bromochloroacetic-acid and Gastrointestinal-Stromal-Tumors

After an initial benefit from tyrosine kinase inhibitors (TKI), most gastrointestinal stromal tumors (GISTs) eventually develop disease progression or secondary resistance. An altered tumor (immune)phenotype with anaplasia and morphological changes secondary to therapy have occasionally been described in the literature. We present a 52-year old patient, diagnosed with high risk, spindle-cell, GIST (CD117 positive, Pankeratin negative) in 2003, showing a c-Kit exon 11 mutation. After TKI therapy, he developed drug resistance and disease progression. Pathological assessment of the last surgical specimen showed a pure epithelioid/clear cell histology, without evidence of cellular anaplasia. Tumor cells were CD117 positive, DOG1 positive but also E-cadherin positive and Pankeratin positive, whereas molecular analysis confirmed the presence of the c-Kit exon 11 mutation, with no additional mutations. We describe an unusual case of GIST showing peculiar (immuno)phenotypic changes under therapy, different from the vast majority of therapy-driven changes, which include marked cellular pleomorphisms and KIT immunonegativity. Possible molecular explanations to understand these phenomena and a brief review of the literature are also addressed.

Topics: Antineoplastic Agents; Cadherins; Gastrointestinal Neoplasms; Gastrointestinal Stromal Tumors; Humans; Keratins; Middle Aged; Phenotype; Protein Kinase Inhibitors

Topics: Actins; Anoctamin-1; Antigens, CD34; Biomarkers, Tumor; Chloride Channels; Desmin; Gastrointestinal Stromal Tumors; Humans; Immunohistochemistry; Keratins; Neoplasm Proteins; Nestin; Proto-Oncogene Proteins c-kit; S100 Proteins

We report a case of microcystic/reticular schwannoma of the proximal sigmoid colon in a 61-year-old man. A 12-mm polyp was detected while the patient was undergoing screening for colorectal neoplasm. This rare variant of schwannoma was initially described in 2008 and shows a predilection for the visceral organs, predominantly the gastrointestinal tract. We also review 11 other reported cases of microcystic/reticular schwannomas in the gastrointestinal tract. Unlike conventional gastrointestinal schwannomas, which are more common in the stomach, this variant appears to be more common in the large intestine. Histologic examination of this polyp showed predominant lipoblast-like vacuolated cells within a myxoid stroma with focal spindle cell areas. Features suggestive of malignancy, like nuclear pleomorphism, mitosis, or necrosis, were absent. Immunohistochemistry for S100 protein showed strong nuclear and cytoplasmic positivity, whereas cytokeratin and CD117 stains were negative. It is important to entertain microcystic/reticular schwannoma in the differential diagnosis of a signet ring cell adenocarcinoma or a myxoid gastrointestinal stromal tumor, particularly on small biopsy specimens.

Topics: Calgranulin A; Carcinoma, Signet Ring Cell; Colonic Neoplasms; Diagnosis, Differential; Gastrointestinal Stromal Tumors; Humans; Immunohistochemistry; Keratins; Male; Microscopy, Electron, Transmission; Middle Aged; Neurilemmoma; Proto-Oncogene Proteins c-kit

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal neoplasms of the digestive tract. They are relatively rare neoplasms compared with gastrointestinal carcinomas and usually can readily be differentiated from carcinomas based on the morphology of the neoplastic cells that are typically spindled (70%), pure epithelioid, or mixed type. GISTs in general lack expression of cytokeratin and exhibit immunoreactivity toward CD117, CD34, or DOG1. GISTs can demonstrate a pure epithelioid morphology that can appear similar histologically to a carcinoma. Very few epithelioid GISTs have been reported to express cytokeratin, which can lead to diagnostic challenges especially in cases with pure epithelioid morphology. Epithelioid GISTs should be considered in the differential diagnosis when evaluating gastrointestinal neoplasms with overlapping epithelioid and carcinoma-like morphology. An accurate diagnosis can be made using additional immunohistochemical studies directed against CD117, CD34, or DOG1. Advanced investigations such as mutation analysis of KIT using molecular pathology methods can further assist in confirming the diagnosis.

