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Multiple myeloma presenting with extensive oral and perioral amyloidosis
Short communications & case reports Multiple myeloma presenting with extensive oral and perioral amyloidosis Erich J. Raubenheimer, iU.Ch+.,* Joseph Dauth, M.Med.(Path.),** and Johannes P. de Coning, B.Sc.(Hons.),*** Pretoria, South Africa MEDICAL
UNIVERSITY
OF SOUTHERN
AFRICA
The case of a young adult patient, with a kappa-light-chain-secreting multiple myeloma and extensive oral and salivary gland amyloid deposits, is presented. This case illustrates the necessity of a multidisciplinary approach using biochemical, radiographic, and relevant histologic investigations in the diagnosis of multiple myeloma. Factors influencing the prognosis of this neoplastic condition are discussed. Microscopic examination of the oral amyloid deposits supports the suggested central role played by the macrophage in amyloidogenesis. (ORAL SURG. ORAL MED. ORAL. PATHOL. 61:492-497, 1986)
M
ultiple myeloma is a condition characterized by uncontrolled proliferation of one or more clones of malignant plasma cells. The average age at the time of diagnosis is 62 years, with fewer than 2% of all cases occurring in persons less than 40 years of age.‘s2 Few well-documented cases in patients younger than the third decade have been reported3-’ There is a moderate male preponderance?’ and black persons are affected twice as often as white patients. 8*9 The neoplasm usually arises in hematopoietic bone marrow, and multiple lytic bone lesions are characteristic radiographic findings. In the majority of cases, proliferating plasma cells are responsible for abnormal protein synthesis, which appears in serum as an increase in the concentration of one of the monoclonal types of immunoglobulins or its subunits (heavy or light chains)1-2 and which may be detected with serum protein electrophoresis (SPE). Abnormal light chains may be excreted in the urine as Bence Jones proteins and, if excessive, may
*Professor, Department of Oral Pathology. **Associate Professor, Department of Chemical Pathology. ***Medical Natural Scientist, Department of Chemical Pathology. 492
cause renal failure.‘O Furthermore, amyloidosis as an additional complication has been reported in 6% to 15% of patients with multiple myeloma.‘1-i4 We present the case of a patient with multiple myeloma in whom oral manifestations of amyloidosis were the most prominent features. CASE
REPORT
A 25-year-old black man was referred from a rural hospitalcomplainingof painlessswellingsbelowthe tongue and over both parotid glandsfor “many years” (Fig. 1, a). His oral mucosawas painful, and he had dysphagia.On examination, bilateral enlargementof the parotid and submandibularsalivary glandsandsubmentallymph nodes was noted. The tongue was enlarged, with a scalloped lateral and anterior border (Fig. 1, b), and limited mobility. Firm gingival enlargementwaspresent(Fig. 1, c) and salivary flow from the major salivary glandswas significantly reduced. Serumprotein electrophoresis showeda faint monoclonal peakin the early gammaarea.BenceJonesprotein was chemically detectedin the urine. IgG, IgA, and IgM, as well as large amountsof kappa light chains,weredemonstrated with immunoelectrophoresis in the serum. The sametechniqueshowedthe presenceof mainly kappalight chainsand small amountsof lambda light chainsin the urine. The serumand urine electrophoreticpatterns are
Volume 61 Number
Multiple
myeloma
with extensive oral and perioral
amyloidosis
493
5
Fig. 1. a, Lateral view of patient, showingenlargementof parotid and submandibularsalivary glands. (Dressingcoversbiopsywound.)b, Anterior borderof enlargedtongueshowingindentationscausedby teeth. c, Enlargementof maxillary gingiva.
Fig. 2. Densitometricscans,electrophoretograms, and iommunoelectrophoretograms of serum(left) and urine (right). Monoclonal peaks are indicated by arrows. On immunoelectrophoreticmembranesthe patient’sspecimens were appliedin the even-numberedwells and control serain the odd-numberedwells. Antisera were placedin the troughsas follows: A, Polyvalent; B, anti-IgG; C, anti-IgA; D, anti-IgM; E, anti-kappa; and F, anti-lambda.
shownin Fig. 2, and the relevant biochemicaland hematologic findingsare presentedin Table I. Radiographicstudiesshowedlytic lesionsin the parietal areaof the skull, posteriorpart of the right sixth rib, right ischium,and pubisand destructionof the sevenththoracic vertebra. No lytic lesionswere presentin the jaws.
In view of these findings, the following differential diagnoses wereconsidered:lymphomawith soft tissueand bony infiltration (probably the adult T-cell lymphomaleukemia syndrome), histiocytosis X, or multiple myeloma. Microscopic examinationof a smearof a bonemarrow
494
Raubenheimer,
Dauth, and de Coning
Oral May,
Surg. 1986
Fig. 3. Photomicrographshowingperivascularpalisadingof plasmacells. (Hematoxylin and eosinstain. Original magnification,X400.)
