American Journal of Hematology 7:77-86 (1979)
Bone Lesions in Primary Amyloidosis Ali Khojasteh, Lowry K. Arnold, and Mehdi Farhangi Division of Hematology-Medical Oncology of the Department of Medicine and the Department of Pathology, University of Missouri-Columbia
Amyloidosis primarily involving bone is described in a 59-year-old male patient. Well circumscribed lytic lesions of the skeleton raised the possibility of myelomatosis. The prolonged insidious course of the disease was uncomplicated by hypercalcemia, pathological fracture, or hematologic abnormalities. The clinical course, together with histological findings and strongly positive bone scan, were the distinguishing features. The osseous manifestation without plasma cell tumor appears to be a rare occurrence in amyloidosis. Key words: amyloidosis, bone lesion, bone scan, amyloid versus myeloma bone lesion
INTRODUCTION
The classification of amyloidosis has long been a controversial issue. Most authors have used the terms “primary” and “secondary” to describe “de novo” amyloidosis and that associated with chronic inflammatory or neoplastic disorders, respectively [ 1,2]. The association of plasma cell dyscrasia (PCD) and “primary” amyloidosis is well established [3]. A Bence-Jones protein andlor a monoclonal immunoglobulin can be identified in urine and/or serum of about 90% of such patients [4,5]. Although marrow plasmacytosis is noted with regularity, evidence of tissue destruction from plasma cell tumors is not demonstrable unless myeloma is also present [5]. A survey of reported series of patients with amyloidosis (excluding myeloma-related amyloidosis) suggests the rarity of osseous lesions [ S , 61. In this report we describe a patient with amyloidosis confined to bone, who presented with multiple osteolytic lesions.
Received for publication February 15, 1979; accepted May 23, 1979. Address reprint requests to Dr. Mehdi Farhangi, Department of Medicine, University of MissouriColumbia, Columbia, MO 65212.
0361-8609/79/0701-0077$02.00 0 1979 Alan R. Liss, Inc.
78
Case Reports: Khojasteh, Arnold, and Farhangi
REPORT OF A CASE
A 59-year-old white male was admitted to the hospital because of mild, constant left-sided chest pain of ten years’ duration. Seven years previously, bone x-rays revealed osteolytic lesions in the ribs, vertebrae, and pelvic bones. The patient, however, refused diagnostic studies at that time. Progressive increases in the size and number of bony lesions were documented by serial radiographic examinations over the ensuing years. Noteworthy in the patient’s past history was the resection of a left pulmonary histoplasmoma. The physical finding was limited to a local tenderness over the left anterior chest wall. Subsequent to the diagnosis of amyloidosis, a careful re-examination revealed none of the physical manifestations of systemic amyloidosis. Laboratory studies showed a hemoglobin of 16 gm/dl; a hematocrit of 48%, WBC of 6,400/mm3 with a normal differential count. The platelet count was 235,000/mm3. The total serum proteins, albumin, calcium, phosphorus, alkaline phosphatase, creatinine, bilirubin, transaminases, blood urea nitrogen, and urinalysis all were within normal range. The serum acid phosphatase, however, was elevated (2.1 and 2.4 milliunits/ml, normal 0-0.8 milliunits/ml). The IgG was 1,059 mg/dl (normal 750-1,500 mg/dl); the IgA was 229 mg/dl (normal 100-350 mg/dl); the IgM was 192 mg/dl (normal 50-180 mg/dl), and the IgD was 2.4 mg/dl (normal 3-40 mg/dl). The serum protein electrophoresis showed no homogeneous peak, and no abnormality was found by the immunoelectrophoresis. Electrophoresis of a concentrated urine showed a distinct beta mobility peak, in addition to a small peak of albumin. Immunoelectrophoretic analysis of urine demonstrated kappa light chain only. The urine contained 0.1-0.15 gni protein per 24-hour collection, with 0.05-0.1 gin Bence-Jones protein. The iliac crest bone marrow aspiration and biopsy was normally cellular with an unremarkable differential count. The plasma cells comprised 1-2% of the nucleated marrow elements. The prostate appeared normal on examination, and a needle biopsy did not disclose any abnormality. The skull x-ray film