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S Pileri

Publications and source records attributed to S Pileri.

At least 19 recordsLinked to original sources

Early positron emission tomography (PET) restaging: a predictive final response in Hodgkin's disease patients.

BACKGROUND: It is important to distinguish between responders to standard treatment and non-responders Hodgkin's disease (HD) patients. PATIENTS AND METHODS: Between June 2003-September 2004, in our institute, 40 newly-diagnosed patients with advanced stage HD were consecutively treated with ABVD chemotherapy for six cycles. All these patients underwent staging/restaging: computed tomography (CT) and positron emission tomography (PET) at time 0, PET after two cycles, CT and PET after four and six cycles. RESULTS: After two cycles (PET-2), the PET was negative in 28/40 (70%), positive in 8/40 (20%), and minimal residual uptake (MRU) was present in the remaining four (10%) patients. After treatment, among eight patients who were PET-2+, seven showed refractory disease and one had relapse after 3 months. All four patients with MRU at the PET-2 became PET- during the further four cycles and, after treatment, three were in complete response (CR) and one relapsed after 5 months. All 28 PET negative patients at the PET-2 remained PET negative and all of them were in CR after treatment. CONCLUSIONS: The PET use for early (after two cycles) response assessment in HD patients is a significant step forward and has the potential to help physicians make crucial decisions about further treatment.

Adolescent↗

Posttransplant lymphoproliferative disorders in liver transplanted patients: a report of four cases.

BACKGROUND: Posttransplant lymphoproliferative disorders (PTLDs) are an uncommon but important cause of morbidity and mortality in solid organ transplant recipients. They are often the result of Epstein-Barr virus (EBV)-induced proliferation of B-lymphocytes in the setting of immunosuppression. PATIENTS AND METHODS: We retrospectively analyzed four cases of PTLD after liver transplantation. In all patients immunosuppression was reduced and anti-CD20 monoclonal antibody (rituximab) was administered. In two of four patients, EBV viral load was positive in the peripheral blood, and gancyclovir was therefore also prescribed. Chemotherapy (CHOP) was used as a rescue in the event of treatment failure. RESULTS: Even if no severe adverse events were observed during the treatment period, our treatment approach to PTLD was not effective, and only one patient out of four is still alive. CONCLUSIONS: Well-designed clinical trials are necessary to evaluate the role of this combined approach in the treatment of PTLD in liver transplant recipients.

Aged↗

[The Haemolymphopathology Italian Group (H.I.G.): an essential resource for the new technical and organization problems troubling modern haemolymphopathology diagnostics].

Recently, many progresses have been recorded in the molecular and histogenetic characterization of the haematopoietic and lymphoid tumours, resulting in important classifying changes. As a consequence, the exact definition of lymphoma subtype requires an integration between traditional morphologic "expertise" and several bio-functional data obtained from advanced and complex ancillary techniques (immunohistochemistry, molecular biology and cytogenetics). At the same time, the data provided by gene expression profiling studies are going to deeply modify the therapies in haematological cancers. These studies are expected to allow the achievement of single-patient-tailored genic therapy; for this reason it is necessary to get biological samples of good quality. Indeed, while these progresses contribute to highlight the pathologist's diagnostic role, they should make us reflect on the state of the art of the Italian haemolymphopathology diagnostics and on its ability to cope up with the new challanges. The aim of this article is to outline a realistic picture of the present condition, and to explain the reasons for setting up, inside SIAPEC-IAP, the Haemolymphopathology Italian Group (H.I.G.). The purpose of H.I.G. will be twofold: first of all, scheduling of a series of projects so as to the haemolymphopathological diagnostic standardization; secondly, building a national network among all the pathologists involved in this exciting and complex field of the anatomic pathology.

Europe↗

Rare expression of KIT (CD117) in lymphomas: a tissue microarray study of 1166 cases.

