Chin-Yuan Tzen

Anaplastic Carcinoma of the Thyroid Arising More Often from Follicular Carcinoma than Papillary Carcinoma

BackgroundAnaplastic thyroid carcinoma (ATC), a rare and highly malignant tumor, has long been thought to arise from well-differentiated carcinoma (WDC) such as follicular thyroid carcinoma (FTC) and papillary thyroid carcinoma (PTC). The purpose of this study was to test this notion by examining whether and, if so, how often ATC harbors the oncogenes that are commonly associated with WDC, such as RAS in FTC and BRAF in PTC.MethodsWe analyzed the mutation hotspots of BRAF (codon 600) and N-, K-, and H-RAS (codons 12, 13, and 61) in 16 ATCs. We also examined two genes, PIK3CA (exons 9 and 20) and TP53 (exons 5–9), both of which have been reported in ATCs.ResultsThe results showed that approximately 31% (5 of 16) of ATCs harbored N-RAS mutation, 6% (1 of 16) had mutated BRAF, and approximately 56% (9 of 16) had mutated TP53. As to the three ATCs that had coexisted PTCs, mutated BRAF was detected in all PTC components but only in one ATC, while mutated PIK3CA was found in only one PTC component but not in the ATC.ConclusionA number of ATCs arise from WDCs, more often from RAS-mutant tumors than from BRAF-mutant tumors, implying that particular attention should be paid to the WDC harboring RAS mutation.

Incidence of gastrointestinal stromal tumor: a retrospective study based on immunohistochemical and mutational analyses.

The aim of this study is to estimate the incidence of the gastrointestinal stromal tumor after the previous diagnoses were confirmed and/or revised by both immunohistochemical and mutational analyses. We reviewed 17,858 surgically excised gastrointestinal lesions in our hospital from 1998 to 2004. All mesenchymal tumors were examined for CD117 expression by immunohistochemistry, and every CD117-negative mesenchymal tumors were further subjected to mutational analysis for KIT and PDGFRA exons. The results showed that approximately 35% of gastrointestinal stromal tumors were misdiagnosed if immunohistochemical analysis of CD117 expression was not performed; and approximately 15% misdiagnosed if mutation analysis was not available. Because approximately 4.72% of patients with gastrointestinal malignancies in Taiwan were treated in our hospital and the average of newly diagnosed gastrointestinal stromal tumors in our hospital was 14.33 cases per year, the estimated annual incidents of gastrointestinal stromal tumor in Taiwan were 303.60. Therefore, the annual incidence of gastrointestinal stromal tumor is 13.74 per million Taiwanese.

Unexpected rapid progression of metastatic adenoid cystic carcinoma during treatment with imatinib mesylate.

There is a lack of effective treatment for metastatic adenoid cystic carcinoma (ACC), a usually indolent tumor. We studied the efficacy of imatinib mesylate, a potent inhibitor of KIT tyrosine kinase, in patients with KIT‐positive metastatic ACC.

Molecular analysis of secondary kinase mutations in imatinib-resistant gastrointestinal stromal tumors

Most gastrointestinal stromal tumors (GISTs) are associated with activating kinase mutation in KIT or platelet-derived growth factor receptor alpha (PDGFRA) gene, and imatinib has revolutionized the care of advanced GISTs. However, most patients gradually developed resistance to imatinib. We intend to identify the secondary kinase mutations in imatinib-resistant GISTs and to study the relationship between secondary kinase mutations and the clinical response to imatinib. Twelve advanced GIST patients, who have developed resistance to imatinib were included in this study. Paraffin-embedded pretreatment GIST specimens and progression lesions of the tumors after resistance to imatinib were analyzed for kinase mutations in exons 9, 11, 13, and 17 of KIT gene and exons of 10, 12, 14, and 18 of PDGFRA gene. Primary KIT mutations have been found in all but one of the primary tumors including one case harboring de novo double KIT exon 11 mutations. Secondary kinase mutations in KIT and PDGFRA were found in seven and 1 of 12 patients, respectively. Two patients harbored more than one secondary KIT mutations in different progression sites, and there are four types of clonal or polyclonal evolution being observed. The secondary PDGFRA exon 14 mutation H687Y is a novel mutation that has never been reported before. Acquired secondary kinase mutations are the most important cause of secondary imatinib resistance in advanced GISTs. The identification of secondary kinase mutations is important in the development of new therapeutic strategies.

Sequence polymorphism in the coding region of mitochondrial genome encompassing position 8389–8865

Analysis of the polymorphic sequences in mitochondrial DNA (mtDNA) has been widely applied to forensic tests and anthropology studies. However, these polymorphic data in human have thus far been derived from the displacement-loop and intergenic regions only. Here, we report the identification of clustered polymorphic sites in the mitochondria coding region encompassing position 8389-8865. The DNA sequences of 119 unrelated Chinese were determined by PCR amplification and direct sequencing. The results showed that heteroplasmy was found in five individuals, 39 sites were noted in this 477 bp region, and 41 haplotypes were identified. The probability of identity and allelic diversity were estimated as 0.1265 and 0.8809, respectively. The results suggest that sequence polymorphism from position 8389-8865 in human mtDNA can be used as a marker for identity investigation.

Neurofibromatosis with gastrointestinal stromal tumors: insights into the association.