showed well-circumscribed osteolytic lesions (Fig. 1). Similar lesions were also found in the second lumbar vertebra, pelvic bones, proximal portion of the right femur (Fig. 2), the right humerus, and the right scapula. In addition, expansile lesions were noted in the right 5th, 11t h , and the left 6th ribs (Fig. 3). Some but not all bone lesions were surrounded by a sclerotic margin. A technetium 99m pyrophosphate (99mT~-PP) bone scan showed areas of increased radionuclide uptake in the skull, the ribs, the pelvic bones, and the thoracic and lumbar vertebrae (Figs. 1 and 4). Excisional biopsies of the two rib lesions showed large areas of eosinophilic materials replacing marrow parenchyma (Fig. 5A). Polarized light microscopy of the Congo red stained tissue showed focal apple green birefringence. The amorphous eosinophilic materials were bordered by normal hematopoietic elements. Plasma cells were estimated at less than 3% of the total cellular compartment. Electron microscopic examination (Fig. 5B) demonstrated a random network of non-branching fibrils measuring 10 nm in width with beaded elements spaced along them at 5.5 nm intervals - an ultrastructural morphology specific for amyloid deposits in tissue [7]. We have followed this patient closely since osseous amyloidosis was diagnosed 18 months ago. He has continued to remain relatively asymptomatic. He has maintained a normal hemogram. Neither pathological fracture, hypercalcemia, nor other manifestations of myelomatosis have occurred despite multiple osteolytic lesions. The Bence-Jones proteinuria has remained stable.
Case Reports: Bone Lesions in Primary Amyloidosis
Fig. 1. Osteolytic lesion of the skull exhibiting a marked technetium 9% nuclide uptake (shown in inset).
79
pyrophosphate radio-
Fig. 2. The proximal portion of the right femur and pelvic bones showing multiple areas of bone resorption with faint sclerotic margin.
80
Case Reports: Khojasteh, Arnold, and Farhangi
Fig. 3. An expansile rib lesion which was later resected. See text for histology. Fig. 4. Technetium 99m pyrophosphate (99mTc-PP)bone scan exhibiting multiple areas of increased radionuclide uptake in the skull, the ribs, thoracic and lumbar vertebrae, and the pelvis.
Case Reports: Bone Lesions in Primary Amyloidosis
81
Fig. 5. A. Amorphous amyloid deposit bordered by normal hematopoietic marrow (hematoxylin and eosin, magnification X 100). B. Amyloid fibrils seen on electron microscopic examination of rib lesion (19,500 X). Large collagen fibrils are seen in upper right, above inset. The inset shows amyloid fibrils at 60,000 X magnification.
82
Case Reports: Khojasteh, Arnold, and Farhangi
DISCUSSION
Recent biochemical characterization of amyloid fibril protein has further elucidated the genesis of this heretofore enigmatic tissue proteinosis. The structure of amyloid fibril protein in “primary amyloidosis” is closely related to the variable region of the light chain. A non-immunoglobulin protein (AA) contributes to the structure of most “secondary” amyloid deposits [8]. At times, however, both light chain-related and AA-related structures have been demonstrated in the same amyloid fibril protein [8]. According to the traditional classification, our patient can at best be placed in the group of “primary” amyloidosis, with the kappa Bence-Jones protein as a marker for associated plasma cell dyscrasia (PCD). In cases of PCD, punched out, well circumscribed osteolytic lesions are often taken to support the diagnosis of multiple myeloma [9]. Similar lesions are rarely seen in Waldenstrom macroglobulinema [ 101 and are invariably absent in benign monoclonal gammopathies [I 11. However, in spite of widespread lytic bone lesions, our patient’s symptoms have been mild and stationary. The progressive anemia, pathologic fracture, and hypercalcemia so characteristic of untreated myeloma have not developed. These clinical features, together with the histological appearance of rib lesions and iliac crest biopsies, lead us to believe that the bone lesions in our patient are due to amyloid deposits. Of course plasma cell tumor as the cause of some of his bone lesions cannot be ruled out. Remarkable in this case is distinctly increased (99mTc-PP) uptake in areas of bone resorption. In our experience and the experience of others, limited or absent uptake of radionuclide is the rule in most myelomatous bone lesions [12, 131. It is doubtful that the sclerotic changes bordering some of the osteolytic lesions seen on x-ray are solely responsible for the scan positivity. Most of the lesions demonstrated in the bone scan are radiographically devoid of osteoblastic activity. In addition, the normal serum alkaline phosphatase level is consistent with limited osteoblastic reaction. Thus, it is conceivable that in this patient amyloid deposits are responsible for pronounced 99mTc-PPuptake. Such a postulation, however, awaits future confirmation. The uptake of gallium 67 citrate [ 141, Indium 111-bleomycin [I 31, technectium 99m sulfur colloid, and technetium 99m pertechnetate [ 1.51 by amyloid deposits has been suspected by others. The elevated levels of serum acid phosphatase in our patient initially suggested prostatic carcinoma as a diagnostic possibility. The rectal examination was normal, however, and no carcinomatous tissue was found in any of the biopsy specimens. An elevated acid phosphatase was also observed in a patient with amyloidosis associated with bone lesions (Case 6, Table I); carcinoma of the prostate in this patient was excluded at postmortem examination. A review of the medical literature reveals that myelomatous lesions have not always been histopathologically excluded in reported cases of amyloidosis of bone. Furthermore, in documented cases, plasmacytoma as the cause of some bone lesions in the same patient could not be ruled out with assurance. Nevertheless, we have found nine cases in the English medical literature in which histological proof of amyloid deposits in at least one site was documented by biopsy or at necropsy (see Table I). This series does not include cases with bone lesions due to amyloid-bearing plasmacytoma [25]. We have also excluded cases in which the deposition of amyloid is found adjacent to certain bone tumors or inflammatory processes in the bone [26].
Femur, humerus. ulna
-k
-
f
F
F
M
61
67
71
(Table I continued on next page)
Spine, ribs, pelvic bones
M
44
Spine
Femur, humerus
Humerus, ulna
4-
M
51
Kidney, pancreas, liver, spleen, gastrointestinal tract, adrenal, thyroid blood vessels Joints, heart, gastr ointestinal tract, blood vessels, tongue, vagina Lip, gingiva, lung, tongue, blood vessels, heart, joints, adrenals, kidney, spleen, liver Liver, spleen, adrenals, kidney, lymph node
Tongue, oral mucosa, joints, tendon, lymph nodes
Bones involved Amyloid deposits in with amyloid extraskeletal sites
Bone pain
Sex
Case Age
Neg
*
1
NR
36
18
30
NR
NR
NR
NR
NR
Serum-M component
Survival time since diagBence-Jones nosis proteinuria (months)
TABLE I. The Clinical, Laboratory, and Histological Findings in 10 Cases With Amyloid Bone Lesions
Amyloid deposited in the neighbor- [ I S ] hood of cancellous bone and hematopoetic elements. Hyperplasia of the myeloid series. Bone lesion secondary to amyloid [ 191 involvement of the joint space and adjacent connective tissue, muscle, tendon and blood vessels Foci of amyloid deposits sur[20] rounded by normal marrow
(171
[I61
Reference
Well-defined amyloid tumors in surrounding tissue. Bone destruction appeared to be due to pressure effect Island of amyloid deposits adjacent to normal hematopoetic elements
Histologic findings of bone lesion
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8
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10
Amyloid deposits in extraskeletal sites
Spine, pelvic bones, humerus, radius, tibia Skull, spine, humerus, rib, scapula, femur, pelvic bones Clinically inapparent
Liver, peripheral nerves
Spine, clavicle, Skin, tongue, oral mucarpal bones cosa, gastrointestinal tract, heart, blood vessels, joints
Liver, spleen, kidney, adrenals, tongue, gastrointestinal tract, prostate, testes, pituitary, pineal body, lymph node, joints, heart, blood vessels Spine, humerus, Heart, liver, spleen, femur kidney, adrends
Humerus, femur, pelvic bones
Bones involved with amyloid
NR = not reported. *Diagnosis of amyloidosis was made postmortem.
+
i
-
F
Bone pain
i
62
6
Sex
M
I
Case Age
TABLE I (continued).
