Light Chain Restricted Plasma Cells Research Articles

Lymphoplasmacytic Lymphoma: An Atypical Presentation with IgG Monoclonal Gammopathy

Introduction Lymphocytic lymphoma (LPL) is a rare type of low-grade mature B-cell non-Hodgkin lymphoma, characterized by a monoclonal population of B lymphocytes, lymphoplasmacytic cells, and plasma cells. In around 95% of LPL cases, the serum immunoglobulin M (IgM) paraprotein is increased, which is correlated to Waldenstrom's Macroglobulinemia (WM), a clinicopathological disease. Only around 5% of LPL cases are associated with the serum paraproteins immunoglobulin G (IgG) or immunoglobulin A (IgA), or light chains alone, or are not linked to a paraprotein. Non-IgM LPLs have a wide range of clinical and pathological features, and MYD88 L265P mutations can occur, though at a lower frequency than WM. Hence, MYD88 testing is advised for prospective therapeutic purposes. Case Presentation A 69-year-old male was referred to a hematologist for uncontrolled epistaxis and periorbital edema. On initial workup, he had high total protein, elevated globulin, hypoalbuminemia, anemia, and proteinuria. Further investigation revealed a high IgG level with low IgM, IgA, and complement levels. Serum Protein Electrophoresis (SPEP): Increased total protein, decreased alpha two and beta globulins with a large monoclonal protein peak migrating in the gamma region, which accounts for 4.77 g/dl of the total 5.38g/dl gamma. Elevated Kappa Quantitative Free Light Chains of 355.39 (3.30 - 19.40mg/L), Decreased Lambda Quantitative Free Light Chains of 1.51 (5.71 - 26.30mg/L), Elevated Kappa Lambda Free Light Chains Ratio of 235.36 (0.26 - 1.65). Serum ImmunoFixation Electrophoresis demonstrated IgG-type kappa monoclonal protein with an additional faint band in IgG kappa. X-Ray skeletal survey showed a possible small lytic area in the inferior aspect of the C2 vertebral body, prompting him to have a cervical spine MRI which revealed no lytic lesions but an 18 mm vertebral body hemangioma inside T2. Molecular testing was positive for MYD88 Mutation c.794T>C (p. L265P) and negative for CXCR4 mutation. Plasma cell myeloma prognostic panel and chromosome analysis were normal. Flow cytometry of bone marrow aspirate showed a kappa light chain restricted plasma cell population (1.6% of total cells) with the following immunophenotype: positive for CD138, CD38, CD45, and negative for CD19, CD20, CD56, CD 117, and lambda light chains. The B-cell population showed kappa light chain restriction with the following immunophenotype: positive for CD19, CD20, and kappa light chains and negative for CD5, CD10, CD11c, CD23, and lambda light chains (Image 2). PET-CT of the whole body was negative for the extension of the disease. Transfusion with the two least incompatible PRBCs had little effect. However, plasmapheresis significantly improved his hemoglobin level by less than 7g/dl. A bone marrow biopsy revealed he had LPL with IgG Monoclonal Gammopathy (Image 1). He received one cycle of CyBorD (Cyclophosphamide, Bortezomib, Dexamethasone), followed by seven cycles of KCD (Carfilzomib, Cyclophosphamide, Dexamethasone) and Rituximab. The patient was diagnosed with low-grade B cell lymphoma with plasmocytic differentiation/lymphoplasmacytic lymphoma, with MYD88 mutation c.794T>C (p. L265P) positivity and CXCR4 mutation negativity. After plasmapheresis, the IgG level dropped to 1958. Follow-up SPEP revealed decreased alpha2 and beta globulins, decreased free lambda light chains, and increased K/L ratio. The patient was treated with Acalabrutinib, and his anemia, epistaxis, and coagulopathy resolved. Repeat PET-CT scan revealed no evidence of illness progression. Discussion LPL is not always linked with IgM monoclonal gammopathy; it can also be associated with IgG or IgA monoclonal gammopathy, light chains alone, or no monoclonal paraprotein. Non-IgM LPL has a high prevalence of extramedullary involvement, a lower rate of MYD88 mutation, and few hyper viscosity symptoms. The MYD88 mutation does not allow WM and Non-IgM LPL to be distinguished from other lymphoproliferative disorders with similar clinical and immunophenotypic features. The case described is unique as the patient has high levels of IgG (11,200) at presentation. In contrast to our patient, who has LPL with IgG Monoclonal gammopathy, approximately 95 percent of LPL patients have IgM Monoclonal gammopathy, which corresponds with WM. As a result, clinicians should be on the lookout for LPL that lacks an IgM Monoclonal Paraprotein.

Amyloid inflammatory myopathy: report of two cases and literature review (P9-8.009)

