An Unusual Cause of Altered Mental Status in Multiple Myeloma: An Extraosseous Manifestation Veeravich Jaruvongvanich MD; Ittikorn Spanuchart MD; Pichaya O-charoen MD; Christian Kitamura MD; Lauren Sumida MD; and Marina Roytman MD Abstract
Multiple myeloma typically presents as lytic bony lesions, hypercalcemia, anemia, and renal failure. Extraosseous manifestations are rare. We report on a patient who was recently diagnosed with multiple myeloma and completed the first cycle of bortezomib, dexamethasone, and palliative radiation therapy with good response. Two weeks after discharge, she became confused and was re-admitted. Despite treatment with lactulose and rifaximin, altered mental status worsened. Computer tomographic scan of abdomen showed hepatomegaly and numerous ill-defined small hyperdense nodules scattered throughout the liver. Liver biopsy demonstrated aggregation of plasma cell myeloma. Magnetic resonance imaging of brain revealed dural thickening. Patient’s altered mental status was likely from leptomeningeal myelomatosis and hyperammonemic encephalopathy. Although extraosseous manifestations in multiple myeloma including liver and leptomeningeal involvement are rare, its incidence has increased. This condition portends a poor prognosis. The non-specific manifestations of extraosseous myeloma can be confused with complications of multiple sclerosis and lead to incorrect management, thus clinicians should be aware of these pathologies and perform proper diagnostic tests including imaging and tissue pathology. The most effective treatment is unknown, however bortezomib and thalidomide show promise.
Keyword
Multiple myeloma, extraosseous manifestation, altered mental status
Background Multiple myeloma (MM) is a neoplastic proliferation of plasma cells that produces a monoclonal immunoglobulin. It accounts for 1% of all malignancies and 10% of all hematologic cancers.1 In 2000, the overall annual incidence rate, on the US population was 4.3 per 100,000.2 More than 20,000 new cases are diagnosed annually in the United States.3 The 5-year survival rate of MM has increased significantly to 39% between 1999 and 2006 from 26% between 1975 and 1977.3 Typical presentations of MM consist of weakness, fatigue, bone pain, and infections. Complications of MM include renal insufficiency, hematologic complications (anemia, bleeding disorder, bone marrow failure), and skeletal complications (pathologic fractures, spinal cord compression, and hypercalcemia). Treatment is not indicated in asymptomatic MM because early treatment shows no survival benefit. Treatment regimens in symptomatic MM generally depend on the patients’ age. Induction with high-dose chemotherapy and autologous stem cell transplantation is recommended for patients less than 65 years old. For older patients who are not candidates for stem cell transplantation, chemotherapy alone is recommended according to the National Comprehensive Cancer Network (NCCN) guidelines. Induction regimens should contain at least one novel agent such as bortezomib, thalidomide, or lenalido-
mide.4 Extraosseous (EO) manifestations of MM, which occur due to myelomatous involvement outside the skeleton system, are rare, associated with advanced stage of MM, and confer a poor prognosis.5 EO plasmacytomas are treated initially with radiation therapy followed by surgery if necessary. We report an unusual case of MM with rare EO manifestations involving the liver, leptomeninges, and hyperammonemic encephalopathy. Case Report A 39 year-old Samoan woman without a significant past medical history was hospitalized for one month due to progressive back pain and significant weight loss. She was found to have normocytic anemia, thrombocytopenia, hypercalcemia, and diffuse heterogeneous demineralization with compression fractures at the T1 and L2 vertebral levels on x-ray. Serum/ urine protein electrophoreses and serum/urine immunofixation electrophoreses were suggestive of IgG lambda monoclonal protein. The bone marrow aspiration and biopsy confirmed the lambda clonal plasma cell population, leading to the diagnosis of IgG lambda multiple myeloma. She completed the first cycle of bortezomib and dexamethasone as well as palliative radiation therapy with good response. Two weeks after discharge, she became progressively confused and was re-admitted. Her initial vital signs were as follows: blood pressure 74/52 mmHg, heart rate 125/min, respiratory rate 18/min, temperature 37.1°C, and oxygen saturation 98% on room air. A physical exam revealed scleral icterus, dry mucous membranes, and right upper quadrant abdominal tenderness. A neurological exam was only significant for asterixis without focal neurological deficit. Laboratory testing revealed acute kidney injury (blood urea nitrogen 64 mg/dL, creatinine 2.7 mg/dL) as well as evidence of tumor lysis syndrome (hyperkalemia, hyperphosphatemia, hyperuricemia, and lactic acidosis). New onset liver function test abnormalities included predominate direct hyperbilirubinemia [total bilirubin 5.6 mg/dL, direct bilirubin 2.7 mg/dL] and transaminitis [aspartate aminotransferase (AST) 110 IU/L, alanine aminotransferase (ALT) 138
