The presence of amyloid in abdominal and oral mucosal tissues in patients initially diagnosed with multiple myeloma: a pilot study Eric T. Stoopler, DMD,a Dan T. Vogl, MD,b Faizan Alawi, DDS,c Martin S. Greenberg, DDS,d Thomas P. Sollecito, DMD,d German Salazar, DMD,e and Edward A. Stadtmauer, MD,f Philadelphia, PA UNIVERSITY OF PENNSYLVANIA SCHOOL OF DENTAL MEDICINE AND UNIVERSITY OF PENNSYLVANIA SCHOOL OF MEDICINE
Objectives. The aims of this study were to (1) determine the feasibility of tandem assessment of the presence of amyloid in subcutaneous abdominal fat by fine-needle aspiration and oral mucosal tissue biopsy in patients initially diagnosed with multiple myeloma (MM) and (2) determine the optimal site for detection of amyloid in the oral cavity (tongue compared with labial minor salivary glands) in the same cohort of patients. Study design. A prospective, cross-sectional study was performed on patients with newly diagnosed MM. Subjects completed an abdominal fat pad aspirate and biopsies of both the tongue and labial minor salivary glands (LMSGs). All specimens were analyzed for presence of amyloid via standard techniques. Results. Eleven subjects completed the protocol. Amyloid was not detected in any abdominal fat pad specimens. Amyloid was not detected in any tongue specimens; however, 2 subjects demonstrated amyloid deposition in LMSGs. Neither of these subjects demonstrated evidence of systemic amyloidosis or recurrence of MM at least 3 years after completing the study protocol. Conclusions. The results of this study suggest that the labial minor salivary glands may be the optimal site to detect amyloid in patients with newly diagnosed MM. Additional studies are warranted to determine if amyloid in the LMSGs represents a high-risk prognostic factor for MM. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2011;111:326-332)
Multiple myeloma (MM) is characterized by the proliferation of malignant plasma cells derived from a single clone in the bone marrow and accounts for 13% of all hematologic cancers.1,2 The frequency of MM in the US population is twice as high among African Americans
Portions of this research were presented at the 62nd Annual Meeting, American Academy of Oral Medicine, Scottsdale, AZ, 2008, and published as an abstract in Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;106:e7-8. Supported by a Senior Research Grant from the Multiple Myeloma Research Foundation (MMRF). a Assistant Professor, Department of Oral Medicine, University of Pennsylvania School of Dental Medicine. b Assistant Professor, Department of Medicine, University of Pennsylvania School of Medicine. c Assistant Professor, Department of Pathology, University of Pennsylvania School of Dental Medicine. d Professor, Department of Oral Medicine, University of Pennsylvania School of Dental Medicine. e Assistant Professor, Department of Graduate Education, School of Dental Medicine, University of Puerto Rico, San Juan, PR. f Professor, Department of Medicine, University of Pennsylvania School of Medicine. Received for publication Sep 27, 2010; returned for revision Oct 19, 2010; accepted for publication Oct 27, 2010. 1079-2104/$ - see front matter © 2011 Mosby, Inc. All rights reserved. doi:10.1016/j.tripleo.2010.10.028
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compared with whites with the median age of diagnosis in the early sixth decade.1-4 Common presenting clinical features of MM are bone pain and pathologic fracture secondary to lytic lesions, renal failure, fatigue secondary to anemia, and recurrent infections.5 Treatment of MM primarily consists of corticosteroid administration, high-dose chemotherapy, and autologous stem cell transplantation (ASCT).6 Newer immunomodulatory drugs, such as thalidomide, lenalidomide, and bortezomib, have played a critical role in successfully treating both newly diagnosed and relapsed MM.7 The use of high-potency intravenous bisphosphonates, such as pamidronate and zolendronate, has provided considerable symptomatic relief of bone pain to patients with MM; however, many reports have implicated these medications in causing osteonecrosis of the jaw.8-15 Many factors are considered when determining appropriate therapy for MM, including patient age, presence of comorbidities, presence of disease-related complications, eligibility for ASCT, patient choice, and disease-related factors, such as presence of cytogenetic abnormalities.16-18 The median survival of patients with MM averages 3 to 5 years dependent on type of clinical treatment and response to therapy; however, overall survival duration ranges from less than 1 year to more than 10 years owing to disease heterogeneity.5 One potential source of variability in out-
