- Email: [email protected]
Synchronous multiple myeloma and Gaucher disease
HEMONC 300 12 October 2019 Hematol Oncol Stem Cell Ther xxx (xxxx) xxx
No. of Pages 4, Model 6+
1
Available at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/hemonc
2
CASE REPORT
5
Synchronous multiple myeloma and Gaucher disease
8
Jorge Monge a,*, Amy Chadburn b, Usama Gergis a
6 7 4
12
a Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College of Cornell University, New York–Presbyterian Hospital, New York, NY, USA b Department of Pathology and Laboratory Medicine, Weill Cornell Medical College of Cornell University, New York– Presbyterian Hospital, New York, NY, USA
13
Received 16 April 2019; received in revised form 13 June 2019; accepted 8 July 2019
9 10 11
14
19 20 16 21 17 22 18 23 24 25 26 27 28 29 30 31 32 33 38 35 34 36 37
KEYWORDS Gaucher disease; Multiple myeloma
Abstract Pseudo-Gaucher cells can be found in multiple hematologic malignancies, hemoglobinopathies, infections, and multiple storage disorders upon bone marrow aspirate and biopsy; however, Gaucher disease (GD) should be ruled out, particularly when the cytoplasmic inclusions cannot be adequately characterized. It is well known that GD may be associated with monoclonal gammopathies; however, although enzyme replacement therapy (ERT) may result in an improvement in polyclonal gammopathies, its effect on the progression of monoclonal gammopathy of undetermined significance to multiple myeloma (MM) remains uncertain. ERT may improve patient’s cytopenias and facilitate administration of anti-myeloma therapy in patients with concurrent GD and MM; however, the current paucity of data makes it challenging to determine its effect on response to anti-myeloma therapy or the risk of relapse. Hematologists should be familiar with the clinical presentation and diagnosis of GD and its association with monoclonal gammopathies. Here we present a case of synchronous smoldering MM and GD. Ó 2019 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/).
Introduction * Corresponding author at: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College of Cornell University, New York–Presbyterian Hospital, 520 East 70th Street, Starr 3, New York, NY 10021, USA. E-mail address: [email protected] (J. Monge).
The increased use of magnetic resonance imaging (MRI) has led to an increase in the incidental finding of bone marrow signal abnormalities. Multiple retrospective studies suggest that further evaluation of an abnormal bone marrow signal may lead to a hematologic or oncologic diagnosis in up to
https://doi.org/10.1016/j.hemonc.2019.07.001 1658-3876/Ó 2019 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article as: J. Monge, A. Chadburn and U. Gergis, Synchronous multiple myeloma and Gaucher disease, Hematol Oncol Stem Cell Ther, https://doi.org/10.1016/j.hemonc.2019.07.001
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6% of all patients, and about half of the patients who undergo a bone marrow biopsy [1]. An abnormal bone marrow signal on MRI may be the presenting feature in some hematologic malignancies, not limited to multiple myeloma (MM), and should prompt a thorough evaluation [1]. The differential diagnosis of a diffuse decrease in T1 signal in the bone marrow includes, among others, hematopoietic hyperplasia or neoplasm, renal osteodystrophy, sarcoidosis, spondyloarthropathy, myelofibrosis, mastocytosis, hemosiderosis, Gaucher disease (GD), and gout [2]. MM is a neoplasm characterized by the proliferation of malignant plasma cells producing a monoclonal immunoglobulin (MIg) [3]. Almost 80% of patients with MM have bone involvement at the time of diagnosis, and MRI is able to detect focal lesions in half of the patients with a negative bone survey [3,4]. The accumulation of MIg crystals in the lysosomes of histiocytes can be seen in the bone marrow or other lymphoid and extralymphoid tissues, and represents a rare complication of plasma cell dyscrasias and other lymphoproliferative disorders named crystalstoring histiocytosis (CSH) [5]. The differential diagnosis of this condition includes the lysosomal storage disorders, as these histiocytes may mimic Gaucher cells, which is why they are occasionally named pseudo-Gaucher cells [6]. GD is a lysosomal storage disorder characterized by an autosomal recessive disorder because of a mutation in GBA [7,8]. This leads to a deficient activity of the glucocerebrosidase enzyme resulting in the accumulation of glycosphingolipids within macrophages (Gaucher cells). GD has been associated with an increased risk of Parkinson disease and cancer [7,9]. Controversy remains whether GD is associated with an increased risk of hematological malignancies other than MM, but there is clear evidence that GD is associated with both polyclonal and monoclonal gammopathies, as well as MM [9–15]. We present a case of a patient diagnosed with synchronous smoldering MM and GD based on a bone marrow biopsy performed after the incidental finding of an abnormal bone marrow signal on MRI performed for persistent shoulder and back pain.