HAWAI‘I JOURNAL OF MEDICINE & PUBLIC HEALTH, APRIL 2016, VOL 75, NO 4 109
List of Abbreviations: CNS: central nervous system CSF: cerebrospinal fluid CT: computer tomography EO: extraosseous MRI: magnetic resonance imaging MM: multiple myeloma
IU/L]. New onset coagulopathy was noted as well. The ammonia level was 75 umol/L. Serum viscosity was normal. An abdomen ultrasound demonstrated hepatomegaly with normal gallbladder and without biliary ductal dilation. A computer tomographic (CT) scan of the abdomen demonstrated numerous ill-defined small hyperdense nodules scattered throughout the liver without evidence of cirrhosis (Figure 1). Subsequently, liver biopsy was performed, which revealed aggregation of plasma cell myeloma (Figure 2). Despite treatment with lactulose and rifaximin as well as normalization of calcium and renal function, her mental status worsened. Liver function following treatment had not significantly changed since initial admission (AST 118 IU/L, ALT 129 IU/L, total bilirubin 4.5 mg/dL, direct bilirubin 3.7 mg/dL), whereas ammonia level had increased to 98 umol/L. Magnetic resonance imaging (MRI) of the brain revealed diffuse dural thickening without stroke or hemorrhage (Figure 3). Lumbar puncture was not performed due to severe coagulopathy. Patient’s altered mental status was attributed to hyperammonemic encephalopathy induced by MM and leptomeningeal myelomatosis. She was treated with bortezomib and dexamethasone resulting in transient improvement in mental status. Nevertheless, the patient developed septic shock and type B lactic acidosis from severe MM. Despite broad treatment with intravenous vancomycin, cefepime, and metronidazole, her condition progressed to multisystem organ failure. She required intensive care and was dependent on mechanical ventilation, vasopressor support, and continuous renal replacement therapy. Later, the blood culture and sputum culture showed pan-sensitive Pseudomonas aeruginosa. A second cycle of chemotherapy was attempted to combat the progression of disease, but she ultimately passed away despite maximal medical management.
Discussion MM is a malignant monoclonal proliferation of plasma cells that typically involves bone marrow. Despite the rarity of EO manifestations, Varettoni, et al,5 reported that the incidence of EO involvement has increased in the past decade likely due to the availability of increased sensitivity with imaging techniques and the prolongation of patients’ survival. Incidence of EO involvement is reported to be 13%, consisting of 7% at diagnosis and 6% during the course of the disease. Damaj, et al,6 reported the cumulative incidence of EO tumors as 4.6%, with a median patient age of 61 years. Pleura, soft tissues, and lymph nodes were the most common sites. Occurrence of EO myeloma is associated with less favorable prognosis, especially in patients who have extramedullary tumors at initial diagnosis of MM, with a median survival time of 12 months.6 Our patient’s survival time was less than 2 months from initial presentation possibly due to presence of EO at initial diagnosis of MM and involvement of two separate sites (liver and CNS). Abdominal involvement in MM is not common; when it occurs, MM can be found in the liver, pancreas, mesentery, adrenal glands, and retroperitoneum. The incidence of liver involvement with MM was around 30% in one autopsy study.7 Diffuse plasma cell infiltration with hepatomegaly was the most common pattern of hepatic involvement. Nodular lesions are much less common.8 Patients may be asymptomatic or present with jaundice, ascites or liver failure. However, liver dysfunction in MM patients results not only from MM itself, but also from amyloidosis or lymphocytic infiltration.9 Thus, it is crucial to perform needle biopsy for pathological confirmation. The most common CT finding is hepatomegaly. Focal hepatic lesions are typically found as low-attenuation lesions with minimal contrast
Figure 1. CT abdomen: Hepatomegaly and hepatic steatosis and numerous ill-defined small hyperdense nodules scattered throughout the liver.
