Transcript Grand Round Presentation - British Division of the I A P

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
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Leiomyomas
Epithelioid leiomyomas
Leiomyosarcomas
Neurofibromas
Schwannomas
Malignant Schwannomas
Immunostaining early 1990s
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Desmin
Smooth muscle actin
Smooth muscle myosin
S-100 protein
Neurofilament
PGP9.5
GI Spindle Cell Tumours
mid 1990s
Many tumours with equivocal immunostaining:
• GISTs
• GANTs
• STUMPs
• SITSFs
• OSTs, GaSTs, DuSTs, JeSTs, ISTs, CoSTs,
ReSTs, ASTs
Gastrointestinal Stromal Tumours
2000s
Immunopositivity
for:
• c-kit (KIT, CD117)
• CD34
• bcl-2
• nestin
• protein kinase C-theta
Leiomyoma
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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
Leiomyosarcoma
• Very rare
• Oesophagus, stomach, small bowel
• Expresses desmin and/or smooth
muscle actin
• Usually high grade (>10 mitoses/10
HPFs)
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
Ganglioneuromatosis
Diffuse submucosal and myenteric:
May cause motility disorders/megacolon
NF-1
Multiple endocrine neoplasia IIb
Polypoid mucosal:
Juvenile polyposis
Cowden’s syndrome
Gastrointestinal “Schwannoma”
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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
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
Gastrointestinal “Schwannoma”
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S-100 positive
GFAP and nestin usually positive
Occasional CD34 positive cell
KIT, SMA, CK, NF, desmin negative
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
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
Gastrointestinal Stromal Tumours
Immunopositivity for:
• vimentin
• nestin
• CD34
• smooth muscle actin
• heavy caldesmon
• connexin 43
• desmin
• S-100
• cytokeratin
95-100%
90-100%
70-85% (low in SI)
20-40% (high in SI)
60-80%
most SI, rare in stomach
5-20%
0-15% (mainly SI)
rare
KIT (CD117)
• Receptor for Stem cell factor
• Trans-membrane tyrosine kinase growth
factor receptor
• Expressed on
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Haemopoietic stem cells
Mast cells
Melanocytes
Breast epithelium
Interstitial cells of Cajal (pacemaker cells)
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
Interstitial cells of Cajal
• Similar cells now described in
– Pancreas
– Portal vein
– Fallopian tube
– Myometrium
– Breast
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
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
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
Familial GISTs
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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
Chromosomal abnormalities in
GISTs
• Most tumours:
– 14q, 22q deletion
• Malignant tumours:
– 1p, 9p deletion
– 8q and 17q amplification
Gastrointestinal Stromal Tumours
(GISTs)
• Incidence 14.5/million/year (prevalence 129/million)
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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
GISTs in NF-1
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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
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
Gastrointestinal Stromal Tumours
(GISTs)
• Small tumours found incidentally
• Symptomatic
– Obstruction
– Bleeding
Malignant GISTs
• Approximately 30-45%
• Notoriously difficult to predict
• Intra-abdominal spread, especially multinodular
peritoneal seeding
• Distant metastases:
– Liver
– Lung
– Bone
GISTs - Outcome
• Resectable
– 10 year survival 30-50%
• Unresectable, metastatic
– median survival 12 months
– no response to conventional chemotherapy
Predictors of Malignant
Behaviour in GISTs
• Uncertain malignant potential
• Low malignant potential
• High malignant potential
Major Predictors of Malignant
Behaviour in GISTs
• Size (>5 cm)
• Mitotic counts (>5/50 HPF)
Risk of Aggressive Behaviour (NIH)
Size
Mitotic Count
Very lo w risk
<2 cm
<5/50 HPF
Low risk
2-5 cm
<5/50 HPF
Intermedi ate risk
<5 cm
5-10 cm
6-10/50 HPF
<5/50 HPF
High risk
>5 cm
>10 cm
Any s ize
>5/50 HPF
Any rate
>10/50 HPF
Fletcher et al 2002 Hum Pathol 33: 459-465
Behaviour of GISTs
Frequency
Tumourrelated deaths
Median
survival
(months)
Low malignant potential
56%
1%
High malignant potential
29%
63%
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Overtly malignant
15%
83%
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Nilsson et al 2005 Cancer 103:821
Other Predictors of Malignant
Behaviour in GISTs
• Site (stomach vs intestine)
Gastric GISTs
Size
Mitotic Count
<2 cm
<5/50 HPF
2-10 cm
<5/50 HPF
Uncertain or low
malignant poten tial
<2cm
>5/50 HPF
Low to moderate
malignant poten tial
2-5 cm
>10 cm
>5/50 HPF
<5/50 HPF
High m alignant
potential
>5 cm
>5/50 HPF
Benign
Probably b enign
Miettinen et al 2005 Am J Surg Pathol 29: 52-68
Other Predictors of Malignant
Behaviour in GISTs
• Site (stomach vs intestine)
• Histological type (epithelioid>spindle)
• Cellularity and pleomorphism
• Invasive pattern
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
Gastrointestinal Stromal Tumours
(GISTs)
• Spindle cell
• Epithelioid
• Round cell
• Clear cell
• Plasmacytoid
• Pleomorphic
Differential Diagnosis
Inflammatory fibroid polyp
Inflammatory myofibroblastic tumour
Solitary fibrous tumour
Mesenteric fibromatosis
Dedifferentiated liposarcoma
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
Inflammatory Fibroid Polyp
CD34 positive
fascin positive
bcl-2 negative
KIT negative
CD99 negative
Pantanowitz et al 2004 Am J Surg Pathol 28: 107
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
Solitary Fibrous Tumour
Wide spectrum histologically
Fascicular or storiform pattern
Ectatic vessels
CD34 positive
Bcl-2 positive
KIT negative
CD99 positive
Mesenteric Fibromatosis
May be KIT positive (depending on
antibody)
beta-catenin positive (nuclear)
CD34 negative
Montgomery al 2002 Am J Surg Pathol 26: 1296
Dedifferentiated Liposarcoma
mdm2 positive
cdk4 positive
S-100 positive
may be KIT positive
Differential Diagnosis
Kaposi’s sarcoma
KIT negative
Angiosarcoma
CD31 positive
Occasionally KIT positive
Mesothelioma
Rare weak positivity for KIT
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
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
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
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
PDGFRA mutation in GISTs
• Autophosphorylation and ligandindependent activation of tyrosine kinase
receptor
Heinrich et al 2003 Science 299:708
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
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
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
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
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
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
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
NICE proposals - Imatinib
• 400mg/day for KIT-positive unresectable or
metastatic disease
• Continue only if response is achieved within
12 weeks
Response to Imatinib
• South West Oncology Group
• Assessed by CT, MRI or PET
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Complete response
Partial response
Stable disease
Progressive disease
Unknown
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
CSTI571-B2222
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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
(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
Imatinib-treated GISTs
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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
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