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Oral amyloidosis: A late complication of multiple myeloma
Oral amyloidosis: A late complication of multiple myeloma Paul Lee Salisbury. III, Chapel Hill, N. C.
D.D.S., and John R. Jacoway, D.D.S., Ph.D., Winston-Salem
THE BOWMAN GRAY SCHOOL OF MEDICINE NORTH CAROLINA SCHOOL OF DENTISTRY
OF WAKE
FOREST
UNIVERSITY
AND
THE
UNIVERSITY
and
OF
Amyloidosis as a complication of multiple myeloma carries with it grave prognostic implications, and the median survival of myeloma patients following a diagnosis of amyloidosis is only 4 months. This article describes a patient who survived 6 years with kappa light chain myeloma, but only 4 months after the development of oral amyloid deposits. Oral amyloidosis may be clinially difficult to distinguish from fibrous, neurogenous. characteristic
or salivary gland pathosis; “apple green” appearance
however, histologic specimens when examined microscopically
M ultiple myeloma is an idiopathic, malignant disease which, in the United States, affects blacks twice as often as whites, males more commonly than females, and occurs almost exclusively in patients past 40 years of age. The disease is characterized primarily by an uncontrolled proliferation of neoplastic plasma cells in bone marrow.’ These cells produce homogenous immunoproteins or fragments which are known as monoclonal or myeloma proteins. When produced in excess, these proteins are detectable in the patient’s serum and urine by electrophoretic techniques.’ As the bone marrow becomes infiltrated with malignant plasma cells, focal or diffuse osteolytic lesions are produced which can cause vertebral collapse, pathologic fractures, severe bone pain, and other neurologic symptoms. These osteolytic lesions have a distinct “punched-out” radiographic appearance and are not uncommonly found in the jaws of myeloma patients.* Plasma cell infiltration of bone marrow may also produce anemia, leukopenia, and thrombocytopenia by the replacement of normal blood cell precursors.’ Other major problems in myeloma patients include renal dysfunction secondary to filtration of large quantities of immunoprotein by the kidney’ and frequent infections caused by leukopenia and abnormal antibody production3 Thrombocytopenia and the complexing of myeloma proteins with certain coagulation factors produce a bleeding diathesis in some patients.3 From 7 to 20 percent of patients with multiple myeloma exhibit focal and/or disseminated amyloid deposits.4-6 48
stained with Congo red have with polarized light.
a
It is impossible to predict which patients will eventually exhibit amyloid formation; however, those with light chain disease demonstrate a higher incidence of amyloidosis than other myeloma subgroups.s Experimentally, it has been found that a major constituent of amyloid fibers in patients with multiple myeloma consists of light chain fragments of myeloma proteins.6 The mechanism of amyloid deposition in the body is unclear; however, it is thought that light chain proteins secreted by plasma cells react with tissue receptors to form insoluble amyloid fibrils.’ Apparently, amyloid can be deposited in connective tissue anywhere in the body, and extensive deposits eventually lead to structural derangement and organ failure.’ The diagnosis of amyloidosis in patients with multiple myeloma confirms a grave prognosis,3 and these patients deteriorate rapidly. The median survival is only 4 months after amyloidosis is diagnosed (61 cases), compared to 20 months for multiple myeloma patients as a whole (717 cases).’ Death is most often due to complications of amyloidosis, and not myeloma. Congestive heart failure, cardiac conduction defects, gastrointestinal malabsorption, and renal failure are the expected terminal effects of amyloid deposition in major organ systems3 Amyloid infiltration of the tongue has been the most frequently reported oral manifestation of this disease8-‘* and may appear clinically as a brawny, indurated macroglossia. The lateral borders are often scalloped from pressure on the teeth, and focal amyloid deposits at the borders of the tongue can appear as yellow, nonulcerated nodules unless trau-
Oral amyloidosis 49
Volume 56 Number 1
Fig.
1. Amyloid deposits,left buccal mucosa.
Fig.