AIMS: Imatinib mesylate specifically inhibits KIT tyrosine kinase activity, and has been proven to be effective in the treatment of gastrointestinal stromal tumours. Because other KIT-expressing malignancies might benefit from Imatinib therapy, we evaluated the distribution and expression of KIT in 1166 cases of malignant lymphoma. MATERIALS AND RESULTS: Tissue microarrays (TMAs) containing 824 non-Hodgkin's lymphoma (NHL) and 342 Hodgkin's lymphoma (HL) cases were immunohistochemically analysed for the expression of the KIT protein. Two KIT-positive NHLs were sequenced using polymerase chain reaction analysis. One T-cell lymphoma and one follicular lymphoma of the 747 NHL cases (0.3%) were positive for KIT. All HLs were Kit-negative. None of the KIT-positive cases showed a kit gene mutation. CONCLUSIONS: KIT expression is a very rare event in NHL and virtually absent in HL. In the few positive cases, the aberrant expression is not caused by a mutation in the 'hot-spots' of the kit gene, indicating that treatment of these tumours with Imatinib may be ineffective.

Adolescent↗

Prognostic significance of CD44 expression in diffuse large B cell lymphoma of activated and germinal centre B cell-like types: a tissue microarray analysis of 90 cases.

BACKGROUND: Gene expression profiling of diffuse large B cell lymphoma (DLBCL) revealed three disease types: germinal centre B cell-like (GC), activated B cell-like (ABC), and a "third" type. Expression of CD44 variant isoforms (CD44v) is associated with an unfavourable clinical outcome in DLBCL, but previous studies did not consider the clinicopathological heterogeneity of this disease. AIMS: To analyse the expression and prognostic significance of CD44 in DLBCL types. METHODS: A tissue microarray (TMA) comprising 90 DLBCLs was constructed. CD10, CD20, bcl-2, bcl-6, CD44 standard isoform (CD44s), and CD44v4, CD44v6, and CD44v9 were analysed immunohistochemically and correlated with clinical follow up. RESULTS: TMA expression of CD10, CD20, bcl-2, and bcl-6 showed 100% concordance with results from conventional sections in 60 cases. Samples were segregated into 22 GC (bcl-6+/CD10+/bcl-2-), 25 ABC (bcl-6-/CD10-/bcl-2+), and 35 unclassifiable DLBCLs. Overall survival (OS) at 30 months was 89%, 44%, and 58% in GC, ABC, and unclassified types, respectively. CD44v6 was coexpressed with bcl-2, appeared predominantly on bcl-6 negative cases, and correlated with disease stage. Cases negative for CD44s could be separated into CD44v6 negative (OS, 82% at 70 months) and CD44v6 positive (OS, 58%). CONCLUSIONS: TMA technology is useful for immunophenotyping and clinicopathological analysis of large lymphoma populations. The GC phenotype of DLBCL is of independent prognostic significance for OS. Expression of CD44v6 correlates with disease stage, and might contribute to lymphoma dissemination. CD44v6 is expressed predominantly in ABC DLBCL, and in CD44 negative cases is associated with worse OS.

Biomarkers, Tumor↗

The importance of endoscopic ultrasonography in the management of low-grade gastric mucosa-associated lymphoid tissue lymphoma.

BACKGROUND: Anti-Helicobacter pylori therapy has been reported to cause regression of low-grade gastric mucosa-associated lymphoid tissue lymphoma in a high percentage of patients. However, in some patients, these lesions persist despite antibiotic treatment. AIM: To determine the various endosonographic findings that may predict the regression of low-grade gastric mucosa-associated lymphoid tissue lymphoma post-antibiotics. METHODS: Seventy-six patients with Helicobacter pylori-positive gastric mucosa-associated lymphoid tissue lymphoma were studied. Follow-up data were available on 51 patients. All patients were treated with antibiotics. Participants underwent pre- and post-anti-Helicobacter pylori therapy endoscopy with gastric biopsies, followed by endoscopic ultrasonography examination of the stomach. RESULTS: Helicobacter pylori was eradicated in 45 of 51 (88%) patients. At the 2-year follow-up, complete regression of mucosa-associated lymphoid tissue lymphoma was seen in 28 of 51 (55%) patients: 12 of 16 (75%) patients in stage T1m N0, 11 of 19 (58%) patients in stage T1sm N0, four of eight (50%) patients in stages T1m N1 and T1sm N1, and one of four (25%) patients in stage T2 N0. None of the stage T2 N1 patients achieved clinical regression. CONCLUSIONS: Endoscopic ultrasonography evaluation of gastric mucosa-associated lymphoid tissue lymphoma plays a pivotal role in the initial staging and post-treatment follow-up evaluation of these lesions. Accurate staging is essential in the determination of the optimal treatment modality.

