Underlying Plasma Cell Dyscrasia Research Articles

Cardiac amyloidosis: the need for early diagnosis.

Amyloidosis is a collection of systemic diseases characterised by misfolding of previously soluble precursor proteins that become infiltrative depositions, thereby disrupting normal organ structure and function. In the heart, accumulating amyloid fibrils lead to progressive ventricular wall thickening and stiffness, resulting in diastolic dysfunction gradually progressing to a restrictive cardiomyopathy. The main types of cardiac amyloidosis are amyloid light chain (AL) amyloidosis caused by an underlying plasma cell dyscrasia, amyloid transthyretin (TTR) amyloidosis of wild-type (normal) TTR at older age (ATTRwt) and hereditary or mutant amyloid TTR (ATTRm) in which a genetic mutation leads to an unstable TTR protein. Overall survival is poor once heart failure develops, underlining the need for early referral and diagnosis. Treatment for AL amyloidosis has improved markedly over the last decades, and TTR amyloidosis gene silencers and orally available transthyretin stabilisers are ready to enter the clinical arena after recent positive outcome trials. Novel therapies aiming at fibril degradation with monoclonal antibodies are under investigation. In this review, we focus on ‘red flag’ signs and symptoms, diagnosis and management of cardiac amyloidosis which differs considerably from the general management of heart failure. Only by increasing awareness, prognosis for patients with this devastating disease can be improved.Electronic supplementary materialThe online version of this article (10.1007/s12471-019-1299-1) contains supplementary material, which is available to authorized users.

Predictors of Mortality in Light Chain Cardiac Amyloidosis with Heart Failure

Cardiac involvement in systemic amyloidosis (AL) occurs in ~50% of all AL patients. However once symptomatic heart failure develops, therapeutic options are limited thereby conferring a poor overall prognosis. The median survival is <6 months when AL patients are untreated for the underlying plasma cell dyscrasia. We thus sought to identify risk factors of increased mortality in treatment-naïve, AL cardiac amyloidosis with heart failure. Patients with biopsy-proven AL cardiac amyloid, who presented with heart failure and did not received prior AL treatment, were enrolled between 2004–2014, at the initial visit to the Amyloidosis Center at Boston University Medical Center. Routine laboratory tests, physical examination and echocardiography data were collected. There were 165 predominantly white (76.4%), and male (61%) patients, with a mean age of 61.6 ± 9.5 years. Median survival was 10.9 months (95% CI 6.2–14.7). By multivariate analysis increased relative wall thickness (RWT) [HR 6.70; 95% CI 2.45–18.30), older age (HR 1.04; 95% CI 1.01–1.06), higher New York Heart Association (NYHA) functional class (HR 1.50; 95% CI 1.02–2.2), log brain natriuretic peptide (BNP) levels (HR 1.45; 95% CI 1.15–1.81) and C-reactive protein (CRP) levels (HR 1.02; 95% CI 1.00–1.04) were significant predictors for increased mortality. In conclusion, in treatment-naïve, AL cardiac amyloidosis patients with heart failure symptoms who lack these high-risk features may have a better outcome. These findings might allow for better risk stratification although outcomes are still poor.

Multiple myeloma with primary systemic amyloidosis affecting cutaneous, gastro intestinal and cardio-vascular system

Amyloidosis refers to a group of disorders characterized by extracellular deposition of protein fibrils. Primary systemic amyloidosis is commonly due to an underlying plasma cell dyscrasia. Infiltrative amyloid cardiomyopathy is a rare cause of predominantly diastolic myocardial disease. Restrictive cardiomyopathy is the main finding in cardiac amyloidosis and results from the replacement of normal myocardial contractile elements by infiltration and interstitial deposits of amyloid, leading to alterations in cellular metabolism, calcium transport, receptor regulation, and cellular edema. Injury can also occur from circulating light chains in the absence of amyloid fibril formation. Cardiac amyloidosis should be considered in any patient presenting with congestive heart failure, preserved systolic function, and a discrepancy between a low QRS voltage on electrocardiography and an apparent left ventricular hypertrophy on sonogram. The pattern of left ventricular diastolic dysfunction changes during the course of amyloidosis and the classically described restrictive physiology occurs only in advanced stages of the disease. This is a case report where an unusual extensive cutaneous and cardiac involvement provided the sign of widespread systemic deposition of amyloid protein which eventually led to the diagnosis of multiple myeloma.

