This paper summarizes two sessions of the workshop during the XIX meeting of the European Association for Haematopathology (EAHP) held in Edinburgh in September 2018 dedicated to lymphomas of the ...gastrointestinal tract. The first session focused on the clinical and pathological features of primary gastrointestinal T cell and NK-cell lymphoproliferative disorders. The distinction between precursor lesions (RCD type 2) and enteropathy-associated T cell lymphoma were stressed, including the discussion of new diagnostic markers for the identification of aberrant phenotypes. Indolent T cell lymphoproliferative disorders of the gastrointestinal tract cases showed phenotypic heterogeneity with novel molecular alterations in few cases, such as
STAT3-JAK2
fusion. In addition, novel clonal markers of disease, such as
AXL
and
JAK3
somatic variants support the neoplastic nature of NK-cell enteropathy. The session on gastrointestinal tract B cell lymphoproliferations was dedicated to B cell lymphoproliferative disorders that arise primarily in the gastrointestinal tract (i.e., duodenal-type follicular lymphoma) or preferentially involve the digestive tract, such as large B cell lymphoma with
IRF4
translocation and mantle cell lymphoma (MCL), including diverse molecular subtypes (i.e.,
CCND3
-positive MCL mimicking MALT lymphoma). Challenging cases of high-grade B cell lymphomas with complex genetic profiles demonstrated the usefulness of novel molecular diagnostic methods such as targeted NGS to identify high-risk genetic features with potential clinical impact.
Session 2 of the 2018 European Association of Hematopathology/Society for Hematopathology Workshop focused on lymphomas arising in immune-privileged sites: both lymphomas arising in the traditionally ...described “immune sanctuary” sites of the central nervous system (CNS) and testes, as well as those arising at sites of local immune privilege. Primary CNS large B cell lymphoma and primary testicular large B cell lymphoma were discussed, and the biology of these unique tumors was highlighted by several cases showing the classic mutation profile including
MYD88
L265P and
CD79B
. The tendency of these tumors to involve both the CNS and testis was also reinforced by several cases. Four cases of low-grade B cell lymphomas (LGBCL) of the CNS were discussed. Two were classic Bing-Neel syndrome associated with LPL, and two were LGBCL with plasmacytic differentiation and amyloid deposition without systemic disease. Rare examples of systemic T and NK cell lymphomas involving the CNS were also discussed. Several cases of breast implant–associated anaplastic large cell lymphoma (BI-ALCL) were submitted showing the typical clinicopathologic features. These cases were discussed along with a case with analogous features arising in a patient with a gastric band implant, as well as large B cell lymphomas arising alongside foreign materials. Finally, large B cell lymphomas arising in effusions or localized sites of chronic inflammation (fibrin-associated diffuse large B cell lymphoma DLBCL and DLBCL associated with chronic inflammation) were described. The pathogenesis of all of these lymphomas is believed to be related to decreased immune surveillance, either innate to the physiology of the organ or acquired at a local site.
EBV-positive mucocutaneous ulcer (EBV-MCU) was classified as a rare new entity of the lymphoproliferative B-cell diseases by the WHO in 2017 and must be distinguished from head and neck squamous cell ...carcinoma by early biopsy. The aim of the study is to raise awareness of the disease and to give a review of the current literature and a recommendation for EBV-MCU management. All EBV-MCU cases of the head and neck region published so far were included. We also report a case of a pharyngeal EBV-MCU in an 89-year-old patient who was immunosuppressed by chronic lymphatic leukaemia/small lymphocytic lymphoma (CLL/SLL). In contrast to all previously described cases, histopathology showed a co-infiltration of EBV-MCU and CLL/SLL. A total of 181 cases were identified on PubMed and summarised. EBV-MCU was predominantly caused by immunosuppressive drug therapy. Complete remission could be achieved in 68% of cases and was mainly attributed to a reduction of the immunosuppressive therapy alone (72%). However, some severe cases require more aggressive treatment. Regarding the various histopathologic similarities to other lymphoproliferative disorders, the diagnosis of EBV-MCU can be misleading, with a great impact on patient care and treatment. This diagnosis must be made with caution and requires a combination of clinical, morphological and immunophenotypic features.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK, VSZLJ
Detection of minimal disseminated disease is a validated prognostic factor in ALK-positive anaplastic large cell lymphoma. We previously reported that quantification of minimal disease by ...quantitative real-time polymerase chain reaction (RQ-PCR) in bone marrow applying a cut-off of 10 copies
10
copies of
identifies very high-risk patients. In the present study, we aimed to confirm the prognostic value of quantitative minimal disseminated disease evaluation and to validate digital polymerase chain reaction (dPCR) as an alternative method. Among 91 patients whose bone marrow was analyzed by RQ-PCR, more than 10 normalized copy-numbers correlated with stage III/IV disease, mediastinal and visceral organ involvement and low anti-ALK antibody titers. The cumulative incidence of relapses of 18 patients with more than 10 normalized copy-numbers of
was 61±12% compared to 21±5% for the remaining 73 patients (
=0.0002). Results in blood correlated with those in bone marrow (r=0.74) in 70 patients for whom both materials could be tested. Transcripts were quantified by RQ-PCR and dPCR in 75 bone marrow and 57 blood samples. Copy number estimates using dPCR and RQ-PCR correlated in 132 samples (r=0.85). Applying a cut-off of 30 copies
/10
copies
for quantification by dPCR, almost identical groups of patients were separated as those separated by RQ-PCR. In summary, the prognostic impact of quantification of minimal disseminated disease in bone marrow could be confirmed for patients with anaplastic large cell lymphoma. Blood can substitute for bone marrow. Quantification of minimal disease by dPCR provides a promising tool to facilitate harmonization of minimal disease measurement between laboratories and for clinical studies.