Table
I. Relevant biochemical
and hematologic
find-
ings Patient’s values Serum Total protein &m/L) Albumin (gm/L) IS tgm/L) IgA (m/L) kM Cm’L) Urea (mmol/L) Creatinine (rmol/L) Uric acid (mmol/L) Total calcium (mmol/L) Urine Total protein (gm/d) Boiling test Bradshaw test Hematology RBC (xlO”/L) WBC @log/L) Hb (g/di) ESR (mm/hr, Wintrobe)
Reference ranges (males)
67 38 12.0 I .2 0.15 4.1 70 0.42 1.94
(60-80) (26-52) (6.4-l 3.5) (0.7-3.12) (0.56-3.5) (2.5-6.7) (53-97) (0.1-0.5) (2.25-2.70)
42 Positive Positive
(<0.08)
4.2 7.8 12.2 45
(5.8 ? 1.0) (7.5 f 3.5) (16.4 + 2.5) (O-20)
aspirateshoweda plasmacytosisof 42 ~01%.Most plasma cells were of the plasmacytoidtype. Sectionsof a bone marrow biopsy specimen(Fig. 3) showedendostealand periarterial accumuiations of plasmacytoid cells with reduction of hematopoietic tissue. Immunoperoxidase staining (Immunolok H&set, Immunoloc Inc., Carpinteria, Calif.) of bonemarrowsectionsshowedthe presence of kappa light chains in the cytoplasmaof the plasma cells.
The tongue, parotid gland, and gingival lesion were biopsiedand containedextensiveamyloid deposits,which reactedpositively with Congored and methylviolet stains. Numerousdilatedcapillarieswith patchy accumulationsof foamy histiocytesand giant cellswerenotedin the amyloid deposits(Fig. 4). A diagnosisof multiple myeloma, plasmacytoidtype, with light-chain secretory activity, Bence Jonesproteinuria, and extensivesecondaryoral amyloidosiswasestablishedand chemotherapywasinstituted. DISCUSSION
Multiple myeloma was placed low on our list of differential diagnoses because of the exceptionally young age of our patient and the faint monoclonal band on SPE. It was after histologic investigations, chemical determinations, and radiographic studies that the diagnosis of multiple myeloma was established. This case illustrates the importance of bone marrow aspiration and biopsy, serum and urine immunoelectrophoretic, and skeletal radiographic studies in the diagnosis, classification, and staging of the disease in suspected cases of multiple myeloma 215.16 It is often impossible to distinguish neoplastic from reactive plasma cell infiltrates on a bone marrow aspirate, as the latter condition could lead to a bone marrow plasmacytosis in excess of 50 v01%.‘~~I* Aspiration cytology, however, gives reliable information regarding the staging of proved’cases of multiple myeloma. Patients with multiple myeloma may be assigned to one of three stages according to the quantity of plasma cells in a bone marrow
Volume Number
6I 5
Multiple
myeloma
with extensive oral and perioral
amyloidosis
495
Fig. 4. Photomicrographshowingextensiveamyloid depositswith associatedgiant cells. (Hematoxylin and eosinstain. Original magnification,x400.)
aspirate: Stage 1, less than 20 ~019%;Stage 2,20 to 50 ~01%; and Stage 3, in excess of 50 vol%. This staging correlates significantly with the clinical progression and survival time of the patient.16 However, microscopic examination of a bone marrow biopsy specimen appears to be more reliable than aspirates in the diagnosis of multiple myeloma, because periarterial and endosteal accumulations of plasma cells, as found in our biopsy material, are characteristic of the neoplastic state. I6 Concomitant hypoplasia of hematopoietic tissue and increased osseous remodeling also favor a neoplastic rather than a reactive plasma cell infiltrate.19 The release of an osteoclastic activating factor by proliferating plasma cells, which causes lytic bone lesions, has previously been demonstrated.*O Multiple myelomas are classified microscopically as plasmacytic and plasmablastic types. The former is characterized by the infiltration of small, normalappearing plasma cells with a low mitotic index and is associated with a longer patient survival time. In contrast to this, the plasmablastic type is characterized by the presence of immature nucleolated plasma cell precursors with a less favorable prognosis.2r’6 The abnormal monoclonal immunoglobulins or subunits produced by the neoplastic cells may be detected in serum and urine before bony lesions or other abnormalities become clinically apparent.‘**’ Renal involvement due to the excretion of excessive amounts of light chains is one of the most important causes of renal failure and death in patients with myeloma.‘” The regular biochemical evaluation of renal function and the quantitation of urinary light
