Immunohistochemical Characterization of Lambda Light-Chain-derived Amyloid in One Feline and Five Canine Plasma Cell Tumors

Light chain proximal tubulopathy (LCPT) is an uncommon renal disease characterized by the accumulation of monoclonal light chains within proximal tubular epithelial cells, with or without crystal formation. We report a rare case of lambda LCPT with crystals. Renal biopsy showed substantial acute tubular injury with unusual cytoplasmic changes affecting proximal tubules. In addition, abnormal tubular casts suggested concomitant light chain cast nephropathy. A clonal plasma cell infiltrate was present in the tubulointerstitial compartment. Immunofluorescence demonstrated strong staining for lambda light chain in tubular epithelial cells. Despite the absence of discernible crystals on light microscopy (LM), they were readily identified when ultrastructural evaluation was undertaken. Crystalline inclusions demonstrated positive immunogold labelling for lambda.

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Coexistence of beta2 microglobulin and lambda light chain in amyloid fibrils of dialysis-unrelated plasma cell dyscrasia-associated systemic amyloidosis

British Journal of Dermatology ◽

10.1046/j.1365-2133.2002.04940.x ◽

2002 ◽

Vol 147 (3) ◽

pp. 549-553 ◽

Cited By ~ 6

Author(s):

N. Fujimoto ◽

N. Wada ◽

M. Akiyama ◽

S. Tajima ◽

A. Ishibashi ◽

...

Keyword(s):

Plasma Cell ◽

Light Chain ◽

Amyloid Fibrils ◽

Systemic Amyloidosis ◽

Plasma Cell Dyscrasia ◽

Lambda Light Chain

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Clinical and Cytogenetic Characterization of Light Chain Amyloidosis Patients with a Low Amyloidogenic Free Light Chain Count at First Diagnosis

Blood ◽

10.1182/blood.v126.23.1790.1790 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1790-1790 ◽

Cited By ~ 1

Author(s):

Tobias Dittrich ◽

Ute Hegenbart ◽

Tilmann Bochtler ◽

Christoph Kimmich ◽

Anna Jauch ◽

...

Keyword(s):