Case presentation A 40-year-old woman was referred to our clinic for further evaluation after she was found to have a diffusely hypointense bone marrow signal on a right shoulder. Lumbar and sacral spine MRI was performed to evaluate persistent pain after being struck by a car 6 months earlier. She denied any weight loss, fever, bleeding, chest pain, palpitations, dyspnea on exertion, cough, abdominal pain, nausea or vomiting, bowel or bladder dysfunction, lightheadedness, skin lesions, lymphadenopathy, or other masses. Other than the right shoulder and low back pain she has had since the car accident, she denied any bone pain, arthralgias, or myalgias. She has a medical history of Gilbert syndrome, low vitamin B12 level, and anxiety. Her family history is negative for hematologic malignancies or GD. She is of Irish and Austrian ancestry and has no siblings or children. She has never smoked tobacco or used illicit drugs, and drinks less
than 4 units of alcohol per month. Her medications include trazodone, tizanidine, meloxicam, and cyanocobalamin; she has no known drug allergies. On review of her laboratory results, she had a mildly decreased hemoglobin (11.5 g/dL; normal range, 11.7– 15.3 g/dL) with normal red cell indices and normal white blood cell and platelet counts. She had a normal serum calcium, renal, and liver function tests except for total hyperbilirubinemia (2.0 mg/dL; normal range, 0.3–1.2 mg/dL), and an elevated ferritin level (1,366 ng/mL; normal range 10.0–291.0 ng/mL). Her Ig profile showed an elevated IgG (1,730 mg/dL; normal range, 610–1,616 mg/dL) with a decreased IgA (43 mg/dL; normal range, 85–499 mg/dL) and IgM (54 mg/dL; normal range, 35–242 mg/dL); free light chain assay showed an elevated kappa light chain (7.3 mg/dL; normal range, 0.33–1.94 mg/dL), a normal lambda light chain (0.79 mg/dL; normal range, 0.57– 2.63 mg/dL), and an abnormal free light chain ratio (9.24; normal range, 0.26–1.65). Serum protein electrophoresis showed a monoclonal protein of 0.5 g/dL, characterized as IgG-kappa by immunofixation; no monoclonal protein was detected in the urine. Further imaging with whole body fluorodeoxyglucose–p ositron emission tomography (FDG–PET)/computed tomography (CT) revealed a normal-sized liver and spleen, and a subacute left anterolateral 10th rib fracture with moderate metabolic uptake (maximal standardized uptake value [SUV] of 7.2); without osteolytic lesions. A CT-guided biopsy of the rib lesion was attempted 6 months later; however, the procedure was aborted after the planning images demonstrated resolution of the previously noted findings. A bone marrow biopsy showed a hypercellular marrow (80%) with 20–30% monotypic kappa-restricted plasma cells along with numerous abnormal cells with abundant cytoplasm that stain positive for periodic acid–Schiff. These abnormal cells (Fig. 1) largely resembled histiocytes, whereas the exact nature of the material within the cytoplasm was not clear—immunostaining for Ig light chains was inconclusive because of background staining and the patchy staining of the histiocytes. Electron microscopy was attempted; however, no cells resembling foamy histiocytes were recovered upon processing, and we were unable to perform an ultrastructural study. Normal female karyotype and an IGH rearrangement were seen on fluorescence in situ hybridization. Both the bone marrow and a fat pad biopsy were negative for Congo red stain. Acid beta-glucosidase enzyme activity was markedly decreased (0.19 nmol/hour/mg, normal range, 4.0– 22.6 nmol/hour/mg), and a homozygous pathogenic variant in GBA was detected (c.1226A > G p.N409S), confirming the diagnosis of type 1 GD. In summary, a thorough hematologic evaluation prompted by an incidental abnormal bone marrow signal on MRI revealed a diagnosis of synchronous smoldering MM and GD. The patient had no indication for anti-myeloma therapy and was started on enzyme replacement therapy (ERT). She is currently undergoing frequent laboratory monitoring as well as imaging to assess the response to ERT and evolution of the lesion seen in her left 10th rib.
