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Spindle Cell Tumours of the Gastro-Intestinal Tract

Spindle Cell Tumours of the Gastro-Intestinal Tract. Geraint T Williams Pathology Department Wales College of Medicine Cardiff University. GI Spindle Cell Tumours early 1990s. Leiomyomas Epithelioid leiomyomas Leiomyosarcomas Neurofibromas Schwannomas Malignant Schwannomas.

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Spindle Cell Tumours of the Gastro-Intestinal Tract

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  1. Spindle Cell Tumours of the Gastro-Intestinal Tract Geraint T Williams Pathology Department Wales College of Medicine Cardiff University

  2. GI Spindle Cell Tumours early 1990s • Leiomyomas • Epithelioid leiomyomas • Leiomyosarcomas • Neurofibromas • Schwannomas • Malignant Schwannomas

  3. Immunostaining early 1990s • Desmin • Smooth muscle actin • Smooth muscle myosin • S-100 protein • Neurofilament • PGP9.5

  4. GI Spindle Cell Tumours mid 1990s Many tumours with equivocal immunostaining: • GISTs • GANTs • STUMPs • SITSFs • OSTs, GaSTs, DuSTs, JeSTs, ISTs, CoSTs, ReSTs, ASTs

  5. Gastrointestinal Stromal Tumours 2000s Immunopositivity for: • c-kit (KIT, CD117) • CD34 • bcl-2 • nestin • protein kinase C-theta

  6. Leiomyoma • Oesophagus, stomach, small bowel • Usually <0.5 cm, polypoid and asymptomatic • Most related to muscularis mucosae • Oesophageal leiomyomas in MEN1 • LOH at 11q13 • Microleiomyomas at oesophago-gastric junction in 8% population • Diffuse oesophageal leiomyomatosis • associated with Alports-type nephropathy • Peritoneal leiomyomatosis

  7. Leiomyosarcoma • Very rare • Oesophagus, stomach, small bowel • Expresses desmin and/or smooth muscle actin • Usually high grade (>10 mitoses/10 HPFs)

  8. Ganglioneuromatosis Diffuse submucosal and myenteric: May cause motility disorders/megacolon NF-1 Multiple endocrine neoplasia IIb Shekitka et al 1994 Am J Surg Pathol 18: 250-7 Smith et al 1999; Gut 45: 143-6

  9. Ganglioneuromatosis Diffuse submucosal and myenteric: May cause motility disorders/megacolon NF-1 Multiple endocrine neoplasia IIb Polypoid mucosal: Juvenile polyposis Cowden’s syndrome

  10. Gastrointestinal “Schwannoma” • Benign • Not associated with NF-1 • No NF2 lesions • Majority gastric, occasionally oesophageal or colonic, virtually never in small bowel • Intramural or polypoid • No necrosis, haemorrhage or cystic change Sarlomo-Rikala & Miettinen 1995 Histopathology 27: 355–60 Hou et al 2005 Histopathology in press

  11. Gastrointestinal “Schwannoma” • Typically brisk lymphoid reaction, usually as a peritumoural lymphoid cuff, often with germinal centres • Mainly spindle, rarely epithelioid • Verocay bodies unusual • Significant nuclear atypia but mitoses very sparse

  12. Gastrointestinal “Schwannoma” • S-100 positive • GFAP and nestin usually positive • Occasional CD34 positive cell • KIT, SMA, CK, NF, desmin negative

  13. Mucosal epithelioid nerve sheath tumours • Small polyps • Epithelioid cells in nests and whorls • Intranuclear pseudoinclusions • S-100 positive • KIT negative Lewin et al 2005 Am J Surg Pathol 29: 1310

  14. Benign fibroblastic polyps of the colon • Solitary • Bland monotonous mucosal spindle cell proliferation • Vimentin positive only Eslami-Varzanehet al 2004 Am J Surg Pathol 28: 374

  15. Gastrointestinal Stromal Tumours Immunopositivity for: • vimentin 95-100% • nestin 90-100% • CD34 70-85% (low in SI) • smooth muscle actin 20-40% (high in SI) • heavy caldesmon 60-80% • connexin 43 most SI, rare in stomach • desmin 5-20% • S-100 0-15% (mainly SI) • cytokeratin rare

