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// Vittorio Perfetti 1, * , Erik Laurini 2, * , Suzana Aulic 2 , Maurizio Fermeglia 2 , Roberta Riboni 3 , Marco Lucioni 3 , Elena Dallera 3 , Sara Delfanti 4 , Luigi Pugliese 5 , Francesco Saverio Latteri 6 , Andrea Pietrabissa 5 and Sabrina Pricl 2 1 Internal Medicine, Ospedale SS Annunziata-ASST Pavia and Department of Molecular Medicine University of Pavia, 27100 Pavia, Italy 2 Molecular Simulation Engineering (MOSE) Laboratory, Pharmaceutical and Molecular Biology Division, DEA, University of Trieste, 34127 Trieste, Italy 3 Department of Molecular Medicine and Anatomic Pathology Section, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy 4 Department of Oncology and Hematology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy 5 Department of Surgery, General Surgery II, University of Pavia and Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy 6 General Surgery, Ospedale Cannizzaro, 95126 Catania, Italy * These authors contributed equally to this work and are First co-authors Correspondence to: Sabrina Pricl, email: sabrina.pricl@dia.units.it Keywords: KIT, GIST, novel deletion mutation, Imatinib, neoadjuvant treatment Received: April 27, 2017 Accepted: June 28, 2017 Published: July 18, 2017 ABSTRACT Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. GISTs express the receptor tyrosine kinase KIT, and the majority of GISTs present KIT gain-of-function mutations that cluster in the 5' end of the receptor juxtamembrane domain. On the other hand, little information is known about GISTs carrying mutations in the 3′ end of the KIT juxtamembrane domain. Here we report and discuss a clinical case of localized duodenal GIST whose molecular characterization revealed the presence of a new 21 nucleotide/7 amino acid deletion in the 3′ end of KIT juxtamembrane domain (Δ574–580). The patient was treated with Imatinib at standard regimen dose (400 mg/day), and responded well as the original tumor mass reduced, ultimately allowing conservative surgery. In line with these clinical evidences computer simulations, biophysical techniques and in vitro experiments demonstrated that the receptor tyrosine kinase KIT carrying the Δ574–580 mutation displays constitutive phosphorylation, which can be switched-off upon Imatinib treatment. In addition, results from this study showed that a clinical useful procedure, neoadjuvant treatment, can occasionally be of value for the understanding of the molecular pathogenesis of GIST.

Categorization of primary cutaneous B‐cell lymphomas (PCBCL) other than marginal zone (MZL) represents a diagnostic challenge with relevant prognostic implications. The 2008 WHO lymphoma classification recognizes only primary cutaneous follicular center cell lymphoma (PCFCCL) and primary cutaneous diffuse large B‐cell lymphoma, leg type (PCDLBCL‐LT), whereas the previous 2005 WHO/EORTC classification also included an intermediate form, namely PCDLBCL, other. We conducted a retrospective, multicentric, consensus‐based revision of the clinicopathologic characteristics of 161 cases of PCBCL other than MZL. Upon the histologic features that are listed in the WHO classification, 96 cases were classified as PCFCCL and 25 as PCDLBCL‐LT; 40 further cases did not fit in the former subgroups in terms of cytology and/or architecture, thus were classified as PCDLBCL, not otherwise specified (PCDLBCL‐NOS). We assigned all the cases a histogenetic profile, based on the immunohistochemical detection of CD10, BCL6, and MUM1, and a “double hit score” upon positivity for BCL2 and MYC. PCDLBCL‐NOS had a clinical presentation more similar to PCFCCL, whereas the histology was more consistent with the picture of a diffuse large B‐cell lymphoma, as predominantly composed of centroblasts but with intermixed a reactive infiltrate of small lymphocytes. Its behavior was intermediate between the other two forms, particularly when considering only cases with a “non‐germinal B‐cell” profile, whereas “germinal center” cases resembled PCFCCL. Our data confirmed the aggressive behavior of PCDLBC‐LT, which often coexpressed MYC and BCL2. The impact of single factors on 5‐year survival was documented, particularly histogenetic profile in PCDLBCL and BCL2 translocation in PCFCCL. Our study confirms that a further group—PCDLBCL‐NOS—exists, which can be recognized through a careful combination of histopathologic criteria coupled with adequate clinical information.