Background: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare B-cell malignancy characterized by infrequent neoplastic cells embedded in an immunologically active tumor microenvironment (TME). The composition of the TME is known to influence the outcomes; cases with a nodular B-cell rich TME (classical histology; Fan A-B) are generally indolent, whereas increased infiltration of T-cells or diffuse growth (variant histology; Fan C-F) is associated with a more aggressive clinical course. The molecular features underlying this association remain to be discovered. To gain further insights into disease biology, we recruited NLPHL cases as part of the Atlas of Blood Cancer Genomes (ABCG) initiative, a consortium consisting of 26 institutions.Design: We collected comprehensive clinicopathological data from 106 NLPHL patients, with centralized review performed by a panel of dedicated hematopathologists to ensure accurate diagnosis. We performed RNA sequencing on formalin-fixed paraffin-embedded (FFPE) diagnostic tumor samples (n=81) and enumerated tumor-infiltrating immune cell compositions using FARDEEP with signature matrix LM22 from CIBERSORT. Results: Patient demographics are shown in Table 1. Classical histology was associated with better survival compared to variant histology (Figure 1A-B). According to in silico immunophenotyping, NLPHLs with variant histology were characterized by a lower proportion of naï B cells and increased proportions of CD8+ T cells and M1-macrophages compared to the classical histology (Figure 1C). Moreover, variant histology was associated with higher expression of checkpoint genes compared to classical histology (Figure 1D; P=0.019). Higher proportions of T cells and macrophages and increased expression of checkpoint genes were particularly prominent in cases with splenic involvement. Finally, we found a strong association between variant histology and gene expression related to inflammatory response (P<0.001), whereas genes related to cell cycle regulation through the E2F pathway were upregulated in NLPHLs with classical histology (P<0.001). Conclusion: Our study represents the largest comprehensive clinical and transcriptomic analyses of NLPHL to-date. Our results indicate that TME is clinically meaningful and provide evidence for distinct signaling pathways and expression patterns of checkpoint genes across histological subtypes.
e19064 Background: LB-based CGP of ctDNA can facilitate the diagnosis, molecular profiling, and monitoring of patients with myeloid neoplasia, particularly when standard CGP is not feasible due to a lack of circulating disease or insufficient tumor in the marrow or tissue. Methods: Retrospective study of LB samples from patients reported to have histiocytic neoplasms (HNs), myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), or acute myeloid leukemia (AML) tested using hybrid-capture next-generation sequencing using the FoundationOne Liquid CDx (targeting 324 genes), FoundationOne Liquid (70 genes), or FoundationACT (62 genes) assays during routine clinical care between 5/2016 and 9/2021. Results: Among 48,459 unique patient samples submitted for CGP, 83 were from myeloid neoplasia: 34 HN, 23 MDS, 15 MPN, and 11 AML. The median cell-free DNA yield was 74.9 ng (interquartile range [IQR]: 52.0-167.4), well above the minimum needed for analysis. Reportable pathogenic alterations were detected in 62.7% (52/83) of cases. The median maximum somatic allele frequency (MSAF) was 17.0% (IQR: 1.7-49.0%), with AML (45.7%), MDS (25.9%), and MPN (43.8%) having higher median MSAFs than HNs (3.2%), not unexpected given that the former naturally circulate. In all, 147 pathogenic short variants and 6 pathogenic rearrangements were detected (median variant allele frequency [VAF]: 2.1%, IQR: 0.3-20.5%, range: 0.11-99.8%). Sixty-one had VAFs < 1.0%, indicating excellent sensitivity. HNs exhibited activating RAS-RAF-MEK pathway alterations in BRAF (31.3% of cases in which pathogenic alterations were identified), NF1 (12.5%), MAP2K1 (6.3%), and NRAS (6.3%), detected at VAFs as low as 0.21%, 0.13%, 0.11%, and 4.0%, respectively. AML cases exhibited pathogenic alterations in TP53 (57.1%), FLT3 (28.6%), IDH2 (28.6%), NPM1 (28.6%), KRAS (14.3%), and NRAS (14.3%), among others. Subclonal heterogeneity was identified, including an AML case with KRAS G12A and G13R and NRAS G12A mutations detected at VAFs of 0.24%, 0.19%, and 0.2%, respectively. Altered genes in patients undergoing workup for MDS or MPN included TP53 (41.4%), JAK2 (37.9%), DNMT3A (13.8%), CHEK2 (10.3%), PTPN11 (10.3%), SF3B1 (10.3%), TET2 (10.3%), ASXL1 (6.9%), MPL (3.5%), and U2AF1 (3.5%), among others. Last, among 48,243 patients with a LB for a solid tumor diagnosis, 3,487 JAK2 V617F, 366 CALR C-terminal truncation, and 343 MPL W515X mutations were detected, potentially indicating a concurrent or occult MPN. Conclusions: LB identified clinically relevant genomic alterations in myeloid neoplasia, offering a powerful tool that may be used pre- or post-treatment when CGP of the buffy coat, marrow, or tissue is infeasible. Given its low limit of detection, LB can also identify low-level emerging or persistent subclones, which may facilitate monitoring and minimal residual disease testing.