  16. KIT (CD117) • Receptor for Stem cell factor • Trans-membrane tyrosine kinase growth factor receptor • Expressed on • Haemopoietic stem cells • Mast cells • Melanocytes • Breast epithelium • Interstitial cells of Cajal (pacemaker cells)

  17. Interstitial cells of Cajal • Gut pacemaker cells • Form intramural network • Develop from intrinsic gut mesenchyme • Common precursor with smooth muscle cells • Express KIT and nestin

  18. Interstitial cells of Cajal • Similar cells now described in • Pancreas • Portal vein • Fallopian tube • Myometrium • Breast

  19. KIT Mutations in GISTs • Activating mutations exon 11, occasionally in exon 9 • ~ 85% of GISTs • More frequent in malignant GISTs • Different mutations (exon 17) in mast cell tumours Hirota et al 1998 Science 279:577

  20. KIT mutations in GISTs • “Early” event in tumorigenesis • Transfection into cell lines leads to transformation by • autophosphorylation of KIT • ligand-independent tyrosine kinase activity • cell proliferation Hirota et al 1998 Science 279:577 Rubin et al 2001 Cancer Res 61:8118

  21. KIT Mutations in GISTs • Present in 72% • 80% exon 11 • 17% exon 9 • Exon 9 more frequent in aggressive small bowel GISTs • Exon 11 nearly all spindle cell Penzel et al 2005 J Clin Pathol 58:634

  22. Familial GISTs • Germline mutations of KIT • Multiple tumours • Cutaneous hyperpigmentation • Hyperplasia of Cajal cells • GI Motility disorders • Some overlap with NF-1 Hirota et al 1998 Nat Genet 19: 323 Chompret et al 2004 Gastroenterology 126: 318

  23. Chromosomal abnormalities in GISTs • Most tumours: • 14q, 22q deletion • Malignant tumours: • 1p, 9p deletion • 8q and 17q amplification

  24. Gastrointestinal Stromal Tumours (GISTs) • Incidence 14.5/million/year (prevalence 129/million) • 5th-7th decade • Decreasing frequency down GI tract • Pedunculated, dumb-bell or ulcerated • May arise in mesentery, omentum, retroperitoneum • Prediction of behaviour unreliable • Predisposition: • Familial • Neurofibromatosis • Carney’s triad Nilsson et al 2005 Cancer 103:821

  25. GISTs in NF-1 • Multiple tumours • Mainly in small intestine • Spindle cell, low grade • Often skeinoid fibres • Often S-100 positive • KIT and PDGFRA mutations uncommon • Background Cajal cell hyperplasia Andersson J et al 2005 Am J Surg Pathol 29: 1170-6 Takazawa et al 2005 Am J Surg Pathol 29: 755-63

  26. Carney Syndromes Carney J A The triad of gastric epithelioid leiomyosarcoma, pulmonary chondroma and functioning extra-adrenal paraganglioma: a 5-year review. Medicine 1983; 62: 159–169 Carney J A, Stratakis C A Familial paraganglioma and gastric stromal sarcoma: a new syndrome distinct from the Carney triad. Am J Med Genet 2002; 108: 132-139

  27. Gastrointestinal Stromal Tumours (GISTs) • Small tumours found incidentally • Symptomatic • Obstruction • Bleeding

  28. Malignant GISTs • Approximately 30-45% • Notoriously difficult to predict • Intra-abdominal spread, especially multinodular peritoneal seeding • Distant metastases: • Liver • Lung • Bone

  29. GISTs - Outcome • Resectable • 10 year survival 30-50% • Unresectable, metastatic • median survival 12 months • no response to conventional chemotherapy

  30. Predictors of Malignant Behaviour in GISTs • Uncertain malignant potential • Low malignant potential • High malignant potential

  31. Major Predictors of Malignant Behaviour in GISTs • Size (>5 cm) • Mitotic counts (>5/50 HPF)

  32. Risk of Aggressive Behaviour (NIH) Fletcher et al 2002 Hum Pathol 33: 459-465

  33. Behaviour of GISTs Frequency Tumour- Median related deaths survival (months) Low malignant potential 56% 1% High malignant potential 29% 63% 40 Overtly malignant 15% 83% 16 Nilsson et al 2005 Cancer 103:821

