A comprehensive review of the impact of obesity on plasma cell disorders.

Multiple myeloma (MM) remains an incurable plasma cell malignancy. Although little is known about the etiology of MM, several metabolic risk factors such as obesity, diabetes, poor nutrition, many of which are modifiable, have been linked to the pathogenesis of numerous neoplasms including MM. In this article, we provide a detailed summary of what is known about the impact of obesity on the pathogenesis of MM, its influence on outcomes in MM patients, and discuss potential mechanisms through which obesity is postulated to influence MM risk and prognosis. Along with advancements in treatment modalities to improve survival in MM patients, focused efforts are needed to prevent or intercept MM at its earliest stages. The consolidated findings presented in this review highlight the need for clinical trials to assess if lifestyle modifications can reduce the incidence and improve outcomes of MM in high-risk populations. Data generated from such studies can help formulate evidence-based lifestyle recommendations for the prevention and control of MM.

Heterogeneity in the diagnosis of plasmablastic lymphoma, plasmablastic myeloma, and plasmablastic neoplasm: a scoping review.

The diagnosis of plasmablastic lymphoma (PBL), plasmablastic myeloma (PBM), and plasmablastic neoplasm (PBN) may be arbitrary in some cases because these entities can be indistinct. We conducted this scoping review to investigate heterogeneity in diagnostic criteria used in previous studies and validate the diagnostic results of previous diagnostic algorithms and the algorithm we developed, which also includes diagnosis of PBN. Using the PRISMA Extension for Scoping Reviews, we analyzed literature published between September 2017 and April 2020. We identified a total of 163 cases (128 PBL, 32 PBM, and 3 PBN) from 77 case reports and 8 case series. We found that diagnostic criteria in the literature varied for PBL but were consistent for PBM. Our algorithm was the first attempt to include PBN in a complete structure. The results of the three diagnostic algorithms varied significantly. Hematologists and pathologists should pay more attention to the differential diagnosis of PBL, PBM, and PBN.

Proliferation to Apoptosis Tumor Cell Ratio as a Biomarker to Improve Clinical Management of Pre-Malignant and Symptomatic Plasma Cell Neoplasms.

Proliferation and apoptosis of neoplastic cells are prognostic biomarkers in plasma cell neoplasms (PCNs). The prognostic capacity of proliferation to apoptosis ratio (Ratio-PA) in the era of immunomodulatory treatments is re-evaluated in 316 gammopathy of undetermined significance (MGUS), 57 smoldering multiple myeloma (SMM), and 266 multiple myeloma (MM) patients. Ratio-PA of 0.77 ± 0.12, 1.94 ± 0.52, and 11.2 ± 0.7 (p < 0.0001) were observed in MGUS, SMM, and MM patients. Ten-year overall survival (10y-OS) rates for patients with low/high Ratio-PA were 93.5%/77.3% p < 0.0001) for MGUS, 82.5%/64.7% (p < 0.05) for SMM, and 62.3%/47.0% (p < 0.05) for MM. For patients with low, intermediate, and high risk, 10y-OS for low/high Ratio-PA were 95.5%/72.9% (p < 0.0001), 74.2%/50.4% (p < 0.0001), and 35.3%/20.0% (p = 0.836), respectively. Ratio-PA was an independent prognostic factor for OS (HR = 2.119, p < 0.0001, Harrell-C-statistic = 0.7440 ± 0.0194) when co-analyzed with sex, age, and standard risk. In patients with Ratio-PAhigh, only first-line therapy with VRd/VTd, but not PAD/VCD, coupled with ASCT was associated with high 10y-OS (82.7%). Tumor cell Ratio-PA estimated at diagnosis offers a prognostic biomarker that complements standard risk stratification and helps to guide the clinical management of pre-malignant and symptomatic PCNs. Every effort should be made to provide first-line therapies including VTd or VRd associated with ASCT to patients with Ratio-PAhigh at higher risk of progression and death.

Initial Whole-Genome Sequencing of Plasma Cell Neoplasms in First Responders and Recovery Workers Exposed to the World Trade Center Attack of September 11, 2001.

