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Prospective and serial study of primary amyloidosis with serum amyloid P component scintigraphy: from diagnosis to prognosis
Prospective and Serial Study of Primary Amyloidosis Serum Amyloid P Component Scintigraphy: From Diagnosis to Prognosis
with
E. Hachulla, MD, PhD, L. Maulin, MD, M. Deveaux, PhD, T. Facon, MD, Lifle, France, 0. B&y, MD, Paris, France, Ph. Vanhille, MD, Vafertciennes, France, B. Wechsler, MD, P. Godeau, MD, Paris, France, H. Levesque, MD, PhD, Rouen, France, P.Y. Hatron, MD, D. Huglo, MD, B. Devulder, MD, X. Marchandise, MD, Li/fe, France
OBJECTIVE: The purpose of this study was to assess the value of the serum amyloid P (SAP) component scintigraphy in patients with primary amyloidosis (AL). MATERIAL AND METHODS: Pure human SAP labeled with iodine-123 (1231-SAP) was given intravenously to 24 patients with biopsy-proven systemic amyloidosis (15 without multiple myeloma = group 1, and 9 with multiple myeloma = group 2) and to 6 patients with multiple myeloma without any clinical or biological signs of amyloidosis (group 3). Whole-body images as well as regional views and tissue retention levels were obtained after 24 hours. Our study was approved by the institutional review committee and all individuals gave informed consent and were prospectively studied (median 13 months, range 1 to 47 from the date of the scintigraphy to May 1995). RESULTS: Organ localization of 1231-SAP, indicating the presence of substantial visceral amyloid deposits, was observed in all patients in group 1 and 2. The organ uptake of 1231-SAP included the spleen (1 patient was splenectomized) in 20 of 23 cases (87%), the liver in 15 of 24 (60%), and the kidneys in 6 of 24 (25%). Myocardial 1231-SAP was never seen although 13 out of the 24 patients had clinical or echographic data for amyloidosis. Twentyfour hour tissue retention was significantly elevated in all patients (group 1 and group 2): 55.66% + 19.16% in group 1 and 34.37% +
From the Department of Internal Medicine, Hdpital Cl. Huriez (EH, LM, PYH, BD), Department of Nuclear Medicine IMD,.DH, XM), and Department of Hematology (TF) CHRU de Lille, France; Department of Internal Medrcine, Hopital Katie Salpetriere (OB, BW, PG) CHRU de Paris, France; Department of Nephrology, Hopital de Valenciennes (Pv), France; and De oartment of Internal Medicine (HL). CHRU de Rouen. France. Requests for reprints should be addressed to Eric Hachulla, MD, PhD, Department of Internal Medicine, Hopital Claude Huriez, Centre Hospitalier RegIonal, University of Lille, Place de Verdun, 59037 Lil e cedex, France. Manuscript submitted November 18, 1994, and accepted in revised form February 26, 1996.
01996 by Excerpta All rights reserved.
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24.92% in group 2, as compared with normal levels ~24%. The sensitivity of the technique was 79% when only organ uptake was considered but reached 100% when tissue retention was also considered. The 24-hour tissue retention might be correlated with the severity of the amyloidosis: mean survival in patients with tissue retention greater than 50% was 11.3 months versus 24.5 months in patients with levels less or equal to 50%. Five of the 6 patients with multiple myeloma without evidence of amyloidosis had abnormal 1:Z31-SAP imaging and 24-hour tissue retention levels. In 2 of them, amyloidosis was secondly detected. In the 9 patients who had two scintigraphies, variations in 24-hour tissue retention values were in accordance with the clinical evaluation. CONCLUSIONS: Spleen and liver distribution of amyloidosis is mostly revealed by 1231-SAP scintigraphy in patients with AL amyloidosis. The uptake of 1231-SAP appeared in proportion to the quantity of amyloidosis present in ‘different tissues, and the relative quantity of amyloid deposits in the myocardium, carpal tunniel, digestive tract, and kidneys was often small and seldom visualized by 1231-SAP scintigraphy. In contrast 24-hour tissue retention levels were abnormal in all cases of known AL amyloidosis. This may