  34. Other Predictors of Malignant Behaviour in GISTs • Site (stomach vs intestine)

  35. Gastric GISTs Miettinen et al 2005 Am J Surg Pathol 29: 52-68

  36. Other Predictors of Malignant Behaviour in GISTs • Site (stomach vs intestine) • Histological type (epithelioid>spindle) • Cellularity and pleomorphism • Invasive pattern

  37. Other Predictors of Malignant Behaviour in GISTs • Chromosome 9q deletion • 1530ins6 mutation of KIT (intestine) • P16 loss • P53 positivity (gastric GISTs) Lasota et al 2003 Hum Pathol 34: 1306 Gunawan et al 2004 J Pathol 202:421 Feakins 2005 Histopathology 46: 270 Schneider-Stock et al 2005 Clin Cancer Res 11: 638

  38. Gastrointestinal Stromal Tumours (GISTs) • Spindle cell • Epithelioid • Round cell • Clear cell • Plasmacytoid • Pleomorphic

  39. Differential Diagnosis Inflammatory fibroid polyp Inflammatory myofibroblastic tumour Solitary fibrous tumour Mesenteric fibromatosis Dedifferentiated liposarcoma

  40. Inflammatory Fibroid Polyp Stomach, ileum, proximal colon Usually presents with intussusception Centred on submucosa Distinctive histology: Thin-walled blood vessels Onion-skin arrangement of palisaded spindle cells around larger blood vessels Oedema Eosinophils

  41. Inflammatory Fibroid Polyp CD34 positive fascin positive bcl-2 negative KIT negative CD99 negative Pantanowitz et al 2004 Am J Surg Pathol 28: 107

  42. Inflammatory Myofibroblastic Tumour • Loose mixture of fibroblasts, myofibroblasts and inflammatory cells • May be ganglion-like cells • CD34 negative • ALK-1 positive • May be KIT positive • ? tumour of fibroblastic reticulum cells Nonaka et al 2005 Histopathology 46: 604

  43. Solitary Fibrous Tumour Wide spectrum histologically Fascicular or storiform pattern Ectatic vessels CD34 positive Bcl-2 positive KIT negative CD99 positive

  44. Mesenteric Fibromatosis May be KIT positive (depending on antibody) beta-catenin positive (nuclear) CD34 negative Montgomery al 2002 Am J Surg Pathol 26: 1296

  45. Dedifferentiated Liposarcoma mdm2 positive cdk4 positive S-100 positive may be KIT positive

  46. Differential Diagnosis Kaposi’s sarcoma KIT negative Angiosarcoma CD31 positive Occasionally KIT positive Mesothelioma Rare weak positivity for KIT

  47. Differential Diagnosis Sarcomatoid carcinoma / carcinosarcoma Rarely KIT positive (GISTs may show perinuclear dot staining for CAM5.2) Small cell carcinoma Metastases: melanoma seminoma myeloproliferative lesions, mast cell tumours breast, ovarian, nasopharyngeal, colorectal carcinoma

  48. Problems with KIT immunostaining • Different antibodies with different sensitivity and specificity (e.g. mesenteric fibromatosis) • Pre-treatment affects staining • Expensive • Level of expression variable • Granular cytoplasmic staining alone unreliable • Membranous and/or paranuclear dot reliable • Use normal stomach as control • watch for aberrant expression in smooth muscle

  49. KIT-negative GISTs • Epithelioid morphology commoner • Usually CD34 and Protein kinase C-theta positive • Usually have 14q and 22q deletions • (and 1p deletions in malignant tumours) Debiec-Rychter et al 2004 J Pathol 202:430

  50. KIT-negative GISTs • ~30% have activating mutations of Platelet derived growth factor receptor-alpha (PDGFRA, tyrosine kinase) • Exon 18, occasionally in exon 12 • KIT and PDGFRA mutations mutually exclusive Heinrich et al 2003 Science 299:708 Debiec-Rychter et al 2004 J Pathol 202:430 Medeiros et al 2004 Am J Surg Pathol 28: 889

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