Adult↗

Expression of the c-met proto-oncogene and its ligand, hepatocyte growth factor, in Hodgkin disease.

The receptor for hepatocyte growth factor (HGF) is a transmembrane tyrosine kinase that is encoded by the proto-oncogene c-met. Recently, c-MET was detected in Reed-Sternberg (RS) cells from Epstein-Barr virus-positive (EBV(+)) Hodgkin disease (HD). The c-MET, EBER-1, and LMP-1 expression in 45 lymph node biopsies and 12 bone marrow biopsies obtained from patients with HD was analyzed. In addition, HGF levels in serum samples from 80 healthy individuals and 135 HD patients in different phases of disease. In all 45 lymph node and 12 bone marrow samples examined, RS cells expressed c-MET but not HGF(+). These results were independent of the EBV infection. Interestingly, several HGF(+) dendritic-reticulum cells were found scattered around c-MET(+) RS cells. The mean +/- SEM serum HGF levels in HD patients at diagnosis and at the time of relapse were 1403 +/- 91 (95% confidence interval [CI], 1221-1585) and 1497 +/- 242 pg/mL (95% CI, 977-2017), respectively. HGF values were significantly higher than those of healthy individuals (665 +/- 28 pg/mL; 95% CI, 600-721; and P <.001 for both groups of patients) and of HD patients in remission (616 +/- 49 pg/mL; 95% CI, 517-714; and P <.001 for both groups of patients). A significant correlation was found between serum HGF levels and B symptoms at diagnosis (P =.014). In conclusion, this study indicates that HGF and c-MET constitute an additional signaling pathway between RS cells and the reactive cellular background, thereby affecting adhesion, proliferation, and survival of RS cells. Furthermore, the serum concentration of HGF in HD patients may be a useful tool in monitoring the status of disease.

Adolescent↗

Iliac crest biopsy versus rib segment resection for the detection of bone marrow isolated tumor cells from lung and esophageal cancer.

OBJECTIVE: The presence of isolated tumor cells in the bone marrow affects the prognosis of both esophageal cancer and non-small cell lung cancer (NSCLC). Therefore, preoperative assessment of isolated tumor cells may be useful to plan multimodality treatment. Rib segment resection at surgery provides adequate amounts of bone marrow for the detection of isolated tumor cells while bone marrow aspirate from the iliac crest does not. The iliac crest biopsy according to the Jamshidi technique procures a core of tissue apt for histology and not simply for cytology. The aim of this study was to compare the accuracy of iliac crest biopsy versus rib segment resection in the diagnosis of isolated tumor cells in order to obtain a useful preoperative approach. MATERIAL AND METHODS: Twenty-one consecutive patients (18 NSCLC, three esophageal cancer) were evaluated. None had chemotherapy prior to evaluation. Bone marrow was obtained preoperatively by iliac crest biopsy using the Jamshidi needle and at surgery by rib segment resection. Positive cytokeratin neoplastic cells were searched by immunohistochemistry on tissue sections from the iliac crest biopsies and by flow cytometry on cell suspensions from the rib segments. RESULTS: Isolated tumor cells were detected in the rib segments of ten patients. In all cases the Jamshidi needle biopsy was not diagnostic. CONCLUSION: Our results suggest that, if the diagnosis of bone marrow isolated tumor cells has clinical relevance, the preoperative assessment should be performed by rib segment resection or methods other than iliac crest aspirate or biopsy. Further investigation is needed to determine whether isolated tumor cells have a preferential spread to chest bones other than distant bone sites.

Adenocarcinoma↗

Peripheral T/NK-cell lymphoma: a report of the IXth Workshop of the European Association for Haematopathology.