be a positive argument for the diagnosis of amyloidosis when histopathological tests are normal. Tissue retention levels appear important as they may be correlated wit:h survival. Am .J Med. 1996;101:77-87. iagnosis of amyloidosis is usually made by the demonstration of apple-green birefringence in Congo red-stained tissue specimens examined with polarized microscopy. There are two main forms of acquired systemic amyloidosis: ’ Primary amyloidosis (AL) occurs in patients with plasma cell dyscrasia, in which fragments of monoclonal immunoglobulin light chains form amyloid fibrils; secondary amyloidosis (AA) occurs in patients with clhronic inflammatory conditions, in which the fibril protein is
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derived from the serum amyloid A protein. In addition to the fibrils, all amyloid deposits contain amyloid P component, a nonfibrillar glycoprotein, derived from the serum amyloid P component (SAP), a normal circulating protein’s3 Both types of amyloidosis are usually fatal due to the accumulation of amyloid fibrils in the tissues, destroying normal structure and function. The median survival of patients with AL amyloidosis is estimated to be less than 15 months.4 Labial salivary gland biopsies using antibodies directed against the SAP component is a reliable test for the diagnosis of amyloidosis (sensitivity of 86%)) 5 but histologic examination provides very limited information about the distribution in tissues and the extent of diseaseprogression. Recently, it has been shown that iodine-labeled SAP can be used for locating foci of amyloidosis.fi,7 In addition, iodine-labeled SAP turnover may be valuable for monitoring systemic amyloidosis.7 We evaluated prospectively 24 patients with biopsy-proven systemic AL amyloidosis and 6 patients with multiple myeloma without any clinical or biological signs of amyloidosis. We discuss here i2”I-SAP scintigraphy in diagnosing amyloidosis, in identifying the distribution of amyloid deposits, and in determining the prognosis. The usefulness of this technique in serial study is equally discussed.
Patients We studied 24 patients with biopsy-proven AL systemic amyloidosis group 1 was 15 patients without multiple myeloma; group 2 was 9 patients with multiple myeloma; and group 3 consisted of 6 patients with multiple myeloma without any clinical or biological signs of amyloidosis. The diagnosisof multiple myeloma was performed using the SWOG criteria and the staging according to Durie and Salmon.11’12 Nine of the patients with AL amyloidosis had two ‘23I-SAP scintigraphies within an interval of 4 to 31 months. Three patients in group 3 had two ‘?-SAP scintigraphies at U&month intervals. From the time of the scintigraphy to May 1995, all patients were prospectively studlied (median 13 months, range 1 to 47) with clinical assessment, serological and urine analysis, and sometimes echocardiography. Six healthy subjects were studied to establish normal data
Scanning
Protocol
Patients with a history of adverse reactions to iodine or intravenous radiological contrast media were excluded. Prior to injection, thyroid uptake of free iodine was blocked by lug01 2 days be:fore the imaging procedure, and by potassium perchlorate administered orally on the day of injection. Intravenous injection consisted of approximately 150 MBq containing 400 yg ‘231-SAP.The effective dose equivalent MATERIALS AND METHODS was 3.5mSv.7 Anterior and posterior whole-body imPreparation of Radiolabeling of SAP ages and regional views were acquired after 3 and 24 Component hours. Whole-body data were acquired with a Sera from regular blood donors were collected in a gamma-camera equipped with a large rectangular blood transfusion center (CRTS) and the SAP com- field (DSX Sopha Medical, But, France) using a meponent was isolated according to the method de- dium-energy high-resolution collimator. Scan speed scribed by De Beer and Pepys’ with several modiflca- was 12 cm/minute. For regional views, a circular tions. The SAP component was purified by field gamma-camera (DS7 Sopha Medical) equipped