POLYPOID MULTIFOCAL ILEO-COLONIC AMYLOIDOMA MASQUERADING MALIGNANCY - A RARE CASE REPORT

Amyloidosis is a group of disorders characterized by extracellular deposition of a proteinaceous homogenous eosinophilic hyaline substance known as amyloid. Congo red staining is a specific stain for amyloid which shows an apple-green birefringence on polarized microscopy. Amyloid deposition can be systemic or localized. Primary amyloidosis (also known as AL amyloidosis) is the most common form of amyloidosis characterized by generalized deposition of excess immunoglobulin light chains. It is associated with an underlying plasma cell dyscrasia and has the maximum gastrointestinal (GI) involvement. Secondary amyloidosis is characterized by deposition of acute-phase reactant - serum amyloid A protein (also known as AA amyloidosis) and it is associated with infectious, inflammatory, or less commonly, neoplastic disorders. Renal dysfunction is the most common symptom of AA amyloidosis at diagnosis. Amyloidosis presenting as a localized mass is known as amyloidoma. Amyloidoma of the GI system is a rare finding in the absence of any systemic involvement. We report a rare case of localized multifocal polypoid amyloidoma in the lower GI tract, which masquerades as malignancy.

Cytogenetic intraclonal heterogeneity of plasma cell dyscrasia in AL amyloidosis as compared with multiple myeloma

AbstractAnalysis of intraclonal heterogeneity has yielded insights into the clonal evolution of hematologic malignancies. We compared the clonal and subclonal compositions of the underlying plasma cell dyscrasia in 544 systemic light chain amyloidosis (PC-AL) patients with 519 patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or symptomatic MM; ie, PC–non-AL patients). Using interphase fluorescence in situ hybridization, subclones were stringently defined as clone size below two thirds of the largest clone and an absolute difference of ≥30%. Subclones were found less frequently in the PC-AL group, at 199 (36.6%) of 544 as compared with 267 (51.4%) of 519 in the PC–non-AL group (P < .001), and were not associated with the stage of plasma cell dyscrasia in either entity. In both groups, translocation t(11;14), other immunoglobulin heavy chain translocations, and hyperdiploidy were typically found as main clones, whereas gain of 1q21 and deletions of 8p21, 13q14, and 17p13 were frequently found as subclones. There were no shifts in the subclone/main clone ratio depending on the MGUS, SMM, or MM stage of plasma cell dyscrasia. In multivariate analysis, t(11;14) was associated with lower rates of subclone formation and hyperdiploidy with higher rates. PC-AL itself lost statistical significance, demonstrating that the lower subclone frequency in AL is a reflection of its exceptionally high t(11;14) frequency. In summary, the subclone patterns in PC-AL and PC–non-AL are closely related, implying that subclone formation depends on the main cytogenetic categories and is independent of disease entity and stage.

Anti-BCMA CAR-T cells for treatment of plasma cell dyscrasia: case report on POEMS syndrome and multiple myeloma

BackgroundPOEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome still has no standard treatment. On the basis that both POEMS syndrome and myeloma have an underlying plasma cell dyscrasia, anti-myeloma therapy can be expected to be useful for POEMS syndrome. Chimeric antigen receptor T (CAR-T) cells targeting B cell maturation antigen (BCMA) has been used in the treatment of relapsed and refractory multiple myeloma (RRMM). No POEMS syndrome cases treated with anti-BCMA CAR-T cells have been reported.Case presentationHere, we, for the first time, report a POEMS syndrome case treated with anti-BCMA CAR-T cells. A 49-year-old female with incapacitating POEMS syndrome that progressed on lenalidomide treatment was enrolled in a phase I study involving anti-BCMA CAR-T cells (ChiCTR-OPC-16009113). Another patient with RRMM who had undergone six prior lines treatments was also enrolled in the study. They received infusions of anti-BCMA CAR-T cells. Both patients achieved a stringent complete response. Complete remission persisted in the patient with POEMS syndrome and lasted for 7.6 months before a relapse in RRMM patient. Both patients had toxicity consistent with the grade 1 cytokine release syndrome.ConclusionsThis is the first report of treatment by anti-BCMA CAR-T cells in POEMS syndrome. Our findings demonstrate the anti-BCMA CAR-T cell treatment may be a feasible therapeutic option for patients with POEMS syndrome and RRMM who do not respond well to traditional therapies.Trial registrationChiCTR-OPC, ChiCTR-OPC-16009113. Registered 29 August 2016.