<h3>Objective:</h3> Our review of the literature revealed a few reported cases of amyloid myopathy (AM) associated with mild to moderate infiltration of inflammatory cells. <h3>Background:</h3> AM is a clinically and etiologically heterogenous group of myopathies. It is rarely associated with myositis, although there have been occasional reports of AM masquerading idiopathic inflammatory myopathies (IIMs) such as polymyositis and inclusion body myositis. Pathologically, AM is characterized by amyloid deposits in the intramuscular blood vessels or connective tissue elements, and reportedly not in myofibers. <h3>Design/Methods:</h3> We present two cases of AM with inflammatory myopathy (IM) features. <h3>Results:</h3> <h3>Case 1:</h3> 62-year-old male with a 1-year history of dilated cardiomyopathy presented with significant proximal muscle weakness. His serum creatine kinase (CK) levels were moderately elevated. A right deltoid muscle biopsy demonstrated myopathic changes with necrotic fibers, many CD68+ macrophages, occasional CD8+ T-cells, MHC-1 sarcolemmal/sarcoplasmic positivity, and amyloid deposits in the intramuscular blood vessels. A subsequent bone marrow biopsy revealed the IGH-CCND1 rearrangement with malignant 25% lambda light-chain restricted plasma cells. <h3>Case 2:</h3> 58-year-old female presented with generalized weakness, lower extremity edema, decreased exercise tolerance and lethargy over 4 weeks. She was recently diagnosed with kappa light-chain multiple myeloma by a bone marrow biopsy showing 80% kappa light-chain restricted plasma cells. Despite normal CK while receiving dexamethasone, the thigh muscle magnetic resonance imaging and clinical features were consistent with IM. A left thigh muscle biopsy demonstrated myopathic changes including necrotic fibers and amyloid deposits in the necrotic fibers, endomysial/perimysial tissue, and blood vessels. It also revealed abundant inflammatory cell infiltrates including CD68+ macrophages, CD8+ T-cells, and CD20+ B-cells with MHC-1 sarcolemmal/sarcoplasmic positivity. <h3>Conclusions:</h3> Our cases and literature review suggest that AM may present with IM features including unusual features such as B-cell inflammatory foci. IM associated with AM (amyloid IM) may be secondary or a subtype of IIMs. <b>Disclosure:</b> Dr. Gupta has nothing to disclose. Dr. Bhavsar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pfizer. Dr. Bhavsar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abbvie. Dr. Bhavsar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB. Dr. Bhavsar has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novartis. Dr. Fareez has nothing to disclose. Dr. Tarnopolsky has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sanofi-Genzyme. Dr. Tarnopolsky has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Reneo. Dr. Tarnopolsky has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion. Dr. Tarnopolsky has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Reneo . Dr. Tarnopolsky has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi-Genzyme. Dr. Tarnopolsky has stock in Synaptive Medical. Dr. Tarnopolsky has stock in CloudDx. The institution of Dr. Tarnopolsky has received research support from Canadian Institute for Health Research. Dr. Tarnopolsky has received intellectual property interests from a discovery or technology relating to health care. Dr. Lu has nothing to disclose.

Primary cutaneous blastic marginal zone lymphoma: A comprehensive clinical, light microscopic, phenotypic and cytogenetic appraisal

BackgroundPrimary cutaneous marginal zone lymphoma (PCMZL) is a form of indolent lymphoproliferative disease where the disease is largely a cutaneous confined process. It is typically a neoplasm composed of post germinal small B-cells and light chain restricted plasma cells in a background of reactive T-cell hyperplasia and benign germinal centers. Rarely a significant degree of large cell infiltration occurs warranting the categorization as blastic marginal zone lymphoma. Materials and methodsWe reviewed our data base over a time period of 2016 to 2022 for cases diagnosed as blastic MZL. Twelve cases were identified. The clinical records and pathological data were reviewed. ResultsNine of the cases represented de novo forms of blastic MZL while in three cases there was a prior history of MZL. Multifocal cutaneous disease was not uncommon and one quarter of the cases had evidence of extracutaneous dissemination. All patients except three achieved remission with varied therapeutic interventions depending on the extent of the disease ranging from conservative re-excision to chemotherapy. No patient died from lymphoma. Light microscopically, there was evidence of a background of conventional MZL in the majority of cases. The large cell component was typically characterized by multiple micronodular aggregates throughout the dermis although in three cases there was a striking diffuse large cell component as the dominant infiltrate. Phenotypically, a third of the cases showed either CD5 or CD23 positivity amidst neoplastic B cells. Significant staining for BCL-2 was noted in the majority of cases tested while extensive MUM-1 positivity was observed in half of the cases tested. Kappa or lambda light chain restriction was seen in most. The Ki67 proliferation index exceeded 30 % in all cases. There was C-MYC positivity in two cases. While most cases did not detect cytogenetic abnormalities, one case had multiple cytogenetic hits that are associated with diffuse large B cell lymphoma. Next generation sequencing showed a Ten-eleven translocation 2 mutation in the earlier biopsy prior to transformation and in the later biopsy after transformation along with an additional B2M mutation in the transformed biopsy. Both types of mutations are very uncommon but held to contribute to tumor progression in the setting of diffuse large B cell lymphoma. ConclusionBlastic MZL is associated with a more aggressive clinical course. Even when there is disseminated disease patients while not always cured did not have a fatal course in this series. The light microscopic findings are reproducible. The background of MZL, identification of larger cells in significant numbers without a follicle center phenotype, at times expressing CD5 or CD23 with variable positivity for MUM1, BCL-2 and C-MYC and a high proliferation index define the pathology in most. Certain cytogenetic abnormalities and genetic mutations implicated in large cell transformation into a diffuse large B cell lymphoma are seen in blastic MZL with earlier biopsies prior to transformation potentially harboring at risk genetic mutations.

The NSG-hIL6 Mouse As a Novel Murine Patient Derived Xenograft Model of Plasma Cell Dyscrasias for Study of Disease Biology and Therapeutic Development

