Growth Factor Receptor Alpha Mutations Research Articles

Gastrointestinal Stromal Tumor – An Overview

AbstractGastrointestinal stromal tumors (GISTs) are rare tumors but are most common mesenchymal tumors of the digestive tract. They are commonly seen in the stomach (60%) and small intestine (30%). GISTs are likely derived from the interstitial cells of Cajal or their stem cell precursors. They are best characterized by computerized tomography and have a specific staining pattern on immunohistochemistry, i.e., C-Kit and DOG-1. The treatment of GIST is based on the risk assessment for relapse, and patients with localized GIST require resection with or without adjuvant imatinib mesylate (IM). Advanced unresectable tumors are usually treated with IM, with a number of further options available for patients post progression on IM. There is an increasing emphasis on identifying C-Kit and platelet-derived growth factor receptor alpha mutations in all patients with GIST, as these are driver mutations with current and future therapeutic implications.

Gastrointestinal stromal tumor with a platelet-derived growth factor receptor-alpha mutation

A 44-year-old man visited a local hospital, complaining of abdominal pain. The patient presented with muscular guarding in the upper abdomen and moderate anemia (hemoglobin, 6.7 g/dL). Computed tomography revealed a 9.0-cm tumor adjacent to the stomach and massive ascites (Panel A). The patient was diagnosed with hemoperitoneum caused by tumor rupture, and underwent laparotomy. Pathological examination revealed that the excised tumor was microscopically composed of cytoplasm-rich polygonal cells that were immunohistochemically positive for CD34 but negative for KIT (Panel B). Gene analyses revealed that the tumor had a deletion mutation in exon 18 (del 842-845) of platelet - derived growth factor receptor alpha ( PDGFRA ). Based on this finding, confirmative diagnosis of gastrointestinal stromal tumor (GIST) of the stomach was made. Despite tumor rupture, which is a significant risk factor for recurrence, the patient was postoperatively followed up without adjuvant treatment with imatinib because the PDGFRA -mutated GIST was reportedly resistant to the tyrosine kinase inhibitor (1). Eight years after the surgery, the patient is alive with no evidence of disease recurrence.

Efficacy of Imatinib in Patients with Platelet-Derived Growth Factor Receptor Alpha-Mutated Gastrointestinal Stromal Tumors.

PurposeThe incidence of gastrointestinal stromal tumors (GISTs) harboring platelet-derived growth factor receptor alpha (PDGFRA) mutations is low, therefore further investigation of the efficacy of imatinib in this subgroup was needed.Materials and MethodsPatients with PDGFRA-mutant GISTs who received imatinib as primary therapy for advanced disease between January 2000 and June 2012 were identified from the GIST registry of Asan Medical Center, Seoul, Korea.ResultsKIT and PDGFRA genotyping in 823 patients identified 18 patients (2%) with PDGFRA mutations who were treated with first-line imatinib. Exon 18 D842V substitution, non-D842V exon 18 mutations, and exon 12 mutations were detected in nine (50%), four (22%), and five (28%) patients, respectively. Objective response rate differed significantly between patients with the D842V mutation and those with non-D842V mutations (0% [0/5] vs. 71% [5/7], p=0.03). In all patients, median progression-free survival (PFS) and overall survival (OS) was 24.8 months (95% confidence interval [CI], 0.0 to 57.2) and 51.2 months (95% CI, 37.1 to 65.3), respectively. Significantly, poorer PFS was observed for patients with D842V-mutant GISTs than those with non-D842V PDGFRA-mutant GISTs: median 3.8 months (95% CI, 1.4 to 6.3) versus 29.5 months (95% CI, 18.3 to 40.7) (p < 0.001). Patients with the D842V mutation had poorer OS than those with non-D842V PDGFRA mutations: median 25.2 months (95% CI, 12.7 to 37.8) versus 59.8 months (95% CI, 43.0 to 76.5) (p=0.02).ConclusionImatinib is active against non-D842V PDGFRA-mutant GISTs, whereas GISTs harboring the D842V mutation are primarily resistant to imatinib.

Chronic eosinophilic leukemia with Fip 1-like 1-platelet-derived growth factor receptor alpha mutation: A rare case report

Chronic eosinophilic leukemia (CEL) is a rare cause of eosinophilia. CEL is known to be associated with BCR-ABL fusion gene or rearrangement of platelet-derived growth factor receptor alpha (PDGFRA), (Platelet-derived growth factor receptor betaPDGFRB or fibroblast growth factor receptor-1. CEL, no specific type excludes patients with the above mutations and necessitates the presence of clonal cytogenetic abnormality or blast cells more than 2% in peripheral blood and more than 5% in bone marrow. Imatinib mesylate inhibits Fip 1-like 1 (FIP1L1)-PDGFRA-induced colony formation, enabling cells to undergo normal differentiation. Our patient was diagnosed as a case of CEL on clinical grounds along with bone marrow morphology, and imatinib therapy was initiated empirically. Results of FIP1L1-PDGFRA gene rearrangements available subsequently were in concordance with patient profile and response to imatinib therapy.

