al 5
11	46	M	Scalp	S100-, SOX10-, MUC4-	2.9	NCOA1	Chen et al 7
12	23	M	Groin	S100-, SOX10-, MUC4-	5.0	NCOA1	Chen et al 7
13	23	M	Shoulder	S100 (focal+), SOX10-	2.5	NCOA1	Cloutier et al 8
14	46	F	Neck	S100 (focal+), SOX10 (focal+)	2.2	NCOA1	Warmke et al 9
15	36	M	Neck	S100 (focal+), SOX10 (focal+)	3.4	NCOA1	Warmke et al 9
16	37	M	Flank	SOX10-, S100-	9.5	NCOA1	Warmke et al 9
17	65	F	Chest wall (intramuscular)	S100 (focal+), SOX10 (focal+)	4.0	KMT2D	Warmke et al 9
18	29	M	Forehead (frontal muscle)	All markers were negative	2.5	NCOA1	Warmke et al 9
19	56	F	Back	S100 (focal+), SOX10-	3.0	NCOA1	Warmke et al 9
20	26	F	Left thigh	S100+, SOX10+, RB1 retained			Cheng et al 10
21	26	F	Left thigh	S100+, MUC4-	4.0	NCOA1	Xu et al 11
22	28	F	Right thigh	S100+, MUC4-	4.0	NCOA1	Xu et al 11
23	40	F	Right lower leg (intramuscular)	S100 weak+, MUC4-	15.8	KMT2D	Xu et al 11
24	42	F	Trunk	S100 weak+, MUC4-	5.5	NCOA1	Xu et al 11
25	40	M	Knee (deep)	S100-	13.0	KMT2D	Puls et al 12
26	70	F	Left thigh	S100+, SOX10 minimal	7.5	NCOA1	Dehner et al 14
27	40	M	Forehead	CD56 (focal+), SOX10-, S100-, MUC4-, RB1 retained	N/A	NCOA1	Dehner et al 14
28	30	M	Left axilla	All markers were negative	N/A	NCOA1	Dehner et al 14
29	25	M	Parapharyngeal	S100 (focal+), RB1 loss, SOX10-	6.7	EP300	Dehner et al 14
30	70	F	Left neck	S100 (focal+), CD10+, SOX10-, MUC4-	7.5	NCOA1	Dehner et al 14
31	24	M	Right lower leg	All markers were negative	7.1	NCOA1	Dehner et al 14
32	53	F	Right chest	All markers were negative	N/A	NCOA1	Dehner et al 14
33	32	F	Neck	S100 (focal+)	N/A	NCOA1	Dehner et al 14
34	41	M	Chest wall	S100 (focal+), SOX10 (focal+), complete RB1 loss	3.5	NCOA1	Dehner et al 14
35	24	F	Neck	S100+, SOX10 (focal+), CD34 (patchy+), complete RB1 loss	4.0	NCOA1	Dehner et al 14
36	28	NB	Midline lower back	Rare S100+, RB1 retained	N/A	NCOA1	Dehner et al 14
37	35	M	Left posterior shoulder	Smooth muscle actin (focal+), MUC4-, S100-	4.0	NCOA1	Dehner et al 14
38	24	M	Left thigh	Smooth muscle actin (focal+), HHF35+, SOX10-, S100-	8.6	NCOA1	Dehner et al 14
39	11	F	Right neck	CD34+, S100 (focal+), complete RB1 loss	N/A	NCOA1	Dehner et al 14
40	68	F	Left upper chest	S100 diffuse, SOX10 (focal+)	N/A	NCOA1	Dehner et al 14
41	41	M	Chest wall	S100 (rare+), smooth muscle actin +, CD31+, Calponin+, desmin (focal+), epithelial membrane antigen-, CD99/Vimentin+, Ki-67 (MKI67) < 5%, complete RB1 loss	N/A	NCOA1	Dehner et al 14
42	43	M	Right lateral groin	p16 (multifocal), smooth muscle actin (scant+), S100-, SOX10-, MUC4-	N/A	NCOA1	Dehner et al 14
43	30	M	Right posterior neck	S100 (focal+), SOX10-, RB1 retained	N/A	NCOA1	Dehner et al 14
44	32	F	Left lower leg	Smooth muscle actin (patchy+), S100+, MUC4-	2.5	NCOA1	Current

Location: subcutis unless stated otherwise; N/A, not available; NB, non-binary.

The majority of the PRRX1::NCOA1 rearranged fibroblastic tumour appear well circumscribed with relatively monomorphic ovoid to spindle cells arranged in loose or short fascicles with a variably collagenous stroma.^4–14 They have irregular, staghorn-like vessels, often prominent at the periphery. Mitotic figures are typically not seen and nuclear atypia and necrosis are not observed.^4–14

Immunohistochemistry for these tumours show similar results with some tumours showing patchy reactivity for smooth muscle actin and positivity for SOX10 and S100, however, most of the tumours are negative for CD34, smooth muscle actin, desmin, STAT6, Melan-A, MUC4 and β-catenin.^4–14 In the case series by Dermawan et al 2021, all but one showed a purely fibroblastic phenotype with the absence of expression of CD34, smooth muscle actin, desmin, S100, SOX10, oestrogen receptor, MUC4, STAT6 and keratin AE1/AE3. ⁵ They tested two tumours for RB1, and both had retained RB1 expression. Cloutier et al in 2022 reported a PRRX1::NCOA1 rearranged fibroblastic tumour with a prominent pigmented component – all pigmented cells were positive for S100 protein, SOX10, MITF, and a pan-melanocytic marker cocktail (Melan-A, HMB45 and tyrosinase). ⁸ Interestingly, nests and clusters of pigment-laden epithelioid and dendritic cells were present in this tumour which were not observed in the others. ⁸ This was the first known tumour of this kind with a pigmented component – unfortunately, clinical follow up was not available for this patient.

All examples of PRRX1::NCOA1 rearranged tumour appear to arise in the subcutaneous tissue and occasionally have secondary dermal involvement with sizes ranging from 2-6cm.^4–14 Resection seems to be curative based on the available literature.^4–14 The lack of long-term follow-up data has been highlighted in many reports for this type of neoplasm; however, it is reassuring that there have been no updated reports of recurrence or metastatic behaviour. It is important to consider some differential diagnosis when it comes to the morphology of PRRX1-rearranged tumours as mentioned earlier in the discussion. As Cloutier et al demonstrates, fibroblastic tumours with pigmented melanocytes may have a differential of spindle cell melanoma. ⁸

In conclusion, this paper represents the 44^th example of PRRX1::NCOA1 rearranged fibroblastic tumour and includes a review of all known tumours including their morphology and immunohistochemistry. This classification is not yet included in the WHO classification of benign soft tissue neoplasms, with fewer than 100 such tumours in the literature but appears to be an emerging entity with the usage of NGS-based molecular technologies. Long term follow-up data is preferred to exclude sinister behaviour; however, the current literature supports the lesion being benign provided malignancies with overlapping morphological features are promptly excluded.