PURPOSE: The World Trade Center (WTC) attack of September 11, 2001 created an unprecedented environmental exposure to known and suspected carcinogens. High incidence of multiple myeloma and precursor conditions has been reported among first responders to the WTC disaster. To expand on our prior screening studies, and to characterize the genomic impact of the exposure to known and potential carcinogens in the WTC debris, we were motivated to perform whole-genome sequencing (WGS) of WTC first responders and recovery workers who developed a plasma cell disorder after the attack. EXPERIMENTAL DESIGN: We performed WGS of nine CD138-positive bone marrow mononuclear samples from patients who were diagnosed with plasma cell disorders after the WTC disaster. RESULTS: No significant differences were observed in comparing the post-WTC driver and mutational signature landscapes with 110 previously published WGSs from 56 patients with multiple myeloma and the CoMMpass WGS cohort (n = 752). Leveraging constant activity of the single-base substitution mutational signatures 1 and 5 over time, we estimated that tumor-initiating chromosomal gains were windowed to both pre- and post-WTC exposure. CONCLUSIONS: Although limitations in sample size preclude any definitive conclusions, our findings suggest that the observed increased incidence of plasma cell neoplasms in this population is due to complex and heterogeneous effects of the WTC exposure that may have initiated or contributed to progression of malignancy.

Mast Cells and Angiogenesis in Human Plasma Cell Malignancies.

Bone marrow angiogenesis plays an important role in the pathogenesis and progression of hematological malignancies. It is well known that tumor microenvironment promotes tumor angiogenesis, proliferation, invasion, and metastasis, and also mediates mechanisms of therapeutic resistance. An increased number of mast cells has been demonstrated in angiogenesis associated with hematological tumors. In this review we focused on the role of mast cells in angiogenesis in human plasma cell malignancies. In this context, mast cells might act as a new target for the adjuvant treatment of these tumors through the selective inhibition of angiogenesis, tissue remodeling and tumor-promoting molecules, permitting the secretion of cytotoxic cytokines and preventing mast cell-mediated immune suppression.

Plasma cell neoplasia after kidney transplantation: French cohort series and review of the literature.

Although post-transplant lymphoproliferative disorder (PTLD) is the second most common type of cancer in kidney transplantation (KT), plasma cell neoplasia (PCN) occurs only rarely after KT, and little is known about its characteristics and evolution. We included twenty-two cases of post-transplant PCN occurring between 1991 and 2013. These included 12 symptomatic multiple myeloma, eight indolent myeloma and two plasmacytomas. The median age at diagnosis was 56.5 years and the median onset after transplantation was 66.7 months (2-252). Four of the eight indolent myelomas evolved into symptomatic myeloma after a median time of 33 months (6-72). PCN-related kidney graft dysfunction was observed in nine patients, including six cast nephropathies, two light chain deposition disease and one amyloidosis. Serum creatinine was higher at the time of PCN diagnosis than before, increasing from 135.7 (±71.6) to 195.9 (±123.7) µmol/l (p = 0.008). Following transplantation, the annual rate of bacterial infections was significantly higher after the diagnosis of PCN, increasing from 0.16 (±0.37) to 1.09 (±1.30) (p = 0.0005). No difference was found regarding viral infections before and after PCN. Acute rejection risk was decreased after the diagnosis of PCN (36% before versus 0% after, p = 0.004), suggesting a decreased allogeneic response. Thirteen patients (59%) died, including twelve directly related to the hematologic disease. Median graft and patient survival was 31.7 and 49.4 months, respectively. PCN after KT occurs in younger patients compared to the general population, shares the same clinical characteristics, but is associated with frequent bacterial infections and relapses of the hematologic disease that severely impact the survival of grafts and patients.

Autophagy in Plasma Cell Ontogeny and Malignancy.