Outcome of Patients with Platelet-Derived Growth Factor Receptor Alpha–Mutated Gastrointestinal Stromal Tumors in the Tyrosine Kinase Inhibitor Era

Platelet-derived growth factor receptor-alpha (PDGFRA) mutations are found in approximately 5% to 7% of advanced gastrointestinal stromal tumors (GIST). We sought to extensively assess the activity of imatinib in this subgroup. We conducted an international survey among GIST referral centers to collect clinical data on patients with advanced PDGFRA-mutant GISTs treated with imatinib for advanced disease. Fifty-eight patients were included, 34 were male (59%), and median age at treatment initiation was 61 (range, 19-83) years. The primary tumor was gastric in 40 cases (69%). Thirty-two patients (55%) had PDGFRA-D842V substitutions whereas 17 (29%) had mutations affecting other codons of exon 18, and nine patients (16%) had mutation in other exons. Fifty-seven patients were evaluable for response, two (4%) had a complete response, eight (14%) had a partial response, and 23 (40%) had stable disease. None of 31 evaluable patients with D842V substitution had a response, whereas 21 of 31 (68%) had progression as their best response. Median progression-free survival was 2.8 [95% confidence interval (CI), 2.6-3.2] months for patients with D842V substitution and 28.5 months (95% CI, 5.4-51.6) for patients with other PDGFRA mutations. With 46 months of follow-up, median overall survival was 14.7 months for patients with D842V substitutions and was not reached for patients with non-D842V mutations. This study is the largest reported to date on patients with advanced PDGFRA-mutant GISTs treated with imatinib. Our data confirm that imatinib has little efficacy in the subgroup of patients with D842V substitution in exon 18, whereas other mutations appear to be sensitive to imatinib.

Plexiform Fibromyxoma

A great majority of gastric mesenchymal tumors are gastrointestinal stromal tumor (GIST). A rare group of non-GISTs include myxoid mesenchymal neoplasms. In this report, we describe 12 cases of a distinctive gastric tumor, named here as plexiform fibromyxoma. These tumors occurred in 5 men and 7 women of ages 7 to 75 years (median, 41 y). All tumors were located in the gastric antrum and 6 of them also extended into extragastric soft tissues or into the duodenal bulb. The tumors measured from 3 to 15 cm (median, 5.5 cm). Histologically typical was a plexiform intramural growth with multiple micronodules containing paucicellular to moderately cellular myxoid to collagenous and fibromyxoid neoplastic elements. A prominent, sometimes plexiform capillary pattern was typically present. Extramural components included subserosal nodules, and sometimes more cellular, solid nonplexiform spindle cell proliferation. The tumor cells varied from oval to spindled and had limited atypia and mitotic activity < 5/50 high-power fields. Frequent ulceration, mucosal invasion, and vascular invasion (4 cases) had no adverse significance in these tumors. Immunohistochemically, the tumor cells were positive for alpha smooth muscle actin, and variably for CD10, and were consistently negative for KIT, DOG1, CD34, desmin, and S100 protein. No KIT or platelet-derived growth factor receptor alpha mutations were present in the 3 examined cases. None of the 4 patients who were followed from 9 to 20 years (median, 19 y) developed recurrences or metastases. Additional 3 patients survived 14 to 25 years with unknown tumor status. Review of large numbers of mesenchymal tumors in the esophagus and intestines did not reveal similar tumors. Plexiform fibromyxoma is a distinctive benign gastric antral neoplasm that should be separated from GIST, nerve sheath tumors, and other fibromyxoid neoplasms.

