The evolving pathology of solitary fibrous tumours. Luciane Dreher Irion MREH / CMFT / NSOPS

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1 The evolving pathology of solitary fibrous tumours Luciane Dreher Irion MREH / CMFT / NSOPS

2 Historical review Haemangiopericytoma (HPC) first described primarily as a soft tissue vascular tumour of pericytic origin (Stout and Murray, Ann Surg 1942) Pericytes described as pericapillary modified smooth muscle cells (Zimmermann, Z Anat Entwicklungsgesch 1923) Characteristic staghorn branching vascular pattern and profuse proliferation of obvious or occult capillaries surrounded by thin or thick layer of connective tissue sheath (Stout, Cancer 1949) en.wikipedia.org/wiki/stag

3 Haemangiopericytoma - Equivocal concept Morphology Characteristic (but not specific) features Vascular component easily identified but questionable pericytic differentiation EM- <30% (elongated cell processes, pericellular basal lamina, plasmalemmal pinocytosis, microfilaments) IHC % (SMA, HHF35 +ve) Difficulty in predicting clinical behaviour of morphologically bland lesions

4 Well defined non-hpc neoplasms that may display HPC-like features Frequent HPC-like features Synovial sarcoma Chondrosarcoma Infantile fibrosarcoma Occasional HPC-like features Nasopharyngeal angiofibroma Spindle cell lipoma Thymoma Sarcomatoid carcinoma Melanoma Mesothelioma Liposarcoma (pleomorphic, dedifferentiated) Leiomyosarcoma MPNST Low grade endometrial stromal sarcoma HPC was a diagnosis of exclusion! (Gengler & Guillou, 2006 Histopathology)

5 Historical review Pleural solitary fibrous tumour (SFT) first histological description (Wagner, Arch Heilk 1870) but recognised as distinct entity (Klemperer & Rabin, Arch Pathol 1931) SFT mesenchymal (mesothelial) neoplasm of the pleura with HPC-like features Later realised SFT in extrapleural sites (soft tissue and visceral organs) SFT indistinguishable from HPC on both light and electron microscopy

6 Historical review Gradual abandonment of HPC in favour of SFT Major histological and immunoprofile overlap Lack of clear criteria for differentiation Questionable pericytic origin Most lesions called HPC in past tend to be diagnosed as SFT now

7 Historical review Giant cell angiofibroma (GCA) first described in the orbit (Di Tos, Am J Surj Pathol 1995) Subsequent multiple extra-orbital descriptions Realisation of morphological and immunoprofile overlap between SFT and GCA

8 Immunoprofile Variable expression - CD34, CD99, BCL-2 Reappraisal of various entities sharing immunoprofile Old designation Conventional SFT Conventional HPC Lipomatous HPC Giant cell angiofibroma New designation Fibrous variant of SFT Cellular variant of SFT Fat rich variant of SFT Giant cell rich variant of SFT

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10 CD34 BCL2 CD99

11 WHO classification of soft tissue tumours 1994 HPC: Benign perivascular tumour SFT: Benign mesothelial tumour of pleura and peritoneum 2002 HPC: Formally abandoned. Fibroblastic rather than pericytic nature. Histologically indistinguishable from SFT. SFT: Fibroblastic tumour; intermediate (rarely metastasising) category 2013 SFT concept and classification unchanged.

12 Recent developments - Cytogenetics NAB2-STAT6 gene fusion - inv(12)(q13q13) Recently identified in SFT

13 Recent developments - Cytogenetics NAB2-STAT6 gene fusion - inv(12)(q13q13) Recently identified in SFT Robinson DR et al. Nat Genet Feb;45(2):180-5

14 Recent developments - Cytogenetics NAB2-STAT6 gene fusion - inv(12)(q13q13) Recently identified in SFT NAB2-STAT6 gene fusion results in overexpression of STAT6 demonstrable on IHC This may help distinguishing SFT from its histological mimics

15 Nuclear expression of STAT6 Tumour type Total cases Cellular angiofibroma 10 0 Dedifferentiated liposarcoma 21 3 (14) Desmoid fibromatosis 10 0 Deep fibrous histiocytoma 10 1 (10) Dermatofibrosarcoma protuberans 20 0 Gastrointestinal stromal tumour 10 0 Low grade fibromyxoid sarcoma 10 0 Malignant peripheral nerve sheath tumour 20 0 Monophasic synovial sarcoma 20 0 Sarcomatoid mesothelioma 10 0 Schwannoma 10 0 Soft tissue perineurioma 10 0 STAT6 positive (%) Solitary fibrous tissue (98) Spindle cell lipoma 10 0 (Doyle et al, Mod Pathol 2013)

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18 Persistent challenge Orbital clearance (resection, debulking) Review 10 orbital SFTs (Chen et al, 2012 Acta Neurochir) 4/10 patients had several local recurrences/operations (1/10 died from recurrence to hypothalamus) Biological behaviour prediction Benign --- Borderline --- Malignant Current IHC markers (STAT6, CD34, CD99, BCL2) do not correlate with prognosis Morphological features remain main features to assess aggressiveness! Malignant SFT: Diffuse hypercellularity Mitoses >4/10HPF Necrosis Cytological atypia (variable) Dedifferentiation (abrupt transition to anaplastic areas)

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21 5-10% of morphologically bland SFT develop recurrence or metastasis

22 Potential prognostic and therapeutic implications in malignant SFT KI67 - Increased proliferation fraction (>30%) Review of 10 cases with malignant / sarcomatous recurrences, all with previous (non-orbital) classic SFT (Collini et al, 2012 Am J Surg Pathol) 7/10 died 5/10 metastases 73 months relapse median time Overexpression of p13 and p53 in SFT anaplastic areas (Mosquera et al, 2009 Am J Surg Pathol) p53 mutation and p16 deletion: Aggressive behavior / worse prognosis / decreased survival in several sarcomas

23 Potential prognostic and therapeutic implications in malignant SFT KI67 - Increased proliferation fraction (>30%) Review of 10 cases with malignant / sarcomatous recurrences, all with previous (non-orbital) classic SFT (Collini et al, 2012 Am J Surg Pathol) 7/10 died 5/10 metastases 73 months relapse median time Overexpression of p16 and p53 in SFT anaplastic areas (Mosquera et al, 2009 Am J Surg Pathol) p53 mutation and p16 deletion: Aggressive behavior / worse prognosis / decreased survival in several sarcomas

24 Initial resection Recurrence KI67 KI67

25 Initial resection Recurrence p53 p53 p16 p16

26 Recurrence Abrupt transition to malignant features p53 p16

27 THANK YOU

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