Neg
Neg
IgD
Neg
NR
Serum-M component
(K)
Bence-Jones
Neg
Neg
18+
6+
2
15
3%
Survival time since diagBence-Jones nosis proteinuria (months)
Amyloid deposits in bone lesion adjacent to hypercellular bone marrow Bone involvement by amyloid mass extended from adjacent joints. Increased plasma cells (20%)in marrow. N o plasma cell tumor in osteolytic lesions. Hypercellular marrow but no evidence of myeloma. Diffuse amyloid deposition in marrow spaces. Islands of amyloid deposits surrounded by normal bone marrow
Amyloid deposits in blood vessels and bone trabeculae. Increased number of plasma cells, but no evidence of myeloma.
Histologic findings of bone lesion
Present case
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Case Reports: Bone Lesions in Primary Amyloidosis
85
Because of limited case reports and the paucity of clinical data, the natural history of this variant of amyloidosis cannot be clearly defined. In reported cases the age range was 42-72 years, and male patients predominated. Bone pain as a presenting symptom of the disease is described in most cases. Hypercalcemia, however, was noted only once (Case l), and a diagnosis of myeloma was excluded in this patient on the basis of histological examination. Osteolytic lesions were present in all cases. In some cases sclerotic changes were noted. Osseous lesions were often distributed in the long bones. The frequency of long bone involvement is noteworthy and is in contrast to myelomatous lesions, which mostly affect the axial skeleton. In most cases, the marrow bordering islands of amyloid deposits contained normal hematopoietic elements. In some cases the bone lesions appeared to be in contiguity with the articular and periarticular amyloid involvement, and the bone lesions could be attributed to the pressure effect of extraosseous amyloid deposits. In one patient (Case 6), involvement of the nutrient artery was thought to be the primary cause of bone resorption. In all patients except our own case, extraskeletal amyloid deposits were shown by histological examination or suspected on clinical grounds. In only five instances were serum and urine analysis for possible monoclonal gammopathy reported. In our patient a Bence-Jones (K) was demonstrated in urine, and in another patient an IgD serum M-component was shown. The survival time from diagnosis varied from one to 36 months. It would appear, however, that the insidious course of the disease and low index of suspicion delayed the diagnosis in most patients. For example in our own patient, the bony lesions were shown to be present in x-ray films taken seven years prior t o bone biopsy.
REFERENCES 1. Kyle RA, Bayrd ED: “Amyloidosis in the Monoclonal Gammopathies.” Springfield, Illinois: Charles C Thomas, 1976, p p 299-283. 2. Cohn AS: Amyloidosis. N Engl J Med 277:522-530; 574-583, 1967. 3. Osserman EF, Takatsuki K, Tala1 N: The pathogenesis of amyloidosis. Semin Hematol 1: 3-86, 1964. 4. Isobe T, Osserman E F : Patterns of amyloidosis and their association with plasma cell dyscrasia, monoclonal immunoglobulins and Bence-Jones proteins. N Engl J Med 290:473-477, 1974. 5. Kyle RA, Bayrd ED: Amyloidosis: Review of 236 cases. Medicine (Baltimore) 54(4):27 1-299, 1975. 6. Brandt K , Cathcart ES, Cohn AS: A clinical analysis of the course and prognosis of 4 2 patients with amyloidosis. Am J Med 44:955-969,1968. 7. Shirahama T, Cohn AS: High resolution electron-microscopic analysis of the amyloid fibril. J Cell Biol 33:679-708, 1967. 8. Glenner GG, Page DL: Amyloid, amyloidosis and amyloidogenesis. Int Rev Exp Pathol 15:l-92, 1976. 9. Leukemia-Myeloma Task Force of the National Cancer Institute: Guidelines for protocol studies of plasma cell myeloma. Cancer Chemother Rep Part 3 1:17, 1968. 10. McKenzie MR, Fudenberg HH: Macroglobulinemia: An analysis of 40 patients. Blood 39:874889,1972. 11. WaldenstrOm JC: Benign monoclonal gammopathy. In Williams WJ, Beutler E, Erslev AJ, Rundle RW (eds): “Hematology,”, 2nd Ed. New York: McGraw-Hill, 1977, pp 988-991. 12. Wahner HW, Kyle RA, Beabout JW: Imaging of multiple myeloma with 99mTc-labeled diphosphonate. J Nucl Med 16:579, 1975 (abstr). 13. Jones SE, Salmon SE: The role of radionuclide in clinical oncology. Semin Nucl Med 6:331-346, 1976. 14. Bekerman C, Vyas MI: Renal localization of 67 Ga-citrate in renal amyloidosis. J Nucl Med 17: 899-901,1976.
