Analysis of the immunoglobulin receptor (IGR) variable heavy- and light-chain sequences on 17 hepatitis C virus (HCV)-associated non-Hodgkin lymphomas (NHLs) (9 patients also had type II mixed cryoglobulinemia [MC] syndrome and 8 had NHL unrelated to MC) and analysis of intraclonal diversity on 8 of them suggest that such malignant lymphoproliferations derive from an antigen-driven pathologic process, with a selective pressure for the maintenance of a functional IgR and a negative pressure for additional amino acid mutations in the framework regions (FRs). For almost all NHLs, both heavy- and light-chain complementarity-determining regions (CDR3) showed the highest similarity to antibodies with rheumatoid factor (RF) activity that have been found in the MC syndrome, thus suggesting that a common antigenic stimulus is involved in MC syndrome and in HCV-associated lymphomagenesis. Moreover, because HCV is the recognized pathologic agent of MC and the CDR3 amino acid sequences of some HCV-associated NHLs also present a high homology for antibody specific for the E2 protein of HCV, it may be reasonable to speculate that HCV E2 protein is one of the chronic antigenic stimuli involved in the lymphomagenetic process. Finally, the use of specific segments, in particular the D segment, in assembling the IgH chain of IgR seems to confer B-cell disorders with the property to produce antibody with RF activity, which may contribute to the manifestation of an overt MC syndrome.

Although Gastrointestinal stromal tumors (GISTs) affect about 0.0014% of the population, GISTs smaller than 1 cm (microGISTs) are detectable in about 20% to 30% of elderly individuals. This suggests that microGISTs likely represent premalignant precursors that evolve only in a minute fraction of cases toward overt GISTs. We sought histopathologic and molecular explanations for the infrequent clinical progression in small GISTs. To investigate the mechanisms of GIST progression and identify subsets with differential malignant potential, we carried out a thorough characterization of 170 GISTs <2 cm and compared their KIT/PDGFRA status with overt GISTs. The proliferation was lower in microGISTs compared with GISTs from 1 to 2 cm (milliGISTs). In addition, microGISTs were more frequently incidental, gastric, spindle, showed an infiltrative growth pattern, a lower degree of cellularity, and abundant sclerosis. The progression was limited to 1 ileal and 1 rectal milliGISTs. KIT/PDGFRA mutations were detected in 74% of the cases. The overall frequency of KIT/PDGFRA mutation and, particularly, the frequency of KIT exon 11 mutations was significantly lower in small GISTs compared with overt GISTs. Five novel mutations, 3 in KIT (p.Phe506Leu, p.Ser692Leu, p.Glu695Lys) 2 in PDGFRA (p.Ser847X, p.Ser667Pro), plus 4 double mutations were identified. Small GISTs share with overt GIST KIT/PDGFRA mutation. Nevertheless, microGISTs display an overall lower frequency of mutations, particularly canonical KIT mutations, and also carry rare and novel mutations. These molecular features, together with the peculiar pathologic characteristics, suggest that the proliferation of these lesions is likely sustained by weakly pathogenic molecular events, supporting the epidemiologic evidence that microGISTs are self-limiting lesions.

Objective. To determine whether the prelymphomatous stages of B cell lymphoproliferation in Sjögren's syndrome (SS) may be better characterized by the integration of clinical, pathologic, and molecular data, the latter focusing on the expansion, persistence, and dissemination of clonal B cells in the course of the disease. Methods. Multiple tissue lesions (synchronous from different tissues and metachronous from the same tissue) were evaluated in biopsy specimens obtained from 6 consecutive patients with SS who had an associated lymphoproliferative disorder. Fully benign gastric lesions were evaluated in tissue from an additional 11 patients with SS who had no associated lymphoproliferative disorder. Multiple and complementary molecular analyses of B cell clonality were used: Southern blot, polymerase chain reaction, single‐strand conformation polymorphism, DNA sequencing, and hybridization with clonospecific oligoprobes. All the patients were then strictly followed up for the appearance of lymphoma. Results. Different scenarios of SS‐associated B cell lymphoproliferation were identified: 1) the ongoing expansion of the same dominant clone, localized or disseminated, in tissue from 2 patients, 1 of whom later developed an overt B cell lymphoma; 2) different dominant clones in different synchronous or metachronous tissues from the remaining 4 patients with an associated lymphoproliferative disorder; and 3) small oligoclonal expansions in 7 of the 11 benign gastric lymphoid infiltrates. Conclusion. Prelymphomatous B cell lymphoproliferation in SS was better characterized following integration of the findings. The different types of B cell clonal expansion (oligoclonal or monoclonal, smaller or larger in size, fluctuating or established, localized or disseminated) may imply a different risk of lymphoma progression. An accurate clinical, histopathologic, and molecular characterization may therefore be crucial in future studies aimed at clarifying the pathobiology of SS‐associated lymphoproliferation.

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