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Department of Orthopaedics, St Vincent’s Hospital Melbourne, Melbourne, Vic, AustraliaDepartment of Surgery, The University of Melbourne, Melbourne, Vic, Australia
The first large series described 25 spindle cell tumours with CD34 and S100 co-expression without SOX10 reactivity, showing recurrent fusions in RAF1, BRAF and NTRK1/2 genes.
These tumours involved 15 adults and 10 children with soft tissue involved in 23 and bones in only two, in the mandible and maxilla, both in children. The histology of these kinase-fusion positive tumours shows a spectrum ranging from lipofibromatosis-like neural tumour, spindle cell tumours with CD34 and S100 reactivity resembling low grade malignant peripheral nerve sheath tumours (MPNST), and infantile fibrosarcoma (IFS) and IFS-like lesions.
The low grade lesions show low cellularity with bland spindle cells in a patternless or fascicular pattern, often with prominent stromal amianthoid and/or perivascular hyalinisation.
These tumours have minimal to mild atypia, very few or no mitotic figures and no necrosis. However, some of the tumours described by Suurmeijer et al. had mixed low and high grade areas.
In 2020, those tumours showing lipofibromatosis-like neural tumour, either pure or in hybrid form with part of the tumour showing lipofibromatosis-like neural tumour, were separated out into a distinct entity.
Of the 36 patients in that study, 94% were aged 30 years or less and most tumours involved extremities or trunk, usually located in the dermis or subcutis.
We describe the first case of a CD34 and S100 co-expressing spindle cell tumour with a BRAF-KIAA1549 fusion arising in a bone of an adult. A 73-year-old female presented with a 4-year history of right third metacarpal swelling. X-ray and computed tomography (CT) scan revealed an expansile lesion in the metacarpal involving almost the entire span of the bone, with a degree of bone loss in the dorsum of the bone. Magnetic resonance imaging (MRI) demonstrated the lesion was a lobulated mass replacing the third metacarpal shaft and head, measuring 28×23×49 mm. It showed intermediate T1 weighted signal, heterogeneous T2 weighted signal, and homogeneous post-contrast enhancement. A lobular portion of the lesion projected distally from the most dorso-radial aspect into the dorsal interval between second and third metacarpophalangeal joints with surrounding musculature effacement. Thallium demonstrated intense early accumulation with moderate retention.
The patient underwent CT core biopsy of the lesion, which identified it as a low grade spindle cell tumour with diffuse strong co-expression of S100 protein and CD34 (Fig. 1). SOX10 immunohistochemistry was negative. A KIAA1549-BRAF fusion was detected by Trusight RNA fusion panel (Illumina, USA). She then underwent surgical management via a third ray amputation. In the distal third of the metacarpal an expansile, solid, tan intramedullary lesion measuring 43×24×21 mm was identified. This lesion demonstrated extensive replacement of bone by a proliferation of spindle cells arranged in short fascicles with perivascular and stromal keloidal collagen similar to the core biopsy. Some of the tumour was low grade with no mitotic figures and low cellularity with strong uniform reactivity for CD34 and S100 protein (Fig. 1). Other areas showed high cellularity with four mitotic figures/mm2 (Fig. 2). Immunohistochemistry showed differential staining between the low and high grade areas with loss of S100 protein or both in the higher grade areas (Fig. 2). Some small immature chondroid islands and focal anaplasia were noted (Fig. 2). No necrosis was identified. The tumour infiltrated into the soft tissue beyond the bone. Margins were clear and no post-operative radiotherapy was administered. The patient is well without evidence of recurrence at 21 months.
Fig. 1(A) Coronal CT: right third metacarpal shaft shows an expansile, lytic lesion. (B) MRI: Tumour arising in third metacarpal. Lobulated, heterogenous T2 weighted signal mass arising from third metacarpal, extending between second and fourth metacarpals. (C) High power of low grade areas showing small spindle cells with prominent amianthoid stromal and perivascular collagen (H&E). (D) High power showing diffuse strong reactivity for S100 protein. (E) High power showing diffuse strong reactivity for CD34.
Fig. 2(A) Low power view of areas of high cellularity alternating with less cellular areas (H&E). (B) Low power of S100 showing areas of absent S100 in both the low and high cellularity foci. (C) Low power of CD34 showing areas of absent CD34. (D) High power of highly cellular mitotically active component. (E) High power of highly cellular component with anaplasia. (F) High power of immature chondroid elements.
Table 1 summarises reported S100+ CD34+ SOX10– spindle cell tumours with kinase fusions which do not have lipofibromatosis-like neural tumour pattern, infantile fibrosarcoma/fibrosarcoma pattern or prominent myopericytoma/haemangiopericytic pattern
Paediatric and adult soft tissue sarcomas with NTRK1 gene fusions: a subset of spindle cell sarcomas unified by a myopericytic/haemangiopericytic pattern.
