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 %
nestin %
CD % (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 % (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:
Takazawa et al 2005 Am J Surg Pathol 29:

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:

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 Unresectable, metastatic
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:

33. Behaviour of GISTs Low malignant potential 56% 1%
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

51. PDGFRA mutation in GISTs
Autophosphorylation and ligand-independent activation of tyrosine kinase receptor
Heinrich et al 2003 Science 299:708

52. PDGFRA mutant, KIT-negative GISTs
Mainly gastric
Mainly epithelioid
Tumour giant cells
Usually low mitotic rate
83% benign behaving
Lasota et al 2004 Lab Invest 84:874
Pauls et al 2005 Histopathology 46:166
Penzel et al 2005 J Clin Pathol 58:634

53. PDGFRA immunostaining
8/125 GISTs (all 8 KIT-negative)
4/15 intra-abdominal desmoids
0/12 leiomyomas
0/8 leiomyosarcomas
0/3 schwannomas
0/2 solitary fibrous tumours
0/1 inflammatory fibroid polyp
0/1 inflammatory myofibroblastic tumour
Rossi et al 2005 Histopathology 46:522

54. DOG-1 “Discovered on GIST-1”
Identified through gene expression profiling
Expressed in 136/139 GISTs irrespective of KIT or PDGFRA mutation status
0/17 fibromatosis
0/3 schwannomas
4/438 non-GISTs
synovial sarcoma, leiomyosaroma, fibrosarcoma, Ewings sarcoma/PNET
West et al 2004 Am J Pathol 165:107

55. Imatinib (ST1571; Glivec)
Tyrosine kinase inhibitor developed as inhibitor of PDGF receptor
Powerful inhibitor of ABL tyrosine kinases
Effective treatment for chronic myeloid leukaemia (ABL and BCR-ABL)
Dramatic response of malignant GIST with relatively mild toxicity
Joenssu et al 2001 NEJM 344:1052

56. Imatinib (ST1571; Glivec) EORTC Phase I study in advanced cases showed
inhibition of tumour growth in 32/36 cases
>50% volume reduction in 19 patients
side effects (nausea, vomiting, oedema, rash) limited treatment in 5 patients
response seen within 2 months
Similar findings in US Study of 36 patients
van Oosterom et al 2001 Lancet 358:1421

57. Imatinib (ST1571; Glivec) Phase III study: 946 patients
5% complete response
47% partial response
32% stable
median time to best response 107 days
73% free from progression at 12 months
serious side effects 37%
Verweij J et al 2004 Lancet 364: 1127

58. Imatinib (ST1571; Glivec) Complete response very unusual
Partial response rates
85 Exon 11 KIT mutations 83.5%
23 Exon 9 KIT mutations 47.8%
“Escape” with time in some cases
associated with novel KIT mutations (exon 17)
Heinrich et al 2003 J Clin Oncol 21: 4342
Chen et al 2004 Cancer Res 64: 5913
Antonescu et al 2005 Clin Cancer Res 11: 4182

59. NICE proposals - Imatinib
400mg/day for KIT-positive unresectable or metastatic disease
Continue only if response is achieved within 12 weeks

60. Response to Imatinib South West Oncology Group
Assessed by CT, MRI or PET
Complete response
Partial response
Stable disease
Progressive disease
Unknown

61. NICE proposals - Imatinib
400mg/day for KIT-positive unresectable of metastatic disease
Continue only if response is achieved within 12 weeks
For responders continue until development of progressive disease
Increased dose not recommended in non-responders
£19,000 per year

62. CSTI571-B2222 Phase II, 147 patients, 91% KIT +ve
Unresectable or metastatic GIST
400mg or 600mg/day for median 21 months
Survival 88% at 1 year 78% at 2 years
No CR, 66% PR, 17% stable, 12% progressive
Improved performance status
15% major adverse events, 10% withdrew
Resistance in 16 pts, 3 primary, 13 secondary

63. (SU11248) Multi-targeted tyrosine kinase inhibitor
Objective response or stable disease in 26/48 progressing tumours on imatinib
Particular benefit in exon 9 mutants
Demetri et al 2004 ASCO Abstract 3001

64. Imatinib-treated GISTs
Myxoid, gelatinous consistency; cystic change
Decreased cellularity
Stromal hyalinisation
More epithelioid
Loss of KIT and/or CD34 immunoreactivity
Acquired desmin immunoreactivity
Novel KIT mutations especially exon 17
Antonescu et al 2005 Clin Cancer Res 11: 4182
Loughrey et al 2005 J Clin Pathol 58: 779
Pauwels et al 2005 Histopathology 47: 41

65. Conclusions
Diagnosis of GI spindle cell tumours, and GIST in particular, is important
Should be made by experienced pathologists with access to quality-assured KIT immunostaining
Molecular diagnosis likely to become important
Managed by MDT
Surgery is first line therapy
Imatinib should be considered for patients with advanced or unresectable tumours
Participate in trials