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comes is comorbidity owing to the presence of occult amyloid deposition. Amyloid is an otherwise normal protein that forms insoluble fibrils in certain disease states.19 It consists of rigid, nonbranching fibrils that range in width from 7.0 to 12.0 nm, with each fibril composed of -pleated sheets that twist, giving amyloid its characteristic cross- spine evident on x-ray diffraction.19 Amyloid precursor proteins vary, but the most common is the monoclonal immunoglobulin light chain that causes amyloid light chain (AL) amyloidosis; this is related to an underlying monoclonal plasma cell proliferation, similar to that seen in MM. AL amyloidosis is a well-recognized complication of MM.20 Clinically, occult AL amyloid occurs in up to 38% of patients with MM,21 whereas 3% to 7% of patients with MM have overt organ dysfunction owing to deposition of AL amyloid.22 AL amyloidosis can result in damage to the kidneys, heart, gastrointestinal tract, liver, spleen, and peripheral and autonomic nervous system.23 Life-threatening illnesses caused by amyloid deposition include nephrotic syndrome, renal failure, cardiac failure, arrhythmias, hepatosplenomegaly, malabsorption, hemorrhage, and infarction.24 Search for amyloidosis is initiated on the basis of clinical suspicion; a tissue biopsy is used to establish a definitive diagnosis.25 The sampling of subcutaneous abdominal fat has been advocated for diagnosis of amyloid,26,27 with 85% of patients demonstrating amyloid deposition with this technique.28 Historically, other biopsy sites that have been reported to have a high predictive value for detection of amyloid include the kidney and the rectum.20,29-34 In the absence of clinical symptoms, oral tissues have been advocated for use in biopsy to detect amyloid deposition; however, the site of biopsy has been controversial. Oral biopsy sites that have demonstrated presence of amyloid are numerous, including the gingiva, palate, parotid gland, and buccal mucosa25,35-45; however, the tongue and labial minor salivary glands (LMSGs) have been consistently reported as the most common intraoral sites of amyloid deposition.46-52 The aims of this pilot study were to (1) determine the feasibility of tandem assessment of the presence of amyloid in subcutaneous abdominal fat by fine-needle aspiration and oral mucosal tissue biopsy in patients with newly diagnosed MM and (2) determine the optimal site for detection of amyloid in the oral cavity (tongue compared with LMSGs) in the same cohort of patients. MATERIALS AND METHODS Study population Patients with newly diagnosed MM (defined as ⬍6 months from the start of myeloma therapy and not yet received a peripheral stem cell transplant) who were not
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previously diagnosed with amyloidosis were eligible to participate in this study. Subjects with a previous diagnosis of amyloidosis before diagnosis of MM were excluded from the study. There were no inclusion/exclusion criteria based on age, gender, race, or ethnicity. Study design This was a prospective, cross-sectional study approved by the institutional review board (IRB) of the University of Pennsylvania and the Clinical Trials Scientific Review Monitoring Committee of the Abramson Cancer Center (ACC) of the University of Pennsylvania Health System. Subjects were identified and recruited, in accordance with the inclusion/exclusion criteria, from the ACC by several coinvestigators (E.A.S., D.T.V., G.S.). The protocol was described and if willing to participate, the subject was presented with an IRB approved Informed Consent Document and HIPAA Document, which were reviewed in detail and signed by the subject and investigator(s). The subject was referred to the Division of Oral Medicine for conduct of the protocol by a board certified specialist in oral medicine (E.T.S., M.S.G., T.P.S.). After reviewing the subject’s medical history and laboratory values, a clinical examination was completed and the subject underwent 2 biopsies of clinically normal-appearing tissue in the oral cavity under local anesthesia (2% lidocaine with 1:100,000 epinephrine). Specimen 1 was taken from the left lateral surface of the tongue, containing mucosal and muscle tissue. Specimen 2 was taken from the labial mucosa on the left side of the lower lip, containing at least 2 to 3 minor salivary glands. Both specimens were formalin fixed and sent to a board-certified oral and maxillofacial pathologist (F.A.) at the Hospital of the University of Pennsylvania (HUP), for histopathologic evaluation for amyloid. Analysis consisted of reviewing each specimen with both hematoxylin and eosin and Congo red stains. The specimens demonstrating amyloid displayed characteristic apple-green birefringence when viewed under polarized light. After the oral tissue biopsies were completed, the subject underwent a subcutaneous abdominal fat biopsy via fine-needle aspiration (FNA) in the dental operatory by the cytopathology service at HUP. This aspirate was analyzed for presence of amyloid via Congo red staining performed with proper controls. Upon the completion of the abdominal fat biopsy, the subject was dismissed and given an appointment to return to the Division of Oral Medicine in 1 week for follow-up evaluation. Subjects undergoing active treatment for MM were scheduled for follow-up with the treating oncologist (E.A.S., D.T.V.) as per their recommendations.