chain levels are therefore prognostically important and serve as valuable indicators of response to treatment.* Light-chain-secreting myelomas are said to have the highest growth rate and are associated with more extensive osteolytic lesions, hypercalcemia, and a higher incidence of renal failure and amyloidosis than the other immunochemical varieties.*, ** Despite the presence of widespread osteolytic lesions and the urinary excretion of large amounts of K-light chains, our patient had hypocalcemia with normal renal function (Table I). The median survival time in X-light-chain disease is reported to be significantly shorter than in K-light-chain disease.‘,22 The aforementioned microscopic and biochemical parameters are useful in predicting the rate of progression and prognosis of the disease. The young age of our patient, and the plasmacytoid cell type place this neoplasm in a category of low proliferation. (The condition is reported to be more benign in younger patients than in older patients.23) The lightchain secretory activity and the presence of Bence Jones protein in the urine, however, are more ominous features, and the extent of plasma cell infiltration of the bone marrow is indicative of the moderately advanced stage of the disease. Amyloidosis occurring with multiple myeloma is characterized by elaboration of light chains by the host. Morphologic evidence indicates that these light chains are converted by proteolytic enzymes in macrophage lysosomes to &pleated sheet fibrils characteristic of amyloid.24-26 These fibrils are excreted extracellularly where polymerization occurs.** The presence of foamy macrophages and giant cells in the
496
Raubenheimer,
Dauth, and de Coning
amyloid deposits in the case under study supports this suggested pathogenesis. Much has been said previously concerning the differential organ involvement in amyloidosis. It was stressed that primary amyloidosis and amyloidosis occurring with multiple myeloma typically involve mesodermal tissues, such as smooth and skeletal muscle, as well as the cardiovascular system, whereas secondary amyloidosis primarily involves the liver, spleen, and kidneys. 29An extensive overlap has been reported recently in large series and review articles,‘*~ I3 and therefore differential organ involvement is no longer considered to be a useful basis for the classification of the different forms of amyloidosis. Modern classification of amyloidosis is therefore based on the composition of the amyloid fibril.2v30 The chemical composition of amyloid secondary to multiple myeloma is related to immunoglobulin light chains and is designated, according to modern nomenclature, A-L protein (A for amyloid fibril protein and L for immunoglobulin light chain).30 Few reports of oral amyloid deposits associated with multiple myeloma are found in the literature.“, 13,31,32 Patients most commonly complain of mucosal pain, often aggravated by the wearing of a denture. Macroglossia and xerostomia due to amyloid deposits in the tongue and salivary glands can lead to dysphagia. The decreased salivary flow noted in our patient was most likely caused by amyloid deposits in the major salivary glands. Reduced lacrimal function has been reported in association with amyloid deposits in the lacrimal glands,32 and it had been noted that exocrine glandular function may be impaired more readily than endocrine function, which is often spared despite extensive amyloid deposits.34.35 Amyloid purpura, a less publicized but valuable diagnostic feature, is most frequently noted in the skin of the head and neck.33s36Purpuric lesions may be produced within 30 to 60 seconds after gentle stroking of this normal-appearing skin. The purpura reflects traumatization of the amyloid-invested small vessels in the upper layers of the dermis. Unfortunately, this technique was not used on our patient. Finally, the absence of lytic jaw lesions in our patient supports the observation of Smith3’ and others”, 32,38that macroglossia secondary to amyloidosis of multiple myeloma has not been associated with myelomatous involvement of the jaws. In view of the advances made in immunochemistry, histopathologic techniques, and a better understanding of multiple myeloma, it has become possible to predict the prognosis of the condition more accurately, provided that a multidisciplinary approach is adopted for diagnosing suspected cases of multiple
Oral Surg. May, 1986
myeloma. Furthermore, therapeutic modulation of macrophage response holds an exciting promise in the prevention of amyloid formation secondary to light-chain-secreting myelomas.39 We are indebted to Prof. J.B. Jordaan for submitting the biopsy specimens and Miss M.M. Holtzhausen, Mrs. C. Begeman, and Mr. C. Lourens for their assistance during the preparation of this manuscript. REFERENCES 1. Farhangi M, Osserman EF: Biology, clinical patterns, and treatment of multiple myeloma and related plasma-cell dyscrasias. In Twomey JJ, Good RA (editors): The immunopathology of lymphoreticular neoplasms, comprehensive immunology, New York, 1978, Plenum Medical Books, pp. 641716. 2. Wintrobe MM, Lee RG, Boggs DR, Bithell TC, Foerster J, Athens JW, Lukens JN: Clinical hematology, ed. 8, Philadelphia, 198 1, Lea & Febiger, pp. 1726-l 760. 3. Hewell GM, Alexanian R: Multiple myeloma in young persons. Ann Intern Med 84: 41 l-443, 1976. 4. Porter SF Jr: Multiple myeloma in a child. J Pediatr 62: 602-604, 1963. 