The frequent association of stromal tumors with neurofobromatosis raises high suspicion of a possible correlation between the two entities. The aim of this study was to analyze clinicopathologic features of patients with concomitant neurofibromatosis and gastrointestinal stromal tumors and to discuss the molecular basis for their possible pathogenesis. Detailed information about clinical presentation, histology, immunostains, polymerase chain reaction amplification, and sequencing in three of our own cases was obtained. Stromal tumors presented with abdominal pain in one case and hemorrhage in another. One patient underwent surgery for malignant transformation of neurofibroma and stromal tumors were found incidentally. Stromal tumors were consistently positive for CD117, while the malignant peripheral sheath tumor was not. Mutation in the KIT juxtamembrane domain was found in one case. In this respect, some stromal tumors lack demonstrable KIT mutations but KIT remains activated. We reasoned that other mechanisms, like the Ras pathway involved in neurofibromatosis type 1, might play a role in KIT activation.

Intrahepatic cholestasis as a paraneoplastic syndrome associated with pheochromocytoma

Pheochromocytoma is a rare tumor of chromaffin cells that secrete catecholamines and several cytokines. The clinical manifestations are protean and may include hypertension, weight loss, sweating, palpitation, headache, anxiety, tremor, nausea, vomiting, and hypercalcemia. The tumor can mimic many unrelated diseases, leading to significant delay and difficulty in diagnosis. We report a case of a 37-yr-old male admitted with jaundice, dark urine, fever, and signs of a systemic inflammatory response. Abdominal computed tomography revealed a heterogeneously enhancing tumor between the pancreatic tail and left kidney. There was no evidence of obstruction to bile flow, neoplastic involvement of the liver or bile ducts, or infectious etiology. The tumor was removed and found to be a pheochromocytoma. Immunohistochemical analysis revealed the presence of interleukin-1β in the tumor cells. After surgery, the jaundice resolved without further treatment, leading us to the conclusion that it was a paraneoplastic phenomenon possibly related to interleukin-1β production. We suggest that occult pheochromocytoma should be added to the differential diagnosis of unexplained intrahepatic cholestasis.

Prophylactic Intravesical Instillation of Epinephrine Prevents Cyclophosphamide-Induced Hemorrhagic Cystitis in Rats

The objective of this study is to investigate the potential protective effects of intravesical instillation of epinephrine in cyclophosphamide-induced hemorrhagic cystitis. In an earlier study, we have shown that epinephrine promotes hemostasis on established hemorrhagic cystitis induced by cyclophosphamide. Female Sprague-Dawley rats were divided into seven groups as follows: group 1: positive control (150 mg/kg, cyclophosphamide, i.p.), group 2: negative control (10 μ g/ml, epinephrine, intravesical), co-administration of cyclophosphamide (150 mg/kg, i.p.), group 3: saline (intravesical), groups 4–6: epinephrine (2.5, 5, and 10 μ g/ml, intravesical), and group 7: mesna (50 mg/kg, i.p.). Rats were sacrificed on 3 consecutive days and the urinary bladders were removed, weighed, and evaluated. The vesical vascular permeability was determined by wet bladder weight and Evan’s blue dye absorbance. After 24 hours of cyclophosphamide administration, severe hemorrhagic cystitis was induced with marked edema, hemorrhage, and inflammation. In the epinephrine-treated groups, symptoms of hemorrhagic cystitis (such as edema, inflammation, and hemorrhage) were reduced significantly. Intravesical instillation of epinephrine prevents edema, hemorrhage, and inflammation in rats with cyclophosphamide-induced hemorrhagic cystitis.

Detection of mycobacteria in Crohn's disease by a broad spectrum polymerase chain reaction.

BACKGROUND The role of mycobacterial infection, particularly related to Mycobacterium avium subsp paratuberculosis (Map), in Crohns disease has long been debated. We developed primer pairs capable of detecting a broad spectrum of mycobacterium and employed them to investigate surgical specimens from patients with Crohns disease. METHODS Pan mycobacterium primers of the 65-kDa heat shock protein gene (Hsp65) were used in a polymerase chain reaction (PCR) to examine 12 surgically-resected, formalin-fixed, paraffin-embedded specimens from 11 patients with Crohns disease. The DNA sequences of amplicons were aligned with those in GenBank. RESULTS Mycobacterial DNA was found in specimens from three of 11 patients. M. mucogenicum was identified in a specimen from one patient and M. tuberculosis in two, but Map was not identified in any. CONCLUSION Hsp65-based PCR can be employed to search for occult mycobacterial infection of the gastrointestinal tract in patients with a diagnosis or suspicion of Crohns disease. This approach may have a therapeutic implication.

Spontaneous rupture of recurrent gastrointestinal stromal tumor associated with neurofibromatosis type 1

The incidence of gastrointestinal stromal tumor (GIST) among neurofibromatosis type 1 (NF-1) patients is approximately 3.9-25%, and this relationship is generally considered to be non-coincidental. We report a patient with NF-1 who underwent laparotomy 3 times due to recurrent intra-abdominal tumor rupture with internal bleeding in the space of 13 years. The pathologic diagnoses were schwannoma, malignant peripheral nerve sheath tumor and GIST. Because of the similar histologic features of these tumors, we considered them to be of the same nature. Immunohistochemical staining can help in the differential diagnosis. We suggest that NF-1 patients with gastrointestinal symptoms receive further survey to rule out GISTs.