The prognostic value of pathologic characteristics of childhood ALK-positive anaplastic large-cell lymphomas (ALCL), such as histologic subtypes, immunophenotype, and presence of the t(2;5) ...translocation or its variants, was assessed.
All 375 patients with systemic ALK-positive ALCL included in an international trial launched by the European Intergroup for Childhood Non-Hodgkin's Lymphoma were reviewed by an international panel of pathologists based on conventional hematoxylin and eosin-stained and immunostained sections and classified according to the 2001 WHO classification.
A small-cell (SC) or lymphohistiocytic (LH) component was observed in 114 (32%) of 361 patients, whereas ALCL of common type was diagnosed in 235 (65%) of 361 patients. Regarding the histologic subtyping of patients within the two categories of ALCL (with v without SC/LH component), the concordance between the national and international reviews was quite good, with a κ index equal to 0.67 (95% CI, 0.57 to 0.75). The presence of an SC/LH component was significantly associated with a high risk of failure (hazard ratio HR, 2.0; 95% CI, 1.3 to 3.0; P = .002) in the multivariate analysis controlling for clinical characteristics, as well as the perivascular pattern (HR, 1.7; 95% CI, 1.1 to 2.7; P = .01), whereas CD3 positivity was significantly associated with a high risk of failure only in univariate analysis.
Our study, which to our knowledge includes the largest series of childhood systemic ALK-positive ALCL so far, demonstrates the adverse prognostic value of SC and/or LH morphologic features. Combining these histologic characteristics with other biologic or clinical factors might have a high potential for future risk stratification and treatment.
Second malignant neoplasms pose a concern for survivors of childhood cancer. We evaluated incidence, type and risk factors for second malignant neoplasms in patients included in ...Berlin-Frankfurt-Muenster protocols for childhood non-Hodgkin lymphoma. 3590 patients <15 years of age at diagnosis registered between 01/1981 and 06/2010 were analyzed. Second malignant neoplasms were reported by the treating institutions and the German Childhood Cancer Registry. After median follow-up of 9.4 years (Quartile, Q1 6.7 and Q3 12.1) 95 second malignant neoplasms were registered (26 carcinomas including 9 basal cell carcinomas, 21 acute myeloid leukemias/myelodysplastic syndromes, 20 lymphoid malignancies, 12 CNS-tumors, and 16 other). Cumulative incidence at 20 years was 5.7±0.7%, standard incidence ratio excluding basal cell carcinomas was 19.8 (95% CI 14.5-26.5). Median time from initial diagnosis to second malignancy was 8.7 years (range: 0.2-30.3). Acute-lymphoblastic-leukemia-type therapy, cumulative anthracycline dose, and cranial radiotherapy for brain tumor-development were significant risk factors in univariate analysis only. In multivariate analysis including risk factors significant in univariate analysis, female sex (HR 1.87, 95% CI 1.23-2.86, p=0.004), CNS-involvement (HR 2.24, 95% CI 1.03-4.88, p=0.042), lymphoblastic lymphoma (HR 2.60, 95% CI 1.69-3.97, p<0.001), and cancer-predisposing condition (HR 11.2, 95% CI 5.52-22.75, p<0.001) retained an independent risk. Carcinomas were the most frequent second malignant neoplasms after non-Hodgkin lymphoma in childhood followed by acute myeloid leukemia and lymphoid malignancies. Female sex, lymphoblastic lymphoma, CNS-involvement, or/and known cancer-predisposing condition were risk factors for second malignant neoplasm-development. Our findings set the basis for individualized long-term follow-up and risk assessment of new therapies.
Mature B-cell non-Hodgkin lymphoma is the most common subtype of non-Hodgkin lymphoma in childhood and adolescence. B-cell non-Hodgkin lymphomas are further classified into histological subtypes, ...with Burkitt lymphoma and Diffuse large B-cell lymphoma being the most common subgroups in pediatric patients. Translocations involving the
oncogene are known as relevant but not sufficient for Burkitt lymphoma pathogenesis. Recently published large-scale next-generation sequencing studies unveiled sets of additional recurrently mutated genes in samples of pediatric and adult B-cell non-Hodgkin lymphoma patients.
and
are potential drivers of Burkitt lymphomagenesis. In the study herein, frequency and clinical relevance of mutations in
and
were analyzed within a well-defined cohort of 84 uniformly diagnosed and treated pediatric B-cell non-Hodgkin lymphoma patients of the Berlin-Frankfurt-Münster group. Mutation frequency was 78% (
), 13% (
) and 36% (
) in Burkitt lymphoma (including Burkitt leukemia).
and
mutations were associated with more advanced stages of the disease in
rearrangement positive Burkitt lymphoma. In conclusion,
pathway genes are mutated in more than 88% of
-rearranged pediatric B-cell non-Hodgkin lymphoma and the pathway may represent a highly relevant second hit of Burkitt lymphoma pathogenesis, especially in children and adolescents.
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