2. Amyloid deposits,right lateral border of tongue.
Fig. 3. Congo red stain revealshyalinized material to be reddishorange and consistentwith amyloid. (Congo red stain. Magnification, X100.) Fig. 4. Examination of samefield as in Fig. 3 with polarized light demonstratesfibrillar birefringent material, apple green in color and supportive of an interpretation of amyloid. (Congo red stain. Magnification, X100.)
matized during mastication.10 Amyloid infiltration of the gingiva and buccal mucosa may also appear as nodules or raised plaques which are sometimes associated with hemorrhagic bullae.4 The preferred treatment of accessible amyloid deposits of the oral cavity, pharynx, and larynx is conservative excision. Lesions frequently recur, and repeated excisions are required.13 CASEREPORT
A 64-year-old black woman with a 6-year history of kappa light chain myelomawas referred to the hospital dental service for evaluation of exophytic lesionsof the buccalmucosawhich had beennoted by her physicianson physical examination. She had first discovereda single asymptomaticnodular lesion in the left cheek 6 weeks previously,and during the interval prior to dental consultation multiple lesionsof the buccal mucosaand tongue haddeveloped.The patient’smajor complaintwasthat she
would bite theselesions,with resultant bleedingand pain. Oral examination revealed firm, hemorrhagic-appearing raisedlesionslocated bilaterally on the buccal mucosaat the occlusalplaneand a tan, papularlesionon the lateral border of the tongue (Figs. 1 and 2). An incisionalbiopsyof the buccalmucosawasperformed, and sectionswere preparedfrom the submittedspecimen. Microscopicevaluationrevealeda portion of fibrous connective tissue containing a hyalinized, eosinophilic, acellular material interpreted as amyloid. The superficial tissuecontaineda numberof thin-walled bloodvesselsand a few inflammatory cells. The specimenwas covered on one surfacewith stratified squamousepithelium.Neutral Congored stainsdemonstratedthe hyalinized material to be metachromaticallyreddishorange (Fig. 3) and, when viewedunder polarizedlight, this appeared“apple green” in color (Fig. 4). For 6 years following a diagnosisof multiple myeloma, this patient’s coursehad beenfairly typical, with severe bonepain as the predominantsymptom. Additional fea-
50
Salisbury
and Jacoway
Oral Surg. July, 1983
tures includedmultiple punched-outradiolucentlesionsof longbones,ribs, andskull, proteinuria,hypercalcemia,and eventually amyloidosis.Treatment consistedof multiple coursesof chemotherapywith alkylating agentsand radiation therapy to symptomaticbonelesions.The patient died 4 monthsafter the diagnosisof amyloidosis. There have been several case reports in the litera-
ture of oral amyloid deposits being discovered prior of multiple myeloma.8s9* I** I4 Oral amyloidosis may also be a late manifestation of multiple myeloma, as described in the foregoing case to a diagnosis
report, and occasionally is clinically
difficult
to
distinguish from fibrous, neurogenous, or even salivary gland pathosis. The presentation of this manifestation clearly indicates a worsening prognosis. Illustrationsweremadepossiblethroughdonationsfrom the American Cancer Society and the Bowman Gray Schoolof Medicine. REFERENCES 1. Kyle, R. A., and Bayrd, E. D.: The Monoclonal Gammopathies. Springfield, Ill., 1976, Charles C Thomas Publisher, chaps. 5, 6, 7, and 19. 2. Bruce, K. W., and Royer, R. Q.: Multiple Myeloma Occurring in the Jaws, ORAL SURG. 6~729-744, 1953. 3. Thorne, G. W. (editor): Harrison’s Principles of Internal Medicine, ed. 8, New York, 1977, McGraw-Hill Book Company, Inc., chaps. 73 and 114. 4. Meyer, I. Lytle, J. J., Cella, R. J., and Alling, C. C.: Amyloidosis of the Tongue Secondary to Multiple Myeloma; Case 23, Part 2, J. Oral Surg. 36: 459-461, 1978.