HAWAI‘I JOURNAL OF MEDICINE & PUBLIC HEALTH, APRIL 2016, VOL 75, NO 4 110
Figure 2. Liver biopsy showed aggregation of atypical mononuclear cells with eccentric, round to oval nuclei [Left]. Atypical cells are positive for CD138 [Middle] and CD56 with lambda [Right].
Figure 3. MRI brain: Mild dural thickening over the convexity bilaterally (arrow). enhancement.10 Our patient’s CT scan showed ill-defined small hyperdense nodules scattered throughout the liver, which was consistent with the characteristics of focal hepatic myeloma and was confirmed by liver biopsy. Central nervous system (CNS) complications occur in 1% of all MM patients and intracranial myeloma occurs in less than 1% of all intracranial tumors. Median interval from the diagnosis of MM to detection of CNS myeloma is 6-18 months.11 Despite its rarity, CNS myeloma might be an initial presentation as observed in our patient. CNS myeloma can occur in many forms including localized intraparenchymal or dural-based lesions and CNS myelomatosis involving leptomeninges and cranial nerves.12,13 Intracranial involvement results from direct spreading of extramedullary tumors from contiguous bone lesions in the cranial vault, skull base, and paranasal sinuses to the dura
mater by breaching through the inner table of the skull and fibrous layer. It is also infrequently spread by the hematogenous route, with parenchyamal infiltration from CNS myelomatosis and dural-based lesions.11,14 Clinical presentations are nonspecific, and may include paraparesis, symptoms of increased intracranial pressure, cranial nerve palsies, convulsions and confusion.15 When neurologic problems cannot be explained by other complications including hypercalcemia, hyperviscosity, uremia, and drug toxicity, clinicians should perform imaging studies. MRI is the most sensitive test for detecting leptomeningeal disease, cranial nerve infiltration, and intracranial involvement.16 MRI of leptomeningeal MM may show focal, multifocal or diffuse patterns, which lack specificity, as they are difficult to differentiate from metastasis, lymphoma, meningioma, dural sarcoma, plasma cell granuloma, infectious meningitis, or leptomeningeal carcinomatosis. Other diagnostic options include surgical biopsy and cerebrospinal fluid (CSF) examination, which remain the most definitive tests for diagnosing leptomeningeal MM. However in clinical practice, most patients do not routinely undergo surgery and CSF examination. The diagnosis is typically based on radiological findings with concurrent clinical manifestations of MM.17 The survival of patients with MM ranges from several months to greater than 10 years. The survival of patients with intracranial MM has been reported up to 96 months after diagnosis, whereas the leptomeningeal myelomatosis had poorer prognosis despite aggressive treatment.11,14,15 Treatment with novel agents including thalidomide and bortezomib seem to increase overall survival and progression-free survival compared to older agents (eg, alkylating agents, steroids). This improvement may be explained by the increase in production of cytokines against angiogenesis by these drugs.18-20 In a large retrospective study involving 50 patients with extramedullary intracranial MM, bortezomib showed promising results compared to older agents with overall survival of 25 months versus 8 months,
HAWAI‘I JOURNAL OF MEDICINE & PUBLIC HEALTH, APRIL 2016, VOL 75, NO 4 111
respectively.19 The common side effects of bortezomib include nausea, vomiting, diarrhea, constipation, skin rash, bone marrow suppression and peripheral neuropathy. Our patient received bortezomib. However she did not respond to it, likely due to advanced multifocal disease. In conclusion, EO manifestations of MM are rare and their non-specific manifestations can be confused with other complications of MM and lead to incorrect management. Thus clinicians should be aware of these pathologies and perform proper diagnostic tests including imaging and tissue pathology. The most effective treatment is unknown, however, newer agents including bortezomib and thalidomide have shown promise. Current treatment strategies of EO MM may be mainly indicated for symptomatic relief and improved quality of life, as the prognosis remains poor despite