Extra‐abdominal subcutaneous metastasis of a gastrointestinal stromal tumor: report of a case and a review of the literature

Gastrointestinal stromal tumors (GISTs) metastasize primarily within the peritoneal cavity and to the liver. Superficial soft tissue metastases occur in about 1% of advanced GIST and are mostly associated with abdominal laparotomy scars and advanced disease. Extra-abdominal subcutaneous metastases of GIST have not been previously reported. Subcutaneous spindle cell tumors constitute a diagnostic challenge of which the differential diagnostic list can be limited by recognition of morphological, immunohistochemical en molecular genetic patterns. A 69-year-old woman presented with a fast growing subcutaneous nodule on her right upper arm. She was known with an imatinib-resistant advanced GIST, treated with sunitinib. The nodule was excised. Histopathological examination revealed a sharply demarcated tumor nodule in the subcutaneous fat with slightly spindled tumor cells, with pleomorphic nuclei and multiple mitoses. There was a hemangiopericytomatous vascular pattern. The cells stained positive for CD117 (KIT) and CD34. No KIT or platelet-derived growth factor receptor-alpha mutations were detected. We report the first case of an extra-abdominal subcutaneous metastasis of GIST. Although rare, metastatic GIST should therefore be included in the differential diagnosis of subcutaneous spindle cell tumors. A comparative survey of the histological, immunohistochemical and molecular genetic features of spindle cell tumors of the subcutis and a review of the literature is presented.

True Smooth Muscle Tumors of the Small Intestine

Gastrointestinal stromal tumors (GISTs) comprise a great majority of small intestinal mesenchymal tumors previously designated as smooth muscle tumors (SMTs), but true SMTs occur with a low-frequency encompassing both leiomyomas and leiomyosarcomas (LMSs). In this study, we analyzed 25 tumors in the spectrum of primary SMTs of the small intestine. Metastatic tumors and those with external attachment only were excluded. These tumors occurred in 15 men and 10 women of median age of 62 years (range: 18 to 80 y). There were 9 well-differentiated SMTs with no atypia and low mitotic activity [< or = 5/50 high-power fields (HPFs)] and these were considered leiomyomas. All 6 tumors examined were positive for SMA and desmin, and negative for KIT; all 3 tumors in female patients that were tested were negative for estrogen receptor. Two leiomyomas, a 5 mm, and another, 2 cm tumor, were examples of a muscularis mucosae leiomyomas. The other 7 were considered intramural leiomyomas; their median diameter was 4.5 cm (range: 0.8 to 9 cm). No patient with these tumors experienced recurrences or metastases, and 6 patients were alive with a median follow-up of 16 years (range: 9 to 28 y). Sixteen tumors had atypia and mitotic activity warranting the designation of LMS. One of these tumors, a 16 cm diverticular tumor, had mitotic activity of only 1/50 HPFs, and this tumor recurred 4 times. All other LMSs had > or =35 mitoses/50 HPFs. Four of 5 such LMSs with follow-up recurred or metastasized, and at least 3 patients died of disease; several others had a short survival but cause of death could not be determined. One patient, an 18-year-old woman, who died of LMS, was a survivor of a Wilms tumor radiated in infancy. All 6 LMSs studied for GIST-specific KIT and platelet-derived growth factor receptor alpha mutations showed wild-type sequences. This series demonstrates that primary small intestinal SMTs are rare (estimated frequency 1 SMT for 36 GISTs). A majority of these are mitotically active tumors with atypia warranting the diagnosis of LMS, and have a high malignant potential. The number of LMS cases is too small for stratification for risk assessment. True SMTs of small intestine should be separated from GISTs because of different pathogenesis and treatment.

A gastrointestinal stromal tumor of the stomach morphologically resembling a neurofibroma: demonstration of a novel platelet-derived growth factor receptor α exon 18 mutation

Gastrointestinal stromal tumors are increasingly being recognized because of their characteristic expression of KIT (CD 117). Most KIT-positive gastrointestinal stromal tumors have activating mutations in the c-kit gene. A subgroup of gastrointestinal stromal tumors are negative for KIT expression, and in these tumors, activating mutations in platelet-derived growth factor receptor alpha are common. Most platelet-derived growth factor receptor alpha mutation-positive gastrointestinal stromal tumors show an epithelioid histology and are located in the stomach. Herein, we describe an unusual gastric stromal tumor. The tumor was negative for KIT expression and the morphology did not show an epithelioid pattern but rather was composed of bland spindle cells reminiscent of a neurofibroma. Molecular analysis revealed a somatic mutation in platelet-derived growth factor receptor alpha exon 18 (D842F). Aside from demonstrating a new platelet-derived growth factor receptor alpha mutation, this case illustrates the usefulness of molecular testing as a diagnostic tool and clearly indicates the wide range of morphology that can be observed in gastrointestinal stromal tumors.