Autophagy is a highly conserved pathway that recycles cytosolic material and organelles via lysosomal degradation. Once simplistically viewed as a non-selective survival strategy in dire straits, autophagy has emerged as a tightly regulated process ensuring organelle function, proteome plasticity, cell differentiation and tissue homeostasis, with key roles in physiology and disease. Selective target recognition, mediated by specific adapter proteins, enables autophagy to orchestrate highly specialized functions in innate and adaptive immunity. Among them, the shaping of plasma cells for sustainable antibody production through a negative control on their differentiation program. Moreover, memory B cells and long-lived plasma cells require autophagy to exist. Further, the plasma cell malignancy, multiple myeloma deploys abundant autophagy, essential for homeostasis, survival and drug resistance.

Histopathological Characteristics of Lymphomas in the Upper Aerodigestive Tract. A Single-Institute Study in Japan.

We analyzed the histopathological characteristics of lymphomas biopsied from the upper aerodigestive tract between 2000 and 2014 at the National Cancer Center Hospital in Japan. Of a total of 309 consecutive cases, the following incidences were observed: mature B-cell neoplasms, 77% (n = 239); mature T- and NK-cell neoplasms, 20% (n = 63); classical Hodgkin lymphomas, 0.7% (n = 2); and lymphoblastic lymphomas, 2% (n = 5). Lymphomas were most frequently (57%) detected in the oropharynx. The majority of cases (89%) were mature B-cell neoplasms (diffuse large B-cell lymphoma, 60%; follicular lymphoma, 10%), and 10% of cases were mature T-cell neoplasms. Six cases of plasma cell neoplasm (4 primary and 2 secondary involvement) and 2 cases of plasmablastic lymphoma in the upper aerodigestive tract were observed. Two out of 3 cases of extraosseous plasmacytoma with available biopsy material were positive for EBER1. All 3 patients received irradiation and achieved complete response; 1 had not relapsed after 17 months and the remaining 2 relapsed as plasma cell myeloma and solitary plasmacytoma of the bone. Of 47 extranodal NK/T-cell lymphoma, nasal-type cases in the upper aerodigestive tract, 38 (81%) were present in the sinonasal region and the remaining 9 (19%) were in the oropharynx (n = 4), nasopharynx (n = 3), and oral cavity (n = 2). In conclusion, since both primary lymphoma and secondary involvement of lymphoma are often diagnosed using biopsied materials from the upper aerodigestive tract, pathologists and hematologists should recognize the characteristics of lymphoma in this tissue.

Increased risk for lymphoid and myeloid neoplasms in elderly solid-organ transplant recipients.

BACKGROUND: By assessing the spectrum of hematologic malignancies associated with solid-organ transplantation in the elderly, we provide information on the pathogenesis of lymphoid and myeloid neoplasms and the clinical manifestations of immunosuppression. METHODS: Using data from the U.S. Surveillance, Epidemiology, and End Results Medicare database, we identified 83,016 cases with a hematologic malignancy (age 66-99 years) and 166,057 population-based controls matched to cases by age, sex, and calendar year. Medicare claims were used to identify a history of solid-organ transplantation. We used polytomous logistic regression to calculate odds ratios (OR) comparing transplantation history among cases with various hematologic malignancy subtypes and controls, adjusting for the matching factors and race. RESULTS: A prior solid-organ transplant was identified in 216 (0.26%) cases and 204 (0.12%) controls. Transplantation was associated with increased risk for non-Hodgkin lymphomas [OR, 2.13; 95% confidence interval (95% CI), 1.67-2.72], especially diffuse large B-cell lymphoma (OR, 3.29; 95% CI, 2.28-4.76), marginal zone lymphoma (OR, 2.48; 95% CI, 1.17-5.22), lymphoplasmacytic lymphoma (OR, 3.32; 95% CI, 1.41-7.81), and T-cell lymphoma (OR, 3.07; 95% CI, 1.56-6.06). Transplantation was also associated with elevated risk of Hodgkin lymphoma (OR, 2.53; 95% CI, 1.01-6.35) and plasma cell neoplasms (OR, 1.91; 95% CI, 1.24-2.93). Risks for myeloid neoplasms were also elevated (OR, 1.99; 95% CI, 1.41-2.81). CONCLUSION: Solid-organ transplantation is associated with a wide spectrum of hematologic malignancies in the elderly. Risk was increased for four specific non-Hodgkin lymphoma subtypes for which a viral agent has been implicated, supporting an added role for immunosuppression. IMPACT: Our results support monitoring for a wide spectrum of hematologic malignancies following solid-organ transplant.

