Contributed by Pranav Patwardhan, MD and Sara Monaghan, MDDISCUSSION
Angioimmunoblastic T cell lymphoma (AITL) usually tends to present with constitutional symptoms, rash and at an advanced stage [1]. However, the lymphadenopathy is usually not bulky. Patients with AITL also tend to have an associated immune dysregulation which may present in the form of hypergammaglobulinemia, Coombs positive hemolytic anemia or other autoimmune complications [2]. Lymph nodes involved by AITL typically show architectural effacement and presence of a polymorphous population of mature lymphocytes, neoplastic T cells, eosinophils, plasma cells and macrophages. It can be difficult to specifically identify and localize the neoplastic cells within such a heterogenous background. However, the neoplastic cells tend to align around the high endothelial venules [3] enmeshed in the dendritic cell networks; [4] they sometimes standout due to clear cytoplasm and other cytologic abnormalities such as nuclear irregularities or larger size. Some cases may harbor multinucleated Hodgkin-like cells, which can be CD30 positive; however, that was not a feature in our case.
Three histologic patterns of AITL (types I-III) are recognized based on the presence or lack of B-cell rich follicles. Type I demonstrates hyperplastic B-cell follicles with reactive features and can be diagnostically challenging to distinguish from a reactive process [5]. Type II demonstrates regressed B-cell follicles while type III shows absence of B-cell rich follicles. This is mainly important so that the pathologist is aware of the different possible histologic patterns that AITL may have and, thus, is less likely to miss the diagnosis.
A diagnosis of AITL and other nodal lymphomas of T follicular helper (TFH) cell origin requires the abnormal cell population to stain positive for at least 2 and, ideally, 3 markers associated with T follicular helper cells [6]. Widely used TFH markers include ICOS, CD10, BCL6, PD1 and CXCL13. PD1 and ICOS are the more sensitive markers while CXCL13 and CD10 are more specific in identifying the TFH phenotype of the cells in these lymphomas [7]. The two other nodal lymphomas of TFH cell origin include "follicular T-cell lymphoma," which is rare, and the more common "nodal peripheral T-cell lymphoma with TFH phenotype." The later designation is used when the phenotype supports a TFH phenotype but the lymphoma lacks the typical polymorphic inflammatory background, vascular proliferation or expanded follicular dendritic cell meshworks.
Individual EBV positive B cells, including larger immunoblasts, are frequently found admixed with the abnormal T-cell proliferation; this is a typical feature that one can look for but up 20% of cases may not have this finding. In our case, we found rare EBV positive cells by EBV-ISH studies. EBV positive B-cells can proliferate and form aggregates. Rarely B-cell lymphoma develops and it can be EBV positive. Monoclonal immunoglobulin gene rearrangements can be detected in about 50% of AITL cases, which is often associated with a proliferation of EBV positive B cells [8]. Plasma cells can also be abundant in AITL and are often polytypic but clonal plasma cell proliferations have been reported. Our patient had a preceding and concurrent MGUS; however, he had neither B-cell lymphoma nor overt plasma cell neoplasm.
Our patient presented with constitutional symptoms and advanced stage on radiology. Morphological evaluation showed features suggestive of AITL pattern II. The abnormal cells were positive for TFH markers and were CD3, CD4 positive. CD57 was strongly positive. CD30 was only seen on scattered cells (<10%) in our case. AITL can be positive for CD30 and the extent of staining should be specifically mentioned in the report because there may be interest to treat these patients with brentuximab especially if the lymphoma is refractory or relapses. Flow cytometry demonstrated that the T cell population expressed CD3, CD4, CD5 (bright), CD57 and was negative for CD7, CD8 and CD56. Lymphoid-panel NGS on paraffin-embedded tissue revealed the following mutations: a pathogenic TP53 p.E180* (VAF 11.0%) and a previously uncharacterized CBLB p.C388F (VAF 6.0%) mutation of uncertain significance. Notably, mutations more often associated with AITL were not detected (IDH2, RHOA, TET2). RHOAG17V mutation is found in around 70% of AITL cases and a significant number of other T Follicular cell type lymphomas. It is rarely detected in other cancers and so, is considered hallmark of these lymphomas [10]. Chromosome analysis was positive for an abnormal karyotype indicative of a neoplasm but the abnormality was not specific for lymphoma: 46,XY,add(1)(p36.3),t(5;5)(q15;q34)[7]/46,XY[3]. In a study by Odejide et al, mutations in TP53 were identified in 4 out of 85 AITL cases [9]. Hence, our case was associated with a more rare mutation that can be detected AITL.
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Contributed by Pranav Patwardhan, MD and Sara Monaghan, MD
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