KEEP THE NECK STRAIGHT: A CASE OF AMYLOID GOITER CAUSING AIRWAY OBSTRUCTION

SESSION TITLE: Obstructive Lung Diseases SESSION TYPE: Fellow Case Report Posters PRESENTED ON: 10/09/2018 01:15 PM - 02:15 PM INTRODUCTION: Primary amyloidosis (PA) is a plasma cell disorder associated with tissue deposition of amyloid fibrils. Thyroid amyloidosis resulting in symptomatic goiter is rare. We report a case of amyloid goiter in setting of PA complicated by airway obstruction requiring urgent tracheostomy. CASE PRESENTATION: A 60 year old male with history of carpal tunnel syndrome presented to an outside facility with progressive tongue swelling. Biopsy revealed amyloidosis by Congo red staining (CRS). Bone marrow biopsy demonstrated 50% of cellularity consisting of plasma cells with kappa restriction. Peripheral blood was notable for elevated kappa free light chain (FLC) at 92.8mg/dL (reference range: 0.3-1.9mg/dL), normal lambda FLC and beta-2-microglobulin. Hemoglobin, calcium, renal function panel and skeletal survey were normal. Two months later, he presented to Barnes-Jewish Hospital with dyspnea, dysphagia and 40-lbs weight loss. Physical exam revealed macroglossia, left submandibular gland swelling and bilateral enlarged thyroid gland. Stridor was audible on minimal neck flexion. Thyroid panel was normal. Computed tomography showed markedly enlarged thyroid gland and isthmus extending inferiorly with mass effect on trachea at thoracic inlet. Tracheostomy was performed urgently to secure the airway. Biopsies of the thyroid, esophagus and left submandibular gland confirmed amyloidosis indicating systemic involvement. Echocardiogram suggested cardiac amyloidosis as well. Patient was subsequently treated with chemotherapy regimen consisting of cyclophosphamide, bortezomib and dexamethasone. After 6 cycles, kappa FLC reduced to 1.8mg/dL with significant improvement in clinical symptoms and tracheostomy was eventually decannulated. DISCUSSION: PA is associated with accumulation of amyloid, derived from immunoglobulin light chain fragments, commonly affecting the heart, liver, kidneys and spleen, which can ultimately lead to organ failure. Incidence of amyloid deposition leading to diffuse thyroid enlargement in PA is rare. Biopsy is required for diagnosis; amyloid emits hallmark apple-green birefringence with CRS. Treatment of the underlying plasma cell dyscrasia is recommended for PA however, little is known about effect of treatment on the goiter. CONCLUSIONS: Amyloid goiter is a rare and potentially life-threatening complication of primary amyloidosis as it can cause upper airway obstruction. It is crucial to ensure a patent airway and tracheostomy may become necessary. Initiating chemotherapy aimed at the plasma cell disorder could result in improvement of goiter and overall disease, as highlighted in this case. Reference #1: Goldsmith JD, et.al: Amyloid goiter: report of two cases and review of literature. Endocr Pract 6: 318-323 Reference #2:Siddiqui M, et. al: Amyloid goiter as a manifestation of primary systemic amyloidosis. Thyroid 2007; 17(1): 77-80 DISCLOSURES: No relevant relationships by Reena Gurung, source=Web Response No relevant relationships by Hrishikesh Kulkarni, source=Web Response no disclosure on file for Colleen McEvoy; No relevant relationships by Keith Stockerl-Goldstein, source=Web Response

Normolipemic Xanthomas in a Patient with Underlying Plasma Cell Dyscrasia.