Board Of Directors ◽

Plasma Cell ◽

Heavy Chain ◽

Light Chain ◽

Research Funding ◽

Advisory Committees ◽

P Values ◽

Mayo Score ◽

M Spike

Abstract Background: Systemic light chain amyloidosis (AL) is a rare and life-threatening protein-deposition disorder. The diagnosis and especially quantification of the underlying, usually small clonal B cell disorder in patients with very low levels of free kappa or lambda light chains in serum (FLC) can be challenging. DFLC (difference of involved minus uninvolved FLC) response to therapy is hardly assessable for initial values below 50 mg/l. Consequently, these patients are frequently excluded from prospective and retrospective studies. Objective: Characterization of AL amyloidosis patients with dFLC<50. Methods: We have retrospectively analysedthe clinical features and long-termoutcome of 611 newly diagnosed AL patients with available dFLC and cytogenetic evaluation by iFISH at their first visit to our center between 2003-2014. Results: Clinical characteristics and detailed results are depicted in table 1. Patients with dFLC<50 significantly showed lower bone marrow plasma cell counts (6% vs. 10%, p<0.001), M-spike (7 g/l vs. 9 g/l, p<0.001) and concentrations of the monoclonal heavy chain (7 g/l vs. 10 g/l, p=0.003), while the mere presence of a monoclonal heavy chain in immunofixation (IF) was more frequent in these patients (55% vs. 38%, p=0.003). All analysed chromosomal aberrations were not associated with dFLC<50 (all p-values >0.05). Patients with cardiac (40% vs. 82%, p<0.001) and soft tissue (26% vs. 42%, p=0.005) involvement, higher Mayo Score and lower Karnofsky Index (KI) were much less frequently found in the group with initial dFLC<50, while kidney involvement was more common (85% vs. 58%, p<0.001). This, however, was not associated with a significantly worse renal function at diagnosis. Median overall survival (OS) was significantly better in patients with dFLC<50 regardless of treatment type (Figure 1): Bortezomib (77 vs. 16 months, p=0.006), Melphalan-Dexamethason (Mdex, 96 vs. 19 months, p=0.001) and high-dose Melphalan (HDM, not reached vs. 99 months, p=0.005). Conclusion: AL patients with an initial dFLC<50 mg/l represent a distinct clinical entity characterized by infiltration of the marrow with a small plasma cell clone and frequent presence of a monoclonal intact heavy chain, but with a low clonal heavy chain load. Importantly, this group of patients is not associated with any particular chromosomal aberrations as revealed by iFISH. This entity is further associated with a distinct pattern of organ involvement, i.e. a low Mayo Score, more than 80% of patients with renal amyloidosis, and very favourable OS irrespective of primary treatment regimens. Results of prospective clinical trials might be adversely influenced by the exclusion of these patients. Table 1. Parameter All patientsn=611 dFLC < 50 mg/ln=85 dFLC ≥ 50 mg/ln=526 p values Age in years, median [range] 66 [38-90] 65 [47-90] 66 [38-90] n.s. Sex female, no. of pts (%) 235 (39) 39 (46) 196 (37) n.s. Plasma cell related factors dFLC in mg/l, median [range] 228 [1-12.078] 29 [1-49] 279 [50-12.078] - Monoclonal heavy chain in IF, no. of pts (%) 248 (41) 47 (55) 201 (38) 0.003 M-spike in g/l, median [range]Evaluable pts (%) 9 [1-41]159 (26) 7 [1-22]31 (36) 9 [1-41]128 (24) <0.001 Involved heavy chain in g/l,median [range]Evaluable pts (%) 9.6 [0.5-197]243 (40) 6.8 [1.2-26]45 (53) 10.2 [0.5-197]198 (38) 0.003 Involved light chain λ, no. of pts (%) 490 (80) 73 (86) 417 (79) n.s. BM plasma cell count in %,median [range] 10 [1-90] 6 [1-40] 10 [1-90] <0.001 iFISH results, no. of pts (%) t(11;14) 350 (58) 42 (51) 308 (59) n.s. del 13q14 201 (33) 27 (33) 174 (33) n.s. gain 1q21 166 (27) 22 (26) 144 (27) n.s. Hyperdiploidy (Wuilleme Score) 98 (16) 12 (14) 86 (16) n.s. High-risk (del 17p13, t(4;14), t(14;16)) 47 (8) 7 (8) 40 (8) n.s. Organ involvement Number of Organs,median [range] 2 [1-6] 2 [1-6] 3 [1-6] 0.001 Heart, no. of pts (%) 463 (76) 34 (40) 429 (82) <0.001 Cardiac Mayo Score 2004: I, no. of pts (%)II, no. of pts (%)III, no. of pts (%) 101 (18)214 (38)255 (45) 35 (46)30 (40)11 (15) 66 (13)184 (37)244 (49) <0.001 Kidney, no. of pts (%) 376 (62) 72 (85) 304 (58) <0.001 MDRD, median [range] 64 [2-264] 68 [8-149] 63 [2-264] n.s. Soft Tissue, no. of pts (%) 243 (40) 22 (26) 221 (42) 0.005 KI %, median [range] 80 [40-100] 90 [50-100] 80 [40-100] 0.001 Treatment groups, no. of pts / median follow-up in months, median OS Bortezomib 214 / 2724 23 / 1977 191 / 2816 0.006 Mdex 156 / 7427 21 / 7596 135 / 7019 0.001 HDM 115 / 75129 24 / 75not reached 91 / 6999 0.005 Figure 1. Figure 1. Disclosures Hegenbart: Janssen: Honoraria. Bochtler:TEVA: Other: travel support. Goldschmidt:Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Chugai: Honoraria, Research Funding, Speakers Bureau; Millenium: Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Schönland:Janssen, Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Phagocytic, Lambda Light Chain, Plasma Cell Myeloma

American Journal of Clinical Pathology ◽

10.1093/ajcp/80.1.75 ◽

1983 ◽

Vol 80 (1) ◽

pp. 75-84 ◽

Cited By ~ 8

Author(s):

Daniel P. Wirt ◽

Thomas M. Grogan ◽

Claire M. Payne ◽

Thomas D. Kummet ◽

Brian G. M. Durie ◽

...