aggressive treatment. A better understanding of the underlying biology is necessary to identify patients at risk and provide appropriate management to improve prognosis. Conflict of Interest None of the authors identify a conflict of interest. Authors’ Affiliations: - Department of Internal Medicine, John A. Burns School of Medicine, University of Hawai‘i, Honolulu, HI (VJ, IS, PO, CK, MR) - Department of Pathology, John A. Burns School of Medicine, University of Hawai‘i, Honolulu, HI (LS) Correspondence to: Veeravich Jaruvongvanich MD; Department of Internal Medicine, John A. Burns School of Medicine, University of Hawai‘i; 1301 Punchbowl St, Honolulu, HI 96813; Ph: (808) 542-1939; E-mail: [email protected]
References
1. Kyle RA, Rajkumar SV. Multiple myeloma. Blood. Mar 15 2008;111(6):2962-2972. 2. Kyle RA, Therneau TM, Rajkumar SV, Larson DR, Plevak MF, Melton LJ, 3rd. Incidence of multiple myeloma in Olmsted County, Minnesota: Trend over 6 decades. Cancer. Dec 1 2004;101(11):2667-2674. 3. Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA: A Cancer Journal For Clinicians. Jul-Aug 2011;61(4):212-236. 4. Anderson KC, Alsina M, Bensinger W, et al. Multiple myeloma. Journal of the National Comprehensive Cancer Network : JNCCN. Oct 2011;9(10):1146-1183. 5. Varettoni M, Corso A, Pica G, Mangiacavalli S, Pascutto C, Lazzarino M. Incidence, presenting features and outcome of extramedullary disease in multiple myeloma: a longitudinal study on 1003 consecutive patients. Annals of Oncology : Official Journal of The European Society for Medical Oncology / ESMO. Feb 2010;21(2):325-330. 6. Damaj G, Mohty M, Vey N, et al. Features of extramedullary and extraosseous multiple myeloma: a report of 19 patients from a single center. European Journal of Haematology. Dec 2004;73(6):402-406. 7. Oshima K, Kanda Y, Nannya Y, et al. Clinical and pathologic findings in 52 consecutively autopsied cases with multiple myeloma. American Journal of Hematology. May 2001;67(1):1-5. 8. Philips S, Menias C, Vikram R, Sunnapwar A, Prasad SR. Abdominal manifestations of extraosseous myeloma: cross-sectional imaging spectrum. Journal of Computer Assisted Tomography. Mar-Apr 2012;36(2):207-212. 9. Thomas FB, Clausen KP, Greenberger NJ. Liver disease in multiple myeloma. Archives of Internal Medicine. Aug 1973;132(2):195-202. 10. Sedlic A, Chingkoe C, Lee KW, Duddalwar VA, Chang SD. Abdominal extraosseous lesions of multiple myeloma: imaging findings. Canadian Association of Radiologists Journal = Journal l’Association Canadienne Des Radiologistes. Feb 2014;65(1):2-8. 11. Shpilberg KA, Esses SJ, Fowkes ME, Chari A, Sacher M, Naidich TP. Imaging of extraosseous intracranial and intraspinal multiple myeloma, including central nervous system involvement. Clinical Imaging. Mar-Apr 2015;39(2):213-219. 12. Nieuwenhuizen L, Biesma DH. Central nervous system myelomatosis: review of the literature. European Journal of Haematology. Jan 2008;80(1):1-9. 13. Moran CC, Anderson CC, Caldemeyer KS, Smith RR. Meningeal myelomatosis: CT and MR appearances. AJNR. American Journal of Neuroradiology. Aug 1995;16(7):1501-1503. 14. Schluterman KO, Fassas AB, Van Hemert RL, Harik SI. Multiple myeloma invasion of the central nervous system. Archives of Neurology. Sep 2004;61(9):1423-1429. 15. Blade J, Rosinol L. Complications of multiple myeloma. Hematology/Oncology Clinics of North America. Dec 2007;21(6):1231-1246, xi. 16. Quint DJ, Levy R, Krauss JC. MR of myelomatous meningitis. AJNR. American Journal of Neuroradiology. Jun-Jul 1995;16(6):1316-1317. 17. Cerase A, Tarantino A, Gozzetti A, et al. Intracranial involvement in plasmacytomas and multiple myeloma: a pictorial essay. Neuroradiology. Aug 2008;50(8):665-674. 18. Gozzetti A, Cerase A, Tarantino A, et al. Multiple myeloma involving the cavernous sinus: a report of 3 cases and response to bortezomib. Clinical Lymphoma & Myeloma. Mar 2007;7(5):376-378. 19. Gozzetti A, Cerase A, Lotti F, et al. Extramedullary intracranial localization of multiple myeloma and treatment with novel agents: a retrospective survey of 50 patients. Cancer. Mar 15 2012;118(6):1574-1584. 20. Synhaeve NE, van der Heul C, Tijssen CC. Intracranial mass of multiple myeloma with good response to chemotherapy. BMJ Case Reports. 2012;2012.
