Hematolymphoid tumors of the mediastinum

2024-05-09   Paola Dal Cin, PhD , Judy A. Ferry  

1.Brigham and Women's Hospital , Harvard Medical School, Boston , MA (USA)
2.Massachusetts General Hospital, Harvard Medical School Boston (MA) USAl

Keywords
Mediastinal lymphoma, B-cell lymphoma, mediastinum

Classification

Definition

A variety of lymphomas arises in the mediastinum, often from the thymus.  These include primary mediastinal large B-cell lymphoma, some cases of nodular sclerosis classic Hodgkin lymphoma, mediastinal gray zone lymphoma, thymic marginal zone lymphoma of mucosa-associated lymphoid tissue, and T lymphoblastic leukemia/ lymphoma.  Primary mediastinal large B-cell lymphoma (PMBCL) is an aggressive B-cell lymphoma of putative thymic B-cell origin, having distinctive clinical and pathologic features. 1  Classic Hodgkin lymphoma is characterized by a small number of highly abnormal neoplastic B cells in an abundant microenvironment; the most common type of Hodgkin lymphoma to involve the mediastinum is nodular sclerosis classic Hodgkin lymphoma (NSCHL). PMBCL and NSCHL share a number of clinical and pathologic features, and in a small number of cases it may be difficult to distinguish between these two types of lymphoma.  The term “mediastinal gray zone lymphoma” has been adopted to describe cases of aggressive B-cell lymphomas with overlapping features between PMBCL and classic Hodgkin lymphoma, in particular NSCHL. 2 Rare cases of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (EMZL) arise in the thymus; they have characteristic clinical and pathologic features that distinguish them EMZL arising in other sites. 3,4 The thymus is the most common site of origin for T lymphoblastic lymphoma, a primitive aggressive neoplasm committed to T lineage.  The term T lymphoblastic leukemia is used for those cases primarily involving bone marrow and peripheral blood.
In addition to lymphoma, rare cases of follicular dendritic cell sarcoma 5 and myeloid sarcoma6 arise in the mediastinum; these neoplasms may enter the differential diagnosis of lymphoma.