Normolipemic Xanthomas in a Patient with Underlying Plasma Cell Dyscrasia.

A Curious Case of Multiple Myeloma Hidden in a Cloud of Severe Cryoglobulinemia

Cryoglobulins are proteins that form ‘cloudy’ precipitates at temperatures <37°C. In type I cryoglobulinemia, the causative protein is a monoclonal immunoglobulin due to an underlying plasma cell dyscrasia. Cryoglobulinemia can present with hyperviscosity syndrome, characterized by headache, fatigue, and blurred vision. In episodes of severe cryoglobulinemia, premature precipitation of proteins can lead to falsely negative diagnostic tests and complications with treatment. The following case exemplifies the complications of diagnosis and treatment of cryoglobulinemia with hyperviscosity syndrome.

Localized Gastric Amyloidosis with Kappa and Lambda Light Chain Co-Expression.

Esophagogastroduodenoscopy for cancer screening was performed in a 55-year-old woman as part of a health screening program, and revealed a depressed lesion approximately 20 mm in diameter in the lesser curvature of the mid-gastric body. Several biopsy specimens were collected as the lesion resembled early gastric cancer; however, histopathologic evaluation revealed chronic active gastritis with an ulcer and amorphous eosinophilic material deposition. Congo red staining identified amyloid proteins, and apple-green birefringence was shown using polarized light microscopy. Immunohistochemical staining revealed the presence of kappa and lambda chain-positive plasma cells. There was no evidence of underlying plasma cell dyscrasia or amyloid deposition in other segments of the gastrointestinal tract. Echocardiography and computed tomography of the chest, abdomen, and pelvis did not show any significant findings. Thus, the patient was diagnosed with localized gastric amyloidosis with kappa and lambda light chain coexpression.

Amyloidosis of the Pancreas Masquerading as Pancreatic Cancer

A previously healthy 62-year-old female presented with a six-month history of early satiety, 30-pound unintentional weight loss, exertional dyspnea, and lower extremity edema. She had no relevant family history and denied tobacco or alcohol abuse. The patient's BMI was 16 kg/m2 and physical exam revealed bibasilar rales with bilateral lower extremity edema. CBC, BMP, and CA19-9 were all normal with mildly elevated ALP of 212 U/L. CT demonstrated an ill-defined and poorly enhancing lesion involving the pancreatic body with no features of chronic pancreatitis. Given the concerning weight loss and imaging findings, the patient was referred to our institution with a diagnosis of pancreatic cancer. We performed EUS which revealed a well-defined hypoechoic lesion involving the pancreatic body measuring 3.0cm x 1.7cm. The remainder of the pancreas and pancreatic duct appeared normal. FNA was performed using a 22g needle. Endoscopic evaluation showed a nodular-appearing stomach. Pathology revealed an eosinophilic infiltrate with Congo red staining demonstrating apple-green birefringence under polarized light. These findings were consistent with a diagnosis of amyloidosis of the pancreas. Biopsy from the stomach showed the same findings. Additional work-up, including bone marrow biopsy, confirmed primary (AL) amyloidosis, kappa type, in the setting of multiple myeloma. In addition, patient had cardiac, pulmonary, renal, and bone involvement. Amyloidosis is a systemic disease involving the deposition of insoluble extracellular low-molecular weight fibrils derived from various serum protein precursors. Primary (AL) amyloidosis results from an underlying plasma cell dyscrasia with deposition of immunoglobulin light chain fragments. While primary (AL) amyloidosis may affect nearly any organ system, pancreatic involvement is exceptionally rare and limited to case reports. In this case, imaging demonstrated a poorly defined lesion initially suspicious for pancreatic cancer. Ultimately the diagnosis was confirmed with EUS and FNA, which revealed typical findings of Congo red staining showing apple-green birefringence under polarized light. To date only one case of amyloidosis of the pancreas diagnosed using EUS-FNA has been reported in the United States. Pancreatic amyloidosis should be considered in patients presenting with a hypovascular pancreatic lesion with multi-organ failure. EUS with FNA is a useful tool in clinching the diagnosis.Figure: Endoscopic Ultrasound (EUS) view of well-defined hypoechoic lesion in the pancreatic body which was subsequently sampled with FNA biopsy.Figure: Congo red stain demonstrating apple-green birefringence under polarized light, characteristic of amyloidosis.

