PDGFRα‐ and c‐kit‐mutated gastrointestinal stromal tumours (GISTs) are characterized by distinctive histological and immunohistochemical features

Pauls, K. Amande M.; Merkelbach‐Bruse, Sabine; Thal, Dietmar Rudolf; Büttner, Reinhard; Wardelmann, Eva

doi:10.1111/j.1365-2559.2005.02061.x

Cited by 109 publications

(105 citation statements)

References 23 publications

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“…27 A recent study showed strong association between perinuclear dotlike KIT expression pattern and presence of KIT mutation, and suggested that such a pattern is a diagnostic feature of KIT-mutant GISTs. 28 PDGFRA N659-mutant GISTs, analyzed in this study, showed either diffuse or focal perinuclear dot-like KIT expression pattern. Based on our previous experience 1,22 and the current study, perinuclear dot-like KIT expression pattern is not necessarily associated with the presence of KIT mutation.…”

Section: Discussionmentioning

confidence: 60%

“…2 However, recently, detection of PDGFRA expression in FFPE tissues using polyclonal antibody provided by Santa-Cruz Biotechnology Inc. (Santa Cruz, CA, USA) has been reported. 28,29 Moreover perinuclear dot-like expression pattern was linked to the tumors with mutations in PDGFRA exon 12 or 18. 28 More studies are required to validate the recently published observations on immunohistochemical detection of PDGFRA in FFPE GISTs.…”

Section: Discussionmentioning

confidence: 99%

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GISTs with PDGFRA exon 14 mutations represent subset of clinically favorable gastric tumors with epithelioid morphology

Lasota

Stachura

Miettinen

2006

Laboratory Investigation

124

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Gastrointestinal stromal tumors (GISTs) are common mesenchymal tumors of the gastrointestinal tract. Activating KIT or PDGFRA (platelet-derived growth factor receptor a) mutations have been shown to be a major force in GIST pathogenesis. Recently, a previously undescribed N659K PDGFRA exon 14 mutation has been reported in GISTs. The purpose of this study was to evaluate the frequency of GISTs with PDGFRA exon 14 mutations and define the clinicopathologic profile of such tumors. In all, 200 GISTs negative for mutations in KIT exons 9, 11, 13 and 17 and PDGFRA exons 12 and 18 were evaluated for PDGFRA exon 14 mutations by PCR amplification and direct sequencing. Mutations were found in 11 of 119 (9%) gastric GISTs. None of the 81 GISTs from other than gastric location had such a PDGFRA mutation. A majority of these mutations (eight cases) represented simple 2125C4A or C4G missense mutations, leading to substitution of the lysine for asparagine (N659K). However, in two cases, 2123A4T missense mutations leading to substitution of the tyrosine for asparagine (N659Y) was found instead. Of 11 PDGFRA N659-mutant GISTs, 10 had pure epithelioid morphology. One tumor had mixed, predominantly spindle and focally epithelioid cell morphology. Frequency of PDGFRA N659-mutant GISTs among pure epithelioid GISTs was almost 19%. Immunohistochemically, the majority (64%) of these tumors lacked KIT expression or showed only focal scattered KIT positivity. Tumor size ranged from 2.5 to 16 cm (average 7.1 cm). Low mitotic activity, r5 mitoses/50 high power field was detected in six GISTs including larger, 45 cm tumors. Based on mitotic activity and tumor size, six tumors were classified as probably benign with very low malignant potential. Low to moderate malignant potential and high malignant potential was suggested in three and two tumors, respectively. In four cases with moderate or high malignant potential GISTs, a long-term follow-up (average 235.5 months) showed favorable course of disease.

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

GISTs with PDGFRA exon 14 mutations represent subset of clinically favorable gastric tumors with epithelioid morphology

Lasota

Stachura

Miettinen

2006

Laboratory Investigation

124

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“…Among the 6 CD117 negative samples, 5 samples were PDGFRA positive, showed that PDGFRA was highly expressed in CD117 negative GISTs, in agreement with references. It can be indicated that the combined detection of CD117 and PDGFRA will have clinical significance, but PDGFRA is not the specific marker of GISTs, there are no reliable antibodies of PDGFRA for paraffin embedded tissues, so the reports of PDGFRA immunohistochemical staining were rare and the results are disaccord (Medeiros et al, 2004;Pauls K et al, 2005;Rossi et al, 2005;Miettinen and Lasota, 2006;Peterson et al, 2006). The diagnose value of PDGFRA is minimized for also the reason that other tumors (leiomyosarcoma and synovial sarcoma) may be PDGFRA positive.…”

Section: Discussionmentioning

confidence: 99%

Expression of DOG1, CD117 and PDGFRA in Gastrointestinal Stromal Tumors and Correlations with Clinicopathology

Sun

Feng²,

Huang³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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“…Histomorphologic subtype was evaluated as previously described (14) and was given as spindle cell type, epithelioid cell type, and mixed type. GIST diagnosis cType of response and progression-free survival after onset of imatinib treatment in months.…”

Section: Methodsmentioning

confidence: 99%

Polyclonal Evolution of Multiple Secondary KIT Mutations in Gastrointestinal Stromal Tumors under Treatment with Imatinib Mesylate

Wardelmann

Merkelbach‐Bruse²,

Pauls³

et al. 2006

Clinical Cancer Research

340

246

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Gastrointestinal stromal tumors (GIST) are characterized by a strong KIT receptor activation most often resulting from KIT mutations. In a smaller subgroup of tumors without KIT mutations, analogous activating mutations are found in the platelet-derived growth factor receptor a (PDGFRa) gene. Both PDGFRa and KIT receptors are targets of the tyrosine kinase inhibitor imatinib (Glivec) which has improved the treatment of advanced GISTs significantly. However, a subgroup of tumors show a secondary progress under therapy with imatinib after initial response. One possible mechanism of secondary resistance is the development of newly acquired KIT mutations. In the present study, we evaluated the frequency of such secondary KIT mutations in a series of GIST patients in which tumor tissue was resected under treatment. We examined one to seven different tumor areas in 32 cases (total of 104 samples) and found up to four newly acquired KIT mutations in 14 patients (43.8%). These were always located in exons encoding the first or second tyrosine kinase domain (exon 13, 14, or 17). Mutations were found only in a subset of samples analyzed from each case whereas others retained the wild-type sequence in the same region. There was never more than one new mutation in the same sample. Consistent with a secondary clonal evolution, the primary mutation was always detectable in all samples from each tumor. According to our results, the identification of newly acquired KIT mutations in addition to the primary mutation is dependent on the number of tissue samples analyzed and has high implications for further therapeutic strategies.

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PDGFRα‐ and c‐kit‐mutated gastrointestinal stromal tumours (GISTs) are characterized by distinctive histological and immunohistochemical features

Cited by 109 publications

References 23 publications

GISTs with PDGFRA exon 14 mutations represent subset of clinically favorable gastric tumors with epithelioid morphology

GISTs with PDGFRA exon 14 mutations represent subset of clinically favorable gastric tumors with epithelioid morphology

Expression of DOG1, CD117 and PDGFRA in Gastrointestinal Stromal Tumors and Correlations with Clinicopathology

Polyclonal Evolution of Multiple Secondary KIT Mutations in Gastrointestinal Stromal Tumors under Treatment with Imatinib Mesylate

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