Topics: Aged; Anoctamin-1; Antigens, CD34; Antineoplastic Agents; Biomarkers, Tumor; Diagnosis, Differential; Follow-Up Studies; Gastrointestinal Neoplasms; Gastrointestinal Stromal Tumors; Humans; Imatinib Mesylate; Immunohistochemistry; Keratins; Male; Mutation; Neoplasm Proteins; Proto-Oncogene Proteins c-kit; Stomach

Topics: Adult; Biomarkers, Tumor; Calmodulin-Binding Proteins; Diagnosis, Differential; Gastrointestinal Neoplasms; Gastrointestinal Stromal Tumors; High-Throughput Nucleotide Sequencing; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Keratins; Male; MART-1 Antigen; Melanoma; Middle Aged; Neoplasm Recurrence, Local; Neuroectodermal Tumors; RNA-Binding Proteins; S100 Proteins; Sarcoma, Ewing; SOXE Transcription Factors; Synaptophysin

Activation of the epithelial-to-mesenchymal transition (EMT) endows extraordinary invasive capability of cancer cells and causes of treatment failure and metastasis in gastrointestinal stromal tumor (GIST); however, the molecular mechanisms governing GIST invasion remain largely unknown. MicroRNAs (miRNAs) have been shown to play critical roles in cell motility and invasion, which promotes us to study the biological functions of miR-137 in the EMT of GIST. We have found that miR-137 was dramatically downregulated in clinical specimen of GIST. Using an in silico analysis approach, Twist1, a key regulator gene of EMT, has been identified as the target of miR-137. Quantitative RT-PCT and western blot were used to confirm that miR-137 directly targeted on Twist1 and repressed Twist1 expression in GIST-H1 human gastrointestinal stromal tumor cell line. Further, miR-137 was found to increase expression of E-cadherin and cytokeratin, but suppress expression of N-cadherin and vimentin. In vitro experiments have shown that miR-137 enhanced the epithelial cell morphology, decreased GIST cell migration, activated G1 cell cycle arrest, and induced cell apoptosis. These results suggest a novel mechanism that miR-137 regulates EMT and inhibits cell migration via Twist1 downregulation. Therefore, miR-137 may function as anti-migration and anti-metastasis in GIST and our study provides a potential approach for developing miR-137-based therapeutic strategy for GIST.

Topics: 3' Untranslated Regions; Apoptosis; Base Sequence; Blotting, Western; Cadherins; Cell Cycle; Cell Line, Tumor; Cell Movement; Down-Regulation; Epithelial-Mesenchymal Transition; Gastrointestinal Neoplasms; Gastrointestinal Stromal Tumors; Gene Expression Regulation, Neoplastic; Humans; Keratins; MicroRNAs; Microscopy, Fluorescence; Nuclear Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Sequence Homology, Nucleic Acid; Twist-Related Protein 1; Vimentin

Topics: Aged; Antigens, CD; Carcinoma; Diagnosis, Differential; Diagnostic Errors; Gastrectomy; Gastrointestinal Stromal Tumors; Humans; Immunohistochemistry; Keratins; Male; Stomach Neoplasms

Topics: Antibodies, Monoclonal; Antibody Specificity; Biomarkers; Gastrointestinal Stromal Tumors; Humans; Keratin-18; Keratin-8; Keratins; Neurofibromatosis 1; Reagent Kits, Diagnostic; Ultrasonography, Doppler, Color

Topics: Adenocarcinoma; Aged; Female; Gastrectomy; Gastrointestinal Stromal Tumors; Humans; Keratins; Neoplasms, Multiple Primary; Proto-Oncogene Proteins c-kit; Stomach Neoplasms

This report describes a tumour in the ileum with clinical features initially suggestive of a gastrointestinal stromal tumour (GIST). Histopathological examination revealed a biphasic tumour in which the spindle cell component showed immunohistochemical evidence of smooth muscle differentiation but without the characteristic profile of a GIST. A well-differentiated epithelial component was also present, comprising glandular structures with immunohistochemical features suggestive of Mullerian differentiation. Similar glandular differentiation has been described in uterine leiomyomas but not, to our knowledge, in tumours associated with the small bowel. None of the characteristic mutations of GISTs were identified in this case. There were no overt features of malignancy but, because of the unusual nature of the case, we assessed the biological behaviour as uncertain.

Topics: Actins; Adult; Biomarkers; Desmin; Female; Gastrointestinal Stromal Tumors; Humans; Ileal Neoplasms; Immunohistochemistry; Keratins; Receptors, Estrogen; Receptors, Progesterone; Smooth Muscle Tumor

In routine practice, gastrointestinal stromal tumor (GIST) can usually be identified with relative ease on the basis of a rather simple immunohistochemical panel besides its characteristic morphology. Still, serious differential diagnostic problems may arise because of the heterogeneity of these tumors in both morphologic appearance and clinical behavior. In our case, we present a metastatic, ulcerative, hemorrhagic GIST with epithelioid appearance, which displayed diffuse pan cytokeratin (AE1/AE3) positivity beside CD117 expression. As carcinomas may also be CD117-positive, definitive diagnosis was confirmed by the detection of a hexanucleotide deletion in the exon 11 of c-kit. This case demonstrates that although gastric carcinoma more commonly ulcerates or causes hemorrhage than GIST, keratin-positive GIST should also be considered from a differential diagnostic point of view. In these cases, c-kit mutation analysis may be necessary.