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Table I. Demographic and histologic characteristics of the study population Subject
Sex
Race
Age, y
Amyloid in abdominal fat
Amyloid in tongue
Amyloid in labial minor salivary glands
01 02 03 04 05 06 07 08 09 10 11 12 13
Male Male Male Male Female Male Male Male Male Male Female Female Female
African American African American White White White White White White African American White White White White
64 44 69 66 64 56 61 44 69 71 65 69 60
Not present Not present Not present Not present Not present Not present Withdrawn Not present Not present Not present Withdrawn Not present Not present
Not present Not present Not present Not present Not present Not present Withdrawn Not present Not present Not present Withdrawn Not present Not present
Not present Not present Not present Not present Present Not present Withdrawn Present Not present Not present Withdrawn Not present Not present
Statistical methods A 95% exact Clopper-Pearson confidence interval was computed for the prevalence of amyloid deposition in the abdominal fat, tongue, and LMSGs. To test equality of prevalences of amyloid deposition in oral tissue and abdominal fat, an exact McNemar test was used. RESULTS This pilot study enrolled 13 subjects during a 3-year period (2006 to 2008). Two subjects withdrew before initiating the protocol; therefore, analysis of biopsy specimens was completed on 11 patients (Table I). Subject demographics (of those who completed the protocol) are as follows: 8 males and 3 females, 8 whites and 3 African Americans, mean age 61.5 years (range of 44 to 71 years). All subjects who participated in the study were classified as Stage 1 MM according to the International Staging System. Fluorescence in situ hybridization and cytogenetic testing were not standard practice at our institution at the time of this study and were therefore not done. Systemic therapy for myeloma at the time of study biopsies was thalidomide/dexamethasone in 5 patients, lenalidomide/dexamethasone in 2 patients, bortezomib/dexamethasone in 1 patient, dexamethasone alone in 1 patient, and no prior systemic therapy in 2 patients; 3 patients had received local radiation. Amyloid was not detected in any abdominal fat specimens. In addition, amyloid was not observed in any tongue specimens from the cohort; however, 2 subjects (05 and 08) demonstrated amyloid deposition in the LMSGs only (Fig. 1, A-D). A further objective was to calculate a McNemar’s test of the null hypothesis that the prevalence of deposition was the same in both oral and abdominal tissues. Because all tests for amyloid deposition in the tongue and abdominal fat were negative, the McNemar statistic for this comparison was undefined. For the comparison of prev-
alences in LMSGs and abdominal fat, the McNemar test was not significant (P ⫽ .5). The 2 subjects positive for LMSG amyloid deposition had both received thalidomide and dexamethasone therapy before their oral biopsies. Both went on to receive further therapy with high-dose cyclophosphamide, peripheral blood hematopoietic stem cell collection, and then high-dose melphalan with ASCT. One of the 2 patients had evidence of myeloma progression approximately 1 year after ASCT and has required ongoing further therapy; the other patient has no evidence of disease recurrence. With more than 3 years of follow-up, neither has demonstrated any signs or symptoms of systemic amyloidosis. DISCUSSION Diagnosis, staging, and risk stratification for patients with newly diagnosed MM is continuously evolving. Currently, MM is diagnosed in accordance with the International Myeloma Working Group Criteria, with 3 major categories based on specific clinical, laboratory, and histopathologic findings: monoclonal gammopathy of unknown significance (MGUS), smoldering MM (SMM), and MM (active or symptomatic) (Table II).1,53,54 It is recommended that therapy should be initiated only for symptomatic disease.7,53,54 The Durie-Salmon staging system uses calcium and hemoglobin levels, presence of lytic bone lesions, and amounts of monoclonal protein to stage MM55 and was used primarily until 2005, when the International Staging System (ISS) was widely adapted (Table III).18,56 The ISS uses 2 markers, albumin and 2 microglobulin, to stage MM and provides useful information regarding biological characteristics of the disease and prognosis.18 The updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) Consensus Guidelines recommends that all MM patients undergo fluo-
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Fig. 1. A, Abdominal fat pad aspirate negative for amyloid (Congo red stain, ⫻63 magnification). B, LMSG biopsy specimen demonstrating amorphous and relatively acellular material adjacent to the salivary gland lobule (Hematoxylin and eosin stain, ⫻100 magnification). C, Congo red stain viewed under white light demonstrates amyloid (orange color) primarily adjacent to and focally within the salivary gland lobule (⫻100 magnification). D, Congo red stain viewed under polarized light confirms the presence of diffuse amyloid deposits (green material) within the salivary gland tissue (⫻100 magnification).