86
Case Reports: Khojasteh, Arnold, and Farhangi
15. Sostre S , Martin ND, Lucas RN, Strauss HW: Scintigraphic findings in primary amyloidosis. An analysis of 7 cases. Radiology 115:675-677, 1975. 16. Von Bonsdorff B: Atypical amyloidosis. Finska Lakaresallskapets Handlingar 75:447, 1933 (Abstracted JAMA, 101:489-490, 1933). 17. Geber IE, Blumental G Jr: Amyloidosis of the bone marrow. Arch Pathol 17:620-630, 1934. 18. Koletsky S, Stecher RM: Primary systemic amyloidosis: Involvement of cardiac valves, joints and bones with pathologic fracture of the femur. Arch Pathol 27:267-288, 1939. 19. Grossman RE, Hensley GT: Bone lesions in primary amyloidosis. Am J Roentgenol Radium Ther Nucl Med 101:872-875,1967. 20. Axellsson U, Hallen A, Rausing A: Amyloidosis of bone - Report of two cases. J Bone Joint Surg 52:717-723, 1970. 21. Weinfeld A, Stern MH, Max LH: Amyloid lesions of bone. Am J Roentgenol Radium Ther Nucl Med 108:799-805,1970. 22. Birchwood B: Primary systemic amyloidosis with bone lesions presenting as hyperlipoproteinemia. Nut1 Metab 17:306-311,1974. 23. Hannon RC, Limas C, Cigtay OS, Twigg HL: Bone and joint involvement in primary amyloidosis. J C a n Assoc Radio1 26:112-115, 1975. 24. Tandon RK, Gupta OK, Kaushik D, Bhargava S: Osteolytic lesions in primary systemic amyloidosis. A case report. J Assoc Physicians India 24:191-194, 1976. 25. Lowell DM: Amyloid producing plasinacytoma of pelvis. Case report and review of the literature. Arch Surg 94:899-903, 1967. 26. Ophills W: Amyloid substance and amylaceous bodies in multiple syphilitic tumors of the bones with remarks on the relation of amylaceous bodies to amyloid substance. J Exp Med 5 : 11 1-130, 1900.
Bone Lesions in Primary Amyloidosis Ali Khojasteh, Lowry K. Arnold, and Mehdi Farhangi Division of Hematology-Medical Oncology of the Department of Medicine and the Department of Pathology, University of Missouri-Columbia
Amyloidosis primarily involving bone is described in a 59-year-old male patient. Well circumscribed lytic lesions of the skeleton raised the possibility of myelomatosis. The prolonged insidious course of the disease was uncomplicated by hypercalcemia, pathological fracture, or hematologic abnormalities. The clinical course, together with histological findings and strongly positive bone scan, were the distinguishing features. The osseous manifestation without plasma cell tumor appears to be a rare occurrence in amyloidosis. Key words: amyloidosis, bone lesion, bone scan, amyloid versus myeloma bone lesion
INTRODUCTION
The classification of amyloidosis has long been a controversial issue. Most authors have used the terms “primary” and “secondary” to describe “de novo” amyloidosis and that associated with chronic inflammatory or neoplastic disorders, respectively [ 1,2]. The association of plasma cell dyscrasia (PCD) and “primary” amyloidosis is well established [3]. A Bence-Jones protein andlor a monoclonal immunoglobulin can be identified in urine and/or serum of about 90% of such patients [4,5]. Although marrow plasmacytosis is noted with regularity, evidence of tissue destruction from plasma cell tumors is not demonstrable unless myeloma is also present [5]. A survey of reported series of patients with amyloidosis (excluding myeloma-related amyloidosis) suggests the rarity of osseous lesions [ S , 61. In this report we describe a patient with amyloidosis confined to bone, who presented with multiple osteolytic lesions.
Received for publication February 15, 1979; accepted May 23, 1979. Address reprint requests to Dr. Mehdi Farhangi, Department of Medicine, University of MissouriColumbia, Columbia, MO 65212.
0361-8609/79/0701-0077$02.00 0 1979 Alan R. Liss, Inc.