Keyword(s):

Plasma Cell ◽

Light Chain ◽

Plasma Cell Myeloma ◽

Lambda Light Chain

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Schwannoma with monoclonal plasma cell infiltration

Journal of Neurosurgery ◽

10.3171/2009.3.17682 ◽

2009 ◽

Vol 111 (3) ◽

pp. 509-511 ◽

Cited By ~ 5

Author(s):

Joshua Plaut ◽

Malcolm Galloway ◽

Anna Childerhouse ◽

Robert Bradford

Keyword(s):

Cell Population ◽

Plasma Cell ◽

Vestibular Schwannoma ◽

Light Chain ◽

Histological Analysis ◽

Plasma Cells ◽

Systemic Disease ◽

Lambda Light Chain ◽

Plasma Cell Neoplasm ◽

Polymerase Chain

The authors report a very rare case of a vestibular schwannoma with an infiltrate of monoclonal plasma cells. A 45-year-old woman underwent routine excision of a presumed vestibular schwannoma. Histological analysis revealed the presence of a distinct lambda light chain restricted plasma cell population within the schwannoma. The light chain restriction and polymerase chain reaction–demonstrated monoclonality of the plasma cell population suggested the co-occurrence of a plasma cell neoplasm within a schwannoma. A search for systemic disease of plasma cell origin was unremarkable. A search of the literature suggests that this is the first report of such an occurrence.

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A Novel Case of Direct Antiglobulin Test-Negative Intravascular Hemolysis in a Patient with Smoldering Myeloma

Blood ◽

10.1182/blood.v126.23.4539.4539 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4539-4539

Author(s):

Selina Dobing ◽

Nikolas Desilet ◽

Irwindeep Sandhu ◽

Lauren Bolster

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Plasma Cell ◽

Light Chain ◽

Plasma Cells ◽

Case Reports ◽

Alternative Pathway ◽

Plasma Cell Dyscrasia ◽

Intravascular Hemolysis ◽

Lambda Light Chain

Abstract Objectives: 1. Describe a case of severe DAT-negative intravascular hemolysis in plasma cell dyscrasia. 2. Discuss a potential novel mechanism of light-chain mediated hemolysis. A 34-year old woman was admitted to hospital with fatigue and severe iron deficiency anemia (hemoglobin 47 g/dL, MCV 59 fL, ferritin 2 mcg/L). Her medical history included a presumptive diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) from five years prior. She was transfused 2 units of red cells, started on oral iron and folate, and was discharged symptom-free with a hemoglobin of 71 g/dL. She returned three days later with abdominal pain, dark urine, and evidence of intravascular hemolysis. She was admitted for empiric treatment of PNH with high-dose glucocorticoids and therapeutic enoxaparin for presumed intra-abdominal thrombosis. Her flow cytometry, including granulocytes, was negative for PNH. Her direct antiglobulin test (DAT) was negative for IgG antibodies but positive for C3 complement. A thorough hemolysis workup was negative, including schistocytes and Donath Landsteiner testing. ADAMTS13 testing was uninterpretable due to high plasma free hemoglobin. Despite corticosteroids, brisk hemolysis continued with 10 units of RBCs required over 5 days to maintain a stable hemoglobin. Plasma free hemoglobin reached 1147 mg/L, prompting therapeutic plasmapheresis for renal protection by the end of day 5. She deteriorated clinically after her first plasmapheresis with acute confusion (GCS 10) and lactic acidosis. She was empirically treated for seizure with levetiracetam. CT and MRI scans of her brain and lumbar puncture were normal. Her consciousness improved with daily plasmapheresis. A bone marrow biopsy performed on day twelve of glucocorticoid therapy found monoclonal plasma cell proliferation of 15% with marked lambda light chain predominance (20:1) (Figure 1). Repeat bone marrow biopsy 3 months post-steroid therapy still revealed 10% clonal plasma cells. Hemolysis can be a rare presentation of plasma cell dyscrasia. Case reports of both autoimmune hemolytic anemia and microangiopathic hemolytic anemia associated with multiple myeloma exist. In our case, there was no evidence of a microangiopathic process, making thrombotic thrombocytopenic purpura (TTP) or atypical hemolytic-uremic syndrome (aHUS) unlikely. DAT was negative for IgG but did demonstrate C3 complement molecules bound to red cells. No previous case reports of complement-mediated hemolysis and multiple myeloma were found on literature review. We report the first in vivo association between complement-mediated hemolysis and plasma cell dyscrasia. Complement pathways bridge the innate and acquired immune systems by helping select cells to be targeted by the acquired immune system. The alternative complement pathway does not require an antigen-antibody interaction to become active; rather, it is controlled by direct binding of complement and regulated by cofactor molecules. Jokiranta et al. (J Immunol 1999) identified a monoclonal Ig-lambda dimer that efficiently activated the alternative pathway of complement, triggering complement molecules to enhance hemolysis of serum in vitro. This "miniautoantibody" specifically bound and blocked the function of complement factor H, inhibiting enzymatic inactivation of fluid-phase C3b with uncontrolled activation of the alternative pathway. It is possible that the relative immune dysfunction in this patient's plasma cell dyscrasia led to a disturbance in the alternate complement pathway, perhaps due to dimerization of abnormal lambda light chains, resulting in complement-mediated intravascular hemolysis. Glucocorticoids and plasmapheresis may have helped manage hemolysis in this case. By diagnostic criteria, this patient has smoldering myeloma, with urine monoclonal protein (1.2 g/24 hours), clonal bone marrow plasma cells (10-15%), and absence of myeloma-defining events. We have elected to manage her as such, with close observation. Further work-up performed for her plasma cell dyscrasia included a normal MRI of spine and pelvis. Over a year later, there has been no recurrence of hemolysis. Consideration will be given to treatment if she progresses to overt multiple myeloma. Figure 1. A. Aspirate showing abnormal plasma cells. B. Trephine CD138 stain. C. Trephine kappa light chain stain. D. Trephine lambda light chain stain. Figure 1. A. Aspirate showing abnormal plasma cells. B. Trephine CD138 stain. C. Trephine kappa light chain stain. D. Trephine lambda light chain stain. Disclosures Sandhu: Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.