POEMS Syndrome: an Enigma.

POEMS syndrome is a paraneoplastic disorder secondary to an underlying plasma cell dyscrasia. By definition, all patients with POEMS syndrome must display polyneuropathy and monoclonal plasma cell disorder. In addition, at least one major criterion (Castleman's disease, sclerotic bone lesions, or vascular endothelial growth factor elevation) and one minor criterion (organomegaly, extravascular volume overload, endocrinopathy, skin changes, papilledema, thrombocytosis, or polycythemia) are required for diagnosis. Treatment is based on extent of the disease. Radiotherapy is used for localized disease. Systemic therapy is required for disseminated disease, with bone marrow involvement by clonal plasma cells, or in patients who progress shortly after radiation. Upfront autologous stem cell transplantation is the treatment of choice for transplant-eligible patients. Outcomes are typically superior to that of standard myeloma. Herein, using a case vignette, we outline the latest evidence regarding the prognostication and management of POEMS syndrome, with a focus on its relapsing-remitting course.

A Paracrine Circuit Regulates Vascular Endothelial Growth Factor Production By Bone Marrow Plasma Cells in Patients with POEMS Syndrome

Background: POEMS syndrome is a rare paraneoplastic disorder, characterized by polyneuropathy, organomegaly, osteosclerosis and extravascular volume overload, due to an underlying plasma cell dyscrasia. Vascular endothelial growth factor (VEGF), a potent angiogenic cytokine that can increase vascular permeability, plays a critical role in its pathogenesis. Despite extensive VEGF studies concerning its role in disease diagnosis, monitoring and response assessment, little is known about its cellular source and mechanisms governing the production of VEGF in POEMS patients.Methods and Materials: Patients with POEMS syndrome, 62 newly diagnosed and 46 of them after lenalidomide-dexamethasone (LenDex) treatment, admitted to Peking Union Medical College Hospital between February 2014 and April 2015, were included in the current study. Clinical information, serum and bone marrow samples were collected with the Institutional approval. Serum levels of VEGF were measured by ELISA. VEGF levels in bone marrow plasma cells were quantified via real-time quantitative PCR and multiparameter flow cytometry, respectively. In addition, the phenotype, clonality and intracellular interleukin-6 (IL-6) expression of bone marrow plasma cells were also analyzed by flow cytometry. Furthermore, immunohistochemical staining was performed to study the plasma cell distribution, clonality and expression of VEGF, IL-6 and hypoxia-inducible factor-1α (HIF-1α) in bone marrow biopsies. Statistical analyses were conducted using SPSS 22, and a p < 0.05 was considered as significant.Results: Serum levels of VEGF were dramatically elevated in patients with newly diagnosed POEMS syndrome (median 5958 pg/mL), significantly higher than both disease and healthy controls (p < 0.001), and can be used as a diagnostic marker (area under curve 0.988, p < 0.001). A cut-off value of 2000 pg/mL had a specificity of 97.7% with a sensitivity of 91.9% in support of the diagnosis. After treatment, VEGF levels decreased gradually (6-cycle after LenDex, median 1184 pg/mL, p < 0.001; 12-cycle after LenDex, median 832 pg/mL, p < 0.001). Bone marrow plasma cells showed remarkable VEGF expression, validated in both mRNA and protein levels, which also decreased in response to LenDex therapy. More importantly, a statistically linear correlation was observed between serum and bone marrow plasma cell VEGF levels (newly diagnosed patients, rho = 0.33, p = 0.01; post-therapeutic patients, rho = 0.53, p < 0.001), supporting that bone marrow plasma cells were the source of circulating VEGF. Intriguingly, immunophenotying revealed that bone marrow plasma cells were polyclonal in most newly diagnosed cases. Monoclonal population, co-existing with polyclonal plasma cells, was observed only in 11 patients (18%). Further analyses showed that the relative amounts of these two populations were similar (41% vs. 59%) and they also had comparable intracellular VEGF expression (mean fluorescent intensity, 2009 vs. 2367, p = 0.594). However, monoclonal plasma cells had significantly higher intracellular IL-6 expression (mean fluorescent intensity, 1635 vs. 865, p = 0.006). In 46 newly diagnosed cases with bone marrow biopsies available, immunohistochemical staining was performed, and plasma cells were typically distributed in a scattered manner, with focal aggregates observed in 21 cases (46%). Intracellular κ and λ light chain staining demonstrated that the background scattered plasma cells were polyclonal, while both monoclonal and polyclonal fractions were observed in the focal area, which showed similar nuclear and intracellular staining of HIF-1α and VEGF, respectively. In contrast, IL-6 was mainly expressed in λ-restricted plasma cells.Conclusion: Bone marrow plasma cells are the potential source of VEGF production in patients with POEMS syndrome. Monoclonal plasma cells, aggregates focally in the bone marrow, may secret IL-6 to stimulate polyclonal plasma cells proliferation, and consequent VEGF production in a paracrine circuit. DisclosuresOff Label Use: Lenalidomide for POEMS syndrome.