rescent in situ hybridization (FISH), metaphase cytogenetics, and when feasible, plasma cell labeling index (PCLI) for risk stratification as standard risk (75% of cases) versus high risk (25% of cases).7 FISH and cytogenetic abnormalities are generally associated with a more proliferative myeloma and increase likelihood of a poor treatment outcome.18 Presence of deletion 13 (del 13), t(4:14), t(14:16), del 17p, and hypodiploidy are associated with significantly shorter overall survival and duration of response.7,18,57 PCLI measures plasma cell proliferative rate; typically plasma cells have a low rate of proliferation with a PCLI index of less than 1%.7 Studies have shown the prognostic value of an elevated PCLI in MM58,59 and the mSMART Consensus Guidelines have established a PCLI of 3% or more to categorize high-risk MM patients.7 The use of these techniques has greatly affected clinical treatment algorithms for patients with MM based on their risk, specifically as it relates to selection and implementation of therapeutic agents as well as timing and number of ASCT procedures.7
A recent study has suggested AL amyloidosis associated with MM as an independent high-risk prognostic factor and presence of amyloid may confer a poor disease prognosis.60 This study evaluated 201 patients with MM for presence of AL amyloid via FNA sampling of periumbilical abdominal fat analyzed via Congo red stain. Sixty-eight patients (34%) demonstrated presence of AL amyloid and during long-term follow-up; 69% of these patients ultimately developed symptoms of systemic amyloidosis. The patients with MM associated AL amyloidosis in this study demonstrated higher frequency of positive disease markers (Bence Jones proteinuria, anemia, hypercalcemia, increased serum alkaline phosphatase, decreased serum albumin, increased serum lactate dehydrogenase [LDH] levels) and demonstrated a poorer response to chemotherapy compared with the group without AL amyloidosis. A previous study also supported the theory that MM patients with coexisting AL amyloid may have a poorer prognosis as compared with patients without AL amyloid present.61 Some authors have advocated man-
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Table II. Criteria for the diagnosis of multiple myeloma and related disorders
Table III. Staging system for multiple myeloma Durie-Salmon
Symptomatic multiple myeloma (all are required): 1. Clonal plasma cells present on biopsy of bone marrow or plasmacytoma 2. M-protein present in serum or urine (either intact immunoglobulin or free light chains) 3. Evidence of related organ or tissue impairment (lytic bone lesions, renal insufficiency, anemia, hypercalcemia, hyperviscosity, amyloidosis, or recurrent infections) Asymptomatic (smoldering) myeloma: 1. Serum M-protein ⱖ3 g/dL and/or clonal plasma cells ⱖ 10% of bone marrow 2. No symptoms or evidence of related organ or tissue impairment Monoclonal gammopathy of unknown significance (MGUS) 1. Serum M-protein present but ⬍3 g/dL 2. Bone marrow plasma cells ⬍ 10% of aspirate and low level of infiltration on biopsy 3. No symptoms or evidence of related organ or tissue impairment Adapted from The International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol 2003;121:749-57. Reprinted from Stoopler ET, Vogl DT, Stadtmauer EA. Medical management update: multiple myeloma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103:599-609; with permission from Elsevier.
datory fat pad analysis for amyloid in patients with MM,60 whereas others suggest that the clinical and therapeutic value of a positive result appears to be inconsequential.21 The results of our pilot study demonstrate that the prevalence of occult amyloid deposition in patients with myeloma may be even higher. In our limited size sample, none of the patients had detectable amyloid deposition on FNA of the abdominal fat pad. However, we were able to detect amyloid deposition in labial minor salivary glands in 2 (18%) of 11 patients. This suggests that subclinical amyloid deposition may be more easily detected on oral biopsy, and the oral cavity may be the preferred biopsy site for detecting amyloid deposition in myeloma patients with no symptoms of systemic amyloidosis. As stated previously, various locations within the oral cavity have been advocated for biopsy to detect amyloid. Historically, the tongue is the most frequently reported intraoral location for amyloid deposition and has been advocated as the optimal site for biopsy within the oral cavity for detection of amyloid.39,47,50-52,62 More recently, various studies have demonstrated the utility of LMSG biopsy for the detection of amyloid with correlation to primary and secondary systemic amyloidosis.46,48,49,63-65 In our study, amyloid was detected only in the LMSGs; these results further support the concept that the LMSGs may be the optimal site for intraoral biopsy for early detection of amyloid.