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Bone Marrow Microenvironment in Light-Chain Amyloidosis: In Vitro Expansion and Characterization of Mesenchymal Stromal Cells

Biomedicines ◽

10.3390/biomedicines9111523 ◽

2021 ◽

Vol 9 (11) ◽

pp. 1523

Author(s):

Chiara Valsecchi ◽

Stefania Croce ◽

Alice Maltese ◽

Lorenza Montagna ◽

Elisa Lenta ◽

...

Keyword(s):

Bone Marrow ◽

Cell Line ◽

Plasma Cell ◽

Mesenchymal Stromal Cells ◽

Light Chain ◽

Stromal Cells ◽

Mononuclear Cells ◽

Light Chain Amyloidosis

Immunoglobulin light-chain amyloidosis (AL) is caused by misfolded light chains produced by a small B cell clone. Mesenchymal stromal cells (MSCs) have been reported to affect plasma cell behavior. We aimed to characterize bone marrow (BM)-MSCs from AL patients, considering functional aspects, such as proliferation, differentiation, and immunomodulatory capacities. MSCs were in vitro expanded from the BM of 57 AL patients and 14 healthy donors (HDs). MSC surface markers were analyzed by flow cytometry, osteogenic and adipogenic differentiation capacities were in vitro evaluated, and co-culture experiments were performed in order to investigate MSC immunomodulatory properties towards the ALMC-2 cell line and HD peripheral blood mononuclear cells (PBMCs). AL-MSCs were comparable to HD-MSCs for morphology, immune-phenotype, and differentiation capacities. AL-MSCs showed a reduced proliferation rate, entering senescence at earlier passages than HD-MSCs. The AL-MSC modulatory effect on the plasma-cell line or circulating plasma cells was comparable to that of HD-MSCs. To our knowledge, this is the first study providing a comprehensive characterization of AL-MSCs. It remains to be defined if the observed abnormalities are the consequence of or are involved in the disease pathogenesis. BM microenvironment components in AL may represent the targets for the prevention/treatment of the disease in personalized therapies.

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