Stone, M. J., and Frankel, E. P.: The Clinical Spectrum of Light Chain Myeloma, Am J. Med. 58: 601-619, 1975. Kyle, R. A.: Multiple Myeloma: Review of 869 Cases, Mayo Clin. Proc. 50: 29-40, 1975. Kossoff, J.: Case II: Generalized Amyloidosis Complicating Multiple Myeloma of the Light Chain Vairety, Radiology 125: 835-837, 1977. 8. Cahn, L.: Oral Amyloid as a Complication of Myelomatosis, ORAL SURG. 10: 735-742, 1957. 9. Cranin, A. N., and Gross, E. R.: Severe Oral and Perioral Amyloidosis as a Primary Complication of Multiple Myeloma, ORAL SURG. 23: 158-163, 1967. IO. Kraut, R. A., Buhler, J. E.. La Rue, J. R., and Acevedo, A.: Amyloidosis Associated With Multiple Myeloma, ORAL SURG. 43: 63-68,
1977.
1I. Akin, R. K., Barton, K., and Walters, P. J.: Amyloidosis, Macroglossia, and Carpal Tunnel Syndrome Associated With Myeloma, J. Oral Surg. 33: 690-692, 1975. 12. Flick, W. G., and Lawrence, F. R.: Oral Amyloidosis as Initial Symptom of Multiple Myeloma: A Case Report, ORAL SURG. 49: 18-20, 1980. 13. Hellquist, H., Olofsson, J., Sakjer, H., and Odkvist, L. M.: Amyloidosis of the Larynx, Acta Otolaryngol. 88: 443-450, 1979. 14. Kielts, T. R.: Amyloidosis of the Buccal Mucosa as a Diagnostic Precursor in Multiple Myeloma: Report of a Case, J. Am. Dent Assoc. 69: 701-705, 1964.
Reprint
requests
to:
Dr. Paul Lee Salisbury III Bowman Gray School of Medicine Wake Forest University 300 S. Hawthorne Rd. Winston-Salem, N. C. 27 103
D.D.S., and John R. Jacoway, D.D.S., Ph.D., Winston-Salem
THE BOWMAN GRAY SCHOOL OF MEDICINE NORTH CAROLINA SCHOOL OF DENTISTRY
OF WAKE
FOREST
UNIVERSITY
AND
THE
UNIVERSITY
and
OF
Amyloidosis as a complication of multiple myeloma carries with it grave prognostic implications, and the median survival of myeloma patients following a diagnosis of amyloidosis is only 4 months. This article describes a patient who survived 6 years with kappa light chain myeloma, but only 4 months after the development of oral amyloid deposits. Oral amyloidosis may be clinially difficult to distinguish from fibrous, neurogenous. characteristic
or salivary gland pathosis; “apple green” appearance
however, histologic specimens when examined microscopically
M ultiple myeloma is an idiopathic, malignant disease which, in the United States, affects blacks twice as often as whites, males more commonly than females, and occurs almost exclusively in patients past 40 years of age. The disease is characterized primarily by an uncontrolled proliferation of neoplastic plasma cells in bone marrow.’ These cells produce homogenous immunoproteins or fragments which are known as monoclonal or myeloma proteins. When produced in excess, these proteins are detectable in the patient’s serum and urine by electrophoretic techniques.’ As the bone marrow becomes infiltrated with malignant plasma cells, focal or diffuse osteolytic lesions are produced which can cause vertebral collapse, pathologic fractures, severe bone pain, and other neurologic symptoms. These osteolytic lesions have a distinct “punched-out” radiographic appearance and are not uncommonly found in the jaws of myeloma patients.* Plasma cell infiltration of bone marrow may also produce anemia, leukopenia, and thrombocytopenia by the replacement of normal blood cell precursors.’ Other major problems in myeloma patients include renal dysfunction secondary to filtration of large quantities of immunoprotein by the kidney’ and frequent infections caused by leukopenia and abnormal antibody production3 Thrombocytopenia and the complexing of myeloma proteins with certain coagulation factors produce a bleeding diathesis in some patients.3 From 7 to 20 percent of patients with multiple myeloma exhibit focal and/or disseminated amyloid deposits.4-6 48
stained with Congo red have with polarized light.