Please cite this article as: J. Monge, A. Chadburn and U. Gergis, Synchronous multiple myeloma and Gaucher disease, Hematol Oncol Stem Cell Ther, https://doi.org/10.1016/j.hemonc.2019.07.001
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Fig. 1 Bone marrow biopsy. (a) The bone marrow was largely replaced by sheets of cells with abundant cytoplasm (black arrows). Residual marrow elements decreased in number (red arrows; hematoxylin and eosin; 4 original magnification). (b) At high power the abnormal cells had bland-appearing nuclei and abundant eosinophilic cytoplasm with a ‘‘tissue paper” appearance (black arrows). Residual maturing marrow elements were also present (red arrows; hematoxylin and eosin; 40 original magnification). (c) The abnormal cells were also seen in the bone marrow aspirate smear (Wright Giemsa; 40 original magnification).
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Discussion An abnormal bone marrow signal should prompt further evaluation by a hematologist in order to rule out a neoplastic diagnosis. Gaucher cells appear as lipid-laden histiocytes with abundant cytoplasm, eccentric nuclei, and basophilic inclusions; however, their presence in a bone marrow biopsy is not diagnostic of GD. Pseudo-Gaucher cells can be found in multiple hematologic malignancies, hemoglobinopathies, infections, and multiple storage disorders; however, GD should be ruled out, especially when the cytoplasmic inclusions cannot be adequately characterized [8,14]. It is well known that GD is associated with monoclonal gammopathies; immune dysregulation within the bone marrow niche, chronic lymphocyte stimulation, and the direct oncogenic effect from accumulated glycosphingolipids are thought to be implicated in the pathogenesis of MGUS and MM in patients with GD [7,8]. GD is a heterogeneous disease with a wide range of clinical presentations that may overlap with MM. Skeletal manifestations in GD are characterized by diffuse bone pain and/or painful crises resulting in osteonecrosis; low bone density, osteolytic lesions, and pathologic fractures may also occur [7,8]. Of note, infiltration of the bone marrow by GD may result in abnormal uptake upon FDG–PET/CT and may be misconstrued as end-organ damage in patients with a monoclonal gammopathy [14]. Anemia is present in half of patients with GD, whereas most patients will present with mild to moderate thrombocytopenia accompanied by splenomegaly [8]. In contrast to MM, renal disease and hypercalcemia are usually not seen in GD. Physicians experienced in the management of patients with GD are usually proficient in detecting a concurrent monoclonal gammopathy; however, hematologist should maintain a high level of suspicion of GD in patients with MM that present with cytopenias not explained by the degree of bone marrow plasmacytosis, hepatosplenomegaly, and the presence of bone disease. Given its rarity, it is difficult to accurately predict the risk of development of MM in patients with GD; however, biannual measurement of serum free light chains, protein electrophoresis, and immunofixation is recommended [8].
Initiation of treatment with ERT in patients with GD is tailored to the individual patient and is aimed at improvement of symptoms, prevention of irreversible complications, and improvement in overall health and quality of life. Although it remains unclear whether the persistent pain suffered by the patient presented in this case is secondary to GD, initiation of ERT may lead to an improvement in quality of life as well as prevention of potential irreversible complications [8]. Although ERT may result in an improvement in polyclonal gammopathies, its effect on the progression of MGUS to active MM remains uncertain [15]. In otherwise stable patients on ERT who develop progression of cytopenias, worsening splenomegaly, or back pain, further workup to rule out the development or progression of a monoclonal gammopathy should be performed [8,15]. In patients with concurrent GD and MM who have severe cytopenias, ERT may result in their improvement and allow for the administration of anti-myeloma therapy. At this point, however, the current paucity of data makes it challenging to determine the effect of ERT on antimyeloma treatment response or the risk of relapse [8]. We echo the call made by Weinreb et al. [14] for all hematologists to be familiar with the clinical presentation and diagnosis of GD and its association with monoclonal gammopathies, as well as to participate in international and national GD registries to attempt to elucidate these unanswered questions [10].
