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Mesenchymal neoplasms
of the gastrointestinal
tract – what’s new?
Newton ACS Wong
Department of Histopathology
Bristol Royal Infirmary
Talk plan
•Summary from 2010 talk.
•What’s happened since 2010.
•GISTs then other neoplasm
types.
•Diagnostic and clinical
relevance.
‘Since 2010’ – DOG1
•Co-expression of CD117 and DOG1:
•Adenocarcinoma and squamous
cell carcinoma (sarcomatoid)
•Neuroendocrine neoplasms
•Melanoma and synovial sarcoma
‘Since 2010’ – DOG1
•Co-expression of CD117 and DOG1:
•Adenocarcinoma and squamous
cell carcinoma (sarcomatoid)
•Neuroendocrine neoplasms
•Melanoma and synovial sarcoma
‘Since 2010’ – DOG1
•Co-expression of CD117 and DOG1:
•Adenocarcinoma and squamous
cell carcinoma (sarcomatoid)
•Neuroendocrine neoplasms
•Melanoma and synovial sarcoma
Prognostication for GIST
•Miettinen/AFIP classification
applies well to most adult GISTs
•Paediatric/wild type GISTs do
better than predicted by AFIP
system.
‘Since 2010’ – Prognostication
•Use 5 mm2 rather than 50
HPFs
•TNM7 – Poor take-up
(ESMO)
•Serosal tumour rupture
(Joensuu)
‘Since 2010’ – Prognostication
•Use 5 mm2 rather than 50
HPFs
•TNM7 – Poor take-up
(ESMO)
•Serosal tumour rupture
(Joensuu)
‘Since 2010’ – Chemotherapy
•Adjuvant imatinib:
− High risk (+/- moderate)
− ?tumour rupture
− Three years
− Mutation analysis
Hornick et al. Hum Pathol 2007; 38: 679.
(Platelet derived growth
factor receptor alpha)
Mutations of tyrosine kinases (TKs)
CD117 / c-
PRIMARY RESISTANCE / SENSITIVITY
IMATINIB: Sensitive primary mutations Resistant primary mutations
------------------------------------------------------------------------------------------------
KIT exon 11 KIT exon 9 (but dose escalation)
Upstream small mutations > KIT exon 17
downstream large deletions PDGFRA exon 18 (e.g. D842V)
Wild type
SUNITINIB: Sensitive primary mutations Resistant primary mutations
------------------------------------------------------------------------------------------------
KIT exon 9 KIT exon 11
Wild type PDGFRA exon 18 (D842V)
Wild type GISTs in adults
•Syndromic (Neurofibromatosis 1,
Carney triad and Carney Stratakis)
•Sporadic / non-syndromic
Wild type GISTs in adults
•Syndromic (Neurofibromatosis 1
and Carney syndromes)
•Sporadic / non-syndromic
Wild type GISTs in adults
•Syndromic (Neurofibromatosis 1
and Carney syndromes)
•Sporadic / non-syndromic
•Gastric
•Epithelioid/MCT
•Multinodular
•Multifocal
•Nodal spread
•Wild type
• Imatinib resistant
•Poorly predicted
by AFIP system
•Gastric
•Epithelioid/MCT
•Multinodular
•Multifocal
•Nodal spread
•Wild type
• Imatinib resistant
•Poorly predicted
by AFIP system
Nodes and GISTs
• If gastric, epithelioid/mixed
cell type and younger
female, should surgeon
harvest nodes?
•Block any lymph nodes
available.
•Gastric
•Epithelioid/MCT
•Multinodular
•Multifocal
•Nodal spread
•Wild type
• Imatinib resistant
•Poorly predicted
by AFIP system
Wild type GISTs
• Immunohistochemical
marker(s) for wild type GISTs
•BRAF and IGFR1 targeted
treatment
Wild type GISTs
• Immunohistochemical
marker(s) for wild type GISTs
•BRAF and IGFR1 targeted
treatment
Gastrointestinal smooth
muscle neoplasms
•‘Post GIST era’
•Diagnosis (new IHC markers)
•Classification
•Grading
Gastrointestinal smooth
muscle neoplasms
•Colorectal mucosal
leiomyomas
•Retroperitoneal uterine-like
leiomyomas [can be DOG1+]
•(Intra)mural smooth muscle
neoplasms
Smooth muscle IHC markers
•Caldesmon vs. smoothelin vs.
PLAP
•31 GI smooth muscle
neoplasms (3
leiomyosarcomas)
•111 other mesenchymal
neoplasms (16 neoplasm
types)
CALDESMON
Leiomyoma: 27/27
Leiomyosarcomas: 4/4 (focally reduced)
GIST: 11/20
Angiomyolipoma: 5/5
Glomus tumour: 6/7
SMOOTHELIN
Leiomyoma: 27/27
Leiomyosarcomas: 4/4 (focally reduced)
Angiomyolipoma: 1/5
Glomus tumour : 4/7
Smooth muscle IHC markers
•Sensitivity: 100% for all three
markers
•Specificity:
− Caldesmon 80%
− PLAP 96%
− Smoothelin 91%
Smooth muscle IHC markers
•PLAP antibodies:
− 8A9 monoclonal (Dako)
− A0268 polyclonal (Dako)
− PL8-Fm6 monoclonal
(Biogenex)
AFIP series Leiomyomas Leiomyosarcomas
Oesophagus 48 [“mitoses were 3 [all >50/50hpf]
rare”]
( Stomach 3 [all 0/50hpf] 1 [25/50hpf] )
Duodenum 4 [max 1/50hpf] 5 [five > 50/50hpf
one 6/50hpf]
Jejunum/Ileum 9 [max 3/50hpf] 16 [all > 35/50hpf
except one]
Colon 0 7 [all > 100/50hpf
except one]
Rectum 3 [all 0/50hpf] 8 [all >28/50hpf]
Intramural GI smooth
muscle neoplasms
•Clearer distinction between
leiomyomas and
leiomyosarcomas.
•Borderline/Low grade
LMS/STUMP neoplasms are
rare and should be treated
with complete surgical
excision.
RNFP
•Hx of intra-abdominal injury.
•Well circumscribed.
•Serosal/subserosal.
•(Myo)fibroblastic.
•Keloidal / collagen bundles.
•Chronic inflammation.
RNFP
•Hx of intra-abdominal injury.
•Well circumscribed.
•Serosal/subserosal.
•(Myo)fibroblastic.
•Keloidal / collagen bundles.
•Chronic inflammation.
•Non-neoplastic (IgG4 related?)
GNET
•Clear cell sarcoma-like
tumours of the GIT (CCSLTGT).
•NOT to be confused with
clear cell sarcoma of soft
parts.
•Small bowel >> Stomach and
large bowel
GNET
•Compared with clear cell
sarcoma of soft parts
(melanoma marker +ve).
•Autonomic NS primitive
neural stem cell?
•Poor prognosis.