Renal impairment in patients with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes syndrome: incidence, treatment and outcome.

Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes (POEMS) syndrome is a multisystem disorder arising from underlying plasma cell dyscrasia. Renal impairment and related pathological changes have been reported, but data on its prevalence, response to therapy and impact on survival are still lacking. We retrospectively reviewed 299 patients diagnosed with POEMS syndrome in a tertiary-care university hospital from 2000 until 2014. The estimated glomerular filtration rate (eGFR) was used to define renal impairment and response, according to International Myeloma Working Group criteria. We examined the impact of renal impairment and response on patient survival. Sixty-seven patients (22.4%) had renal impairment (eGFR < 60 mL/min/1.73 m(2)) at baseline. In a multivariate analysis, ascites was independently associated with renal impairment [odds ratio (OR) 12.366, P < 0.001]. Renal impairment was reversible in 66.0% of patients receiving therapy and was associated with a shorter time interval between symptom onset and treatment (OR 0.059, P = 0.043) and a vascular endothelial growth factor remission (OR 15.958, P = 0.050) in a multivariate analysis. In terms of therapy, patients with a renal response more commonly received a novel agent-based regimen (P = 0.037), which also led to a shorter response time (P = 0.001). With a median follow-up of 27.4 months, inferior survival was observed in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m(2)), but not in those with moderate dysfunction (eGFR 30-59 mL/min/1.73 m(2)), compared with patients without renal impairment. A renal response, if achieved, predicted improved survival. Renal impairment is a common complication of POEMS syndrome, but can be reversed with effective therapy in most cases.

Abdominal subcutaneous fat pad aspiration and bone marrow examination for the diagnosis of AL amyloidosis: the reliability of immunohistochemistry.

Tissue biopsy is essential for the diagnosis and typing of amyloidosis. Given its safety and ease, abdominal fat pad (AFP) is the first biopsy site of choice; bone marrow (BM) biopsy should additionally be performed to identify underlying plasma cell dyscrasia. The aim of the present study was to assess the usefulness of combined biopsy and immunohistochemical staining of AFP and BM tissues for the diagnosis and typing of amyloidosis. A total of 65 patients were examined. Congo red staining and immunohistochemical staining with antibodies were performed. Of 51 patients with systemic amyloidosis, 50 patients were examined with fat pad aspirates and 38 (76 %) cases were positive. All 51 patients were also examined by BM analysis and 25 (49 %) cases were positive. Including both AFP aspirates and BM specimens, 90 % of patients with systemic amyloidosis were Congo red positive. Of the 49 patients with AL amyloidosis, immunohistochemical stains were positive in 67.6 % of patients with AFP aspirates and in 50 % with BM specimens. Combining AFP aspirate and BM examination, immunohistochemical stains yielded positive stains for the corresponding circulating monoclonal immunoglobulin in 72.7 % of cases, and hence these analyses appear to be valuable in diagnosing the type of amyloidosis.