Genetic and immune-related factors in the pathogenesis of lymphoproliferative and plasma cell malignancies.

There are data to support a role for genetic and immune-related factors in the pathogenesis of lymphomas and plasma cell diseases. In this paper, we review our published large population-based studies and other relevant studies in Hodgkin's and non-Hodgkin's lymphomas, multiple myeloma, and the precursor condition monoclonal gammopathy of undetermined significance. We discuss the overlap in risk factors between related malignancies and explore the underlying mechanisms. Based on these studies, we provide clinical implications and discuss the relevance of these data for patient counseling and clinical follow-up. Finally, we suggest future directions for new studies designed to increase our current knowledge and to define underlying biological mechanisms of our findings.

Risk of plasma cell and lymphoproliferative disorders among 14621 first-degree relatives of 4458 patients with monoclonal gammopathy of undetermined significance in Sweden.

Familial clustering of the precursor condition, monoclonal gammopathy of undetermined significance (MGUS) has been observed in case reports and in smaller studies. Using population-based data from Sweden, we identified 4458 MGUS patients, 17505 population-based controls, and first-degree relatives of patients (n = 14621) and controls (n = 58387) with the aim to assess risk of MGUS and lymphoproliferative malignancies among first-degree relatives of MGUS patients. Compared with relatives of controls, relatives of MGUS patients had increased risk of MGUS (relative risk [RR] = 2.8; 1.4-5.6), multiple myeloma (MM; RR = 2.9; 1.9-4.3), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM; RR = 4.0; 1.5-11), and chronic lymphocytic leukemia (CLL; RR = 2.0; 1.2-2.3). Relatives of patients with IgG/IgA MGUS had a 4.0-fold (1.7-9.2), 2.9-fold (1.7-4.9), and 20-fold (2.3-170) elevated risk of developing MGUS, MM, and LPL/WM, respectively. Relatives of IgM MGUS patients had 5.0-fold (1.1-23) increased CLL risk and nonsignificant excess MM and LPL/WM risks. The results were very similar when we assessed risk by type of first-degree relative, age at MGUS (above/below 65 years), or sex. Risk of non-Hodgkin lymphoma or Hodgkin lymphoma was not increased among MGUS relatives. Among first-degree relatives of a nationwide MGUS cohort, we found elevated risks of MGUS, MM, LPL/WM, and CLL, supporting a role for germline susceptibility genes, shared environmental influences, or an interaction between both.

Plasmablastic lymphoma: CNS involvement, coexistence of other malignancies, possible viral etiology, and dismal outcome.

The clinical and pathological findings of plasmablastic lymphoma (PBL) have been described in the literature but the etiology is not well established, and treatment options are poorly defined. We reviewed patients with PBL in our institution to characterize the clinicopathologic features in our patient population. In this retrospective analysis from a single academic institution, five patients with PBL were identified and analyzed. Human immunodeficiency virus and human herpesvirus 8 (HHV-8) were identified in 40% (two out of five) and 80% (four out of five) of these patients, respectively. Central nervous system (CNS) involvement was identified in four out of five (80%) patients. Interestingly, three out of five patients had a concurrent or preceding second primary malignancy including small lymphocytic lymphoma, endometrial cancer, and nonsmall cell lung cancer. Most of the patients had advanced disease and a poor performance status at diagnosis. Only two of the patients received systemic chemotherapy with an initial partial response. All five patients died; the median overall survival was 1 month. Our experience in patients with PBL indicates that CNS involvement is more common than reported in the literature. Coexistence of a second primary malignancy may be frequent, and prognosis remains dismal with standard lymphoma therapy. Lastly, the role of HHV-8 in the etiopathogenesis needs further trials.