a
It is impossible to predict which patients will eventually exhibit amyloid formation; however, those with light chain disease demonstrate a higher incidence of amyloidosis than other myeloma subgroups.s Experimentally, it has been found that a major constituent of amyloid fibers in patients with multiple myeloma consists of light chain fragments of myeloma proteins.6 The mechanism of amyloid deposition in the body is unclear; however, it is thought that light chain proteins secreted by plasma cells react with tissue receptors to form insoluble amyloid fibrils.’ Apparently, amyloid can be deposited in connective tissue anywhere in the body, and extensive deposits eventually lead to structural derangement and organ failure.’ The diagnosis of amyloidosis in patients with multiple myeloma confirms a grave prognosis,3 and these patients deteriorate rapidly. The median survival is only 4 months after amyloidosis is diagnosed (61 cases), compared to 20 months for multiple myeloma patients as a whole (717 cases).’ Death is most often due to complications of amyloidosis, and not myeloma. Congestive heart failure, cardiac conduction defects, gastrointestinal malabsorption, and renal failure are the expected terminal effects of amyloid deposition in major organ systems3 Amyloid infiltration of the tongue has been the most frequently reported oral manifestation of this disease8-‘* and may appear clinically as a brawny, indurated macroglossia. The lateral borders are often scalloped from pressure on the teeth, and focal amyloid deposits at the borders of the tongue can appear as yellow, nonulcerated nodules unless trau-
Oral amyloidosis 49
Volume 56 Number 1
Fig.
1. Amyloid deposits,left buccal mucosa.
Fig.
2. Amyloid deposits,right lateral border of tongue.
Fig. 3. Congo red stain revealshyalinized material to be reddishorange and consistentwith amyloid. (Congo red stain. Magnification, X100.) Fig. 4. Examination of samefield as in Fig. 3 with polarized light demonstratesfibrillar birefringent material, apple green in color and supportive of an interpretation of amyloid. (Congo red stain. Magnification, X100.)
matized during mastication.10 Amyloid infiltration of the gingiva and buccal mucosa may also appear as nodules or raised plaques which are sometimes associated with hemorrhagic bullae.4 The preferred treatment of accessible amyloid deposits of the oral cavity, pharynx, and larynx is conservative excision. Lesions frequently recur, and repeated excisions are required.13 CASEREPORT
A 64-year-old black woman with a 6-year history of kappa light chain myelomawas referred to the hospital dental service for evaluation of exophytic lesionsof the buccalmucosawhich had beennoted by her physicianson physical examination. She had first discovereda single asymptomaticnodular lesion in the left cheek 6 weeks previously,and during the interval prior to dental consultation multiple lesionsof the buccal mucosaand tongue haddeveloped.The patient’smajor complaintwasthat she