78
Case Reports: Khojasteh, Arnold, and Farhangi
REPORT OF A CASE
A 59-year-old white male was admitted to the hospital because of mild, constant left-sided chest pain of ten years’ duration. Seven years previously, bone x-rays revealed osteolytic lesions in the ribs, vertebrae, and pelvic bones. The patient, however, refused diagnostic studies at that time. Progressive increases in the size and number of bony lesions were documented by serial radiographic examinations over the ensuing years. Noteworthy in the patient’s past history was the resection of a left pulmonary histoplasmoma. The physical finding was limited to a local tenderness over the left anterior chest wall. Subsequent to the diagnosis of amyloidosis, a careful re-examination revealed none of the physical manifestations of systemic amyloidosis. Laboratory studies showed a hemoglobin of 16 gm/dl; a hematocrit of 48%, WBC of 6,400/mm3 with a normal differential count. The platelet count was 235,000/mm3. The total serum proteins, albumin, calcium, phosphorus, alkaline phosphatase, creatinine, bilirubin, transaminases, blood urea nitrogen, and urinalysis all were within normal range. The serum acid phosphatase, however, was elevated (2.1 and 2.4 milliunits/ml, normal 0-0.8 milliunits/ml). The IgG was 1,059 mg/dl (normal 750-1,500 mg/dl); the IgA was 229 mg/dl (normal 100-350 mg/dl); the IgM was 192 mg/dl (normal 50-180 mg/dl), and the IgD was 2.4 mg/dl (normal 3-40 mg/dl). The serum protein electrophoresis showed no homogeneous peak, and no abnormality was found by the immunoelectrophoresis. Electrophoresis of a concentrated urine showed a distinct beta mobility peak, in addition to a small peak of albumin. Immunoelectrophoretic analysis of urine demonstrated kappa light chain only. The urine contained 0.1-0.15 gni protein per 24-hour collection, with 0.05-0.1 gin Bence-Jones protein. The iliac crest bone marrow aspiration and biopsy was normally cellular with an unremarkable differential count. The plasma cells comprised 1-2% of the nucleated marrow elements. The prostate appeared normal on examination, and a needle biopsy did not disclose any abnormality. The skull x-ray film showed well-circumscribed osteolytic lesions (Fig. 1). Similar lesions were also found in the second lumbar vertebra, pelvic bones, proximal portion of the right femur (Fig. 2), the right humerus, and the right scapula. In addition, expansile lesions were noted in the right 5th, 11t h , and the left 6th ribs (Fig. 3). Some but not all bone lesions were surrounded by a sclerotic margin. A technetium 99m pyrophosphate (99mT~-PP) bone scan showed areas of increased radionuclide uptake in the skull, the ribs, the pelvic bones, and the thoracic and lumbar vertebrae (Figs. 1 and 4). Excisional biopsies of the two rib lesions showed large areas of eosinophilic materials replacing marrow parenchyma (Fig. 5A). Polarized light microscopy of the Congo red stained tissue showed focal apple green birefringence. The amorphous eosinophilic materials were bordered by normal hematopoietic elements. Plasma cells were estimated at less than 3% of the total cellular compartment. Electron microscopic examination (Fig. 5B) demonstrated a random network of non-branching fibrils measuring 10 nm in width with beaded elements spaced along them at 5.5 nm intervals - an ultrastructural morphology specific for amyloid deposits in tissue [7]. We have followed this patient closely since osseous amyloidosis was diagnosed 18 months ago. He has continued to remain relatively asymptomatic. He has maintained a normal hemogram. Neither pathological fracture, hypercalcemia, nor other manifestations of myelomatosis have occurred despite multiple osteolytic lesions. The Bence-Jones proteinuria has remained stable.
Case Reports: Bone Lesions in Primary Amyloidosis
Fig. 1. Osteolytic lesion of the skull exhibiting a marked technetium 9% nuclide uptake (shown in inset).
79
pyrophosphate radio-
Fig. 2. The proximal portion of the right femur and pelvic bones showing multiple areas of bone resorption with faint sclerotic margin.
80
Case Reports: Khojasteh, Arnold, and Farhangi
Fig. 3. An expansile rib lesion which was later resected. See text for histology. Fig. 4. Technetium 99m pyrophosphate (99mTc-PP)bone scan exhibiting multiple areas of increased radionuclide uptake in the skull, the ribs, thoracic and lumbar vertebrae, and the pelvis.