Background Plasma cell dyscrasias include pre-malignant and malignant conditions spanning the spectrum from monoclonal gammopathy of undetermined significance (MGUS) to smoldering multiple myeloma (SMM) to active multiple myeloma (aMM) and include the disorders AL amyloidosis and plasma cell leukemia (PCL). Though the last 2 decades has yielded effective therapies against these disorders, there remain no reliably curative treatments, and complications due to multiple myeloma are most often the cause of death. A major reason for the lack of curative therapies is the dearth of relevant research models in which to study these diseases and test new drug candidates. Cell lines that do not reflect the biology of mainstream myeloma are currently the mainstay of disease modeling. Plasma cells do not survive well outside the bone marrow and to this point, little success has been made using primary tumors from patients to model disease. Thus, there is a significant need for more relevant models to build the next, hopefully curative, generation of therapeutics for these diseases. Research Significance We present a novel immunodeficient murine model able to engraft plasma cell dyscrasias from primary patient tumors and the ability to study basic biology and test efficacy of cellular therapies, representing a significant advance in this field. Methods The NSG-h(IL6) mouse, developed by Dr. Shultz, builds on the background NSG mouse that lacks adaptive immunity and has limited innate immunity. It expresses a BAC with a piece of human chromosome 7, containing the human IL-6 gene and all associated local promoter and enhancer elements. With the expertise of the stem cell and xenograft core facility (SCXC), mice were preconditioned with busulfan, and 1e6 mononuclear cells (MNCs) isolated from human myeloma patient marrow aspirate were injected into the murine femur. Blood and urine were sampled every 4-5 weeks and analyzed for the presence of human antibodies by ELISA. Deceased mice were sent for histology and their spleens and marrow analyzed for the presence of clonal plasma cells by flow cytometry. Serum protein electrophoresis (SPEP) and complete blood counts (CBC) were noted as hallmarks of disease. Samples from patients with MGUS, SMM, aMM (both newly diagnosed and relapsed/refractory), PCL and AL amyloidosis were engrafted into mice as above. Mice were treated with untraduced T-cells (UTD) or BCMA-directed CARTs 10 weeks after engraftment of active myeloma and blood was assayed for level of immunoglobulins to follow response. Results Analysis of murine serum and urine by ELISA revealed the presence of rising titers of human antibodies in all engrafted mice and the presence of an M-spike on SPEP. NSG-hIL6 mice conditioned with busulfan showed greater engraftment than non-IL6 containing mice and non-conditioned mice (7 vs 2 vs 0, p<0.005). Light chain specific ELISA showed a clear predominance of one light chain, congruent with the patient sample that was engrafted. Flow cytometric analysis of engrafted murine bone marrow showed the presence of light chain restricted plasma cells. Histology showed the presence of plasma cells in the marrow, spleen and liver of engrafted animals with IHC positivity for specific light chain and CD138. CBC showed pancytopenia (p<0.005) with anemia being most significant in engrafted vs. unengrafted animals. All fresh samples and nearly all frozen samples of MGUS, SMM, aMM, PCL and AL amyloidosis were able to be engrafted at high rates (>50% of mice). Mice injected with column separated CD138+ cells alone showed no engraftment vs. mice injected with total MNCs from the marrow of the same myeloma (3 vs 0, p<0.005 ). BCMA directed CARTs significantly decreased circulating antibody compared to UTD controls (p<0.005). Conclusion Using the NSG-hIL6 mouse, busulfan conditioning and intrafemur injections, we have been able to engraft all the major plasma cell dyscrasias as denoted by the presence of monoclonal human antibody in these mice and presence of light chain restricted plasma cells congruent with the patient's paraprotein. We have preliminarily shown that the ability to engraft disease is dependent on human supporting cells. Additionally, treatment with BCMA directed CARTs is showing a response. This simple model will allow for further preclinical testing of new agents against multiple myeloma and associated plasma cell neoplasms and allow for study of basic biology of these diseases. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Overlapping Features of Primary Cutaneous Marginal Zone Lymphoproliferative Disorder and Primary Cutaneous CD4 + Small/Medium T-Cell Lymphoproliferative Disorder : A Diagnostic Challenge Examined by Genomic Analysis.

Primary cutaneous marginal zone lymphoproliferative disorder (PCMZL) and primary cutaneous CD4 + small/medium T-cell lymphoproliferative disorder (CD4 + TLPD) are indolent lymphoproliferative disorders. However, cases with overlapping features can be challenging. We identified 56 CD4 + TLPD and 38 PCMZL cases from our pathology archives. Clinical, morphologic, and immunophenotypic features were reviewed. Polymerase chain reaction for immunoglobulin (IG) and T-cell receptor gamma (TRG) gene rearrangements were analyzed. Next-generation sequencing studies were performed on 26 cases with adequate material, 19 with CD4 + TLPD, and 7 with PCMZL. CD4 + TLPD presented mostly (91%) as solitary lesions, located in the head and neck area (64%), while PCMZL occurred mostly in the upper extremity (47%) and trunk (34%). Lesions were sometimes multiple (40%) and recurrences (67%) were more common. Cases of PCMZL had an increase in reactive CD3 + T cells, with frequent programmed cell death protein 1 expression, whereas cases of CD4 + TLPD often contained abundant reactive B cells. Twenty-five cases were identified as having overlapping features: 6 cases of PCMZL were clonal for both IG and TRG; 11 cases of CD4 + TLPD were clonal for IG and TRG and 6 cases of CD4 + TLPD had light chain-restricted plasma cells. By next-generation sequencing, 23 variants were detected in 15 genes, with PCMZL more likely to show alterations, most commonly affecting TNFAIP3 and FAS, altered in 5 cases. Both entities have an indolent clinical course with response to conservative therapy and management, and warrant interpretation as a lymphoproliferative disorder rather than overt lymphoma.