Conjunctival extranodal marginal zone B‐cell lymphoma with crystal‐storing histiocytosis

Crystal-storing histiocytosis (CSH) is a rare immunoglobulin storage disorder, associated with lymphoproliferative diseases or seldom with inflammatory or infective conditions (Coupland et al. 2002). The head-and-neck region is most commonly affected by CSH, usually in association with plasma cell neoplasms (Tsuji et al. 2014). Conjunctival involvement by CSH is distinctly uncommon (Yu et al. 2013). Herein, we describe a case of conjunctival CSH associated with an extranodal marginal zone B-cell lymphoma (EMZL). A 58-year-old man was referred to the Liverpool Ocular Oncology Centre in 2008 with a tumour of the right (OD) eye of 2 years duration. The patient had been treated previously for retinal detachment OD, bilateral cataracts and bilateral primary open-angle glaucoma. The best-corrected visual acuity was 6/60 OD and 6/6 OS. A subconjunctival, pink ‘salmon-coloured’ tumour with prominent blood vessels was visible infero-temporally OD (Fig. 1A), extending up to the fornix. There was restriction of right lateral gaze. On echography, the conjunctival tumour had a low internal acoustic reflectivity and measured 12.4 × 10.4 × 6.2 mm on magnetic resonance imaging (MRI). The clinical suspicion was of lymphoma: consequently, a large incisional biopsy was performed and processed for pathological assessment. Conventional histological sections demonstrated conjunctival tissue with diffuse and dense infiltration of small- to medium-sized lymphoid cells (Fig. 1B), comprising small lymphocytes, centrocyte-like cells, monocytoid cells and plasma cells. There were interspersed sheets of larger ‘Gaucher-like’ cells taking up at least 40% of the lesion with abundant eosinophilic pale cytoplasm and small-sized nuclei (Fig. 1C). At higher magnification, ill-defined crystal-like structures could be seen within the cytoplasm of these cells. Immunohistochemically, the atypical lymphoid cells expressed B-cell antigens (Fig. 1E) and demonstrated a monotypical expression for IgM. They were negative for CD5, CD23, CD10 and cyclin D1. In contrast, the above-described larger cells were immunoreactive for CD68 (Fig. 1F), and the cytoplasmic crystals were positive for immunoglobulin kappa light chain. These findings were consistent with conjunctival EMZL with CSH, confirmed on polymerase chain reaction. Subsequent clinical staging investigations revealed Ann-Arbor stage III disease and T2N3 with involvement of mediastinal and abdominal lymph nodes. The bone marrow trephine excluded any underlying plasma cell dyscrasia, such as multiple myeloma or monoclonal gammopathy of unclear significance. The patient was subsequently treated with R-CHOP (rituximab 375 mg/m2 iv; cyclophosphamide 750 mg/m2 iv; vincristine 1.4 mg/m2 iv; prednisone 40 mg/m2 iv). Two months after initiation of chemotherapy, MRI scanning showed complete regression of the residual conjunctival tumour. Five years after initial diagnosis, the patient was disease free but undertaking regular oncological review. This case illustrates a very rare example of conjunctival EMZL with CSH: to date only nine cases of CSH involving the ocular adnexa have been described (Grossniklaus et al. 1990; Coupland et al. 2002; Yu et al. 2013; Radhakrishnan et al. 2014). Most CSH cases have involved the orbit with the conjunctiva being less commonly affected. The CSH component of the tumour can be extensive and can potentially lead to misdiagnoses through sampling error, particularly if a fine needle (aspiration) biopsy has been employed. CSH associated with EMZL typically has a good prognosis, particularly if diagnosed at an early clinical stage, and it usually responds either to localized surgery, radiotherapy and chemotherapy, or combinations thereof. Included in the list of differential diagnosis are infectious aetiologies – for example tuberculosis and fungal infections – as well as non-lymphoid neoplastic conditions, including rhabdomyosarcoma, and pleomorphic sarcoma. These diagnoses are, however, usually possible to exclude on the basis of morphological and immunohistochemical features, as well as special stains for micro-organisms. In conclusion, when diagnosing conjunctival EMZL, a simultaneous CSH should always be considered.