immunoaffinity chromatography, obtaining a purity of with a medium-energy high-resolution collimator more than 99%. Virus inactivation was performed ac- was used. Preset time was 600 s. All pictures were cording to the technique described by Horowitz et al9 displayed on x-ray film. All first scans were interNo contaminating bands were detected in 4% to 30?! preted without knowledge of clinical data. Then the gradient non-denaturing gels or with SDS-PAGE. Pu- results were considered in relation to clinical data. rified SAP was iodinated by a modified iodogen’s Discrepancies such as heart localization are evoked method. Briefly, to 500 ,ug SAP in 0.5 mL of 0.1 M PBS in the discussion section. (pH 7.4), 10 PL of 0.8 mM KI and 185 MBq of 1231 (I123LAB-B, CIS Bio International, Gifsur, Yvette, Clearance of 1231-SAP Component and Tissue France) were added. This suspension was transferred Retention Activity Venous samples were obtained at 5, 15, and 30 to a vial containing iodogen previously solubilized in dichloromethane. Each time labeling yield was mea- minutes, and at 1, 2, 3, 4, 24 and 48 hours after insured, it was greater than 97%.Electrophoretic and im- jection. All urine samples were collecte’d separately munoelectrophoretic controls did not indicate that la- within 2 days. One mL of each plasma sample, and beling of the purified SAP component caused 5 mL of the urine samples were each counted toalteration of the molecule. Furthermore, functional in- gether with an aliquot of the injected material in 1 tegrity of labeled SAP component was confirmed, since mL and 5 mL, respectively. As no other significant it retained its calcium-dependent binding to sepharose excretion route exists for SAP, whole-body retention and to amyloid fibrils in vitr~.~~~’Final preparation of was calculated at 24 hours, by subtracting the cumulative activity excreted in the urine from the total ‘?-SAP was sterile and nonpyrogenic. 78
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injected dose. In all patients the remaining tissue retention activity was evaluated at 24 hours after injection, by subtracting plasma activity from wholebody retention values. The analysis of variance (ANOVA or Kruskal-Wallis depending on the data) was used to compare groups. The chi-square test was used for the comparison of percentages. Survival analysis was performed using the Kaplan-Meier method for representation and the Mantel-Menszel test for comparison of groups. Multifactoral analysis of survival was performed by the Cox model. The study was approved by the institutional review committee and all individuals gave informed consent.
dosis (nephrotic syndrome or g1omeruk-x proteinuria) and only 6 out of the 13 patients had a,bnormal kidney ‘231-SAPfixations. The mean 24-hour tissue retention was 45.66% -C 15.83% in the patients with kidney fixation (6 of 13) versus 65.57% t 17.17 in the patients without kidney fixation (7 of 13; P = 0.05). Myocardial 1231-SAP fixation was never seen, although 13 out of the 24 patients had clinical or echography data of amyloidosis. Twenty-four hour tissue retention was elevated in 19 of 24 patients with proven amyloidosis: 55.66% ? 19.16%in group 1 and 34.37% ? 24.92%in group 2 (P = 0.005). This gave a sensitivity of 79%, a specificity and a. positive predictive value of lOO%,and a negative predictive value of 54%.But when organ uptake was considered RESULTS with the 24-hour tissue retention (abnormdl >24%), Healthy Subjects the ‘231-SAPscintigraphy was abnormal in all 24 paAbnormal 1231-SAF’ uptake was never observed in tients with proven amyloidosis; the specificity and the 6 normal subjects. The 24-hour tissue retention the negative predictive value reached lOO%.. values were 2%, 5%, 6%, 8%, 13%,and 24%. Nine of the patients with proven amyloidosis had two ‘?