5. Dauth J, de Coning JP, Politzer WM, Robertson T, Raubenheimer EJ: Unusual presentation of multiple myeloma: a report of 2 cases. S Afr Med J 65: 968-97 1, 1984. 6. Epstein JB, Voss NJS, Stevenson-Moore P: Maxillofacial manifestations of multiple myeloma: an unusual case and a review of the literature. ORAL SURG ORAL MED ORAL PATHOL 57: 267-27 1, 1984. 7. Sippel HW, Natiella JR, Greene GW Jr: Multiple myeloma: review and report of case. J Oral Surg 27: 808-819, 1969. 8. McPhedran P, Heath CW, Garcia J: Multiple myeloma incidence in metropolitan Atlanta, Georgia: racial and seasonal variations. Blood 39: 866-873, 1972. 9. Blattner WA, Mason TJ, Blair A: Changes in mortality rates from multiple myeloma. N Engl J Med 302: 814-815, 1980. 10. Jones DB: Kidney. In Kissane JM (editor): Anderson’s pathology, ed. 8, St. Louis, 1985, The C.V. Mosby Company, pp. 730-77 1. II. Cranin AN, Gross ER: Severe oral and perioral amyloidosis as a primary complication of multiple myeloma: report of a case. ORAL SURG ORAL MED ORAL PATHOL 23: 158-163, 1967. 12. Cohen AS: Amyloidosis. N Engl J Med 277: 574-583. 1967. 13. Limas C, Wright JR, Matsuzaki M, Calkins E: Amyloidosis and multiple myeloma: a reevaluation using a control population. Am J Med 54: 166-173. 1973. 14. Kimball KG: Amyloidosis in association with neoplastic disease: report of an unusual case and clinicopathological experience-at Memorial Center for Cancer and Allied Diseases during eleven years (1948-1958). Ann Intern Med 55: 958-974, 1961. 15. Hobbs JR: Immunochemical classes of myelomatosis, including data from a therapeutic trial conducted by a Medical Research Council working-. party._ Br J Haematol 16: 599-606, 1969. 16. Bartl R, Frisch B, Burkhardt R, Fateh-Moghadam A, Mahl G, Gierster P, Sund M, Kettner G: Bone marrow histology in myeloma: its importance in diagnosis, prognosis, classification and staging. Br J Haematol 51: 361-375, 1982. 17. Canale DD, Collins RD: Use of bone marrow particle sections in the diagnosis of multiple myeloma. Am J Clin Path01 61: 383-392, 1974. 18. Huyn BH, Kua D, Gabaldon H, Ashton JK: Reactive plasmacytic lesions of the bone marrow. Am J Pathol 65: 921-928, 1975.
Multiple myeloma with extensive oral and perioral amyloidosis
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19. Hansen 00: Bone marrow studies in myelomatosis. Stand J Haematol 21: 265-272, 1978. 20. Mundy GR, Raisz LG. Cooper RA, Schechter GP, Solomon SE: Evidence for the secretion of an osteoclast stimulating factor in myeloma. N Engl J Med 291: 1041-1046, 1974. 21. Stevens S, Alexander R: Evaluation of multiple myeloma. Arch Intern Med 115: 90-93, 1965. 22. Shustik C, Bergsagel DE, Pruzanski W: K and X-light chain disease: survival rates and clinical manifestations. Blood 48: 41-51, 1976. 23. Lazarus HM, Kellermeyer RW, Aikawa M, Herzig RH: Multiple myeloma in young men: clinical course and electron microscopic studies of bone marrow plasma cells. Cancer 46: 1397-1400, 1980. 24. Glenner GG: Amyloid deposits and amyloidosis: the pfibrilloses (first of two parts). N Engl J Med 302: 1283-1292, 1980. 25. Glenner GG: Amyloid deposits and amyloidosis: the pfibrilloses (second of two Darts). N Enal J Med 302: 1333-
32. 33.
35.
26.
21.
28.
29. 30. 31.
198d.
Glenner GG, Ein D, Eanes ED, Bladen HA, Terry W, Page DL: Creation of “amyloid” fibrils from Bence Jones proteins in vitro. Science 174: 712-714. 1971. Scheinberg MA, Cathcart ES: ‘New concepts in the pathogenesis of primary and secondary amyloid disease. Clin Exp Immunol 33: 185-190, 1978. Glenner GG, Page DL: Amyloid, amyloidosis and amyloidogenesis. In Richter GW, Epstein MA (editors): International review of experimental pathology, New York, 1976 Academic Press, Vol. 15, pp. l-92. Dahlin DC: Secondary amyloidosis. Ann Intern Med 31: 105-132, 1949. Cohen AS, Wegelius 0: Classification of amyloid: 1979-1980. Arthritis Rheum 23: 644-645, 1980. Brandt K, Cathc.lrt ES, Cohen AS: A clinical analysis of the course and prognosis of forty-two patients with amyloidosis. Am J Med 44: 955-969. 1968.
1969.
O’Donnel WM: Changing pathogenesis of Addison’s disease with special reference to amyloidosis. Arch Intern Med 86: 266-271, 1950. Pocock DS, Dickens J: Paramyloidosis with diabetes mellitus and gastro-intestinal hemorrhage. N Engl J med 248: 359364,1953.
30.
Brunsting LA, MacDonald IA: Primary systematized amyloidosis with macroglossia: a syndrome related to Bence Jones proteinuria an.: myeloma. J Invest Dermatol 8: 145-154,
37.
Smith DB: Multiple myeloma involving the jaws: review with report of an additional case. ORAL SURG ORAL MED ORAL
1947.
PATHOL
.
1343,
Cahn L: Oral amyloid as a complication of myelomatosis. ORAL SURGORAL MED ORAL PATHOL 10: 735-742, 1957. Barth WF, Willerson JT, Waldmann TA, Decker JL: Primary amyloidosis: clinical, immunochemical and immunoglobulin metabolism studies in fifteen patients. Am J Med 47: 259-213,
34.