Authors’ contributions JM wrote the manuscript. AC reviewed the histology, provided the figure and revised the manuscript. UG designed and revised the manuscript. All authors read and approved the final manuscript.
Declaration of Competing Interest The authors declare no conflicts of interest.
Please cite this article as: J. Monge, A. Chadburn and U. Gergis, Synchronous multiple myeloma and Gaucher disease, Hematol Oncol Stem Cell Ther, https://doi.org/10.1016/j.hemonc.2019.07.001
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References [1] Gronningsaeter IS, Ahmed AB, Vetti N, Johansen S, Bruserud O, Reikvam H. Bone marrow abnormalities detected by magnetic resonance imaging as initial sign of hematologic malignancies. Clin Pract 2018;8:1061. [2] Hanrahan CJ, Shah LM. MRI of spinal bone marrow: Part 2. T1weighted imaging-based differential diagnosis. AJR Am J Roentgenol 2011;197:1309–21. [3] Kyle RA, Gertz MA, Witzig TE, Lust JA, Lacy MQ, Dispenzieri A, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc 2003;78:21–33. [4] Walker R, Barlogie B, Haessler J, Tricot G, Anaissie E, Shaughnessy Jr JD, et al. Magnetic resonance imaging in multiple myeloma: diagnostic and clinical implications. J Clin Oncol 2007;25:1121–8. [5] Yamamoto T, Hishida A, Honda N, Ito I, Shirasawa H, Nagase M. Crystal-storing histiocytosis and crystalline tissue deposition in multiple myeloma. Arch Pathol Lab Med 1991;115:351–4. [6] Schaefer HE. Gammopathy-related crystal-storing histiocytosis, pseudo- and pseudopseudo-Gaucher cells. Critical commentary and mini-review. Pathol Res Pract 1996;192:1152–62. [7] Ayto R, Hughes DA. Gaucher disease and myeloma. Crit Rev Oncog 2013;18:247–68. [8] Thomas AS, Mehta A, Hughes DA. Gaucher disease: haematological presentations and complications. Br J Haematol 2014;165:427–40.
[9] Shiran A, Brenner B, Laor A, Tatarsky I. Increased risk of cancer in patients with Gaucher disease. Cancer 1993;72:219–24. [10] Rosenbloom BE, Weinreb NJ, Zimran A, Kacena KA, Charrow J, Ward E. Gaucher disease and cancer incidence: a study from the Gaucher registry. Blood 2005;105:4569–72. [11] Pratt PW, Kochwa S, Estren S. Immunoglobulin abnormalities in Gaucher’s disease. Report of 16 cases. Blood 1968;31:633–40. [12] de Fost M, Out TA, de Wilde FA, Tjin EP, Pals ST, van Oers MH, et al. Immunoglobulin and free light chain abnormalities in Gaucher disease type I: data from an adult cohort of 63 patients and review of the literature. Ann Hematol 2008;87:439–49. [13] de Fost M, Vom Dahl S, Weverling GJ, Brill N, Brett S, Haussinger D, et al. Increased incidence of cancer in adult Gaucher disease in Western Europe. Blood Cells Mol Dis 2006;36:53–8. [14] Weinreb NJ, Mistry PK, Rosenbloom BE, Dhodapkar MV. MGUS, lymphoplasmacytic malignancies, and Gaucher disease: the significance of the clinical association. Blood 2018;131:2500–1. [15] Arends M, van Dussen L, Biegstraaten M, Hollak CE. Malignancies and monoclonal gammopathy in Gaucher disease; a systematic review of the literature. Br J Haematol 2013;161:832–42.