69-Year-Old Man With Dysuria and Right Lower Abdominal Pain

69-Year-Old Man With Dysuria and Right Lower Abdominal Pain

EXTRAMEDULLARY PLASMACYTOMA: A RARE PRESENTATION

TOPIC: Disorders of the Mediastinum TYPE: Medical Student/Resident Case Reports INTRODUCTION: Extramedullary plasma cell tumors are unusual. Their presence in the breast tissue is extremely rare. We present a case of incidental diagnosis of a primary extramedullary lesion in a previously healthy female. CASE PRESENTATION: 45-year-old female presented with a several-week history of persistent, sharp back pain radiating to the epigastric region associated with abdominal pain and worsening numbness of the left lower extremity. She complained of a growing mass over her sternal region that she noticed five months prior. Vital signs were within normal limits, and physical exam noted a large, non-mobile, firm nodule located over the sternum. Bloodwork was unremarkable. Computed Tomography of the abdomen and pelvis revealed multiple bulky masses involving the anterior chest wall, skeleton, pleural space, and vertebral bodies (T4 and T5) with extension to the spinal canal in addition to hepatosplenomegaly. Magnetic Resonance Imaging of the spine revealed moderate cord compression at T3-T4, with no acute neurosurgical intervention recommended. Biopsy of the anterior chest wall mass revealed a plasma cell neoplasm with plasmablastic features, and flow cytometry noted approximately 46% cytoplasmic lambda light chain restricted plasma cells with expression of CD38, CD19, CD20, CD56, and CD117 with negative CD45. Bone marrow biopsy confirmed plasma cell myeloma, with the neoplastic cells in both biopsies morphologically identical. The patient was diagnosed with multiple myeloma with cord compression and started on radiation and chemotherapy. 11 months after treatment initiation, she presented to our office with a 2cm mobile, firm, irregular mass in the upper outer quadrant of the right breast and a mass in the lower inner left breast confirmed by mammogram. There was no associated nipple discharge, pain, and weight loss. Core biopsy of the masses diagnosed plasma cell myeloma, with the tumor cells morphologically similar to those of the anterior chest wall mass. DISCUSSION: Plasmacytoma is a malignant proliferation of plasma cells[1,2,3] and is considered to be extramedullary when situated outside the bone marrow. It may occur in the lungs, gastrointestinal tract, spleen, pancreas and very rarely in the breast [4-7]. The likelihood of diagnosing a breast extramedullary plasmacytoma is approximately 0.01%[4,5,6]. Confirmation of the diagnosis is by the demonstration of monoclonal plasma cells and plasma cell markers, such as CD38 from immunohistology. Bone marrow biopsy is required to confirm or rule out the presence of plasma cells in the bone marrow. Radiation therapy over a course of four weeks is the treatment of choice [8]. Smaller lesions may be treated with surgery alone. CONCLUSIONS: Extramedullary plasmacytoma involving the breast is a very rare, underdiagnosed form of multiple myeloma, and should be part of the differential for breast masses to avoid misdiagnosis and improve outcomes. REFERENCE #1: Carson C P, Ackerman L V, Malty J D. Plasma cell myeloma. Annals of Clinical Pathology. 1955;25:849–888. [PubMed] [Google Scholar] REFERENCE #2: Cutler C W J. Plasma cell tumour of the breast with metastases. Annals of Surgery. 1934;100:392–395. [Google Scholar] REFERENCE #3: Booomberg TH, Glees JP, Williams JE. Bilateral breast lumps; an unusual feature of extramedullary plasmacytoma. Br J Radiol. 1980;53:498–501. [PubMed] [Google Scholar] DISCLOSURES: No relevant relationships by Muhammad Hanif, source=Web Response No relevant relationships by Samia Hossain, source=Web Response No relevant relationships by SANA MULLA, source=Web Response No relevant relationships by Ruqqiya Mustaqeem, source=Web Response No relevant relationships by Rajesh Thirumaran, source=Web Response No relevant relationships by Vihitha Thota, source=Web Response

Age Related Distribution of Cytogenetic Abnormalities in Multiple Myeloma

Introduction . Cytogenetic abnormalities (CA) detected by iFISH are among the most powerful prognostic factors in multiple myeloma (MM). With the advent of an unpreceded therapeutic armamentarium during the last years, a thoroughly assessment of individual patients characteristics is necessary in order to choose the best therapy. Among the former, age is an important biologic feature that stratifies patients with regard to treatment intensity.Aims . To study the distribution of individual CA by iFISH according to different age groups and to evaluate the relationship between age and different cytogenetic profiles.Materials and methods . We retrospectively evaluated 1116 patients (pts) analyzed in our laboratory between 01/2010 and 12/2016 for whom baseline cytogenetics by iFISH was available. iFISH was carried out on CD138 enriched plasma cells combined with immunofluorescent detection of light chain (LC) restricted plasma cells. The following CA were considered: gain(1q21), gain(9q34), del(13q14), del(17p13), t(4;14), t(11;14), t(14;16). Commercially available DNA probes were used according to manufacturer protocols (MetaSystems, Vysis). In house cutoff levels of 15% and 17% were set for chromosomal imbalances and IgH translocations respectively. Patients were stratified into 3 age groups: 1st group ≤ 45 years (y), 2nd group > 45y and ≤ 65y and 3th group > 65y. High risk cytogenetics (HRC) were defined according to IMWG criteria as at least one of the following by iFISH: del(17p), t(4;14) and t(14;16). Pairwise comparisons between subgroups were performed by the Mann-Whitney or Kruskal Wallis test for continuous variables and by Fisher's exact test for categorical variables. All statistical analyses were conducted in R, version 3.0.1.Results . The 1st group comprised 92 (8%) pts, the 2nd 581 (52%) pts and the 3rd 443 (40%) pts. The t(4;14) was detected in 109 (9.8%) pts with higher prevalence in the 2nd and 3rd groups (7.6% vs 10.3% vs 9.5%, p=0.67). The t(11;14) was detected in 198 (18%) pts with a higher prevalence in younger pts (26% vs 18 % vs 16%, p=0.15); age density plots showed two prevalence peaks at 45y and 65y respectively (Fig 1). The t(14;16) was identified in 26 pts (2.3%) and occurred more frequent under 65y (2.7% vs 4.2% vs 1.6%, p=0.11). Gain(9q) was identified in 365 (32%) of 781 evaluable patients occurring less frequently under the age of 45y (22% vs 35% vs 31%, p=0.4). Gain(1q) was detected in 249 (22%) pts with a trend towards higher prevalence in pts over 45y (14% vs 23% vs 23%, p=0.09). Del(17p) was detected in 153 pts (14%) slightly more frequent in the 2nd age group (13% vs 15% vs 12%, p=0.4). Del(13q) was more frequent in the 2nd group (32% vs 42% vs 37%, p=0.12).Next, we analyzed the distribution of HRC according to age category and identified 36 (21%) pts in the 1st group, 188 (26%) pts in the 2nd group and 119 (22%) pts in the 3rd group (p= 0.21). If gain(1q) was added to the HRC profile, the distribution of the HRC between groups differed significantly (27% vs 40% vs 34%, p=0.012).For the entire cohort, we further looked how t(4;14) and t(11;14) co-occur with gain(1q) and del(17p). Overall, 38% of the patients with t(4;14) had a gain(1q) (OR 2.8, p< 0.001). Conversely, no significant relation was detected for t(11;14) and for both translocations and del(17p). An inverse relation was found for del(17p) and gain(1q), with only 22% of pts with del(17p) harboring gain(1q) (OR 0.59, p=0.03). An interesting observation was the distribution of the k and λ LC across different CA. We found a significantly higher prevalence of k LC in MM with t(11;14) (60%, p=0.015), gain(1q) (54%, p=0.001) and HRC (67%, p<0.001). Regarding age, no significant difference was identified for the frequency of one type LC or another between age groups (p=0.978).Conclusion. In line with previous data,our study on a large unselected patient cohort suggests an age dependent distribution of CA. Though not reaching statistical significance, t(11;14) tends to occur more often in younger pts. The HRC profile is found more frequently in pts between 45y and 65y . Adding gain(1q) to the HRC panel delineates this group more clearly. Still, the prognostic value of 1q in the era of novel agents is controversial and might be related to the strong association with t(4;14). [Display omitted] DisclosuresKnop:Takeda: Consultancy.