HAWAI‘I JOURNAL OF MEDICINE & PUBLIC HEALTH, APRIL 2016, VOL 75, NO 4 112
Multiple myeloma typically presents as lytic bony lesions, hypercalcemia, anemia, and renal failure. Extraosseous manifestations are rare. We report on a patient who was recently diagnosed with multiple myeloma and completed the first cycle of bortezomib, dexamethasone, and palliative radiation therapy with good response. Two weeks after discharge, she became confused and was re-admitted. Despite treatment with lactulose and rifaximin, altered mental status worsened. Computer tomographic scan of abdomen showed hepatomegaly and numerous ill-defined small hyperdense nodules scattered throughout the liver. Liver biopsy demonstrated aggregation of plasma cell myeloma. Magnetic resonance imaging of brain revealed dural thickening. Patient’s altered mental status was likely from leptomeningeal myelomatosis and hyperammonemic encephalopathy. Although extraosseous manifestations in multiple myeloma including liver and leptomeningeal involvement are rare, its incidence has increased. This condition portends a poor prognosis. The non-specific manifestations of extraosseous myeloma can be confused with complications of multiple sclerosis and lead to incorrect management, thus clinicians should be aware of these pathologies and perform proper diagnostic tests including imaging and tissue pathology. The most effective treatment is unknown, however bortezomib and thalidomide show promise.
Keyword
Multiple myeloma, extraosseous manifestation, altered mental status
Background Multiple myeloma (MM) is a neoplastic proliferation of plasma cells that produces a monoclonal immunoglobulin. It accounts for 1% of all malignancies and 10% of all hematologic cancers.1 In 2000, the overall annual incidence rate, on the US population was 4.3 per 100,000.2 More than 20,000 new cases are diagnosed annually in the United States.3 The 5-year survival rate of MM has increased significantly to 39% between 1999 and 2006 from 26% between 1975 and 1977.3 Typical presentations of MM consist of weakness, fatigue, bone pain, and infections. Complications of MM include renal insufficiency, hematologic complications (anemia, bleeding disorder, bone marrow failure), and skeletal complications (pathologic fractures, spinal cord compression, and hypercalcemia). Treatment is not indicated in asymptomatic MM because early treatment shows no survival benefit. Treatment regimens in symptomatic MM generally depend on the patients’ age. Induction with high-dose chemotherapy and autologous stem cell transplantation is recommended for patients less than 65 years old. For older patients who are not candidates for stem cell transplantation, chemotherapy alone is recommended according to the National Comprehensive Cancer Network (NCCN) guidelines. Induction regimens should contain at least one novel agent such as bortezomib, thalidomide, or lenalido-
mide.4 Extraosseous (EO) manifestations of MM, which occur due to myelomatous involvement outside the skeleton system, are rare, associated with advanced stage of MM, and confer a poor prognosis.5 EO plasmacytomas are treated initially with radiation therapy followed by surgery if necessary. We report an unusual case of MM with rare EO manifestations involving the liver, leptomeninges, and hyperammonemic encephalopathy. Case Report A 39 year-old Samoan woman without a significant past medical history was hospitalized for one month due to progressive back pain and significant weight loss. She was found to have normocytic anemia, thrombocytopenia, hypercalcemia, and diffuse heterogeneous demineralization with compression fractures at the T1 and L2 vertebral levels on x-ray. Serum/ urine protein electrophoreses and serum/urine immunofixation electrophoreses were suggestive of IgG lambda monoclonal protein. The bone marrow aspiration and biopsy confirmed the lambda clonal plasma cell population, leading to the diagnosis of IgG lambda multiple myeloma. She completed the first cycle of bortezomib and dexamethasone as well as palliative radiation therapy with good response. Two weeks after discharge, she became progressively confused and was re-admitted. Her initial vital signs were as follows: blood pressure 74/52 mmHg, heart rate 125/min, respiratory rate 18/min, temperature 37.1°C, and oxygen saturation 98% on room air. A physical exam revealed scleral icterus, dry mucous membranes, and right upper quadrant abdominal tenderness. A neurological exam was only significant for asterixis without focal neurological deficit. Laboratory testing revealed acute kidney injury (blood urea nitrogen 64 mg/dL, creatinine 2.7 mg/dL) as well as evidence of tumor lysis syndrome (hyperkalemia, hyperphosphatemia, hyperuricemia, and lactic acidosis). New onset liver function test abnormalities included predominate direct hyperbilirubinemia [total bilirubin 5.6 mg/dL, direct bilirubin 2.7 mg/dL] and transaminitis [aspartate aminotransferase (AST) 110 IU/L, alanine aminotransferase (ALT) 138