Please cite this article as: J. Monge, A. Chadburn and U. Gergis, Synchronous multiple myeloma and Gaucher disease, Hematol Oncol Stem Cell Ther, https://doi.org/10.1016/j.hemonc.2019.07.001
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1
Available at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/hemonc
2
CASE REPORT
5
Synchronous multiple myeloma and Gaucher disease
8
Jorge Monge a,*, Amy Chadburn b, Usama Gergis a
6 7 4
12
a Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College of Cornell University, New York–Presbyterian Hospital, New York, NY, USA b Department of Pathology and Laboratory Medicine, Weill Cornell Medical College of Cornell University, New York– Presbyterian Hospital, New York, NY, USA
13
Received 16 April 2019; received in revised form 13 June 2019; accepted 8 July 2019
9 10 11
14
19 20 16 21 17 22 18 23 24 25 26 27 28 29 30 31 32 33 38 35 34 36 37
KEYWORDS Gaucher disease; Multiple myeloma
Abstract Pseudo-Gaucher cells can be found in multiple hematologic malignancies, hemoglobinopathies, infections, and multiple storage disorders upon bone marrow aspirate and biopsy; however, Gaucher disease (GD) should be ruled out, particularly when the cytoplasmic inclusions cannot be adequately characterized. It is well known that GD may be associated with monoclonal gammopathies; however, although enzyme replacement therapy (ERT) may result in an improvement in polyclonal gammopathies, its effect on the progression of monoclonal gammopathy of undetermined significance to multiple myeloma (MM) remains uncertain. ERT may improve patient’s cytopenias and facilitate administration of anti-myeloma therapy in patients with concurrent GD and MM; however, the current paucity of data makes it challenging to determine its effect on response to anti-myeloma therapy or the risk of relapse. Hematologists should be familiar with the clinical presentation and diagnosis of GD and its association with monoclonal gammopathies. Here we present a case of synchronous smoldering MM and GD. Ó 2019 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/).
Introduction * Corresponding author at: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College of Cornell University, New York–Presbyterian Hospital, 520 East 70th Street, Starr 3, New York, NY 10021, USA. E-mail address: [email protected] (J. Monge).
The increased use of magnetic resonance imaging (MRI) has led to an increase in the incidental finding of bone marrow signal abnormalities. Multiple retrospective studies suggest that further evaluation of an abnormal bone marrow signal may lead to a hematologic or oncologic diagnosis in up to
https://doi.org/10.1016/j.hemonc.2019.07.001 1658-3876/Ó 2019 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article as: J. Monge, A. Chadburn and U. Gergis, Synchronous multiple myeloma and Gaucher disease, Hematol Oncol Stem Cell Ther, https://doi.org/10.1016/j.hemonc.2019.07.001
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6% of all patients, and about half of the patients who undergo a bone marrow biopsy [1]. An abnormal bone marrow signal on MRI may be the presenting feature in some hematologic malignancies, not limited to multiple myeloma (MM), and should prompt a thorough evaluation [1]. The differential diagnosis of a diffuse decrease in T1 signal in the bone marrow includes, among others, hematopoietic hyperplasia or neoplasm, renal osteodystrophy, sarcoidosis, spondyloarthropathy, myelofibrosis, mastocytosis, hemosiderosis, Gaucher disease (GD), and gout [2]. MM is a neoplasm characterized by the proliferation of malignant plasma cells producing a monoclonal immunoglobulin (MIg) [3]. Almost 80% of patients with MM have bone involvement at the time of diagnosis, and MRI is able to detect focal lesions in half of the patients with a negative bone survey [3,4]. The accumulation of MIg crystals in the lysosomes of histiocytes can be seen in the bone marrow or other lymphoid and extralymphoid tissues, and represents a rare complication of plasma cell dyscrasias and other lymphoproliferative disorders named crystalstoring histiocytosis (CSH) [5]. The differential diagnosis of this condition includes the lysosomal storage disorders, as these histiocytes may mimic Gaucher cells, which is why they are occasionally named pseudo-Gaucher cells [6]. GD is a lysosomal storage disorder characterized by an autosomal recessive disorder because of a mutation in GBA [7,8]. This leads to a deficient activity of the glucocerebrosidase enzyme resulting in the accumulation of glycosphingolipids within macrophages (Gaucher cells). GD has been associated with an increased risk of Parkinson disease and cancer [7,9]. Controversy remains whether GD is associated with an increased risk of hematological malignancies other than MM, but there is clear evidence that GD is associated with both polyclonal and monoclonal gammopathies, as well as MM [9–15]. We present a case of a patient diagnosed with synchronous smoldering MM and GD based on a bone marrow biopsy performed after the incidental finding of an abnormal bone marrow signal on MRI performed for persistent shoulder and back pain.