497
38.
39.
10: 910-919,1957.
Bruce KW, Royer RQ: Multiple myeloma occurring in the jaws: a study of 17 cases. ORAL SURG ORAL MED ORAL PATHOL 6: 729-744, 1953. Durie BGM, Perskry B, Soehnlen BJ, Grogan TM, Salmon SE: Amyloid production in human myeloma stem-ceil culture, with morphologic evidence of amyloid secretion by associated macrophages. N Engl J med 307: 1689-1692, 1982.
Reprint
requests
to:
Dr. E. J. Raubenheimer Department of Oral Pathology and Oral Biology Medical University of Southern Africa P.O. Medunsa 0204 Republic of South Africa
UNIVERSITY
OF SOUTHERN
AFRICA
The case of a young adult patient, with a kappa-light-chain-secreting multiple myeloma and extensive oral and salivary gland amyloid deposits, is presented. This case illustrates the necessity of a multidisciplinary approach using biochemical, radiographic, and relevant histologic investigations in the diagnosis of multiple myeloma. Factors influencing the prognosis of this neoplastic condition are discussed. Microscopic examination of the oral amyloid deposits supports the suggested central role played by the macrophage in amyloidogenesis. (ORAL SURG. ORAL MED. ORAL. PATHOL. 61:492-497, 1986)
M
ultiple myeloma is a condition characterized by uncontrolled proliferation of one or more clones of malignant plasma cells. The average age at the time of diagnosis is 62 years, with fewer than 2% of all cases occurring in persons less than 40 years of age.‘s2 Few well-documented cases in patients younger than the third decade have been reported3-’ There is a moderate male preponderance?’ and black persons are affected twice as often as white patients. 8*9 The neoplasm usually arises in hematopoietic bone marrow, and multiple lytic bone lesions are characteristic radiographic findings. In the majority of cases, proliferating plasma cells are responsible for abnormal protein synthesis, which appears in serum as an increase in the concentration of one of the monoclonal types of immunoglobulins or its subunits (heavy or light chains)1-2 and which may be detected with serum protein electrophoresis (SPE). Abnormal light chains may be excreted in the urine as Bence Jones proteins and, if excessive, may
*Professor, Department of Oral Pathology. **Associate Professor, Department of Chemical Pathology. ***Medical Natural Scientist, Department of Chemical Pathology. 492
cause renal failure.‘O Furthermore, amyloidosis as an additional complication has been reported in 6% to 15% of patients with multiple myeloma.‘1-i4 We present the case of a patient with multiple myeloma in whom oral manifestations of amyloidosis were the most prominent features. CASE
REPORT
A 25-year-old black man was referred from a rural hospitalcomplainingof painlessswellingsbelowthe tongue and over both parotid glandsfor “many years” (Fig. 1, a). His oral mucosawas painful, and he had dysphagia.On examination, bilateral enlargementof the parotid and submandibularsalivary glandsandsubmentallymph nodes was noted. The tongue was enlarged, with a scalloped lateral and anterior border (Fig. 1, b), and limited mobility. Firm gingival enlargementwaspresent(Fig. 1, c) and salivary flow from the major salivary glandswas significantly reduced. Serumprotein electrophoresis showeda faint monoclonal peakin the early gammaarea.BenceJonesprotein was chemically detectedin the urine. IgG, IgA, and IgM, as well as large amountsof kappa light chains,weredemonstrated with immunoelectrophoresis in the serum. The sametechniqueshowedthe presenceof mainly kappalight chainsand small amountsof lambda light chainsin the urine. The serumand urine electrophoreticpatterns are
Volume 61 Number
Multiple
myeloma
with extensive oral and perioral
amyloidosis
493
5
Fig. 1. a, Lateral view of patient, showingenlargementof parotid and submandibularsalivary glands. (Dressingcoversbiopsywound.)b, Anterior borderof enlargedtongueshowingindentationscausedby teeth. c, Enlargementof maxillary gingiva.
Fig. 2. Densitometricscans,electrophoretograms, and iommunoelectrophoretograms of serum(left) and urine (right). Monoclonal peaks are indicated by arrows. On immunoelectrophoreticmembranesthe patient’sspecimens were appliedin the even-numberedwells and control serain the odd-numberedwells. Antisera were placedin the troughsas follows: A, Polyvalent; B, anti-IgG; C, anti-IgA; D, anti-IgM; E, anti-kappa; and F, anti-lambda.
shownin Fig. 2, and the relevant biochemicaland hematologic findingsare presentedin Table I. Radiographicstudiesshowedlytic lesionsin the parietal areaof the skull, posteriorpart of the right sixth rib, right ischium,and pubisand destructionof the sevenththoracic vertebra. No lytic lesionswere presentin the jaws.