Case Reports: Bone Lesions in Primary Amyloidosis
81
Fig. 5. A. Amorphous amyloid deposit bordered by normal hematopoietic marrow (hematoxylin and eosin, magnification X 100). B. Amyloid fibrils seen on electron microscopic examination of rib lesion (19,500 X). Large collagen fibrils are seen in upper right, above inset. The inset shows amyloid fibrils at 60,000 X magnification.
82
Case Reports: Khojasteh, Arnold, and Farhangi
DISCUSSION
Recent biochemical characterization of amyloid fibril protein has further elucidated the genesis of this heretofore enigmatic tissue proteinosis. The structure of amyloid fibril protein in “primary amyloidosis” is closely related to the variable region of the light chain. A non-immunoglobulin protein (AA) contributes to the structure of most “secondary” amyloid deposits [8]. At times, however, both light chain-related and AA-related structures have been demonstrated in the same amyloid fibril protein [8]. According to the traditional classification, our patient can at best be placed in the group of “primary” amyloidosis, with the kappa Bence-Jones protein as a marker for associated plasma cell dyscrasia (PCD). In cases of PCD, punched out, well circumscribed osteolytic lesions are often taken to support the diagnosis of multiple myeloma [9]. Similar lesions are rarely seen in Waldenstrom macroglobulinema [ 101 and are invariably absent in benign monoclonal gammopathies [I 11. However, in spite of widespread lytic bone lesions, our patient’s symptoms have been mild and stationary. The progressive anemia, pathologic fracture, and hypercalcemia so characteristic of untreated myeloma have not developed. These clinical features, together with the histological appearance of rib lesions and iliac crest biopsies, lead us to believe that the bone lesions in our patient are due to amyloid deposits. Of course plasma cell tumor as the cause of some of his bone lesions cannot be ruled out. Remarkable in this case is distinctly increased (99mTc-PP) uptake in areas of bone resorption. In our experience and the experience of others, limited or absent uptake of radionuclide is the rule in most myelomatous bone lesions [12, 131. It is doubtful that the sclerotic changes bordering some of the osteolytic lesions seen on x-ray are solely responsible for the scan positivity. Most of the lesions demonstrated in the bone scan are radiographically devoid of osteoblastic activity. In addition, the normal serum alkaline phosphatase level is consistent with limited osteoblastic reaction. Thus, it is conceivable that in this patient amyloid deposits are responsible for pronounced 99mTc-PPuptake. Such a postulation, however, awaits future confirmation. The uptake of gallium 67 citrate [ 141, Indium 111-bleomycin [I 31, technectium 99m sulfur colloid, and technetium 99m pertechnetate [ 1.51 by amyloid deposits has been suspected by others. The elevated levels of serum acid phosphatase in our patient initially suggested prostatic carcinoma as a diagnostic possibility. The rectal examination was normal, however, and no carcinomatous tissue was found in any of the biopsy specimens. An elevated acid phosphatase was also observed in a patient with amyloidosis associated with bone lesions (Case 6, Table I); carcinoma of the prostate in this patient was excluded at postmortem examination. A review of the medical literature reveals that myelomatous lesions have not always been histopathologically excluded in reported cases of amyloidosis of bone. Furthermore, in documented cases, plasmacytoma as the cause of some bone lesions in the same patient could not be ruled out with assurance. Nevertheless, we have found nine cases in the English medical literature in which histological proof of amyloid deposits in at least one site was documented by biopsy or at necropsy (see Table I). This series does not include cases with bone lesions due to amyloid-bearing plasmacytoma [25]. We have also excluded cases in which the deposition of amyloid is found adjacent to certain bone tumors or inflammatory processes in the bone [26].