Hematolymphoid tumors of the mediastinumGenetic markers(s)
Primary mediastinal large B-cell lymphoma (PMBCL)PMBCL is large B-cell lymphoma arising from the thymus, predominantly in young adult females, showing distinctive clinical, immunophenotypic and genetic features. Gene expression profiling has shown some molecular features reminiscent of nodular sclerosis classic Hodgkin lymphoma (cHL). PMBCL is characterized by activation of NF-κB 7 and JAK/STAT signalling pathways,8 and by alterations promoting immune escape.9-11 Recurrent somatic mutations of SOCS1, GNA13, STAT6, B2M and others; copy number alterations, in particular amplification of 2p16.1 REL and of 9p24.1 CD274/ PDCD1LG2/JAK2 and deletions of 6q23 TNFAIP3, 9p21 CDKN2A, and 17p13 TP53; 12 and translocation of 16p13 /CIITA are described. No MYC or BCL2 translocations are reported. BCL6 mutation is more common than translocation.13 A recent large-scale genomic characterization of PMBCL detected a total of 50 candidate PMBCL drivers, with 24 of them not previously reported in PMBCL and four of them [PLXNC1, SZT2,CD80, and LHFPL3], not reported in any lymphoma. In addition, novel treatment targets and genetic lesions were identified for refined risk stratification, mainly adverse prognostic significance of the CD58 mutation status and durable responses for DUSP2-mutated patients.14 Interesting , rarely, DLBCL cases with a non-mediastinal location may show a molecular signature reminiscent of PMBCL. 15
Mediastinal (thymic) extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)MALT lymphomas arising in thymus are rare; they preferentially affect Asian women and are strongly associated with autoimmune disease, especially Sjögren syndrome OMIM:270150. Translocations of MALT1 and IGH have been absent. 4,16,17,17,18,18 Trisomy 3 is common (40-50%)3,17and trisomy 18 is occasionally found (7% in two reports).3,17. One case with dup(X)(p22p11)19 and one with add(8)(q24) (not involving MYC) are described.4 In one small series, most cases carried mutations of one or more genes (e.g., TNFAIP3, CARD11) expected to result in NFkB pathway activation, suggesting NFkB dysregulation plays a major role in the pathogenesis of thymic MALT lymphoma.18 One case showed mutated CCND3, suggesting that PI3K pathway activation may also have a role in lymphomagenesis.18 Frequent methylation of tumor suppressor genes, including DAPK1, CDH1, TIMP3 and p14ARF, is also described.3 Evaluation of immunoglobulin (Ig) genes shows Vh usage restricted to the Vh3 family and biased toward Vh3-30 and Vh3-23, both often expressed by autoimmune B cells.20 Jh segment usage is confined to Jh4.20 Somatic hypermutation of Ig genes is absent. The findings suggest that specific antigens may play a role in the genesis of thymic MALT lymphoma.20
Mediastinal T-lymphoblastic leukemia/lymphoma (T-ALL/LBL)The mediastinum (specifically, the thymus) is the most common primary site for T lymphoblastic lymphoma. Mediastinal T-LBL occurs more frequently in children and young adults. However, no specific molecular studies are available regarding mediastinal T-LBL 21 T-ALL/LBL shows clonal rearrangement of T-cell receptor (TCR) genes and, in up to 20% of cases, and may show concurrent clonal IGH rearrangement.22-24 The karyotype is abnormal in most cases; translocations involving TCR genes TCRα/d, TCRβ, and TCRγ] are common, with multiple different partners. In addtion deletion of 9p/CDKN2A, mutations of NOTCH1, FBXW7 and TP53 are recurrent. 25 T-ALL/LBL can be divided into five main genetic subgroups, corresponding to arrested maturation at different stages: (1) the TAL/LMO subgroup; (2) the TLX1 activation subgroup; (3) the TLX3 subgroup; (4) the HOXA subgroup; and (5) the MYB oncogene activation subgroup.26,26,27
Mediastinal classic Hodgkin lymphoma (cHL) Nodular sclerosis cHL is by far the most common type of Hodgkin lymphoma to involve the mediastinum. Hodgkin/Reed-Sternberg (HRS) cells show clonal rearrangement of IGH and somatic hypermutation of IGHV (highly sensitive techniques usually required to demonstrate these changes),28 mutations associated with constitutive activation of NFkB and JAK-STAT signalling pathways and changes associated with immune evasion. There are frequent copy number alterations, mainly at 9p24 involving CD274/PDCD1LG2 and at 2p16/REL , and, in a minority, CIITArearrangement.25,29-31 Abnormalities of MAPK/ERK, PI3K/AKT, and NOTCH1 pathways may also contribute to the pathogenesis of cHL.31
Mediastinal gray zone lymphoma (MGZL)MGZL is a B-cell neoplasm with pathologic features, including genetic features, that overlap with both PMBCL and cHL, suggesting a common or similar origin.13,32 SOCS1, GNA13, TNFAIP3, NFKBIE and XPO1  are the genes most commonly mutated. NFkB and JAK-STAT signalling pathways are activated. Translocations of BCL2/BCL6 are virtually absent.2,33,34. There are rare cases of extramediastinal lymphomas with some features of gray zone lymphoma, but BCL2, TP53 and CREBBP mutations are significantly more common in nonthymic cases, and a subset of cases has translocations of BCL2 or BCL6.2,35 Overall these extramediastinal lymphomas are better classified as diffuse large B-cell lymphoma, NOS.
Mediastinal follicular dendritic cell sarcoma (FDCS)Rare cases of mediastinal FDCS are described, including rare cases arising from hyaline-vascular Castleman disease.36 No studies of molecular genetic features focusing specifically on mediastinal FDCS are available. In FDCS in general, karyotypes have often been complex.37 Recurrent mutations in NFkB pathway genes and tumor suppressor genes are commonly found.38-40 Other alterations are uncommon. In contrast to histiocytic neoplasms, MAPK pathway mutations are typically absent,5 although BRAF V600E has been reported rarely.41
Mediastinal myeloid sarcoma (MS)Mediastinal MS occurring as an isolated tumor and also preceding a diagnosis of acute myeloid leukemia (AML) with bone marrow +/- blood involvement has been reported.6 Detailed genetic findings are often not available, but many are reported to have a complex karyotype.6 Individual cases of mediastinal MS have shown: FUS::ERG,42 ASXL1p.R693X mutation; 43 and t(10; 11)(p12;q21) associated with PICALM::MLLT10 fusion with TP53 mutation.44 A mediastinal MS showing 2 distinct FLT3 mutations is reported. The MS was refractory to treatment and a second biopsy showed persistent disease with a FLT3-TKD mutation, a TP53 mutation and an EP300 mutation, as well as aberrant clonal rearrangement of T-cell receptor genes.45 A pediatric case of AML with NPM1 mutation that relapsed as an isolated mediastinal MS has been described.46 A case of AML accompanied by MS in multiple sites, including the mediastinum, with a t(8:21), associated to RUNX1::RUNX1T1 fusion, is reported.47

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Citation

Paola Dal Cin ; Judy A. Ferry

Hematolymphoid tumors of the mediastinum

Atlas Genet Cytogenet Oncol Haematol. 2024-05-09

Online version: http://atlasgeneticsoncology.org/solid-tumor/209213