Case presentation A 40-year-old woman was referred to our clinic for further evaluation after she was found to have a diffusely hypointense bone marrow signal on a right shoulder. Lumbar and sacral spine MRI was performed to evaluate persistent pain after being struck by a car 6 months earlier. She denied any weight loss, fever, bleeding, chest pain, palpitations, dyspnea on exertion, cough, abdominal pain, nausea or vomiting, bowel or bladder dysfunction, lightheadedness, skin lesions, lymphadenopathy, or other masses. Other than the right shoulder and low back pain she has had since the car accident, she denied any bone pain, arthralgias, or myalgias. She has a medical history of Gilbert syndrome, low vitamin B12 level, and anxiety. Her family history is negative for hematologic malignancies or GD. She is of Irish and Austrian ancestry and has no siblings or children. She has never smoked tobacco or used illicit drugs, and drinks less
than 4 units of alcohol per month. Her medications include trazodone, tizanidine, meloxicam, and cyanocobalamin; she has no known drug allergies. On review of her laboratory results, she had a mildly decreased hemoglobin (11.5 g/dL; normal range, 11.7– 15.3 g/dL) with normal red cell indices and normal white blood cell and platelet counts. She had a normal serum calcium, renal, and liver function tests except for total hyperbilirubinemia (2.0 mg/dL; normal range, 0.3–1.2 mg/dL), and an elevated ferritin level (1,366 ng/mL; normal range 10.0–291.0 ng/mL). Her Ig profile showed an elevated IgG (1,730 mg/dL; normal range, 610–1,616 mg/dL) with a decreased IgA (43 mg/dL; normal range, 85–499 mg/dL) and IgM (54 mg/dL; normal range, 35–242 mg/dL); free light chain assay showed an elevated kappa light chain (7.3 mg/dL; normal range, 0.33–1.94 mg/dL), a normal lambda light chain (0.79 mg/dL; normal range, 0.57– 2.63 mg/dL), and an abnormal free light chain ratio (9.24; normal range, 0.26–1.65). Serum protein electrophoresis showed a monoclonal protein of 0.5 g/dL, characterized as IgG-kappa by immunofixation; no monoclonal protein was detected in the urine. Further imaging with whole body fluorodeoxyglucose–p ositron emission tomography (FDG–PET)/computed tomography (CT) revealed a normal-sized liver and spleen, and a subacute left anterolateral 10th rib fracture with moderate metabolic uptake (maximal standardized uptake value [SUV] of 7.2); without osteolytic lesions. A CT-guided biopsy of the rib lesion was attempted 6 months later; however, the procedure was aborted after the planning images demonstrated resolution of the previously noted findings. A bone marrow biopsy showed a hypercellular marrow (80%) with 20–30% monotypic kappa-restricted plasma cells along with numerous abnormal cells with abundant cytoplasm that stain positive for periodic acid–Schiff. These abnormal cells (Fig. 1) largely resembled histiocytes, whereas the exact nature of the material within the cytoplasm was not clear—immunostaining for Ig light chains was inconclusive because of background staining and the patchy staining of the histiocytes. Electron microscopy was attempted; however, no cells resembling foamy histiocytes were recovered upon processing, and we were unable to perform an ultrastructural study. Normal female karyotype and an IGH rearrangement were seen on fluorescence in situ hybridization. Both the bone marrow and a fat pad biopsy were negative for Congo red stain. Acid beta-glucosidase enzyme activity was markedly decreased (0.19 nmol/hour/mg, normal range, 4.0– 22.6 nmol/hour/mg), and a homozygous pathogenic variant in GBA was detected (c.1226A > G p.N409S), confirming the diagnosis of type 1 GD. In summary, a thorough hematologic evaluation prompted by an incidental abnormal bone marrow signal on MRI revealed a diagnosis of synchronous smoldering MM and GD. The patient had no indication for anti-myeloma therapy and was started on enzyme replacement therapy (ERT). She is currently undergoing frequent laboratory monitoring as well as imaging to assess the response to ERT and evolution of the lesion seen in her left 10th rib.
Please cite this article as: J. Monge, A. Chadburn and U. Gergis, Synchronous multiple myeloma and Gaucher disease, Hematol Oncol Stem Cell Ther, https://doi.org/10.1016/j.hemonc.2019.07.001
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Fig. 1 Bone marrow biopsy. (a) The bone marrow was largely replaced by sheets of cells with abundant cytoplasm (black arrows). Residual marrow elements decreased in number (red arrows; hematoxylin and eosin; 4 original magnification). (b) At high power the abnormal cells had bland-appearing nuclei and abundant eosinophilic cytoplasm with a ‘‘tissue paper” appearance (black arrows). Residual maturing marrow elements were also present (red arrows; hematoxylin and eosin; 40 original magnification). (c) The abnormal cells were also seen in the bone marrow aspirate smear (Wright Giemsa; 40 original magnification).