International staging system
Stage I (associated with a low cell mass of ⬍0.6 ⫻ 1012 cells/m2): All of the following are required: ● Hemoglobin ⬎10 g/dL ● Low serum monoclonal protein (IgG ⬍5 g/dL or IgA ⬍3 g/dL) ● Normal serum calcium level ● Low urinary monoclonal protein excretion (⬍4 g/24 hours) ● Absence of lytic bone lesions Stage II Any patient not meeting criteria for Stages I or III Stage III (associated with a high cell mass of ⬎1.2 ⫻ 1012 cells/m2): At least one of the following is required: ● Hemoglobin ⬍8.5 g/dL ● High serum monoclonal protein (IgG ⬎7 or IgA ⬎5) ● Serum calcium ⬎ 12 mg/dL ● High urinary monoclonal protein excretion (⬎12 g/24 hours) ● Advanced lytic bone lesions (usually ⱖ3 lesions) Stage I: serum albumin ⱖ 3.5 g/dL and serum 2-microglobulin ⬍ 3.5 mg/L Stage II: serum albumin ⬍ 3.5 g/dL or 2-microglobulin 3.5 to 5.5 mg/L Stage III: 2-microglobulin ⱖ 5.5 mg/L
IG, immunoglobulin. Adapted from Durie BG, Salmon SE. A clinical staging system for multiple myeloma: correlation of measured myeloma cell mass with presenting features, response to treatment and survival. Cancer 1975;36: 842-54. Adapted from Greipp PR, Miguel JS, Durie BG, Crowley JJ, Barlogie B, Blade J, et al. International staging system for multiple myeloma. J Clin Oncol 2005;23:3412-20. Reprinted from Stoopler ET, Vogl DT, Stadtmauer EA. Medical management update: multiple myeloma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103:599-609; with permission from Elsevier.
There were limitations of this study that may have affected research outcomes. The sample size of the study was small and may not accurately represent the true prevalence of amyloid deposition in this patient population. Although each operator performing the procedures was standardized, biopsy techniques are operator and patient sensitive and may not have been consistent. Most patients enrolled had already received some form of treatment for MM—this could have potentially affected the overall course of disease as well as amyloid burden. Subjects did not complete FISH and cytogenetic testing and, therefore, it was not known whether these subjects were considered standard- versus high risk-patients. Although 2 of 11 subjects demonstrated amyloid in the oral cavity without evidence of deposition in the abdominal fat, the clinical significance of these findings remains unclear, as neither has devel-
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oped signs or symptoms of systemic amyloidosis. Amyloidosis has been generally recognized as a long-term complication of MM.45 The 2 subjects reported here with occult amyloidosis received active treatment, which caused disease remission and this may decrease the risk of late development of amyloid-related organ dysfunction. The amyloid detected in the LMSG biopsies was not analyzed for type; however, there is a high probability that it was of AL type because of (1) the concurrent myeloma disease process and (2) neither of these subjects had a history of chronic infectious, inflammatory, or neoplastic diseases responsible for production of other types of amyloid. CONCLUSIONS The results of this study support the oral cavity as an important location for diagnostic testing for presence of amyloid in patients with MM. Specifically, this pilot study demonstrates the value of LMSG biopsy as a more reliable intraoral location for detection of amyloid as compared with other anatomical locations in the oral cavity. Additional studies are warranted to further support LMSG biopsy as a potential site for establishing presence of amyloid early in the MM disease process and to validate previous studies that the presence of amyloid may be an independent high-risk factor for MM. The authors thank and acknowledge Dr Prabodh Gupta and the cytopathology team at the University of Pennsylvania Medical Center for services provided. The authors also thank and acknowledge Dr Daniel Heitjan in the Department of Biostatistics and Epidemiology at the University of Pennsylvania School of Medicine for statistical design and analysis completed for this study. REFERENCES 1. Raab MS, Podar K, Breitkreutz I, Richardson PG, Anderson KC. Multiple myeloma. Lancet 2009;374:324-39. 2. Rajkumar SV. Multiple myeloma. Curr Probl Cancer 2009; 33:7-64. 3. Landgren O, Gridley G, Turesson I, Caporaso NE, Goldin LR, Baris D, et al. Risk of monoclonal gammopathy of undetermined significance (MG, US) and subsequent multiple myeloma among African American and white veterans in the United States. Blood 2006;107:904-6. 4. Landgren O, Weiss BM. Patterns of monoclonal gammopathy of undetermined significance and multiple myeloma in various ethnic/racial groups: support for genetic factors in pathogenesis. Leukemia 2009;23:1691-7. 5. Lin P. Plasma cell myeloma. Hematol Oncol Clin North Am 2009;23:709-27. 6. Stoopler ET, Vogl DT, Stadtmauer EA. Medical management update: multiple myeloma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103:599-609. 7. Kumar SK, Mikhael JR, Buadi FK, Dingli D, Dispenzieri A, Fonseca R, et al. Management of newly diagnosed symptomatic multiple myeloma: updated Mayo stratification of myeloma and risk-adapted therapy (mSMART) consensus guidelines. Mayo Clin Proc 2009;84:1095-110.