HAWAI‘I JOURNAL OF MEDICINE & PUBLIC HEALTH, APRIL 2016, VOL 75, NO 4 109
List of Abbreviations: CNS: central nervous system CSF: cerebrospinal fluid CT: computer tomography EO: extraosseous MRI: magnetic resonance imaging MM: multiple myeloma
IU/L]. New onset coagulopathy was noted as well. The ammonia level was 75 umol/L. Serum viscosity was normal. An abdomen ultrasound demonstrated hepatomegaly with normal gallbladder and without biliary ductal dilation. A computer tomographic (CT) scan of the abdomen demonstrated numerous ill-defined small hyperdense nodules scattered throughout the liver without evidence of cirrhosis (Figure 1). Subsequently, liver biopsy was performed, which revealed aggregation of plasma cell myeloma (Figure 2). Despite treatment with lactulose and rifaximin as well as normalization of calcium and renal function, her mental status worsened. Liver function following treatment had not significantly changed since initial admission (AST 118 IU/L, ALT 129 IU/L, total bilirubin 4.5 mg/dL, direct bilirubin 3.7 mg/dL), whereas ammonia level had increased to 98 umol/L. Magnetic resonance imaging (MRI) of the brain revealed diffuse dural thickening without stroke or hemorrhage (Figure 3). Lumbar puncture was not performed due to severe coagulopathy. Patient’s altered mental status was attributed to hyperammonemic encephalopathy induced by MM and leptomeningeal myelomatosis. She was treated with bortezomib and dexamethasone resulting in transient improvement in mental status. Nevertheless, the patient developed septic shock and type B lactic acidosis from severe MM. Despite broad treatment with intravenous vancomycin, cefepime, and metronidazole, her condition progressed to multisystem organ failure. She required intensive care and was dependent on mechanical ventilation, vasopressor support, and continuous renal replacement therapy. Later, the blood culture and sputum culture showed pan-sensitive Pseudomonas aeruginosa. A second cycle of chemotherapy was attempted to combat the progression of disease, but she ultimately passed away despite maximal medical management.
Discussion MM is a malignant monoclonal proliferation of plasma cells that typically involves bone marrow. Despite the rarity of EO manifestations, Varettoni, et al,5 reported that the incidence of EO involvement has increased in the past decade likely due to the availability of increased sensitivity with imaging techniques and the prolongation of patients’ survival. Incidence of EO involvement is reported to be 13%, consisting of 7% at diagnosis and 6% during the course of the disease. Damaj, et al,6 reported the cumulative incidence of EO tumors as 4.6%, with a median patient age of 61 years. Pleura, soft tissues, and lymph nodes were the most common sites. Occurrence of EO myeloma is associated with less favorable prognosis, especially in patients who have extramedullary tumors at initial diagnosis of MM, with a median survival time of 12 months.6 Our patient’s survival time was less than 2 months from initial presentation possibly due to presence of EO at initial diagnosis of MM and involvement of two separate sites (liver and CNS). Abdominal involvement in MM is not common; when it occurs, MM can be found in the liver, pancreas, mesentery, adrenal glands, and retroperitoneum. The incidence of liver involvement with MM was around 30% in one autopsy study.7 Diffuse plasma cell infiltration with hepatomegaly was the most common pattern of hepatic involvement. Nodular lesions are much less common.8 Patients may be asymptomatic or present with jaundice, ascites or liver failure. However, liver dysfunction in MM patients results not only from MM itself, but also from amyloidosis or lymphocytic infiltration.9 Thus, it is crucial to perform needle biopsy for pathological confirmation. The most common CT finding is hepatomegaly. Focal hepatic lesions are typically found as low-attenuation lesions with minimal contrast
Figure 1. CT abdomen: Hepatomegaly and hepatic steatosis and numerous ill-defined small hyperdense nodules scattered throughout the liver.