In view of these findings, the following differential diagnoses wereconsidered:lymphomawith soft tissueand bony infiltration (probably the adult T-cell lymphomaleukemia syndrome), histiocytosis X, or multiple myeloma. Microscopic examinationof a smearof a bonemarrow
494
Raubenheimer,
Dauth, and de Coning
Oral May,
Surg. 1986
Fig. 3. Photomicrographshowingperivascularpalisadingof plasmacells. (Hematoxylin and eosinstain. Original magnification,X400.)
Table
I. Relevant biochemical
and hematologic
find-
ings Patient’s values Serum Total protein &m/L) Albumin (gm/L) IS tgm/L) IgA (m/L) kM Cm’L) Urea (mmol/L) Creatinine (rmol/L) Uric acid (mmol/L) Total calcium (mmol/L) Urine Total protein (gm/d) Boiling test Bradshaw test Hematology RBC (xlO”/L) WBC @log/L) Hb (g/di) ESR (mm/hr, Wintrobe)
Reference ranges (males)
67 38 12.0 I .2 0.15 4.1 70 0.42 1.94
(60-80) (26-52) (6.4-l 3.5) (0.7-3.12) (0.56-3.5) (2.5-6.7) (53-97) (0.1-0.5) (2.25-2.70)
42 Positive Positive
(<0.08)
4.2 7.8 12.2 45
(5.8 ? 1.0) (7.5 f 3.5) (16.4 + 2.5) (O-20)
aspirateshoweda plasmacytosisof 42 ~01%.Most plasma cells were of the plasmacytoidtype. Sectionsof a bone marrow biopsy specimen(Fig. 3) showedendostealand periarterial accumuiations of plasmacytoid cells with reduction of hematopoietic tissue. Immunoperoxidase staining (Immunolok H&set, Immunoloc Inc., Carpinteria, Calif.) of bonemarrowsectionsshowedthe presence of kappa light chains in the cytoplasmaof the plasma cells.
The tongue, parotid gland, and gingival lesion were biopsiedand containedextensiveamyloid deposits,which reactedpositively with Congored and methylviolet stains. Numerousdilatedcapillarieswith patchy accumulationsof foamy histiocytesand giant cellswerenotedin the amyloid deposits(Fig. 4). A diagnosisof multiple myeloma, plasmacytoidtype, with light-chain secretory activity, Bence Jonesproteinuria, and extensivesecondaryoral amyloidosiswasestablishedand chemotherapywasinstituted. DISCUSSION
Multiple myeloma was placed low on our list of differential diagnoses because of the exceptionally young age of our patient and the faint monoclonal band on SPE. It was after histologic investigations, chemical determinations, and radiographic studies that the diagnosis of multiple myeloma was established. This case illustrates the importance of bone marrow aspiration and biopsy, serum and urine immunoelectrophoretic, and skeletal radiographic studies in the diagnosis, classification, and staging of the disease in suspected cases of multiple myeloma 215.16 It is often impossible to distinguish neoplastic from reactive plasma cell infiltrates on a bone marrow aspirate, as the latter condition could lead to a bone marrow plasmacytosis in excess of 50 v01%.‘~~I* Aspiration cytology, however, gives reliable information regarding the staging of proved’cases of multiple myeloma. Patients with multiple myeloma may be assigned to one of three stages according to the quantity of plasma cells in a bone marrow
Volume Number
6I 5
Multiple
myeloma
with extensive oral and perioral
amyloidosis
495
Fig. 4. Photomicrographshowingextensiveamyloid depositswith associatedgiant cells. (Hematoxylin and eosinstain. Original magnification,x400.)
aspirate: Stage 1, less than 20 ~019%;Stage 2,20 to 50 ~01%; and Stage 3, in excess of 50 vol%. This staging correlates significantly with the clinical progression and survival time of the patient.16 However, microscopic examination of a bone marrow biopsy specimen appears to be more reliable than aspirates in the diagnosis of multiple myeloma, because periarterial and endosteal accumulations of plasma cells, as found in our biopsy material, are characteristic of the neoplastic state. I6 Concomitant hypoplasia of hematopoietic tissue and increased osseous remodeling also favor a neoplastic rather than a reactive plasma cell infiltrate.19 The release of an osteoclastic activating factor by proliferating plasma cells, which causes lytic bone lesions, has previously been demonstrated.*O Multiple myelomas are classified microscopically as plasmacytic and plasmablastic types. The former is characterized by the infiltration of small, normalappearing plasma cells with a low mitotic index and is associated with a longer patient survival time. In contrast to this, the plasmablastic type is characterized by the presence of immature nucleolated plasma cell precursors with a less favorable prognosis.2r’6 The abnormal monoclonal immunoglobulins or subunits produced by the neoplastic cells may be detected in serum and urine before bony lesions or other abnormalities become clinically apparent.‘**’ Renal involvement due to the excretion of excessive amounts of light chains is one of the most important causes of renal failure and death in patients with myeloma.‘” The regular biochemical evaluation of renal function and the quantitation of urinary light