-SAF’ scintigraphies at different interlrals (TaPatients with Proven AL Amyloidosis ble IV). A concordance between stable or diminishing There were 15 patients in group 1 (6 men and 9 24hour tissue retention values and a stabilization or women), age (mean t SD) 56.8 2 10.9 years; and 9 improvement of clinical or biological data was noticed patients in group 2 (7 men and 2 women), age 58.5 t- in patient number 3, 10, 11, and 19. In patient number 8.6. No statistically significant difference was found be- 4, 21, and 22, the augmentation in the 24hour tissue tween the two groups concerning ageand gender. Clin- retention value was associated with the degradation of ical, pathological, and laboratory flndings are summa- clinical data The results observed in patient 8 and 24 rized in Table I and Table II. Results of ‘?SAP scans are controversial: in the first one, the nephrotic synand the values of ‘231-SAF’tissue retention at 24 hours drome disappeared despite an enhancement in the 24 are expressed in these same tables. Uptake into thy- hour tissue retention (31% to 49%) ; in the sec’ondcase, roid, salivary glands or gastrointestinal tract must be a stable condition (no deterioration in organ function) considered with caution due to the possible concen- was associated with an increase in the 24hour tissue tration of free iodine in these tissues. Figure 1 shows retention (8% to 24%) coupled with the apparition of whole-body scans obtained in a control and in two pa- liver and spleen uptake. The median follow-up in this study was 13 tients with amyloidosis. Histological proven amyloidosis was demon- months (range 1 to 47) from the first scintigraphy. strated in 18 of 22 patients via a minor salivary gland The 24-hour tissue retention is important .asit may biopsy, in 4 of 6 with an abdominal fat biopsy, in 5 be correlated with the severity of the amyloidosis: of 7 with a rectal submucosa biopsy, and in 7 of 8 15 patients died during the period of study, 9 had with a renal biopsy. Organ localization of 1231-SAP, more than 50% 24-hour tissue retention. Figure 2 indicating the presence of substantial visceral amy- shows the Kaplan-Meier survival curves after the scintigraphy, dividing the patients into two groups, loid deposits, was observed in all patients. Table III shows the involvement of different organs compared greater than and less than or equal to 50% retenwith scanning imaging. The organ uptake of ‘“31-SAP tion. The adjusted relative risks derived from the Cox regression model included the variables age, included the spleen in 20 of 23 cases (87%; 1 patient was splenectomized) , the liver in 15 of 24 (60%)) and multiple myeloma, congestive heart failure, and the kidneys in 6 of 24 (25%). All patients with clini- tissue retention. Only congestive heart failure sigcally or biologically suspected liver amyloidosis (he- nificantly influenced the survival (P = 0.04). Mean patomegalia or cholestasis, n = 8), had abnormal survival for the patients with less than or equal to ‘231-SAPcomponent fixation in the liver (5 of 8 had 50% retention was 24.5 months (the mesdian surpositive a liver biopsy, the 3 others did not have a vivan was not reached), mean survival for the patients with more than 50% retention was 11.3 liver biopsy done). In 7 out of the 24 patients without suspected liver amyloidosis, an abnormal liver lz31- months (median 4.5) but this did not reach a sigSAP fixation was found. In contrast, 13 out of the 24 nificant level in the Cox regression model (P = patients had biologically suspected kidney amyloi- 0.08). July 1996
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TABLE I Characteristics
Patient Number
of 15 Patients with AL Amyloidosis without Multiple Myeloma (Group 1). Results of 1231-SAP Component Scans and 9-SAP Component Tissue Retention
Gender and Age (Years)
1
F/71
2
M/54
3
F/62
4
M/42
5
F/5 1
6
M/69
7
M/47
8
F/61
9
F/80
Clinical, Biological or Echographic Data at Time of Scintigraphy
IgG kappa Proteinura 6 g/24 h and renal insufficiency Congestive heart failure IgG lambda Congestive heart failure Splenomegaly Purpura Neuropathy Urinary light lambda chains Congestive heart failure Carpal tunnel syndrome Orthostatic hypotension Nephrotic syndrome Urinary light lambda chains Congestive heart failure Splenomegaly Cholestasis Nephrotic syndrome Orthostatic hypotension Gastric bleeding Urinary light lambda chains Purpura Myocardial hypertrophia Goiter Urinary light lambda chains Macroglossia Congestive heart failure Urinary light lambda chains Purpura Hepatomegaly Cholestasis Neuropathy Nephrotic syndrome Renal insufficiency IgA lambda and IgG lambda Neuropathy Nephrotic syndrome No detectable light chains Hepatomegalia Cholestasis Renal insufficiency