Stoopler et al. 331 8. Migliorati CA, Schubert MM, Peterson DE, Seneda LM. Bisphosphonate-associated osteonecrosis of mandibular and maxillary bone: an emerging oral complication of supportive cancer therapy. Cancer 2005;104:83-93. 9. Migliorati CA, Siegel MA, Elting LS. Bisphosphonate-associated osteonecrosis: a long-term complication of bisphosphonate treatment. Lancet Oncol 2006;7:508-14. 10. Sawatari Y, Marx RE. Bisphosphonates and bisphosphonate induced osteonecrosis. Oral Maxillofac Surg Clin North Am 2007; 19:487-98, v-vi. 11. Grewal VS, Fayans EP. Bisphosphonate-associated osteonecrosis: a clinician’s reference to patient management. Todays FDA 2008;20:38-41, 43-6. 12. Migliorati CA. Intravenous bisphosphonate therapy may lead to osteonecrosis of the jaw in multiple myeloma, breast, and prostate cancer patients. J Evid Based Dent Pract 2008;8:93-4. 13. Almazrooa SA, Woo SB. Bisphosphonate and nonbisphosphonate-associated osteonecrosis of the jaw: a review. J Am Dent Assoc 2009;140:864-75. 14. Ruggiero SL, Dodson TB, Assael LA, Landesberg R, Marx RE, Mehrotra B, et al. Position paper on bisphosphonate-related osteonecrosis of the jaws—2009 update. J Oral Maxillofac Surg 2009;67:2-12. 15. Migliorati CA, Woo SB, Hewson I, Barasch A, Elting LS, Spijkervet FK, et al. Bisphosphonate Osteonecrosis Section, Oral Care Study Group, multinational association of supportive care in cancer (MASCC)/International Society of Oral Oncology (ISOO). A systematic review of bisphosphonate osteonecrosis (BON) in cancer. Support Care Cancer 2010;18:1099-106. 16. Harousseau JL, Dreyling M, ESMO Guidelines Working Group. Multiple myeloma: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2009;20(Suppl 4):97-9. 17. Kumar S. Multiple myeloma— current issues and controversies. Cancer Treat Rev 2010;36(Suppl 2):S3-11. 18. Lonial S. Presentation and risk stratification—improving prognosis for patients with multiple myeloma. Cancer Treat Rev 2010;36(Suppl 2):S12-7. 19. Sideras K, Gertz MA. Amyloidosis. Adv Clin Chem 2009; 47:1-44. 20. Bayer-Garner IB, Smoller BR. AL amyloidosis is not present as an incidental finding in cutaneous biopsies of patients with multiple myeloma. Clin Exp Dermatol 2002;27:240-2. 21. Desikan KR, Dhodapkar MV, Hough A, Waldron T, Jagannath S, Siegel D, et al. Incidence and impact of light chain associated (AL) amyloidosis on the prognosis of patients with multiple myeloma treated with autologous transplantation. Leuk Lymphoma 1997;27:315-9. 22. Kyle RA. Multiple myeloma: review of 869 cases. Mayo Clin Proc 1975;50:29-40. 23. Barlogie B, Shaughnessy J, Tricot G, Jacobson J, Zangari M, Anaissie E, et al. Treatment of multiple myeloma. Blood 2004;103:20-32. 24. Rocken C, Sletten K. Amyloid in surgical pathology. Virchows Arch 2003;443:3-16. 25. Stoopler ET, Sollecito TP, Chen SY. Amyloid deposition in the oral cavity: a retrospective study and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003;95:674-80. 26. Libbey CA, Skinner M, Cohen AS. Use of abdominal fat tissue aspirate in the diagnosis of systemic amyloidosis. Arch Intern Med 1983;143:1549-52. 27. Duston MA, Skinner M, Shirahama T, Cohen AS. Diagnosis of amyloidosis by abdominal fat aspiration. Analysis of four years’ experience. Am J Med 1987;82:412-4. 28. Falk RH, Comenzo RL, Skinner M. The systemic amyloidoses. N Engl J Med 1997;337:898-909. 29. Bergesio F, Ciciani AM, Santostefano M, Brugnano R, Manganaro M, Palladini G, et al., Immunopathology Group, Italian Society of
332
30.