Topics: Carcinoma; Diagnosis, Differential; DNA Mutational Analysis; Exons; Female; Gastrointestinal Stromal Tumors; Gene Deletion; Humans; Keratins; Middle Aged; Proto-Oncogene Proteins c-kit; Sequence Deletion; Stomach Neoplasms

Synchronous tumors of the stomach are uncommon. We present a unique case of gastric synchronous tumors composed of signet-ring cell adenocarcinoma and gastrointestinal stromal tumor (GIST). The two tumors arose at the same site and were sharply juxtaposed without intermingling of morphologically distinct elements. Coincidence probably accounts for this occurrence, even if a common carcinogenic agent had been hypothesized. Preoperative imaging and endoscopic biopsy could lead to the suspicion of synchronous tumors, and an accurate histological identification of both tumors could be achieved by multiple deep endoscopic biopsies. The presence in our case of diffuse carcinomatosis indicates that the signet-ring cell adenocarcinoma had a greater adverse effect on the prognosis than the GIST.

Topics: Aged, 80 and over; Biomarkers, Tumor; Biopsy; Carcinoma, Signet Ring Cell; Endoscopy, Gastrointestinal; Gastrointestinal Stromal Tumors; Humans; Keratins; Male; Mucins; Neoplasms, Multiple Primary; Periodic Acid-Schiff Reaction; Stomach Neoplasms; Tomography, X-Ray Computed

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.. 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.. 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.

Topics: Actins; Adult; Aged; Antigens, CD34; Antineoplastic Agents; Benzamides; Biomarkers, Tumor; Desmin; Gastrointestinal Stromal Tumors; Gastrointestinal Tract; Humans; Imatinib Mesylate; Immunohistochemistry; Keratins; Middle Aged; Muscle, Smooth; Piperazines; Proto-Oncogene Proteins c-kit; Pyrimidines; Reproducibility of Results; Sensitivity and Specificity

The expression of cytokeratins in gastrointestinal stromal tumours (GISTs) is rare and may lead to diagnostic confusion when it occurs. This report describes a metastatic GIST that stained strongly for cytokeratins, CD117, and CD34 in a patient who was previously diagnosed with gastric epithelioid angiosarcoma. A review of both tumours showed the same histological and immunohistochemical profiles, and c-kit molecular analysis revealed an insertional mutation at codon 558 of exon 11 in both tumours. Thus, pathologists should be aware that GISTs can occasionally express cytokeratins, and that c-kit mutational investigations may have a key diagnostic role and may prevent diagnostic mistakes that could have important clinical implications.

Topics: Adult; Biomarkers, Tumor; Diagnosis, Differential; Female; Gastrointestinal Stromal Tumors; Hemangiosarcoma; Humans; Keratins; Mutation; Pelvic Neoplasms; Proto-Oncogene Proteins c-kit; Stomach Neoplasms

Immunostaining depending on antigen-antibody specificity is the commonest approach for determining the localization of specific antigens in tissue sections. This procedure is applicable not only with frozen or specially fixed samples, but also has proved reliable with formalin-fixed paraffin-embedded tissue sections through improvement of antigen-retrieval. Immunostaining is thus firmly established as a tool for diagnostic pathology and in our institute multiple antibodies are applied for 13-15% of the cases examined, as well as H and E staining. With the standard approach, approximately 3 h is necessary from the beginning of deparaffinization till covering sections with the Envision system. We utilized intermittent microwave irradiation for 10 min during hybridization with primary and secondary antibodies in a special moist-chamber, to achieve all immunostaining steps within 1 h in 178 primary antibodies frequently used for diagnostic pathology. According to our 5 years experience, such microwave irradiation not only obtained significant specific staining for enhancing the specificity of antigen-antibody reactions, but also inhibited nonspecific binding. We present herein the details of the methodology and recommendations for its application with particular primary antibodies. This method can contribute to savings in time and energy, allowing pathologists to rapidly obtain diagnostic information.

Topics: Antibodies, Monoclonal; Carcinoma, Squamous Cell; Gastrointestinal Stromal Tumors; Hospitals, University; Humans; Immunohistochemistry; Japan; Keratin-5; Keratins; Microwaves; Proto-Oncogene Proteins c-kit; Reproducibility of Results; Schools, Medical; Staining and Labeling; Time Factors