Changing phenotype of gastrointestinal stromal tumours under imatinib mesylate treatment: a potential diagnostic pitfall.
OBJECTIVE
The diagnosis of gastrointesinal stromal tumours (GISTs) is widely based on morphological features and KIT (CD117) immunoreactivity. Most patients with advanced GISTs show a major clinical response after treatment with imatinib mesylate. The histopathological features of GISTs in patients on prolonged imatinib treatment have, thus far, not been addressed in detail. In this report, we present three patients with metastatic GISTs, who received more than 1 year of therapy with imatinib, and whose tumours changed their morphological and immunohistochemical characteristics during continued treatment with the drug.


RESULTS
All three primary GISTs from these patients were classical spindle-type tumours, showing diffuse, strong CD117, CD34, and focal alpha-smooth muscle actin expression. During treatment, two clinically progressive and one clinically stable GIST revealed a diffuse epithelioid, or pseudopapillary epithelioid growth pattern, characterized by rounded cells with eosinophilic cytoplasm and uniform round-to-ovoid nuclei. In addition, GIST specimens from patients on therapy showed complete loss of CD117 immunoreactivity. Remarkably, two of these tumours also became CD34 immunonegative and in one case the progression was accompanied by desmin expression. KIT mutational analysis revealed the presence of distinct exon 11 mutant isoforms in all cases examined, while the same genotype was sustained in the base line and on-therapy tumour specimens, proving the common origin of analysed specimens.


CONCLUSIONS
GISTs subject to imatinib treatment can undergo striking (immuno)phenotypic changes, which are not necessarily corroborated by new genotypic modifications. Because these may mimic other tumour types, this feature creates a differential diagnostic challenge, of which the pathologist should be aware.
Department of Human Genetics, Catholic University of Leuven, Leuven, Belgium.
P
P
Pauwels
M
M
Debiec-Rychter
M
M
Stul
I
I
De Wever
A T
AT
Van Oosterom
R
R
Sciot
D000199:Actins / Q000032:analysis; D000328:Adult; D000368:Aged; D018952:Antigens, CD34 / Q000032:analysis; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D014408:Biomarkers, Tumor / Q000032:analysis; D003893:Desmin / Q000032:analysis; D046152:Gastrointestinal Stromal Tumors / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry / Q000379:methods / Q000592:standards*; D007633:Keratins / Q000032:analysis; D008875:Middle Aged; D009130:Muscle, Smooth / Q000737:chemistry; D010879:Piperazines / Q000627:therapeutic use*; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis; D011743:Pyrimidines / Q000627:therapeutic use*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
D000199:Actins; D018952:Antigens, CD34; D000970:Antineoplastic Agents; D001549:Benzamides; D014408:Biomarkers, Tumor; D003893:Desmin; D010879:Piperazines; D011743:Pyrimidines; D007633:Keratins; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit