Clinical characteristics, prognostic indicators, and survival outcomes in intravascular lymphoma: Mayo Clinic experience (2003-2018).

Intravascular lymphoma (IVL) is a rare extranodal non-Hodgkin lymphoma. We performed a retrospective analysis of 55 IVL patients who were treated at our institution 2003-2018. Median age at diagnosis was 68 years, and 64% were males. The most frequent presenting symptoms were skin rash 43% and weight loss 30%. MRI brain on IVL patients with CNS involvement (CNS-IVL) showed multifocal involvement in 76% (13/17). 89% (17/19) of non-CNS-IVL patients with abnormal FDG-PET had biopsy of an avid lesion resulting in definitive diagnosis. The top diagnostic biopsy site was the bone marrow (45%). 56% had multiorgan involvement. Based on CNS involvement, 36.5% (20/55) had CNS-IVL and 63.5% (35/55) had non-CNS-IVL. CNS-IVL group consists of clinically isolated CNS involvement (CNS-only IVL) (22%;12/55) and mixed clinical CNS and peripheral site involvement (M-IVL) (14.5%; 8/55). Non-CNS-IVL group consists of clinically isolated skin involvement (skin-only IVL) (9%; 5/55) and peripheral IVL with or without skin involvement (P-IVL); (54.5%; 30/55). Skin involvement was predominantly in the lower extremities. Pathologically, 89% (48/54) were B-cell IVL. Rituximab + high-dose methotrexate-based regimen were used in 75% (12/16) of CNS-IVL patients and RCHOP in 60% (17/28) of non-CNS-IVL patients. Estimated 5-year progression free survival (PFS) and overall survival (OS) for the entire cohort were 38.6% and 52%, respectively. Skin-only IVL was associated with excellent survival. Platelet count <150x109 /L, age > 60Y, and treatment without Rituximab were poor prognostic factors. Further research is necessary to identify novel therapies.

International, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease.

Human herpesvirus-8 (HHV-8)-negative, idiopathic multicentric Castleman disease (iMCD) is a rare and life-threatening disorder involving systemic inflammatory symptoms, polyclonal lymphoproliferation, cytopenias, and multiple organ system dysfunction caused by a cytokine storm often including interleukin-6. iMCD accounts for one third to one half of all cases of MCD and can occur in individuals of any age. Accurate diagnosis is challenging, because no standard diagnostic criteria or diagnostic biomarkers currently exist, and there is significant overlap with malignant, autoimmune, and infectious disorders. An international working group comprising 34 pediatric and adult pathology and clinical experts in iMCD and related disorders from 8 countries, including 2 physicians that are also iMCD patients, was convened to establish iMCD diagnostic criteria. The working group reviewed data from 244 cases, met twice, and refined criteria over 15 months (June 2015 to September 2016). The proposed consensus criteria require both Major Criteria (characteristic lymph node histopathology and multicentric lymphadenopathy), at least 2 of 11 Minor Criteria with at least 1 laboratory abnormality, and exclusion of infectious, malignant, and autoimmune disorders that can mimic iMCD. Characteristic histopathologic features may include a constellation of regressed or hyperplastic germinal centers, follicular dendritic cell prominence, hypervascularization, and polytypic plasmacytosis. Laboratory and clinical Minor Criteria include elevated C-reactive protein or erythrocyte sedimentation rate, anemia, thrombocytopenia or thrombocytosis, hypoalbuminemia, renal dysfunction or proteinuria, polyclonal hypergammaglobulinemia, constitutional symptoms, hepatosplenomegaly, effusions or edema, eruptive cherry hemangiomatosis or violaceous papules, and lymphocytic interstitial pneumonitis. iMCD consensus diagnostic criteria will facilitate consistent diagnosis, appropriate treatment, and collaborative research.

The clinical spectrum of Castleman's disease.

Castleman's disease (CD) is a rare, poorly understood lymphoproliferative disease. The spectrum of symptoms and course of disease are broad, but there is no large study describing the natural history of this disease. Basic clinic and laboratory data from the records of 113 patients with CD evaluated at the Mayo Clinic and University of Nebraska were abstracted. The impact of these variables on overall survival (OS) from time of diagnosis was evaluated. Sixty patients had multicentric disease. Of the patients with multicentric CD, 32% had criteria sufficient for a diagnosis of POEMS syndrome. For all patients, 2, 5, and 10-year OS was 92%, 76%, 59%, respectively. Most of the factors identified as risk factors for death on univariate analysis cosegregated with diagnostic criteria for POEMS syndrome, which supported the concept of four categories of CD, which are (along with their 5-year OS): (1) unicentric CD (91%); (2) multicentric CD associated with the osteosclerotic variant of POEMS syndrome (90%); (3); multicentric CD without POEMS syndrome (65%); and (4) multicentric CD with POEMS syndrome without osteosclerotic lesions (27%). We have demonstrated that CD represents a spectrum of disease that can be differentiated by simple prognostic factors that provide a framework for further study.

A Previously Unrecognized Granulomatous Variant of Gamma-Delta T-Cell Lymphoma.

Primary cutaneous γδ T-cell lymphoma (PCGD-TCL) is an extremely rare and aggressive T-cell neoplasm with complex heterogeneity. We present a series of two patients who presented with firm, subcutaneous nodules and were diagnosed with PCGD-TCL. In both cases, biopsies demonstrated a both superficial and deep adnexotropic infiltrate comprised of angiocentric, medium- to large-sized atypical lymphocytes. The infiltrate extended into the panniculus. Immuno-histochemical stains highlighted atypical lymphocytes that expressed CD3, CD8 and CD56 but were negative for EBV ISH. A brisk histiocytic response with focal aggregation into granulomas was highlighted with a PG-M1 stain. The atypical lymphocytes were positive for gene rearrangements on a TCR delta stain and negative for ßF-1. CT and PET scan in one of the two patients demonstrated diffuse, subcutaneous, ground-glass foci; hypermetabolic soft tissue nodules; and lymphadenopathy in the lungs, as well as splenomegaly. A diagnosis of histiocyte-rich PCGD-TCL was rendered. A histiocyte-rich, granulomatous variant of γδ T-cell lymphoma is extremely rare. Its potentially misleading resemblance to inflammatory granulomatous conditions could pose a diagnostic pitfall in this already challenging condition. This variant may resemble granulomatous mycosis fungoides and granulomatous slack skin syndrome, but it has a distinct, aggressive clinical outcome.

Primary peritoneal myeloid sarcoma in association with CBFB/MYH11 fusion.

Myeloid sarcoma, also known as chloroma or granulocytic sarcoma is an extramedullary disease process that typically presents in association with acute myeloid leukemia during initial presentation or at relapse. Often associated with cytogenetic mutations, including t(8;21)(q22;q22); RUNX1/RUNX1T1, and less frequently with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB/MYH11, myeloid sarcoma is most commonly discovered in skin, soft tissue, bone, and connective tissue. In rare circumstances, myeloid sarcoma can present without any evidence of bone marrow or leukemic involvement. These cases of de novo myeloid sarcoma are rare, and are commonly misdiagnosed due to similarities with other entities. We report an unusual case of a primary de novo peritoneal myeloid sarcoma, in association with inv(16)(p13;q22) and clonal heterogeneity at different sites of involvement, that has responded well to AML induction therapy and consolidation treatment with gemtuzumab ozogamicin and high dose cytarabine. Cytogenetics, immunophenotyping, and chromosomal analysis, were each critical in establishing a proper diagnosis as well as helping to develop appropriate therapeutic strategies for this rare entity.

Primary age-related EBV-associated effusion-based lymphoma successfully treated with rituximab and thoracentesis.

EBV-positive HHV8-negative EBL is part of the spectrum of EBV-positive diffuse large B-cell lymphoma NOS. This entity can be labeled as primary age-related EBV-associated EBL and appears to respond well to rituximab and thoracentesis.

Outcomes of Hepatosplenic T-Cell Lymphoma: The Mayo Clinic Experience.

BACKGROUND: Hepatosplenic T-cell lymphoma (HSTCL) is a rare subtype of peripheral T-cell lymphoma accounting for less than 1% of non-Hodgkin lymphomas. It is generally associated with poor prognosis. PATIENTS AND METHODS: We performed a cohort study of patients with HSTCL treated at the Mayo Clinic between 1996 and 2020 exploring the clinical characteristics and therapeutic outcomes. RESULTS: Twenty-two cases of HSTCL were identified with a median (range) age at diagnosis of 45.5 (15.5-80.6) years and a male predominance (15/22, 68.2%). Clinical characteristics include massive splenomegaly in 16 patients (73%), hepatic involvement in 13 (59%), and chronic immunosuppressed state in 8 (36%). Phenotypically, lymphoma cells had gamma/delta T-cell receptor expression in 18 (82%) and alpha/beta in 4 patients. Cytogenetic abnormalities included isochromosome 7q (i7q) in 8 (62%) of 13 and trisomy 8 in 4 (44%) of 9. The median (range) follow-up of surviving patients was 33 (2.5-137) months. The median progression-free and overall survival were 9.5 months (95% CI, 1.8, 16.3) and 12.4 months (95% CI, 4.9, 18.5), respectively. Long-term survival was seen in 4 (18%) of 22 patients, with survival of 55, 74, 95, and 137 months. Moreover, 3 of 4 long-term survivors had splenectomy as part of initial treatment, and 2 of 4 long-term survivors received an allogeneic hematopoietic cell transplant (allo-HCT). CONCLUSION: Liver involvement and chronic immunosuppression were associated with shorter survival. Although splenectomy and allo-HCT have anecdotal benefit in the literature, our data do not show a statistically significant benefit of splenectomy and/or allo-HCT, likely as a result of our small sample size.

Comparable Efficacy of Reduced Dose Radiation Therapy for the Treatment of Early Stage Gastric Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue.

PURPOSE: This study compares reduced (<27 Gy) to standard dose (≥30 Gy) radiation therapy (RT) in the treatment of gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (gMALT lymphoma). METHODS AND MATERIALS: Forty-two patients with stage I or II disease were retrospectively reviewed. Response to RT was assessed with endoscopy after RT. Complete response rate (CR), freedom from treatment failure, and overall survival (OS) were calculated. RESULTS: All patients were stage I (n = 40) or II (n = 2). All patients had residual biopsy proven gMALT lymphoma before RT. Twenty-six patients (61.9%) were treated with standard dose RT, 30 to 36 Gy, and 16 (38.1%) with the reduced dose RT, 23.5 to 27 Gy. The median follow-up was 29.5 months (range, 6-85). Thirty-six patients (86%) achieved complete response (CR), and 6 patients (14%) achieved partial response (PR). The complete response rate (CR) at the first endoscopic assessment, median time of 3 months, was 81% (95% confidence interval, 0.61%-0.93%) for standard RT, and 94% (confidence interval, 0.69%-0.99%) for reduced RT. Among CR patients, one patient had locally relapsed disease at 50 months. The 1-year overall survival (OS) was 100% in both groups. The 1-year freedom from treatment failure (FFTF) was 100% in the reduced RT group and 92% in the standard RT group. The 2-year FFTF and OS of the whole cohort were 92% and 96%, respectively. There was no significant difference in the OS, FFTF, and CR between the 2 treatment groups (P = .38, P = .18, and P = .267, respectively). For toxicity, the mean liver dose and the mean V20 heart dose were significantly lower in the reduced RT group (P <.001 and P = .001, respectively). However, incidence and severity of reported toxicities were similar between the 2 groups. CONCLUSIONS: Reduced dose RT (23.5-27 Gy) achieved excellent complete response rates with minimal toxicity, comparable with standard dose RT (30-36 Gy), for gMALT.

Use of Tocilizumab in Management of Post-Operative Myelomonocytic Leukemoid Reaction.

Interleukin 6 receptor (IL6R) inhibitor, tocilizumab, has been effectively used in the treatment of cytokine release syndrome in patients receiving chimeric antigen receptor T-cell therapy. Here we present a patient with chronic myelomonocytic leukemia (CMML) who developed a steroid refractory, post-operative myelomonocytic leukemoid reaction (PO-MMLR), effectively treated with tocilizumab. Although, further studies are needed to validate the effectiveness of tocilizumab in management of PO-MMLR, this case serves to provide a new management approach in treatment of this rare but lethal syndrome with no standardized treatment options.