AIMS: In April 1998, The European Association for Haematopathology organized the IXth workshop on peripheral T-cell and NK-cell lymphomas and leukaemias. The workshop focused on unusual subtypes of these rare malignancies, allowing evaluation of the recently published WHO classification of neoplastic diseases of the lymphoid tissues. METHODS AND RESULTS: One-hundred and three cases were centrally immunophenotyped and hybridized for EBER1/2 of Epstein--Barr virus. All cases were reviewed by a panel of experienced haematopathologists and classified according to the new WHO classification for lymphoid neoplasms. Three cases were considered as precursor T-cell and 95 cases as peripheral T/NK-cell lymphoma/leukaemia. Although the cases represented a selected series of unusual cases, the following conclusions could be made: (i) Most lymphomas except the hepatosplenic gamma/delta T-cell lymphomas showed a rather broad morphological spectrum, with differences both between and within individual tumours. (ii) This heterogeneity was also reflected by the immunophenotype, for instance a variable expression of CD30 was found in many enteropathy type T-cell lymphomas. (iii) Exceptions in phenotype were regularly found in almost all categories, indicating that phenotype should not be the final determining factor in classification. (iv) The great majority of T-cell lymphomas expressed the alpha/beta T-cell receptor, with the exception of all but one hepatosplenic T-cell lymphomas and a few other extranodal peripheral T cell lymphomas. (v) Malignancies of precursor cells, blastic NK-cell lymphoma/leukaemia, adult T-cell lymphoma/leukaemia and most AIL-type T-cell lymphomas did not express cytotoxic molecules such as TIA1 and granzyme-B. In contrast, all five aggressive NK/T-cell lymphomas/leukaemias, a single case of large granular lymphocyte leukaemia and 40 of 47 primary extranodal lymphoma/leukaemias expressed these molecules. In hepatosplenic gamma/delta T-cell lymphoma, five of six cases showed expression of TIA1 but not of granzyme-B. (vi) Seven tumours developed after organ-transplant, four cases being EBV-positive. No distinct phenotype could be attributed to these cases. CONCLUSIONS: Most peripheral T/NK cell lymphomas could be categorized as distinct entities as described in the recently proposed WHO classification for lymphoid neoplasms.

Adult↗

Expression profile of human herpesvirus 8 (HHV-8) in pyothorax associated lymphoma and in effusion lymphoma.

AIMS: Pyothorax associated lymphoma (PAL) occurs in a clinical setting of longstanding pyothorax or chronic inflammation of the pleura. Like primary effusion lymphoma, it has an association with Epstein-Barr virus (EBV), and is confined to the pleural cavity, but has differing morphological and phenotypic features. Human herpesvirus 8 (HHV-8) has been consistently reported in primary effusion lymphoma. This study examines the immunophenotype of two European cases of PAL, investigates the presence of HHV-8 and its expression profile, and assesses whether PAL is similar to other effusion lymphomas. METHODS: Material was obtained from two European cases of PAL. Immunocytochemical analysis was performed using antibodies against CD45, CD20, CD79a, CD45RAA, CD3, CD43, CD45RO (UCHL1), CD30, BCL-2, CD68, epithelial membrane antigen (EMA), BCL-6, p53, Ki-67, kappa light chain, lambda light chain, and the EBV antigens latent membrane protein 1 (LMP-1) and EBV encoded nuclear antigen 2 (EBNA-2). The cases were examined for HHV-8 by means of polymerase chain reaction in situ hybridisation (PCR-ISH), solution phase PCR, in situ hybridisation (ISH), and real time quantitative TaqMan PCR to HHV-8 open reading frame 26 (ORF-26) and viral (v) cyclin encoding regions. The expression profile of HHV-8 in PAL and in BC-1 and BC-3 cells was assessed by RNA TaqMan PCR to the HHV-8 genes encoding v-cyclin, v-IL-6, and G protein coupled receptor (GPCR). RESULTS: Both cases expressed CD24, CD20, CD79a, BCL-2, light chain restriction, and high Ki-67 staining. EBV was identified by EBER-ISH in one case. HHV-8 was not identified by solution phase PCR, but was detected by PCR-ISH (sensitivity of 1 viral genome copy/cell) in 35% of the cells and by TaqMan PCR, which showed 50-100 HHV-8 copies/2,000 cell genome equivalents (sensitivity of 1 viral genome in 10(6) contaminating sequences). HHV-8 v-IL-6, v-cyclin, and GPCR encoded transcripts were identified using RNA TaqMan PCR. v-IL-6 was high in PAL and in BC-1 and BC-3 cells. CONCLUSION: The presence of HHV-8 in one of two patients with PAL raises interesting questions in relation to the pathobiology of the condition. Clearly, the results indicate that HHV-8 is not an obligate pathogen, necessary for the effusion phenotype, but might contribute to it by its secretion of specific cytokines.

Aged↗

CD30(+) anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features.