chain levels are therefore prognostically important and serve as valuable indicators of response to treatment.* Light-chain-secreting myelomas are said to have the highest growth rate and are associated with more extensive osteolytic lesions, hypercalcemia, and a higher incidence of renal failure and amyloidosis than the other immunochemical varieties.*, ** Despite the presence of widespread osteolytic lesions and the urinary excretion of large amounts of K-light chains, our patient had hypocalcemia with normal renal function (Table I). The median survival time in X-light-chain disease is reported to be significantly shorter than in K-light-chain disease.‘,22 The aforementioned microscopic and biochemical parameters are useful in predicting the rate of progression and prognosis of the disease. The young age of our patient, and the plasmacytoid cell type place this neoplasm in a category of low proliferation. (The condition is reported to be more benign in younger patients than in older patients.23) The lightchain secretory activity and the presence of Bence Jones protein in the urine, however, are more ominous features, and the extent of plasma cell infiltration of the bone marrow is indicative of the moderately advanced stage of the disease. Amyloidosis occurring with multiple myeloma is characterized by elaboration of light chains by the host. Morphologic evidence indicates that these light chains are converted by proteolytic enzymes in macrophage lysosomes to &pleated sheet fibrils characteristic of amyloid.24-26 These fibrils are excreted extracellularly where polymerization occurs.** The presence of foamy macrophages and giant cells in the
496
Raubenheimer,
Dauth, and de Coning
amyloid deposits in the case under study supports this suggested pathogenesis. Much has been said previously concerning the differential organ involvement in amyloidosis. It was stressed that primary amyloidosis and amyloidosis occurring with multiple myeloma typically involve mesodermal tissues, such as smooth and skeletal muscle, as well as the cardiovascular system, whereas secondary amyloidosis primarily involves the liver, spleen, and kidneys. 29An extensive overlap has been reported recently in large series and review articles,‘*~ I3 and therefore differential organ involvement is no longer considered to be a useful basis for the classification of the different forms of amyloidosis. Modern classification of amyloidosis is therefore based on the composition of the amyloid fibril.2v30 The chemical composition of amyloid secondary to multiple myeloma is related to immunoglobulin light chains and is designated, according to modern nomenclature, A-L protein (A for amyloid fibril protein and L for immunoglobulin light chain).30 Few reports of oral amyloid deposits associated with multiple myeloma are found in the literature.“, 13,31,32 Patients most commonly complain of mucosal pain, often aggravated by the wearing of a denture. Macroglossia and xerostomia due to amyloid deposits in the tongue and salivary glands can lead to dysphagia. The decreased salivary flow noted in our patient was most likely caused by amyloid deposits in the major salivary glands. Reduced lacrimal function has been reported in association with amyloid deposits in the lacrimal glands,32 and it had been noted that exocrine glandular function may be impaired more readily than endocrine function, which is often spared despite extensive amyloid deposits.34.35 Amyloid purpura, a less publicized but valuable diagnostic feature, is most frequently noted in the skin of the head and neck.33s36Purpuric lesions may be produced within 30 to 60 seconds after gentle stroking of this normal-appearing skin. The purpura reflects traumatization of the amyloid-invested small vessels in the upper layers of the dermis. Unfortunately, this technique was not used on our patient. Finally, the absence of lytic jaw lesions in our patient supports the observation of Smith3’ and others”, 32,38that macroglossia secondary to amyloidosis of multiple myeloma has not been associated with myelomatous involvement of the jaws. In view of the advances made in immunochemistry, histopathologic techniques, and a better understanding of multiple myeloma, it has become possible to predict the prognosis of the condition more accurately, provided that a multidisciplinary approach is adopted for diagnosing suspected cases of multiple
Oral Surg. May, 1986