HAWAI‘I JOURNAL OF MEDICINE & PUBLIC HEALTH, APRIL 2016, VOL 75, NO 4 110
Figure 2. Liver biopsy showed aggregation of atypical mononuclear cells with eccentric, round to oval nuclei [Left]. Atypical cells are positive for CD138 [Middle] and CD56 with lambda [Right].
Figure 3. MRI brain: Mild dural thickening over the convexity bilaterally (arrow). enhancement.10 Our patient’s CT scan showed ill-defined small hyperdense nodules scattered throughout the liver, which was consistent with the characteristics of focal hepatic myeloma and was confirmed by liver biopsy. Central nervous system (CNS) complications occur in 1% of all MM patients and intracranial myeloma occurs in less than 1% of all intracranial tumors. Median interval from the diagnosis of MM to detection of CNS myeloma is 6-18 months.11 Despite its rarity, CNS myeloma might be an initial presentation as observed in our patient. CNS myeloma can occur in many forms including localized intraparenchymal or dural-based lesions and CNS myelomatosis involving leptomeninges and cranial nerves.12,13 Intracranial involvement results from direct spreading of extramedullary tumors from contiguous bone lesions in the cranial vault, skull base, and paranasal sinuses to the dura
mater by breaching through the inner table of the skull and fibrous layer. It is also infrequently spread by the hematogenous route, with parenchyamal infiltration from CNS myelomatosis and dural-based lesions.11,14 Clinical presentations are nonspecific, and may include paraparesis, symptoms of increased intracranial pressure, cranial nerve palsies, convulsions and confusion.15 When neurologic problems cannot be explained by other complications including hypercalcemia, hyperviscosity, uremia, and drug toxicity, clinicians should perform imaging studies. MRI is the most sensitive test for detecting leptomeningeal disease, cranial nerve infiltration, and intracranial involvement.16 MRI of leptomeningeal MM may show focal, multifocal or diffuse patterns, which lack specificity, as they are difficult to differentiate from metastasis, lymphoma, meningioma, dural sarcoma, plasma cell granuloma, infectious meningitis, or leptomeningeal carcinomatosis. Other diagnostic options include surgical biopsy and cerebrospinal fluid (CSF) examination, which remain the most definitive tests for diagnosing leptomeningeal MM. However in clinical practice, most patients do not routinely undergo surgery and CSF examination. The diagnosis is typically based on radiological findings with concurrent clinical manifestations of MM.17 The survival of patients with MM ranges from several months to greater than 10 years. The survival of patients with intracranial MM has been reported up to 96 months after diagnosis, whereas the leptomeningeal myelomatosis had poorer prognosis despite aggressive treatment.11,14,15 Treatment with novel agents including thalidomide and bortezomib seem to increase overall survival and progression-free survival compared to older agents (eg, alkylating agents, steroids). This improvement may be explained by the increase in production of cytokines against angiogenesis by these drugs.18-20 In a large retrospective study involving 50 patients with extramedullary intracranial MM, bortezomib showed promising results compared to older agents with overall survival of 25 months versus 8 months,
HAWAI‘I JOURNAL OF MEDICINE & PUBLIC HEALTH, APRIL 2016, VOL 75, NO 4 111
respectively.19 The common side effects of bortezomib include nausea, vomiting, diarrhea, constipation, skin rash, bone marrow suppression and peripheral neuropathy. Our patient received bortezomib. However she did not respond to it, likely due to advanced multifocal disease. In conclusion, EO manifestations of MM are rare and their non-specific manifestations can be confused with other complications of MM and lead to incorrect management. Thus clinicians should be aware of these pathologies and perform proper diagnostic tests including imaging and tissue pathology. The most effective treatment is unknown, however, newer agents including bortezomib and thalidomide have shown promise. Current treatment strategies of EO MM may be mainly indicated for symptomatic relief and improved quality of life, as the prognosis remains poor despite aggressive treatment. A