Plasma cell neoplasms of the bladder: a series of 9 cases

From 2009 to 2017, we identified 9 cases of plasma cell neoplasms on biopsies of the bladder in patients without a history of plasma cell myeloma or transplantation (6 men and 3 women). Four of the nine showed amyloid deposition, of which one additionally revealed a clear cell adenocarcinoma of the bladder. Follow-up was obtained in 7 cases. Of 3 cases (including 2 with amyloid) for which electrophoresis and immunofixation results were obtained, the 2 amyloid cases showed evidence of serum or urine paraproteins: serum IgM kappa in a patient with kappa light chain–restricted plasma cell neoplasm and urine IgA lambda in a patient with lambda light chain–restricted plasma cell neoplasm. By way of contrast, 1 case with kappa light chain–restricted plasma cell neoplasm in the absence of amyloid showed no serum monoclonal protein. Bone marrow biopsy results were obtained in the 2 amyloid cases revealing a population of 5% or less plasma cells with no assessment of clonality and, thus, were not diagnostic of plasma cell myeloma. In congruence, the 2 amyloid cases also showed no radiologic evidence of systemic plasma cell myeloma. One patient with plasma cell neoplasm only received chemotherapy and radiation without subsequent biopsies; one patient with plasma cell neoplasm, amyloid, and clear cell adenocarcinoma received radiation with an absence of neoplastic disease on subsequent biopsies. In addition, no evidence of systemic amyloid was found in the cases with bladder amyloidosis. Plasma cell neoplasms of the bladder, with and without amyloid deposition, are rare; this is the first known case series. In 7 cases with follow-up, plasma cell myeloma did not appear to manifest in a 1- to 127-month follow-up. However, paraproteins were identified on further testing in 2 cases with amyloid. Although bladder plasma cell neoplasms with and without amyloid tend to have a favorable prognosis in short-term follow-up, our study supports the need for additional workup for systemic disease, particularly in those with concurrent amyloidosis.

Monoclonal plasma cell infiltrates in the setting of cutaneous follicular helper T cell lymphoproliferative disorders

There is a growing recognition that some primary cutaneous T cell lymphomas of the skin exhibit a follicular helper T cell phenotype best exemplified by primary cutaneous CD4+ small/medium sized pleomorphic T cell lymphoma. The follicular helper T cells is an evolutionary function in a common TH1 cell under the influence of other cell types most notably monocyte derived dendritic cells but also plasma cells. In addition, the skin defines a characteristic organ site of involvement for angioimmunoblastic T-cell lymphoma (AITL); the first recognized form of follicular helper T cell lymphoma.One of the hallmarks of the follicular helper T cell lymphomas a significant degree of post germinal center B cell hyperplasia. We encountered 7 cases of primary cutaneous follicular helper T cell and four cases of AITL, in which the biopsies contained a light chain restricted plasma cell infiltrate in the skin. There were no features that suggested an atypical or more aggressive clinical course in association with the identification of this light chain restricted plasmacytic infiltrates except one case of AITL in whom a diffuse large cell B cell lymphoma subsequently developed.There was no association with Epstein–Barr virus (EBV) infection light chain restricted plasma cell infiltrate in any of the eleven cases. The basis of these infiltrates is likely a reciprocal functional one reflecting the role of follicular helper T cells in the induction of B cell hyperplasia and the role of plasma cells as a countercheck balance controlling the extent of follicular helper T cell hyperplasia. B cell clonality, plasma cell atypia and blastic B cell transformation can occur without implying a malignant transformation.

A case of multiple myeloma presenting with uric acid kidney stones

Kidney disease is common in patients with multiple myeloma. Patients often present with acute kidney failure most commonly the result of light chain cast nephropathy. Presentation can also be in the form of nephrotic syndrome associated with immunoglobulin light chain amyloidosis or monoclonal immunoglobulin deposition disease and tubulopathy as in acquired light chain Fanconi syndrome. We present a case of a 56-year-old male with multiple myeloma who presented with chronic kidney disease and uric acid stones. Chemical analysis of the nephrolithiasis showed it to be entirely composed of uric acid. Fractional excretion of uric acid was elevated at 35.9%. Kidney biopsy was consistent with light chain proximal tubulopathy. Bone marrow biopsy showed 30% kappa light chain–restricted plasma cells. Genetic sequencing identified the light chain to be from the Vk1-33 subgroup. The patient was treated with bortezomib, cyclophosphamide, and dexamethasone, with improvement of his kidney function. This case illustrates a rare presentation of multiple myeloma.

Utility of Fine Needle Aspiration for Diagnosis of Plasmacytoma

Plasmacytomas are rare extramedullary plasma cell neoplasms that present in bone and/or soft tissue. Diagnosis can require a variety of laboratory approaches such as serum protein electrophoresis, bone marrow biopsy, Bence Jones protein assays, and imaging. However, few case reports describe using fine needle aspiration for diagnosis. We present a case of a plasmacytoma diagnosis in a 55-year-old patient, who initially presented to the emergency room with symptoms of chest pain. Imaging revealed right apical and medial lung mass extending just posterior to the trachea with invasion and destruction of the anterolateral T3 vertebral body. Multiple smaller hypodensities were also present in thoracic vertebral bodies, ribs, and sternum. Biopsies were performed on the mediastinal mass. Fine needle aspiration revealed groups of mature and immature plasma cells at various stages of maturation. Flow cytometry demonstrated a kappa light chain-restricted plasma cell population. Paraffin immunoperoxidase studies showed that the neoplastic cells bore monotypic kappa light chains. The patient’s presentation emphasizes the utility of fine needle aspiration, in conjunction with other ancillary studies, for diagnosing plasmacytomas. J Med Cases. 2019;10(2):37-40 doi: https://doi.org/10.14740/jmc3223