31.
32.
33.
34. 35.
36. 37.
38.
39. 40.
41.
42.
43.
44. 45.
46.
47. 48.
49.
OOOOE March 2011
Stoopler et al.
Nephrology. Renal involvement in systemic amyloidosis—an Italian retrospective study on epidemiological and clinical data at diagnosis. Nephrol Dial Transplant 2007;22:1608-18. von Hutten H, Mihatsch M, Lobeck H, Rudolph B, Eriksson M, Rocken C. Prevalence and origin of amyloid in kidney biopsies. Am J Surg Pathol 2009;33:1198-205. Osawa Y, Kawamura K, Kondo D, Imai N, Ueno M, Nishi S, et al. Renal function at the time of renal biopsy as a predictor of prognosis in patients with primary AL-type amyloidosis. Clin Exp Nephrol 2004;8:127-33. Kyle RA, Spencer RJ, Dahlin DC. Value of rectal biopsy in the diagnosis of primary systemic amyloidosis. Am J Med Sci 1966;251:501-6. Kuroda T, Tanabe N, Sakatsume M, Nozawa S, Mitsuka T, Ishikawa H, et al. Comparison of gastroduodenal, renal and abdominal fat biopsies for diagnosing amyloidosis in rheumatoid arthritis. Clin Rheumatol 2002;21:123-8. Hachulla E, Grateau G. Diagnostic tools for amyloidosis. Joint Bone Spine 2002;69:538-45. Balatsouras DG, Eliopoulos P, Assimakopoulos D, Korres S. Primary local amyloidosis of the palate. Otolaryngol Head Neck Surg 2007;137:348-9. Selikoff IJ, Robitzek EH. Gingival biopsy for the diagnosis of generalized amyloidosis. Am J Pathol 1947;23:1099-111. Gorlin R, Gottsegen R. The role of the gingival biopsy in secondary amyloid disease. Oral Surg Oral Med Oral Pathol 1949;2:864-6. Nandapalan V, Jones TM, Morar P, Clark AH, Jones AS. Localized amyloidosis of the parotid gland: a case report and review of the localized amyloidosis of the head and neck. Head Neck 1998;20:73-8. Fahrner KS, Black CC, Gosselin BJ. Localized amyloidosis of the tongue: a review. Am J Otolaryngol 2004;25:186-9. Stoopler ET, Alawi F, Laudenbach JM, Sollecito TP. Bullous amyloidosis of the oral cavity: a rare clinical presentation and review. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006;101:734-40. Kokong DD, Ibekwe TS, Okolo CA, Kodiya AM, Fasunla JA, Nwaorgu OG, et al. Amyloid angiopathy of the floor of the mouth: a case report and review of the literature. J Med Case Reports 2007;1:117. Lee SY, Chang H, Chen TC, Hsu HH, Fang JT, Yang CW. Lingual amyloidosis—a rare complication of long-term haemodialysis. Nephrol Dial Transplant 2007;22:1471-2. Shah SS, Freedman PD. Amyloidomas of the jawbones with underlying occult plasma cell dyscrasias: a report of 2 cases with review of the literature. J Oral Maxillofac Surg 2007;65:1655-60. Henley E, Houghton N, Bucknall R, Triantafyllou A, Field EA. Localized amyloidosis of the palate. Clin Exp Dermatol 2008;33:100-1. Elad S, Czerninski R, Fischman S, Keshet N, Drucker S, Davidovich T, et al. Exceptional oral manifestations of amyloid light chain protein (AL) systemic amyloidosis. Amyloid 2010;17:27-31. Delgado WA, Mosqueda A. A highly sensitive method for diagnosis of secondary amyloidosis by labial salivary gland biopsy. J Oral Pathol Med 1989;18:310-4. Madani M, Harwick RD, Chen SY, Miller AS. Amyloidosis of the oral cavity: report of five cases. Compendium 1991;12:338-42. Hachulla E, Janin A, Flipo RM, Saile R, Facon T, Bataille D, et al. Labial salivary gland biopsy is a reliable test for the diagnosis of primary and secondary amyloidosis. A prospective clinical and immunohistologic study in 59 patients. Arthritis Rheum 1993;36:691-7. Delgado WA, Arana-Chavez VE. Amyloid deposits in labial salivary glands identified by electron microscopy. J Oral Pathol Med 1997;26:51-2.