better understanding of the underlying biology is necessary to identify patients at risk and provide appropriate management to improve prognosis. Conflict of Interest None of the authors identify a conflict of interest. Authors’ Affiliations: - Department of Internal Medicine, John A. Burns School of Medicine, University of Hawai‘i, Honolulu, HI (VJ, IS, PO, CK, MR) - Department of Pathology, John A. Burns School of Medicine, University of Hawai‘i, Honolulu, HI (LS) Correspondence to: Veeravich Jaruvongvanich MD; Department of Internal Medicine, John A. Burns School of Medicine, University of Hawai‘i; 1301 Punchbowl St, Honolulu, HI 96813; Ph: (808) 542-1939; E-mail: [email protected]
References
1. Kyle RA, Rajkumar SV. Multiple myeloma. Blood. Mar 15 2008;111(6):2962-2972. 2. Kyle RA, Therneau TM, Rajkumar SV, Larson DR, Plevak MF, Melton LJ, 3rd. Incidence of multiple myeloma in Olmsted County, Minnesota: Trend over 6 decades. Cancer. Dec 1 2004;101(11):2667-2674. 3. Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA: A Cancer Journal For Clinicians. Jul-Aug 2011;61(4):212-236. 4. Anderson KC, Alsina M, Bensinger W, et al. Multiple myeloma. Journal of the National Comprehensive Cancer Network : JNCCN. Oct 2011;9(10):1146-1183. 5. Varettoni M, Corso A, Pica G, Mangiacavalli S, Pascutto C, Lazzarino M. Incidence, presenting features and outcome of extramedullary disease in multiple myeloma: a longitudinal study on 1003 consecutive patients. Annals of Oncology : Official Journal of The European Society for Medical Oncology / ESMO. Feb 2010;21(2):325-330. 6. Damaj G, Mohty M, Vey N, et al. Features of extramedullary and extraosseous multiple myeloma: a report of 19 patients from a single center. European Journal of Haematology. Dec 2004;73(6):402-406. 7. Oshima K, Kanda Y, Nannya Y, et al. Clinical and pathologic findings in 52 consecutively autopsied cases with multiple myeloma. American Journal of Hematology. May 2001;67(1):1-5. 8. Philips S, Menias C, Vikram R, Sunnapwar A, Prasad SR. Abdominal manifestations of extraosseous myeloma: cross-sectional imaging spectrum. Journal of Computer Assisted Tomography. Mar-Apr 2012;36(2):207-212. 9. Thomas FB, Clausen KP, Greenberger NJ. Liver disease in multiple myeloma. Archives of Internal Medicine. Aug 1973;132(2):195-202. 10. Sedlic A, Chingkoe C, Lee KW, Duddalwar VA, Chang SD. Abdominal extraosseous lesions of multiple myeloma: imaging findings. Canadian Association of Radiologists Journal = Journal l’Association Canadienne Des Radiologistes. Feb 2014;65(1):2-8. 11. Shpilberg KA, Esses SJ, Fowkes ME, Chari A, Sacher M, Naidich TP. Imaging of extraosseous intracranial and intraspinal multiple myeloma, including central nervous system involvement. Clinical Imaging. Mar-Apr 2015;39(2):213-219. 12. Nieuwenhuizen L, Biesma DH. Central nervous system myelomatosis: review of the literature. European Journal of Haematology. Jan 2008;80(1):1-9. 13. Moran CC, Anderson CC, Caldemeyer KS, Smith RR. Meningeal myelomatosis: CT and MR appearances. AJNR. American Journal of Neuroradiology. Aug 1995;16(7):1501-1503. 14. Schluterman KO, Fassas AB, Van Hemert RL, Harik SI. Multiple myeloma invasion of the central nervous system. Archives of Neurology. Sep 2004;61(9):1423-1429. 15. Blade J, Rosinol L. Complications of multiple myeloma. Hematology/Oncology Clinics of North America. Dec 2007;21(6):1231-1246, xi. 16. Quint DJ, Levy R, Krauss JC. MR of myelomatous meningitis. AJNR. American Journal of Neuroradiology. Jun-Jul 1995;16(6):1316-1317. 17. Cerase A, Tarantino A, Gozzetti A, et al. Intracranial involvement in plasmacytomas and multiple myeloma: a pictorial essay. Neuroradiology. Aug 2008;50(8):665-674. 18. Gozzetti A, Cerase A, Tarantino A, et al. Multiple myeloma involving the cavernous sinus: a report of 3 cases and response to bortezomib. Clinical Lymphoma & Myeloma. Mar 2007;7(5):376-378. 19. Gozzetti A, Cerase A, Lotti F, et al. Extramedullary intracranial localization of multiple myeloma and treatment with novel agents: a retrospective survey of 50 patients. Cancer. Mar 15 2012;118(6):1574-1584. 20. Synhaeve NE, van der Heul C, Tijssen CC. Intracranial mass of multiple myeloma with good response to chemotherapy. BMJ Case Reports. 2012;2012.
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