would bite theselesions,with resultant bleedingand pain. Oral examination revealed firm, hemorrhagic-appearing raisedlesionslocated bilaterally on the buccal mucosaat the occlusalplaneand a tan, papularlesionon the lateral border of the tongue (Figs. 1 and 2). An incisionalbiopsyof the buccalmucosawasperformed, and sectionswere preparedfrom the submittedspecimen. Microscopicevaluationrevealeda portion of fibrous connective tissue containing a hyalinized, eosinophilic, acellular material interpreted as amyloid. The superficial tissuecontaineda numberof thin-walled bloodvesselsand a few inflammatory cells. The specimenwas covered on one surfacewith stratified squamousepithelium.Neutral Congored stainsdemonstratedthe hyalinized material to be metachromaticallyreddishorange (Fig. 3) and, when viewedunder polarizedlight, this appeared“apple green” in color (Fig. 4). For 6 years following a diagnosisof multiple myeloma, this patient’s coursehad beenfairly typical, with severe bonepain as the predominantsymptom. Additional fea-
50
Salisbury
and Jacoway
Oral Surg. July, 1983
tures includedmultiple punched-outradiolucentlesionsof longbones,ribs, andskull, proteinuria,hypercalcemia,and eventually amyloidosis.Treatment consistedof multiple coursesof chemotherapywith alkylating agentsand radiation therapy to symptomaticbonelesions.The patient died 4 monthsafter the diagnosisof amyloidosis. There have been several case reports in the litera-
ture of oral amyloid deposits being discovered prior of multiple myeloma.8s9* I** I4 Oral amyloidosis may also be a late manifestation of multiple myeloma, as described in the foregoing case to a diagnosis
report, and occasionally is clinically
difficult
to
distinguish from fibrous, neurogenous, or even salivary gland pathosis. The presentation of this manifestation clearly indicates a worsening prognosis. Illustrationsweremadepossiblethroughdonationsfrom the American Cancer Society and the Bowman Gray Schoolof Medicine. REFERENCES 1. Kyle, R. A., and Bayrd, E. D.: The Monoclonal Gammopathies. Springfield, Ill., 1976, Charles C Thomas Publisher, chaps. 5, 6, 7, and 19. 2. Bruce, K. W., and Royer, R. Q.: Multiple Myeloma Occurring in the Jaws, ORAL SURG. 6~729-744, 1953. 3. Thorne, G. W. (editor): Harrison’s Principles of Internal Medicine, ed. 8, New York, 1977, McGraw-Hill Book Company, Inc., chaps. 73 and 114. 4. Meyer, I. Lytle, J. J., Cella, R. J., and Alling, C. C.: Amyloidosis of the Tongue Secondary to Multiple Myeloma; Case 23, Part 2, J. Oral Surg. 36: 459-461, 1978.
Stone, M. J., and Frankel, E. P.: The Clinical Spectrum of Light Chain Myeloma, Am J. Med. 58: 601-619, 1975. Kyle, R. A.: Multiple Myeloma: Review of 869 Cases, Mayo Clin. Proc. 50: 29-40, 1975. Kossoff, J.: Case II: Generalized Amyloidosis Complicating Multiple Myeloma of the Light Chain Vairety, Radiology 125: 835-837, 1977. 8. Cahn, L.: Oral Amyloid as a Complication of Myelomatosis, ORAL SURG. 10: 735-742, 1957. 9. Cranin, A. N., and Gross, E. R.: Severe Oral and Perioral Amyloidosis as a Primary Complication of Multiple Myeloma, ORAL SURG. 23: 158-163, 1967. IO. Kraut, R. A., Buhler, J. E.. La Rue, J. R., and Acevedo, A.: Amyloidosis Associated With Multiple Myeloma, ORAL SURG. 43: 63-68,
1977.
1I. Akin, R. K., Barton, K., and Walters, P. J.: Amyloidosis, Macroglossia, and Carpal Tunnel Syndrome Associated With Myeloma, J. Oral Surg. 33: 690-692, 1975. 12. Flick, W. G., and Lawrence, F. R.: Oral Amyloidosis as Initial Symptom of Multiple Myeloma: A Case Report, ORAL SURG. 49: 18-20, 1980. 13. Hellquist, H., Olofsson, J., Sakjer, H., and Odkvist, L. M.: Amyloidosis of the Larynx, Acta Otolaryngol. 88: 443-450, 1979. 14. Kielts, T. R.: Amyloidosis of the Buccal Mucosa as a Diagnostic Precursor in Multiple Myeloma: Report of a Case, J. Am. Dent Assoc. 69: 701-705, 1964.
Reprint
requests
to:
Dr. Paul Lee Salisbury III Bowman Gray School of Medicine Wake Forest University 300 S. Hawthorne Rd. Winston-Salem, N. C. 27 103