50. van der Waal RI, van de Scheur MR, Huijgens PC, Starink TM, van der Waal I. Amyloidosis of the tongue as a paraneoplastic marker of plasma cell dyscrasia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002;94:444-7. 51. Went R, Chan-Lam D, Thornhill M. Isolated tongue amyloid in a patient with multiple myeloma. Br J Haematol 2008;143:606. 52. Angiero F, Seramondi R, Magistro S, Crippa R, Benedicenti S, Rizzardi C, et al. Amyloid deposition in the tongue: clinical and histopathological profile. Anticancer Res 2010;30:3009-14. 53. International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol 2003;121:749-57. 54. Rajkumar SV, Buadi F. Multiple myeloma: new staging systems for diagnosis, prognosis and response evaluation. Best Pract Res Clin Haematol 2007;20:665-80. 55. Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer 1975;36:842-54. 56. Greipp PR, San MJ, Durie BG, Crowley JJ, Barlogie B, Blade J, et al. International staging system for multiple myeloma. J Clin Oncol 2005;23:3412-20. 57. Avet-Loiseau H, Attal M, Moreau P, Charbonnel C, Garban F, Hulin C, et al. Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe francophone du Myelome. Blood 2007;109:3489-95. 58. Greipp PR, Lust JA, O’Fallon WM, Katzmann JA, Witzig TE, Kyle RA. Plasma cell labeling index and beta 2-microglobulin predict survival independent of thymidine kinase and C-reactive protein in multiple myeloma. Blood 1993;81:3382-7. 59. Witzig TE, Timm M, Larson D, Therneau T, Greipp PR. Measurement of apoptosis and proliferation of bone marrow plasma cells in patients with plasma cell proliferative disorders. Br J Haematol 1999;104:131-7. 60. Vela-Ojeda J, Garcia-Ruiz Esparza MA, Padilla-Gonzalez Y, Sanchez-Cortes E, Garcia-Chavez J, Montiel-Cervantes L, et al. Multiple myeloma-associated amyloidosis is an independent high-risk prognostic factor. Ann Hematol 2009;88:59-66. 61. Abraham RS, Geyer SM, Price-Troska TL, Allmer C, Kyle RA, Gertz MA, et al. Immunoglobulin light chain variable (V) region genes influence clinical presentation and outcome in light chainassociated amyloidosis (AL). Blood 2003;101:3801-8. 62. Pan WH, Li NP. Clinical pathological feature of early tongue amyloidosis. Chin Med Sci J 2006;21:104-6. 63. Finkel KJ, Kolansky DM, Giorgadze T, Thaler E. Amyloid infiltration of the salivary glands in the setting of primary systemic amyloidosis without multiple myeloma. Otolaryngol Head Neck Surg 2006;135:471-2. 64. Caporali R, Bonacci E, Epis O, Bobbio-Pallavicini F, Morbini P, Montecucco C. Safety and usefulness of minor salivary gland biopsy: retrospective analysis of 502 procedures performed at a single center. Arthritis Rheum 2008;59:714-20. 65. do Amaral B, Coelho T, Sousa A, Guimaraes A. Usefulness of labial salivary gland biopsy in familial amyloid polyneuropathy Portuguese type. Amyloid 2009;16:232-8. Reprint requests: Eric T. Stoopler, DMD University of Pennsylvania School of Dental Medicine 240 South 40th Street Philadelphia, PA 19104
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