Treating Cancer by Blocking Cell Signals

Cancer development and propagation occur through defects inside and outside the cancer cell. Extracellular events occur in the stroma and vasculature. A central role in dysregulated cell function is attributed to signaling systems. In multicellular organisms, a diverse array of growth factors, cytokines, and proto-oncogenes transduce their growth-promoting signals through the activation of phosphor-relay modules. These modules, composed of protein kinases, transduce signals from the cell surface to the nucleus, leading to gene transcription and the activation of myriad metabolic processes. Cell signaling is tightly controlled for normal cell functioning, and dysregulation of this system through genetic alterations can lead to the malignant phenotype of uncontrolled proliferation, inhibition of apoptosis, metastasis, and angiogenesis. Protein kinases play a central role in dysregulated cell signaling. In particular, two pathways have been found to be critical for maintenance of the malignant phenotype. The lipid kinase phosphoinositide 3-OH kinase (PI3K) pathway and its downstream targets, such as the protein-serine/threonine kinases Akt and p70 S6 kinase (p70), are crucial effectors in oncogenic signaling, as is the Ras-Raf-MAP (mitogen-activated protein) kinase pathway. Due to cross talk between signaling pathways, these two signaling modules are inter-related rather than linear, and they interact with important cytoplasmic protein kinases (of which at least 32 have been described) such as bcr-abl, src, and JAK/STAT (Janus kinase/signal transducer and activators of transcription). The central role of protein kinases in oncogenesis makes these molecules attractive targets for cancer therapy. However, despite the wealth of potential targets, the most advanced compounds currently on the market or in clinical development target only a handful of the bestcharacterized kinases. The modulation of kinase activity can be achieved through several strategies: blocking of circulating ligand, inhibition of ligand binding to extracellular components of membrane receptors, inhibition of phosphorylation activity by blocking adenosine triphospage (ATP) binding, disruption of protein-protein interactions, and downregulation of kinase gene expression by antisense or RNA interference approaches. Blocking of circulating ligand and inhibition of ligand binding to membrane receptors have been achieved through the use of monoclonal antibodies, and represent a successful strategy, as evidenced by the approval of trastuzumab, bevacizumab, and cetuximab for a number of solid tumor indications. While the inhibition of intracellular signaling represents an opportunity for the design of multiple approaches, the inhibition of ATP binding to the kinase domain of multiple proteins appears to be the most druggable strategy, and represent the only successful approach to date, as evidenced by the approvals of imatinib, gefitinib, and erlotinib for various indications. A problem that has emerged with this approach is the emergence of resistance due to specific mutations in these kinase domains. This issue reviews a number of these agents in clinical trials. Platelet derived growth factor receptor alpha mutations in a panel of more than 1,000 gastrointestinal stromal tumors and their relationship to imatinib sensitivity have been elegantly described. A phase I study of the first-generation MEK (MAP kinase– extracelluar receptor kinase [ERK]) inhibitor CI-1040 is presented here. Although the development of this agent has been discontinued because of poor pharmacologic properties, two second-generation agents in this class are currently undergoing clinical testing. Multikinase inhibitors are undoubtedly attracting attention currently. A number of these are highlighted in Table 1. The initial phase I studies of the dual HER1/HER2 kinase inhibitor, lapatinib is reported in this volume. Finally, several studies of the mammalian target of rapamycin (mTOR) inhibitor CCI-779 are presented here. This illustrates the pivotal role of the Akt-mTOR axis in malignant cell survival and apoptosis, as well as its role in transducing signals from VOLUME 23 d NUMBER 23 d AUGUST 1

PKC theta, a novel immunohistochemical marker for gastrointestinal stromal tumors (GIST), especially useful for identifying KIT‐negative tumors

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor in the digestive tract and the majority of GIST has characteristic gain-of-function mutations of the c-kit gene, which encodes the KIT receptor for stem cell factor. The present study aimed to establish the usefulness of protein kinase C theta (PKC theta) as an immunohistochemical marker for GIST in comparison with KIT immunohistochemistry. PKC theta immunohistochemistry was carried out not only on 48 cases of GIST and another 40 cases of gastrointestinal mesenchymal tumors, but also on 24 cases of various tumors known to be immunohistochemically positive for KIT. Immunohistochemically, 41 out of 48 cases (85%) of GIST were positive for PKC theta, and its expression was confirmed by Western blot analysis using six cases of surgically resected GIST. In the present study there were six GIST immunohistochemically negative for KIT, which histologically revealed a myxoid epithelioid appearance characteristic to that of GIST with platelet-derived growth factor receptor alpha mutation. All six GIST were immunohistochemically positive for PKC theta. No PKC theta immunoreactivity was observed in other gastrointestinal mesenchymal tumors and various KIT-positive tumors except for three cases (14%) of gastrointestinal schwannomas. The present study revealed that PKC theta is an immunohistochemically novel and useful marker for GIST, especially for GIST negative for KIT.