Femur, humerus. ulna
-k
-
f
F
F
M
61
67
71
(Table I continued on next page)
Spine, ribs, pelvic bones
M
44
Spine
Femur, humerus
Humerus, ulna
4-
M
51
Kidney, pancreas, liver, spleen, gastrointestinal tract, adrenal, thyroid blood vessels Joints, heart, gastr ointestinal tract, blood vessels, tongue, vagina Lip, gingiva, lung, tongue, blood vessels, heart, joints, adrenals, kidney, spleen, liver Liver, spleen, adrenals, kidney, lymph node
Tongue, oral mucosa, joints, tendon, lymph nodes
Bones involved Amyloid deposits in with amyloid extraskeletal sites
Bone pain
Sex
Case Age
Neg
*
1
NR
36
18
30
NR
NR
NR
NR
NR
Serum-M component
Survival time since diagBence-Jones nosis proteinuria (months)
TABLE I. The Clinical, Laboratory, and Histological Findings in 10 Cases With Amyloid Bone Lesions
Amyloid deposited in the neighbor- [ I S ] hood of cancellous bone and hematopoetic elements. Hyperplasia of the myeloid series. Bone lesion secondary to amyloid [ 191 involvement of the joint space and adjacent connective tissue, muscle, tendon and blood vessels Foci of amyloid deposits sur[20] rounded by normal marrow
(171
[I61
Reference
Well-defined amyloid tumors in surrounding tissue. Bone destruction appeared to be due to pressure effect Island of amyloid deposits adjacent to normal hematopoetic elements
Histologic findings of bone lesion
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59
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8
9
10
Amyloid deposits in extraskeletal sites
Spine, pelvic bones, humerus, radius, tibia Skull, spine, humerus, rib, scapula, femur, pelvic bones Clinically inapparent
Liver, peripheral nerves
Spine, clavicle, Skin, tongue, oral mucarpal bones cosa, gastrointestinal tract, heart, blood vessels, joints
Liver, spleen, kidney, adrenals, tongue, gastrointestinal tract, prostate, testes, pituitary, pineal body, lymph node, joints, heart, blood vessels Spine, humerus, Heart, liver, spleen, femur kidney, adrends
Humerus, femur, pelvic bones
Bones involved with amyloid
NR = not reported. *Diagnosis of amyloidosis was made postmortem.
+
i
-
F
Bone pain
i
62
6
Sex
M
I
Case Age
TABLE I (continued).
Neg
Neg
IgD
Neg
NR
Serum-M component
(K)
Bence-Jones
Neg
Neg
18+
6+
2
15
3%
Survival time since diagBence-Jones nosis proteinuria (months)
Amyloid deposits in bone lesion adjacent to hypercellular bone marrow Bone involvement by amyloid mass extended from adjacent joints. Increased plasma cells (20%)in marrow. N o plasma cell tumor in osteolytic lesions. Hypercellular marrow but no evidence of myeloma. Diffuse amyloid deposition in marrow spaces. Islands of amyloid deposits surrounded by normal bone marrow
Amyloid deposits in blood vessels and bone trabeculae. Increased number of plasma cells, but no evidence of myeloma.
Histologic findings of bone lesion
Present case
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Case Reports: Bone Lesions in Primary Amyloidosis
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Because of limited case reports and the paucity of clinical data, the natural history of this variant of amyloidosis cannot be clearly defined. In reported cases the age range was 42-72 years, and male patients predominated. Bone pain as a presenting symptom of the disease is described in most cases. Hypercalcemia, however, was noted only once (Case l), and a diagnosis of myeloma was excluded in this patient on the basis of histological examination. Osteolytic lesions were present in all cases. In some cases sclerotic changes were noted. Osseous lesions were often distributed in the long bones. The frequency of long bone involvement is noteworthy and is in contrast to myelomatous lesions, which mostly affect the axial skeleton. In most cases, the marrow bordering islands of amyloid deposits contained normal hematopoietic elements. In some cases the bone lesions appeared to be in contiguity with the articular and periarticular amyloid involvement, and the bone lesions could be attributed to the pressure effect of extraosseous amyloid deposits. In one patient (Case 6), involvement of the nutrient artery was thought to be the primary cause of bone resorption. In all patients except our own case, extraskeletal amyloid deposits were shown by histological examination or suspected on clinical grounds. In only five instances were serum and urine analysis for possible monoclonal gammopathy reported. In our patient a Bence-Jones (K) was demonstrated in urine, and in another patient an IgD serum M-component was shown. The survival time from diagnosis varied from one to 36 months. It would appear, however, that the insidious course of the disease and low index of suspicion delayed the diagnosis in most patients. For example in our own patient, the bony lesions were shown to be present in x-ray films taken seven years prior t o bone biopsy.
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Case Reports: Khojasteh, Arnold, and Farhangi
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