Anaplastic large cell lymphoma (ALCL) represents a generally recognized group of large cell lymphomas. Defining features consist of a proliferation of predominantly large lymphoid cells with strong expression of the cytokine receptor CD30 and a characteristic growth pattern. With the use of molecular and clinical criteria, 3 entities of ALCL have been identified: primary systemic anaplastic lymphoma kinase (ALK)(+) ALCL, primary systemic ALK(-) ALCL, and primary cutaneous ALCL. ALK expression is caused by chromosomal translocations, most commonly t(2;5). ALK(+) ALCL predominantly affects young male patients and, if treated with chemotherapy, has a favorable prognosis. It shows a broad morphologic spectrum, with the "common type," the small cell variant, and the lymphohistiocytic variant being most commonly observed. The knowledge of the existence of these variants is essential in establishing a correct diagnosis. ALK(-) ALCL occurs in older patients, affecting both genders equally and having an unfavorable prognosis. The morphology and the immunophenotype of primary cutaneous ALCL show an overlap with that of lymphomatoid papulosis. Both diseases have an excellent prognosis, and secondary systemic dissemination is only rarely observed. The described ALCL entities usually derive from cytotoxic T cells. In contrast, large B-cell lymphomas with anaplastic morphology are believed to represent not a separate entity but a morphologic variant of diffuse large B-cell lymphoma. Malignant lymphomas with morphologic features of both Hodgkin disease and ALCL have formerly been classified as Hodgkin-like ALCL. Recent immunohistologic studies, however, suggest that ALCLs Hodgkin-like represent either cases of tumor cell-rich classic Hodgkin disease or (less commonly) ALK(+) ALCL or ALK(-) ALCL. (Blood. 2000;96:3681-3695)

Anaplastic Lymphoma Kinase↗

Expression of the ALK protein by anaplastic large-cell lymphomas correlates with high proliferative activity.

A variable fraction of anaplastic large-cell lymphomas (ALCLs) exhibits a t(2;5)(p23;q35) translocation that results in expression of the chimeric hyperphosphorylated protein NPM-ALK (p80). Tumor cells expressing NPM-ALK exhibit markedly enhanced proliferative activity, but comparative cellular kinetic studies on ALK(+) (ALK lymphomas) and ALK(-) lymphomas are lacking. The present study showed that ALK(+) lymphomas, detected with the monoclonal antibody ALKc (n = 17), had significantly higher average values for the proliferation-associated parameters mitotic index, ana/telophase index, growth index (x x mitotic index - apoptotic index, assuming x = 3), percentages of Ki-67(+) cells and fraction of cells expressing cyclin A or B or the cell cycle-regulatory protein p34(cdc2) than did ALK(-) ALCLs (n = 15). Whether this intense proliferative activity contributes to the good response to chemotherapy and favorable outcome of ALK(+) ALCLs remains to be assessed in a larger series of patients. Our findings support the notion that ALK(+) and ALK(-) ALCLs are 2 distinct disease entities.

Adolescent↗

A monoclonal antibody (MUM1p) detects expression of the MUM1/IRF4 protein in a subset of germinal center B cells, plasma cells, and activated T cells.

A new monoclonal antibody (MUM1p) was used to study the cell/tissue expression of human MUM1/IRF4 protein, the product of the homologous gene involved in the myeloma-associated t(6;14) (p25;q32). MUM1 was expressed in the nuclei and cytoplasm of plasma cells and a small percentage of germinal center (GC) B cells mainly located in the "light zone." Its morphologic spectrum ranged from that of centrocyte to that of a plasmablast/plasma cell, and it displayed a phenotype (MUM1(+)/Bcl-6(-)/Ki67(-)) different from that of most GC B cells (MUM1(-)/Bcl-6(+)/Ki67(+)) and mantle B cells (MUM1(-)/Bcl-6(-)/Ki67(-)). Polymerase chain reaction (PCR) analysis of single MUM1(+ )cells isolated from GCs showed that they contained rearranged Ig heavy chain genes with a varying number of V(H) somatic mutations. These findings suggest that these cells may represent surviving centrocytes and their progeny committed to exit GC and to differentiate into plasma cells. MUM1 was strongly expressed in lymphoplasmacytoid lymphoma, multiple myeloma, and approximately 75% of diffuse large B-cell lymphomas (DLCL-B). Unlike normal GC B cells, in which the expression of MUM1 and Bcl-6 were mutually exclusive, tumor cells in approximately 50% of MUM1(+) DLCL-B coexpressed MUM1 and Bcl-6, suggesting that expression of these proteins may be deregulated. In keeping with their proposed origin from GC B cells, Hodgkin and Reed-Sternberg cells of Hodgkin's disease consistently expressed MUM1. MUM1 was detected in normal and neoplastic activated T cells, and its expression usually paralleled that of CD30. These results suggest that MUM1 is involved in the late stages of B-cell differentiation and in T-cell activation and is deregulated in DLCL-B. (Blood. 2000;95:2084-2092)

