4. Hrvatski kongres kliniËke citologije 4th Croatian Congress ... - Penta

Clinical Cytology - Plenary and Invited Lectures
MORPHOLOGICAL AND MOLECULAR ANALYSIS OF GISTS ON CYTOLOGY
Schmitt FC
Medical Faculty of Porto University, Unit of Molecular Pathology - IPATIMUP, Porto,
Portugal
The term “targeted therapies” refers to treatment strategies directed against molecular
targets considered to be involved in the process of neoplastic transformation. One of the
most attractive molecular targets for therapeutic intervention in cancer is the protein tyrosine
kinase (TK) family. More than 100 dominant oncogenes are recognized to data and
many encode receptor and cytoplasmic TKs known to be mutated and/or overexpressed
in human cancers. Targeting receptor protein kinases family as cancer therapy has continued
to become a compelling approach with time. However, some general conditions
should be considered prior to selecting a TK as a therapeutic target in cancer. It should
be involved in experimental tumour progression and be demonstrable in diagnostic tumour
tissue. (Cyto)pathology is crucial for the accurate assessment of the target to ensure
that the patients who may benefit from the therapy are correctly identified.
Since the last decade, there have been an increasing number of new drugs which indications
depends upon a pathological report. Fine needle aspiration (FNA) cytology has
proven its value as a minimally invasive, easy, accurate and reliable technique for the
diagnosis of tumours and has also been used for the assessment of prognostic and predictive
factors. The evaluation of predictive factors in FNA specimens should be largely
confined to patients who will undergo neoadjuvant chemotherapy before surgery or in
the setting of metastatic disease. FNA is a less traumatic method that provides a good
source of cancer cells to study therapeutic targets.
Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of
the gastrointestinal tract, with an annual incidence of 10 to 20 cases per million, being
most commonly found in the stomach (40 to 70%), in the small intestine (20 to 50%), in
the colon and rectum (5 to 15%), and in the esophagus (< 2%). Activating mutations of
c-kit oncogene are the major genetic alterations in GISTs. c-kit is a proto-oncogene
that codes for a transmembrane TK receptor: CD117. Once activated, KIT propagates
signalling events throughout the cell via multiple signal transduction pathways. Until
recently, the prognosis of patients with GISTs was poor due to its frequent recurrence
and resistance to chemo and radiotherapy regimens. The development and current
treatment with specific RTK inhibitors is changing this scenario. Imatinib mesylate is
a selective inhibitor of RTKs, by competing with the ATP for its binding site, preventing
further phosphorylations of signaling molecules downstream of the receptor, responsible
for abnormal viability and proliferation signals in these cells. Several studies have
linked different responses to the drug with c-kit alterations. In particular, tumors harboring
exon 11 c-kit mutations are more likely to respond to an Imatinib therapy than
those with either exon 9 c-kit mutations or no detectable mutation. Currently, Imatinib is
used for the treatment of Kit positive GIST patients with unresectable and/or metastatic
malignant tumor. Besides Imatinib, another RTK inhibitor, Sunitinib has been approved
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4 th Croatian Congress of Clinical Cytology / 1 st Croatian Symposium of Analytical Cytology / 2 nd Croatian Symposium of Cytotechnology