Of 28 patients, there were equal numbers of males and females. Fifty percent were aged less than 30 years and 50% were older adults ranging from 35 to 77 years. Soft tissues were involved in 23/28 (82%), bones in 3/28 (11%) and viscera in 2/28 (7%). Sites affected included extremities in 15 (54%), trunk in eight (29%), head and neck in three (11%) and viscera in two (7%). Follow-up was available in 15 patients. Three (20%) died of or with disease at 25–375 months.
Three (20%) were alive with disease at 27–60 months. Eight (53%) have no evidence of disease at 9–248 months. Two older adults (13%) had documented visceral metastases.
Table 1Reported cases of S100+ CD34+ spindle cell tumours with protein kinase fusions excluding lipofibromatosis-like neural tumours, tumours with infantile fibrosarcoma/fibrosarcoma-like pattern and myopericytic pattern
AWD, alive with disease; CT, chemotherapy; DOD, died of disease; DOO, died other causes; DWD, died with disease; F, female; IC, increased cellularity; IM, intramuscular; LC, low cellularity; LR, local recurrence; M, male; mo, months; NA, not available; NED, no evidence of disease; RT, radiotherapy; SC, subcutis.
a Targeted therapy included bevacizumab, temsirolimus and sorafenib.
Recognition of this group of spindle cell tumours in soft tissue and bone by the unusual S100+ CD34+ S0X10– immunohistochemical profile is important so that investigation by an RNA fusion panel can be performed to look for BRAF, RAF1, RET, NTRK1-3, MET, ROS1 and ALK fusions. If these fusions are identified, there is potential for using specific kinase inhibitors such as BRAF and MEK inhibitors, NTRK inhibitors (entrectinib and larotrectinib), and crizotinib for ALK fusions. Efficacy has been demonstrated for these in soft tissue malignancies.
Some response has been reported in a high grade CD34+ S100+ spindle cell sarcoma with a KIAA1549-BRAF fusion to the combination targeted therapy comprising bevacizumab, temsirolimus and sorafenib.
The finding of negative reactivity for SOX10 is critical to exclude a low grade MPNST which can mimic this group of tumours. However, MPNST often shows loss of H3K27me and there is often associated neurofibroma, history or concurrent diagnosis of NF1 or intimate association with a peripheral nerve on imaging or at surgery.
The low grade cytology, low or absent mitotic activity and lack of necrosis in this group of CD34+ S100+ SOX10– spindle cell tumours may suggest a benign neoplasm, but even the low grade lesions have infiltrative margins so that wide local excision is recommended. A reported case of a 4-year-old boy with a tumour with low grade morphology in the mandible showed local recurrence which was treated with surgery and radiotherapy with no evidence of disease at 12 years follow-up.
Although there are some common morphological features to this group of spindle cell tumours, such as bland spindle cells with fascicular or patternless pattern and prominent stromal and perivascular hyalinisation, it is worth noting that some tumours like ours may appear low grade on initial core biopsies but harbour higher grade sarcomatous areas on resection with marked cellularity and mitotic activity. Focal heterologous immature chondroid matrix similar to our case was noted in one of the cases with sarcomatous areas in the series of Suurmeijer et al.
Although the typical immunophenotype includes diffuse S100 and CD34 reactivity, spindle cell tumours with similar histology and RAF1 fusions may show patchy or focal reactivity for one of these markers.
In conclusion, we have presented the first case of an S100+ CD34+ SOX10– spindle cell tumour with KIAA1549-BRAF fusion occurring in a bone (metacarpal) in an adult. Although initial histology of the core biopsies showed a low grade spindle cell tumour with patternless pattern and typical stromal and perivascular hyalinisation, the resection showed a biphasic tumour with foci of high cellularity and focal chondroid matrix. The immunohistochemical pattern also varied with the grade. There is a morphological spectrum ranging from low grade lipofibromatosis-like neural tumour to high grade sarcoma and there can be tumours similar to our case with both low and high grade morphology and increased mitotic activity. It is important to recognise them and treat appropriately, with consideration of targeted therapy with specific kinase inhibitors in advanced local or metastatic disease.
Conflicts of interest and sources of funding
The authors state that there are no conflicts of interest to disclose.
References
Suurmeijer A.J.H.
Dickson B.C.
Swanson D.
et al.
A novel group of spindle cell tumors defined by S100 and CD34 co-expresion shows recurrent fusions involving RAF1, BRAF, and NTRK1/2 genes.
Paediatric and adult soft tissue sarcomas with NTRK1 gene fusions: a subset of spindle cell sarcomas unified by a myopericytic/haemangiopericytic pattern.
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