Molecular spectrum of c-KIT and PDGFRA gene mutations in gastro intestinal stromal tumor: determination of frequency, distribution pattern and identification of novel mutations in Indian patients.

KIT and PDGFRA gene mutations are the major genetic alterations seen in gastrointestinal stromal tumors (GISTs) and are being used clinically for predicting response to imatinib therapy. In the current study, we set out to explore the frequency and distribution pattern of c-KIT (exons 9, 11 and 13) and PDGFRA (exons 12 and 18) by direct sequencing in a series of 70 Indian GIST cases. Overall, 27 (38.5 %) and 4 (5.7 %) of the cases had c-KIT and PDGFRA mutations, respectively. Majority of KIT mutations involved exon 11 (85.7 %), followed by exon 9 (14.3 %), while none showed exon 13 mutation. Most exon 9 mutations showed Ala503-Tyr504 duplication, while one had novel point mutation at codon 476 (S476G). In contrast to exon 9 mutations, most exon 11 mutations were in-frame deletions (79 %, 19/24), predominantly at codons 550-560, while remaining exon 11 mutant cases were point mutations at codons 559, 560, 568, 573 and 575. Interestingly, P573T, Q556_V560delinsH, Q575H and Q575_P577 were novel variations observed in exon 11. The PDGFRA mutations were seen mostly in exon 18, which showed point mutation at codon 842 (D842V), while exon 12 showed a novel indel variation (V561_H570delinsT). No significant correlation between c-KIT/PDGFRA mutations and clinicopathological data was observed. In conclusion, this study highlights the frequency and distribution pattern of c-KIT/PDGFRA mutation in Indian cohort. The current study identified novel variations that added new insights into the genetic heterogeneity of GIST patients. Furthermore, this is the first study to report the presence of PDGFRA mutation from Indian subcontinent.

Interobserver variation is a significant limitation in the diagnosis of Burkitt lymphoma.

CONTEXT: The pathology of classic Burkitt lymphoma (BL) remains a challenge despite being a well-defined entity, in view of the significant overlap with atypical BL and B-cell lymphoma intermediate between DLBL (diffuse large B cell lymphoma) and BL. They are difficult to be segregated in resource-limited setups which lack molecular testing facilities. This is further affected by interobserver variability and experience of the reporting pathologist. AIMS: The aim of our study was to quantitate variability among a group of pathologists with an interest in lymphomas (albeit with variable levels of experience) and quantitate the benefit of joint discussions as a tool to increase accuracy and reduce interobserver variability of pathologists, in the diagnosis of BL in a resource-limited setup. MATERIALS AND METHODS: A set of 25 non-Hodgkin lymphoma cases in which a diagnosis of BL was entertained were circulated to 14 participating pathologist within the Mumbai lymphoma study group. A proforma recorded the morphologic and immunohistochemical features perceived during the initial independent diagnosis followed by a consensus meeting for discussion on morphology and additional information pertinent to the case. STATISTICAL ANALYSIS AND RESULTS: The concordance was poor for independent diagnosis among all the pathologists with kappa statistics (±SE) of 0.168 (±0.018). Expert lymphoma pathologists had the highest (albeit only fair) concordance (kappa = 0.373 ± 0.071) and general pathologists the lowest concordance (kappa = 0.138 ± 0.035). Concordance for morphological diagnosis was highest among expert lymphoma pathologists (kappa = 0.356 ± 0.127). Revision of diagnoses after consensus meeting was highest for B-cell lymphoma intermediate between DLB and BL. To conclude, interobserver variation is a significant problem in BL in the post WHO 2008 classification era. Experience with a larger number of cases and joint discussion exercises such as the one we conducted are needed as they represent a simple and effective way of improving diagnostic accuracy of pathologists working in a resource-limited setup.