Circulating Monoclonal Light Chains and Acute Kidney Injury: The Role of the Renal Biopsy with Emphasis on Ultrastructural Evaluation in Assessing and Understanding Renal Injury

Tubular interstitial injury as a consequence of circulating monotypical light chains in patients with an underlying plasma cell dyscrasia may be difficult to identify. Renal involvement is a common early manifestation in these patients, and accurate/careful pathologic evaluation can uncover an underlying plasma cell dyscrasia. While immunofluorescence evaluation can detect monotypical deposition of light chains in the tubular interstitial compartment and may suggest a possible underlying plasma cell dyscrasia, electron microscopic examination is crucial in documenting such involvement. Ultrastructural immunolabeling can help in solidifying the pathological assessment.

Paraprotein-related Bleeding as a First Symptom of Multiple Myeloma

Specific affinity characteristics of the neoplastic paraprotein have been established as exceptional causes of bleeding in patients with malignant gammopathies. We describe a case in which a relationship between impaired coagulation parameters and the concentration of serum paraprotein, without specific affinity for any coagulation protein, could be established. Alternative causes of bleeding were discarded and a correlation between serum monoclonal paraprotein concentration and activated partial thromboplastin time was established. Multiple myeloma treatments achieved minor responses only, but were otherwise associated with partial improvement in coagulation parameters and, most importantly, control of the bleeding episodes. The interference in the coagulation process appeared to be non-specific and related to paraprotein concentration only but was not related to hyperviscosity. The case emphasizes the need to suspect of atypical effects of paraproteinemia in patients with monoclonal gammopathy of unknown significance and eventually to treat the underlying plasma cell dyscrasia if symptoms, like severe bleeding, justify that intervention.

Endoscopic Mucosal Resection (EMR) for the Management of Solitary Extramedullary Plasmacytoma of the Esophagus

Introduction: We present a first report of EMR for management of Solitary Extramedullary Plasmacytoma (EMP) of the esophagus. Case Report: A 50-year-old man with chronic intermittent dysphagia secondary to eosinophilic esophagitis (EoE) was referred for management of an incidental mid-esophageal mass which was biopsy proven to be an EBV+ plasma cell neoplasm. Extensive work-up for an underlying plasma cell dyscrasia including multiple myeloma confirmed this to be a solitary EMP. Endoscopic reassessment demonstrated an irregular sessile 1.0-1.5 cm mid-esophageal nodule at 25 cm. EUS showed a hypoechoic nodule involving the mucosa and submucosa with intact muscularis propria. The lesion was successfully resected by EMR using a multi-band mucosectomy device without submucosal injectate. The primary lesion was resected with a single band ligation although a second ligation was performed given a grossly close margin. No additional thermal ablation therapy was used. No endoclip closure was required. No immediate or delayed complications were observed. Pathologic and immunohistochemistry assessment was compatible with solitary EMP with marked expansion of the submucosa by sheets of large plasmacytoid cells without blastic appearance. Despite EBV+, there were no features of plasmablastic lymphoma. Peripheral and deep resected margins from the primary band ligation were free of tumor. Only 5-13% of EMPs occur in the gastrointestinal tract. Standard therapy for solitary plasmacytoma involving extramedullary sites involves definitive radiation therapy, followed by surgery if necessary with an overall good prognosis. Endoscopic management has not been well described given limited data. Only one prior case report has described successful endoscopic management of a subcentimeter mucosal EMP using endoscopic submucosal resection (ESD). However this technique is not yet widely performed and is associated with a higher risk for perforation. EMR is already widely used for the diagnostic and therapeutic management of mucosal and submucosal neoplastic lesions. EMR appears to be a feasible and less invasive alternative to radiation and surgery for select small, well defined EMP lesions limited to the mucosa and submucosa of the esophagus. EUS can help assess those lesions appropriate for EMR. Long term follow up of endoscopic treatment of solitary esophageal EMPs is needed. Surveillance EGD with biopsies will be repeated at three months. Repeat endoscopic management, radiation and surgery remain potential salvage therapeutic options.

44-Year-Old Man With Exertional Dyspnea, Weight Loss, and Palpitations

44-Year-Old Man With Exertional Dyspnea, Weight Loss, and Palpitations