Antibodies, Monoclonal↗

Expression of the CD30 antigen in non-lymphoid tissues and cells.

Originally, expression of the CD30 antigen was shown to be typical of the tumour cells of Hodgkin's disease (HD) and of anaplastic large cell lymphomas (ALCLs). In reactive lymphoid tissue, CD30 is expressed only in a small population of activated lymphoid blasts. Since then, several reports have been published describing CD30 expression in non-lymphoid tissues and malignancies, such as embryonal carcinomas (ECs), seminomas, cultivated macrophages, two histiocytic neoplasms, decidual cells, and mesotheliomas. As CD30 detection is important in the differential diagnosis of HD and ALCL, the expression of CD30 in different non-lymphoid tissues was re-evaluated by immunohistology and in situ hybridization. Extra-lymphoid CD30 expression was found in 48/51 cases of EC or EC components of germ cell tumours, in decidual cells of 1/10 cases, in activated mesothelium in 16/28 pleural and peritoneal effusions, and in small foci of tumour cells in 2/8 mesotheliomas. CD30 expression was not confirmed in 27 germ cell tumours of the testis without an EC component nor in cultivated macrophages and 17 histiocytic malignancies. The knowledge of these CD30 expression patterns is important for the immunohistological differential diagnosis of anaplastic tumours. The absence of CD30 expression in reactive and neoplastic macrophages does not favour the concept that HD and ALCL are derived from these cells.

Adolescent↗

Oligoclonal non-neoplastic B cell expansion is the key feature of type II mixed cryoglobulinemia: clinical and molecular findings do not support a bone marrow pathologic diagnosis of indolent B cell lymphoma.

OBJECTIVE: Type II mixed cryoglobulinemia (type II MC) is often characterized by features of indolent B cell lymphoma (IBCL) found on pathologic examination of bone marrow, whereas the clinical evidence does not indicate a neoplastic disorder. To better address the issue of indolent malignant versus nonmalignant bone marrow lymphoproliferation underlying type II MC, molecular analyses of B cell clonality were performed in the present study, in conjunction with clinical and pathologic characterization. METHODS: Polymerase chain reaction DNA amplification of immunoglobulin heavy chain genes was performed in bone marrow biopsy specimens obtained from 15 selected patients with type II MC, all infected with hepatitis C virus. Five of them had also developed overt B cell lymphoma (OBCL) during followup. Bone marrow features were consistent with IBCL in 9 of the 15 patients (group 1) and with reactive lymphoplasmacytosis in 6 of the 15 (group 2). RESULTS: An oligoclonal B cell expansion was detected in 6 of 9 baseline bone marrow lesions from group 1 patients (biclonal or monoclonal expansion in the remaining 3 cases), and in 6 of 6 from group 2 patients. OBCL was always monoclonal. Selected lesions were analyzed by clonospecific hybridization and by cloning and sequence analysis in patients who had developed OBCL at followup. In 4 of 5 cases, OBCL did not originate from the dominant B cell clones that were overexpanded in the putative neoplastic baseline bone marrow lesions. OBCL clones showed significant homology with rheumatoid factor database sequences. CONCLUSION: Based on the present results, as well as on evidence from previous studies of liver lesions, oligoclonal non-neoplastic B cell proliferation in the course of chronic infection-related inflammation appears to be the key feature of type II MC. Of note, molecular evidence from target tissues supports the clinical findings both at the time of type II MC diagnosis and in cases of OBCL complication. Bone marrow pathologic findings resembling those of IBCL should thus be considered in the light of clinical and molecular evidence.

Adult↗