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Discussion An abnormal bone marrow signal should prompt further evaluation by a hematologist in order to rule out a neoplastic diagnosis. Gaucher cells appear as lipid-laden histiocytes with abundant cytoplasm, eccentric nuclei, and basophilic inclusions; however, their presence in a bone marrow biopsy is not diagnostic of GD. Pseudo-Gaucher cells can be found in multiple hematologic malignancies, hemoglobinopathies, infections, and multiple storage disorders; however, GD should be ruled out, especially when the cytoplasmic inclusions cannot be adequately characterized [8,14]. It is well known that GD is associated with monoclonal gammopathies; immune dysregulation within the bone marrow niche, chronic lymphocyte stimulation, and the direct oncogenic effect from accumulated glycosphingolipids are thought to be implicated in the pathogenesis of MGUS and MM in patients with GD [7,8]. GD is a heterogeneous disease with a wide range of clinical presentations that may overlap with MM. Skeletal manifestations in GD are characterized by diffuse bone pain and/or painful crises resulting in osteonecrosis; low bone density, osteolytic lesions, and pathologic fractures may also occur [7,8]. Of note, infiltration of the bone marrow by GD may result in abnormal uptake upon FDG–PET/CT and may be misconstrued as end-organ damage in patients with a monoclonal gammopathy [14]. Anemia is present in half of patients with GD, whereas most patients will present with mild to moderate thrombocytopenia accompanied by splenomegaly [8]. In contrast to MM, renal disease and hypercalcemia are usually not seen in GD. Physicians experienced in the management of patients with GD are usually proficient in detecting a concurrent monoclonal gammopathy; however, hematologist should maintain a high level of suspicion of GD in patients with MM that present with cytopenias not explained by the degree of bone marrow plasmacytosis, hepatosplenomegaly, and the presence of bone disease. Given its rarity, it is difficult to accurately predict the risk of development of MM in patients with GD; however, biannual measurement of serum free light chains, protein electrophoresis, and immunofixation is recommended [8].
Initiation of treatment with ERT in patients with GD is tailored to the individual patient and is aimed at improvement of symptoms, prevention of irreversible complications, and improvement in overall health and quality of life. Although it remains unclear whether the persistent pain suffered by the patient presented in this case is secondary to GD, initiation of ERT may lead to an improvement in quality of life as well as prevention of potential irreversible complications [8]. Although ERT may result in an improvement in polyclonal gammopathies, its effect on the progression of MGUS to active MM remains uncertain [15]. In otherwise stable patients on ERT who develop progression of cytopenias, worsening splenomegaly, or back pain, further workup to rule out the development or progression of a monoclonal gammopathy should be performed [8,15]. In patients with concurrent GD and MM who have severe cytopenias, ERT may result in their improvement and allow for the administration of anti-myeloma therapy. At this point, however, the current paucity of data makes it challenging to determine the effect of ERT on antimyeloma treatment response or the risk of relapse [8]. We echo the call made by Weinreb et al. [14] for all hematologists to be familiar with the clinical presentation and diagnosis of GD and its association with monoclonal gammopathies, as well as to participate in international and national GD registries to attempt to elucidate these unanswered questions [10].
Authors’ contributions JM wrote the manuscript. AC reviewed the histology, provided the figure and revised the manuscript. UG designed and revised the manuscript. All authors read and approved the final manuscript.
Declaration of Competing Interest The authors declare no conflicts of interest.
Please cite this article as: J. Monge, A. Chadburn and U. Gergis, Synchronous multiple myeloma and Gaucher disease, Hematol Oncol Stem Cell Ther, https://doi.org/10.1016/j.hemonc.2019.07.001
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Please cite this article as: J. Monge, A. Chadburn and U. Gergis, Synchronous multiple myeloma and Gaucher disease, Hematol Oncol Stem Cell Ther, https://doi.org/10.1016/j.hemonc.2019.07.001
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