AL amyloidosis with a localized B cell neoplasia

Immunoglobulin light chain-derived (AL) amyloidosis may occur as a systemic disease usually with dismal prognosis and a localized variant with favorable outcome. We report 29 patients with AL amyloidosis and associated lymphoplasmacytic infiltrate spatially related to amyloid deposits. In 17 cases, the amyloid deposits were classified as ALλ and 12 as ALκ Histopathology in all cases showed relatively sparse plasma cells and B cells without tumor or sheet formation by the lymphoplasmacytic infiltrate. The B cells predominantly showed an immunophenotype of the marginal zone. In situ, hybridization revealed 17 cases with λ− and 10 with κ light chain restricted plasma cells, which was concordant with the AL subtype in each case. Clonal immunoglobulin heavy variable gene (IGHV) or κ light chain rearrangement was found in 23/29 interpretable cases. A single case harbored a MYD88L265P-mutation. Taken together, we detected 27 (93%) cases of AL amyloidosis with an associated light chain restricted and predominantly molecularly clonal plasma cell population. Clinical data were available in 18 patients. Five patients suffered from systemic lymphoma and two from systemic AL amyloidosis. The remaining cases were classified as localized with regard to both, the AL amyloidosis and the light chain restricted plasma cell population. To the best of our knowledge, we herein present the largest cohort of AL amyloidosis associated with a light chain restricted and predominantly molecularly clonal plasma cell population, which we designate as a distinct disease entity: “AL amyloidosis with a localized B cell neoplasia of undetermined significance”.

V(D)J Sequence Capture for DNA-Based Minimal Residual Disease Detection in Multiple Myeloma

IntroductionMinimal residual disease (MRD) negativity after initial therapy is a strong predictor of survival in multiple myeloma. Tracking of clonal immunoglobulin V(D)J rearrangements by next generation sequencing is highly sensitive for MRD and does not require immediate analysis of fresh samples. However, previous studies have found variable rates of baseline V(D)J sequence capture, which could limit tracking. In this study, we aimed to define the sample-related and disease-related factors that influence V(D)J capture.MethodsWe included 177 patients with plasma cell myeloma who had available stored mononuclear cells from a baseline bone marrow aspirate. Each sample was sequenced by two assays: The LymphoTrack® VDJ assays from Invivoscribe, and our in-house myeloma panel myTYPE, as a molecular control for detectable tumor derived DNA in the samples. MyTYPE positivity was defined by one or more single nucleotide variant, insertion, deletion, translocation or copy number variation that is known to occur in myeloma.Results and discussionThe V(D)J capture rate in our whole cohort was 81 %, as compared with 95 % in the myTYPE positive samples, demonstrating the importance of tumor cell content for V(D)J capture. This was confirmed in multivariate logistic regression (Figure 1), where myTYPE positivity was a strong independent predictor of V(D)J capture success, with an odds ratio (OR) of 6.61 (95 % CI 2.22-24.81, p = 0.002). Plasma cell content estimated from bone marrow aspirate smears also contributed to the multivariate model, with an OR of 1.3 for each 10 % increase in plasma cell content (95 % CI 0.96-1.84, p=0.109), but this did not reach statistical significance after accounting for the strong effect of myTYPE. Finally, having lambda light chain restricted plasma cells was a strong predictor of V(D)J capture success (OR 6.91, 95 % CI 2.4-25.32, p = 0.001).Higher V(D)J capture rate in lambda-restricted myeloma as compared with kappa-restricted was mostly driven by a difference in immunoglobulin kappa gene (IGK) rearrangement capture (73 vs. 44 %, p < 0.001). As a potential explanation, we found up to 4 unique IGK rearrangements that are amenable to capture in lambda-restricted cases, as well as dramatically lower somatic hypermutation (SHM) of the IGK variable region in clonal rearrangements, as compared with kappa-restricted cases. SHM has previously been shown to cause V(D)J capture failure by interfering with PCR primer annealing. Both of these factors can be attributed to IGK inactivation by rearrangements involving the “kappa deleting element” region, affecting both IGK alleles in lambda-restricted plasma cells (Perfetti et al, Immunology, 2004).As an explanation for low plasma cell content in the samples used in this study, we describe how the tumor cell content of bone marrow aspirates decrease gradually in sequential pulls because of hemodilution: from the initial pull used for aspirate smear, to the final pull that is commonly used for research. Supporting the important role of hemodilution, we found V(D)J capture rates of 97 % in clinical samples (early pull aspirates) from our institution that were analyzed with the same NGS assays, as long as the bone marrow plasma cell infiltration was above 5 %.V(D)J capture probability appears to be determined by two factors: The abundance of clonal cells (i.e. tumor cell content), and the degree to which clonal sequences can be amplified by the assay (which is negatively affected by SHM). Thus, increasing the tumor cell content in samples as much as practically possible (i.e., optimal bone marrow aspirates and enrichment of CD138+ plasma cells) may compensate for SHM and improve V(D)J capture rates beyond 95 %.ConclusionV(D)J capture rates of at least 95 % are feasible in multiple myeloma using LymphoTrack® NGS assays, when the sample quality is good. The most important reason for V(D)J capture failure is low tumor cell content due to bone marrow aspirate hemodilution. Optimal performance depends on the use of early pull aspirates and/or subsequent tumor cell enrichment.Figure 1: Predicting V(D)J capture. Regression lines and individual data points are colored according to myTYPE status (red = positive; blue = negative); V(D)J capture probability on the y-axis (capture yes/no on the second y-axis) and bone marrow plasma cell percentage by aspirate smear on the x-axis; split into panels according to light chain restriction (right = lambda; left = kappa). [Display omitted] DisclosuresHo:Invivoscribe, Inc.: Honoraria. Arcila:Invivoscribe, Inc.: Consultancy, Honoraria. Jacobsen:Invivoscribe, Inc.: Employment. Huang:Invivoscribe, Inc.: Employment. Miller:Invivoscribe, Inc.: Employment, Equity Ownership. Landgren:Pfizer: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Light Chain Amyloidosis Presenting as Bilateral External Auditory Canal Obstructing Masses.