To report a case of iris non-Hodgkin lymphoma initially thought to be uveitis-glaucoma-hyphema (UGH) syndrome.We reviewed the clinical, radiographic, and histopathologic findings in a patient with recurrent hyphemas and increased ocular pressure who eventually was found to have a rapidly growing iris mass.An 89-year-old man with a history of cataract extraction and mantle cell lymphoma developed recurrent hyphema, which was subsequently revealed to be due to an iris mass. A biopsy revealed non-Hodgkin lymphoma that could not be formally subclassified but was suspicious for mantle cell lymphoma. The tumor showed a partial response to ibrutinib.Iris lymphoma can masquerade as a cause of recurrent hyphema after cataract extraction. Ophthalmologists should be aware of this presentation, especially in patients with a history of lymphoma.
Abstract Objectives Plasma cell myeloma (PCM) involving skin is rare and occurs in 1% to 4% of patients with PCM. We evaluated the clinicopathologic features, cytogenetic findings and clinical follow-up in a series of PCM cases with cutaneous involvement. Methods Cases of PCM with cutaneous involvement were retrospectively reviewed with clinical data. Results Skin involvement in PCM occurred in older individuals (mean, 75 years) and was more frequent in men (7/10 patients). All cases showed bone marrow involvement preceding the cutaneous lesions. Histopathologically, the infiltrate was plasmacytic (n = 5) or primitive or plasmablastic (n = 4), and 1 case showed predominantly lymphoplasmacytic features with cyclin D1 immunoreactivity and CCND1 gene rearrangement. Concurrent amyloid deposition was seen in one biopsy, and another case demonstrated coexisting squamous cell carcinoma. The most common immunophenotype was CD138+, CD20–, and CD56+ with light chain restriction. Cytogenetic analysis (available for 7 cases) showed multiple hyperdiploid abnormalities. Follow-up was available for 8 cases (mean, 42 months; range, 11-156 months) and showed short-term disease-related death in 7 of 8 patients. Conclusions Cutaneous involvement in PCM demonstrates a diverse cytomorphologic spectrum with plasmacytic, plasmablastic, or lymphoplasmacytic features and may show concurrent amyloid deposition or neoplasms such as squamous cell carcinoma. Cutaneous involvement typically occurs late in the course of the disease and likely portends poor outcome.
Russell bodies are eosinophilic intracytoplasmic globules which are likely the result of disturbed secretion of immunoglobulins that accumulate within the plasma cell. Russell body collections have been identified within the stomach, known as Russell body gastritis. Similar lesions within the duodenum are referred to as Russell body duodenitis, which is rare. Several Russell body gastritis case reports are associated with Helicobacter pylori. However, the etiology of Russell body duodenitis remains unclear. Here we report the first case of Russell body duodenitis with immunoglobulin light chain restriction in a background of peptic duodenitis.