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M-Hour Tissue Retention (Normal <24%)
Biopsy-proven Amyloidosis
Pathological Sites of lz31SAP Uptake
Labial salivary gland
Spleen
28%
21 months Colchicine and VAD: death from congestive heart failure
Skin Spleen Negative labial salivary Orbitar gland and abdominal fat biopsy
51%
5 months VMCP: death from congestive heart failure
Labial salivary gland Abdominal fat Liver
Spleen Liver Carpal
72%
26 months VBMCP: decrease of proteinuria, heart condition stable
Bone marrow Gastric Kidney Negative rectal submucosa and labial salivary gland biopsy
Spleen Liver
68%
15 months Colchicine and V&MCP: increase of proteinuria, death from evolutive amyloidosis
Thyroid Labial salivary gland
Spleen Thyroid
54%
3 months VAD: death from congestive heart failure
Labial salivary gland Abdominal fat Bone marrow Rectal submucosa Ocular conjonctive Labial salivary gland Bone marrow Rectal submucosa Kidney
Spleen
64%
4 months VAD: death from congestive heart failure
Spleen Liver
65%
13 months VBMCP: death from congestive heart failure
Labial salivary gland Abdominal fat Kidney Vesical
Kidney Salivary glands Lombar rachis
31%
Kidney with positive anti-kappa staining Negative abdominal fat biopsy
Spleen Liver Salivary glands Thyroid Digestive tract
67%
25 months Colchicine and VBMCP: disappearance of the nephrotic syndrome, persistence of proteinuria <1,5 g/24 h 3 months Absence of treatment, death of unknown origin
Only one autopsy had to be done, making it possible to compare the quantity of amyloid deposits in different organs with the SAP scans (patient 7, 80
ET AL
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Follow-up Evolution
Study and after Scintigraphy
only liver and spleen showed ‘231-SAP uptake): Massive amyloid deposits were found in spleen, liver, and adrenal gland, whereas only perivascular
SCINTIGRAPHY STUDY OF PRIMARY AMYLOIDOSIS/HACHULLA TABLE
ET AL
I Continued
Patient Number
Gender and Age (Years)
10
F/54
11
M/44
12
M/54
13
F/59
14
F/44
15
F/61
Clinical, Biological or Echographic Data at Time of Scintigraphy
IgG kappa Hepatomegalia Nephrotic syndrome IgG lambda Nephrotic syndrome Urinary light lambda chains Hepatomegalia Cholestasis Neuropathy Nephrotic syndrome No detectable light chains Hepatomegalia Cholestasis Congestive heart failure No detectable light chains Arthropathy Nephrotic syndrome Renal insufficiency No detectable light chains Macroglossia
VAD = vincristine/doxorubicin/dexamethasone;
VBMCP
Pathological Sites of lz31SAP Uptake
Biopsy-proven Amyloidosis
Labial salivary gland Kidney Kidney
Labial salivary gland Liver Spleen Rectal submucosa Labial salivary gland with anti-kappa staining Gastric with anti-kappa staining Labial salivary gland with anti-kappa staining Kidney with anti-kappa staining Negative rectal submucosa biopsy Labial salivary gland with anti-lambda staining Liver Rectal submucosa
24-Hour Tissue Retention (Normal <24%)
Spleen Liver Kidney Spleen Liver Kidney Adrenal glands Liver (splenectomy)
72% 53%
Follow-up Evolution
Study and after Scintigraphy
42 months VAD: disappearance of the nephrotic syndrome 16 months Colchicine and VAD: stabilization
69%
4 months VAD: death from liver and kidney failure
Spleen Liver Bone marrow
40%
7 months VAD: death from liver failure
Spleen
75%
12 months VAD: stabilization
Spleen Liver
14%
39 months VBMCP: stabilization
= vincristlne~CNU/melphalan/cyclophosphamide/prednisone.
deposits were observed in myocardium, digestive tract, kidneys, and lungs. This confirms that in patients with massive amyloidosis deposits in the liver or spleen, a major percentage of the injected lz31-SAP was concentrated rapidly in these areas after injection.