: A morbidly-obese 57-year-old diabetic and hypertensive man with chronic kidney disease, diastolic heart failure, and bilateral hearing loss was found to have soft tissue masses/densities in the lateral aspect of both auditory canals on local examination and on imaging. He underwent biopsies of both ear canal masses and histologic examination revealed amyloid deposits in the dermis. These deposits were confirmed as AL (amyloid light chain) kappa-type amyloid by laser mass spectrometry. A systemic work-up showed plasma cell dyscrasia with 9% kappa light chain restricted plasma cells in the bone marrow as well as amyloid deposits on a kidney biopsy.Involvement of the external auditory canals is a rare manifestation of systemic amyloidosis with only 13 cases reported so far, of which four cases had bilateral external auditory canal involvement, associated with multiple myeloma. Interpretation of small biopsies can be challenging especially with early, scant amyloid deposits, but a sufficient biopsy to type amyloid by immunohistochemistry or laser mass spectrometry is imperative for further management. Early diagnosis and treatment of systemic light chain amyloidosis translates to better patient outcomes, while delay in management could lead to dismal prognosis.

A Rare Cause of Gastric Ulcer

An 84-year-old man was admitted to our hospital with melena. He was on aspirin, ibuprofen and warfarin. He had history of atrial fibrillation and ischemic cardiomyopathy. He was on no GI prophylaxis. After appropriate resuscitation and PPI therapy, an EGD was performed. 4 clean based gastric ulcers were found (30 mm in the body, 5 mm in the antrum and two 15 mm in the fundus). Because the patient's INR was 1.6, biopsies were not obtained. H. pylori IgG was found positive.EGD was repeated in 3 days. The ulcers were identified again. Multiple biopsies were obtained to rule out neoplasia. Histopathology showed gastric mucosa with severe acute/chronic inflammation of the lamina propria with slight gland distortion. The patient was discharged home on PPI. Therapy for H. pylori was also started. Five weeks later, another EGD was performed in order to evaluate healing. The ulcers in the antrum and fundus have healed. The large ulcer of the gastric body was almost unchanged. Multiple biopsies were obtained. The mucosa was extensively infiltrated by an abnormal plasma cell population. The cells had rounded nuclei, distinct nucleoli, partially clumped chromatin, and abundant eccentrically distributed cytoplasm. They were not associated with a substantial abnormal lymphocyte population, and the morphologic features typically associated with a MALT lymphoma were not observed. The abnormal plasma cells expressed IRF4 (MUM1), and they had a monotypic staining pattern for lambda light chains. They were negative for the other markers for which they were tested. No H. pylor organisms were present. The abnormal plasma cells were negati EBV. The morphologic and phenotypic features indicated the diagnosis of a lambda light chain-restricted plasma cell neoplasm involving the stomach. The differential diagnosis rested between a solitary plasmacytic neoplasm of the stomach and unusual presentation of multiple myeloma.Hem-Onc was consulted. Bone survey did not reveal changes consistent with MM or plasmacytoma. Peripheral morphology showed normocytic anemia. Lambda and Kappa chains were elevated. PET-CT showed abnormal uptake in the distal stomach. Bone marrow biopsy was unremarkable. Chemotherapy was started with CyBorD with bortezomib, cyclophosphamide omitted and dexamethasone. After 3 cycles of chemotherapy, gastric biopsies showed only few reactive plasma cells. Primary extramedullary plasmacytomas account for approximately 4% of all plasma cell neoplasms. Gastric plasmacytoma is rare and constitutes in turn less than 5% of these tumors. Accordingly, the literature about this entity consists of anecdotal reports or small case series. This entity is usually localized and frequently pursues an indolent clinical course, but has a tendency for local recurrence and may rarely progress to MM. Its link with H. pylori infection is unclear.

MYD88 (L265P) somatic mutation in marginal zone B-cell lymphoma.

MYD88 L265P is a somatic mutation that has been identified in about 90% of Waldenström macroglobulinemia/lymphoplasmacytic lymphomas (LPLs). It has also been detected in a subset of marginal zone lymphoma (MZL) cases, but the frequency and clinical and histologic features of these mutated MZL cases has only been partially characterized. We have developed a customized TaqMan allele-specific polymerase chain reaction for sensitive detection of this mutation in paraffin-embedded tissue. We analyzed samples from 19 patients with LPL, 88 patients with splenic marginal zone lymphoma (SMZL), 8 patients with nodal marginal zone lymphoma (NMZL), 21 patients with extranodal mucosa-associated lymphoid tissue (MALT), and 2 patients with B-cell lymphoma not otherwise specified. By integrating mutational, histologic, and clinical data, 5 cases were reclassified as LPL. After reclassification, MYD88 L265P was detected in 13/86 (15%) SMZL and in 19/24 LPL (79%) cases. The mutation was absent from NMZL and MALT cases. A strong correlation was found between the presence of an IgM monoclonal paraproteinemia and the MYD88 L265P mutation (P<0.0001). SMZL cases positive for MYD88 L265P were also associated with monoclonal IgM paraproteinemia (4/13 cases; P<0.0283), although with less serum paraproteinemia. They also had a higher frequency of plasmacytic differentiation (9/13) but with no correlation between the presence of mutation and of light chain-restricted plasma cells in tissue. Demonstration of the MYD88 L265 mutation is a valuable tool for the diagnosis of LPL, although some SMZL cases carrying the mutation do not fulfill the diagnostic criteria for LPL.

Paraneoplastic Scleroderma-Like Tissue Reactions in the Setting of an Underlying Plasma Cell Dyscrasia

Systemic plasma cell dyscrasias have diverse manifestations in the skin and include an inflammatory paraneoplastic process. We encountered cases of scleroderma and eosinophilic fasciitis in the setting of an underlying plasma cell dyscrasia. Ten cases of scleroderma-like tissue reactions in the setting of an underlying plasma cell dyscrasia were encountered. The biopsies were stained for Transforming growth factor (Transforming growth factor) beta, IgG4, kappa, and lambda. Patients presented with a sclerodermoid reaction represented by eosinophilic fasciitis (5 cases), morphea (3 cases), and systemic scleroderma (2 cases). The mean age of presentation was 70 years with a striking female predominance (4:1). Acral accentuation was noted in 8 cases. In 6 of the cases, the cutaneous sclerosis antedated (4 cases) by weeks to 2 years or occurred concurrently (2 cases) with the initial diagnosis of the plasma cell. The biopsies showed changes typical of eosinophilic fasciitis and/or scleroderma. In 5 cases, light chain-restricted plasma cells were present on the biopsy. There was staining of the plasma cells for Transforming growth factor beta in 3 out of 5 cases tested. In any older patient presenting with a sudden onset of eosinophilic fasciitis or scleroderma especially with acral accentuation, investigations should be conducted in regards to an underlying plasma cell dyscrasia.