myeloma. Furthermore, therapeutic modulation of macrophage response holds an exciting promise in the prevention of amyloid formation secondary to light-chain-secreting myelomas.39 We are indebted to Prof. J.B. Jordaan for submitting the biopsy specimens and Miss M.M. Holtzhausen, Mrs. C. Begeman, and Mr. C. Lourens for their assistance during the preparation of this manuscript. REFERENCES 1. Farhangi M, Osserman EF: Biology, clinical patterns, and treatment of multiple myeloma and related plasma-cell dyscrasias. In Twomey JJ, Good RA (editors): The immunopathology of lymphoreticular neoplasms, comprehensive immunology, New York, 1978, Plenum Medical Books, pp. 641716. 2. Wintrobe MM, Lee RG, Boggs DR, Bithell TC, Foerster J, Athens JW, Lukens JN: Clinical hematology, ed. 8, Philadelphia, 198 1, Lea & Febiger, pp. 1726-l 760. 3. Hewell GM, Alexanian R: Multiple myeloma in young persons. Ann Intern Med 84: 41 l-443, 1976. 4. Porter SF Jr: Multiple myeloma in a child. J Pediatr 62: 602-604, 1963. 5. Dauth J, de Coning JP, Politzer WM, Robertson T, Raubenheimer EJ: Unusual presentation of multiple myeloma: a report of 2 cases. S Afr Med J 65: 968-97 1, 1984. 6. Epstein JB, Voss NJS, Stevenson-Moore P: Maxillofacial manifestations of multiple myeloma: an unusual case and a review of the literature. ORAL SURG ORAL MED ORAL PATHOL 57: 267-27 1, 1984. 7. Sippel HW, Natiella JR, Greene GW Jr: Multiple myeloma: review and report of case. J Oral Surg 27: 808-819, 1969. 8. McPhedran P, Heath CW, Garcia J: Multiple myeloma incidence in metropolitan Atlanta, Georgia: racial and seasonal variations. Blood 39: 866-873, 1972. 9. Blattner WA, Mason TJ, Blair A: Changes in mortality rates from multiple myeloma. N Engl J Med 302: 814-815, 1980. 10. Jones DB: Kidney. In Kissane JM (editor): Anderson’s pathology, ed. 8, St. Louis, 1985, The C.V. Mosby Company, pp. 730-77 1. II. Cranin AN, Gross ER: Severe oral and perioral amyloidosis as a primary complication of multiple myeloma: report of a case. ORAL SURG ORAL MED ORAL PATHOL 23: 158-163, 1967. 12. Cohen AS: Amyloidosis. N Engl J Med 277: 574-583. 1967. 13. Limas C, Wright JR, Matsuzaki M, Calkins E: Amyloidosis and multiple myeloma: a reevaluation using a control population. Am J Med 54: 166-173. 1973. 14. Kimball KG: Amyloidosis in association with neoplastic disease: report of an unusual case and clinicopathological experience-at Memorial Center for Cancer and Allied Diseases during eleven years (1948-1958). Ann Intern Med 55: 958-974, 1961. 15. Hobbs JR: Immunochemical classes of myelomatosis, including data from a therapeutic trial conducted by a Medical Research Council working-. party._ Br J Haematol 16: 599-606, 1969. 16. Bartl R, Frisch B, Burkhardt R, Fateh-Moghadam A, Mahl G, Gierster P, Sund M, Kettner G: Bone marrow histology in myeloma: its importance in diagnosis, prognosis, classification and staging. Br J Haematol 51: 361-375, 1982. 17. Canale DD, Collins RD: Use of bone marrow particle sections in the diagnosis of multiple myeloma. Am J Clin Path01 61: 383-392, 1974. 18. Huyn BH, Kua D, Gabaldon H, Ashton JK: Reactive plasmacytic lesions of the bone marrow. Am J Pathol 65: 921-928, 1975.
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19. Hansen 00: Bone marrow studies in myelomatosis. Stand J Haematol 21: 265-272, 1978. 20. Mundy GR, Raisz LG. Cooper RA, Schechter GP, Solomon SE: Evidence for the secretion of an osteoclast stimulating factor in myeloma. N Engl J Med 291: 1041-1046, 1974. 21. Stevens S, Alexander R: Evaluation of multiple myeloma. Arch Intern Med 115: 90-93, 1965. 22. Shustik C, Bergsagel DE, Pruzanski W: K and X-light chain disease: survival rates and clinical manifestations. Blood 48: 41-51, 1976. 23. Lazarus HM, Kellermeyer RW, Aikawa M, Herzig RH: Multiple myeloma in young men: clinical course and electron microscopic studies of bone marrow plasma cells. Cancer 46: 1397-1400, 1980. 24. Glenner GG: Amyloid deposits and amyloidosis: the pfibrilloses (first of two parts). N Engl J Med 302: 1283-1292, 1980. 25. Glenner GG: Amyloid deposits and amyloidosis: the pfibrilloses (second of two Darts). N Enal J Med 302: 1333-
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Glenner GG, Ein D, Eanes ED, Bladen HA, Terry W, Page DL: Creation of “amyloid” fibrils from Bence Jones proteins in vitro. Science 174: 712-714. 1971. Scheinberg MA, Cathcart ES: ‘New concepts in the pathogenesis of primary and secondary amyloid disease. Clin Exp Immunol 33: 185-190, 1978. Glenner GG, Page DL: Amyloid, amyloidosis and amyloidogenesis. In Richter GW, Epstein MA (editors): International review of experimental pathology, New York, 1976 Academic Press, Vol. 15, pp. l-92. Dahlin DC: Secondary amyloidosis. Ann Intern Med 31: 105-132, 1949. Cohen AS, Wegelius 0: Classification of amyloid: 1979-1980. Arthritis Rheum 23: 644-645, 1980. Brandt K, Cathc.lrt ES, Cohen AS: A clinical analysis of the course and prognosis of forty-two patients with amyloidosis. Am J Med 44: 955-969. 1968.
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Bruce KW, Royer RQ: Multiple myeloma occurring in the jaws: a study of 17 cases. ORAL SURG ORAL MED ORAL PATHOL 6: 729-744, 1953. Durie BGM, Perskry B, Soehnlen BJ, Grogan TM, Salmon SE: Amyloid production in human myeloma stem-ceil culture, with morphologic evidence of amyloid secretion by associated macrophages. N Engl J med 307: 1689-1692, 1982.
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Dr. E. J. Raubenheimer Department of Oral Pathology and Oral Biology Medical University of Southern Africa P.O. Medunsa 0204 Republic of South Africa