Intracellular and extracellular immunoglobulin crystals assuming a multitude of geometric shapes in an IgG‐λ plasma cell neoplasm

Intracytoplasmic immunoglobulin deposition is frequently associated with plasma cell neoplasms but generally takes on a globular form (Russell bodies). The presence of crystalline immunoglobulin structures within malignant plasma cells occurs rarely 1-7. Here we show images of a post-treatment bone marrow biopsy from a 47-year-old woman diagnosed with a plasma cell neoplasm based on the presence of a serum monoclonal IgG-λ paraprotein (0.5 g/dL) and 30% plasma cells with cytoplasmic λ light chain restriction demonstrated by flow cytometry 8. Although she initially achieved a complete remission with intensive therapy, this bone marrow biopsy shows early progression of disease with 10–15% monoclonal λ light chain-restricted plasma cells. Additionally, focal areas containing large, rhomboidal-, hexagonal-, rectangular-, and square-shaped crystalline structures were noted in both the bone marrow aspirate (Image 1A, Wright-Geimsa stain, arrowheads) and trephine biopsy specimens [Image 1B, hematoxylin & eosin (H&E) stain]. Scattered lymphohistiocytic aggregates infiltrated by eosinophils and occasional multinucleated giant cells were present (Image 1C and inset, H&E). Some of the crystals are clearly extracellular (Image 1C, arrows) while others appear to be intracytoplasmic as suggested by flattening of the nuclei in cells juxtaposed to crystals (Image 1C, arrowheads). An immunohistochemical stain for CD138 highlights plasma cells (Image 1D) and outlines the intracellular subset of crystals. Stains for κ and λ light chains show λ light chain restriction, and the crystals are similarly outlined by the λ (Image 1E), but not the κ, stain (Image 1F). Immunostaining for CD68 delineated macrophages and giant cells but did not outline the crystalloid structures, thus supporting the plasma cell localization of the crystals. Staining for acid-fast bacteria and fungus was negative throughout, and a congo red stain did not highlight any amyloid deposits nor did it mark the crystals. Of note, the patient's CBC showed no cytopenias at this time, though there was recurrence of the serum monoclonal paraprotein (0.86 g/dL IgG-λ). She remains alive with a normal CBC and stable marrow disease 18 months after high-dose therapy. Although crystal deposition within plasma cells has been reported in reactive conditions, including rheumatologic disorders and helicobacter-associated gastritis, the monoclonal nature of the immunoglobulin in this case as demonstrated by both flow cytometry and immunohistochemical analysis argues against a reactive process. Crystal storing histiocytosis (CSH), in which immunoglobulin crystals are deposited in macrophages is an unusual variant of this phenomenon and is also associated with plasma cell and other lymphoproliferative neoplasms 9. The κ light chains predominate in CSH, as they appear to be more resistant to degradation by macrophage lysosomal enzymes than λ light chains. The mechanism underlying the accumulation of immunoglobulin crystals within neoplastic plasma cells as presented here is not certain but does not appear to favor either κ or λ light chains and may involve abnormalities in protein synthetic and transport pathways. The significance of immunoglobulin crystals in plasma cell myeloma is unknown, but it has been hypothesized that their presence may portend a nonprogressive clinical course and therefore a favorable prognosis 10.

Mott cells in CD20‐positive myeloma

A 63-year-old woman presented with a 2-month history of left thigh pain, no ‘B’ symptoms, no significant past medical illness and normal clinical examination. Her full blood count was normal. The erythrocyte sedimentation rate was elevated at 115 mm/h, total globulins were elevated but the rest of the serum biochemistry was normal. Serum immunoglobulin electrophoresis with immunofixation showed an IgGλ paraprotein at a concentration of 22 g/l and elevated IgM at 10·4 g/l. Urinary Bence–Jones protein was absent and the serum free light chain ratio was normal. A skeletal survey was normal. A bone marrow aspirate showed a lymphoplasmacytic infiltrate of 30% and cells with large intracytoplasmic inclusions (top right) often in doublets or triplets with the nuclei pushed to the rim of the cell. A bone marrow trephine biopsy showed extensive infiltration by lymphoplasmacytic cells and huge plasma cells (top left). Plasma cells with large Russell body inclusions occupied both paratrabecular and intertrabecular areas and stained positively for CD20, nuclear Cyclin D1 and lambda light chain (bottom right). Flow cytometry initially failed to identify light chain restricted plasma cells. It was recognised that the large sized plasma cells were outside the conventional lymphoid/plasma cell gate. Repeat ungated flow cytometric analysis demonstrated CD45+ cytoplasmic kappa+ = 11%; CD45+ cytoplasmic lambda+ = 17%; CD19+ cytoplasmic kappa+ = 12%; CD19+ cytoplasmic lambda+ = 14% and a reversed kappa: lambda ratio of 11:17. Fluorescence in situ hybridisation on separated plasma cells (CD138+ve) was carried out using the IGH/CCND1 dual fusion dual colour probe (Vysis, Berkshire, UK). Of 100 cells analysed, 78 showed a pattern of one fusion signal, which indicated the presence of the t(11;14) translocation (bottom left). The combined clinicopathologic features confirmed the diagnosis of myeloma. The patient remains asymptomatic and no therapeutic options have yet been offered. This case demonstrates an infrequent but impressive morphological appearance of plasma cells with huge intracytoplasmic immunoglobulin inclusions (Mott cells). The presence of t(11;14) is most commonly associated with mantle cell lymphoma but is found in up to 20% of patients with myeloma, using interphase cytogenetics. Lymphoplasmacytoid appearances, high CD20 expression and t(11;14) has been described as a sub-entity in myeloma. This case demonstrates the importance of always reviewing the flow cytometry data in conjunction with morphology.