acute carpal tunnel syndrome, which required surgery. Histopathological study confirmed the diagnosis of amyloidosis. At the time of the second scintigraphy, cardiac localization was found after echography and the retention raised froim 37% to 46%. In patient 26, 24-hour tissue retention value was 40%. A systematic labial salivary gland biopsy Multiple Myeloma Patients Without Evidence of revealed asymptomatic amyloid deposits. This patient had a severe myeloma that required polyAL Amyloidosis Among the 6 patients with myeloma without ev- chemotherapy. The second 24-hour tissue retenidence of amyloidosis, 3 had serial 1231-SAPscintig- tion 10 months later was less than 14% and no signs of amyloidosis appeared. Patients 27 and 28 raphies at lo-month intervals (Table IV and Table V ). Four of the 6 patients had high 24-hour tissue had abnormal 24-hour tissue retention levels but retention values, with a mean value of 31.16% L 9% no signs of amyloidosis appeared after more than 1 year of follow-up. with occasional abnormal visceral visualization. One patient had normal imaging and normal 24hour tissue retention values; the other had normal DISCUSSION There is no gold standard for the evalluation of 24-hour tissue retention but had pathological spleen uptake values. Patient 25 had a high 24-hour amyloidosis. Various treatments have been attissue retention (37%). Three months after the first tempted guided by biological and echographic data4 scintigraphy patient 25 suddenly developed an Repeated biopsies are often impractical, and the July 1996
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rABLE II Characteristics
‘atient lumber 16
17
18
19
20
21
22
23
24
of 9 Patients with AL Amyloidosis and Multiple Myeloma (Group 2). Results of 1231-SAP Compcbnent Scans and ‘*‘I-SAP Component Tissue Retention 24-Hour Tissue Clinical, Pathological RetenDurie and Biological or BiopsySites of 1231- tion Gender and Salmon Echographic proven SAP (Normal Follow-up Study and Age (years) Classification Data Amyloidosis Fixation ~24%) Evolution F/48 Stage III Urinary light kappa Labial salivary Spleen 34% 3 months chains gland Kidney VAD: stabilization; death from Skin Lombar spine septic process Purpura Proteinuria Negative kidney biopsy 14% 23 months M/56 Stage I IgG lambda Labial salivary Spleen Congestive heart gland Colchicine and VMCP-VBAP: failure death from congestive heart Diarrhea failure M/62 Stage I IgA kappa Labial salivary Spleen 59% 3 months Liver Diarrhea gland VMCP-VBAP: death from Occlusion Gastric tract Left lung occlusive syndrome and and colic cachexia Liver Rectal submucosa Digestive tract Gastric 15% 47 months M/58 Stage I IgA kappa MP: stabilization of Malabsorption Negative labial Lungs amyloidosis; death from salivary cerebral tumor gland biopsy Labial salivary Spleen 50% 28 months M/64 Stage I IgG lambda Liver MPC: stabilization of Congestive heart gland Kidney neuropathy, but increase of failure nephrotic syndrome and Nephrotic syndrome onset of orthostatic hypotension Neuropathy Skin Spleen 34% 32 months M/72 Stage I IgA lambda Colchicine and MP: Macroglossia Negative labial Liver aggravation of nephrotic Purpura salivary Kidney Nephrotic gland biopsy syndrome and appearance of congestive heart failure syndrome 12% 10 months M/51 Stage I IgG lambda Labial salivary Spleen Purpura gland Liver VBMCP: death from congestive heart failure Congestive heart Skin Salivary glands failure 76% 1 month Stage Ill IgG kappa Labial salivary Spleen F/68 VMCP: death from digestive Submaxillar gland gland Liver hemorrhage and cardiac Gastric hypertrophy Bone marrow failure Macroglossia Myocardial hypertrophy Digestive hemorrhage 8% 34 months M/48 Stage I IgM kappa Labial salivary Kidney Shoulder Chloraminophene: stabilization Arthropathy gland Neuropathy Skin Lungs Bone marrow
MP = Melphalan/prednisone; phalan/cyclophosphamtde/predisone; sone.
MPC = melphalan/prednisone/cyclophosphamide; VBAP = vincristine/BCNU/adriamycln/prednisone;
clinical evaluation remains the sole criteria for continued treatment with mainly alkylating agents. A few years ago, Hawkins et al6,7developed a diagnos82
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VAD = vincristine/doxorubicin/dexamethasone; VMCP VBMCP = vincristine/BCNU/melphalan/cyclophos(,hamide/predn
= vincristine/mel
tic tool for amyloidosis, using ‘231-SAPscintigraphy. It was rapidly considered to be a technique that localized amyloid deposits with the gamma camera in
SCINTIGRAPHY STUDY OF PRIMARY AMYLOIDOSIS/HACHULLA
FA
C
24
H
ET AL
FP
‘.
Figure 1. Whole-body scan obtained in a control patient (A), in a patient with liver and spleen uptake (B), and in patient with spleen, kidney, and adrenal gland uptake (Cl.
patients with systemic and localized amyloidosis.6 Moreover, the uptake of ‘231-SAPis proportional to the quantity of amyloid deposits appearing in particuIar tissues7 The myocardium could not be adequately visualized; the relative quantity appearing in the heart was often rather small. The lack of uptake
in some organs such as kidney, heart, bone marrow, salivary glands, carpal regions, and digestive tract, in cases of proven amyloidosis may have been due to the accumulation of a major part of the ‘231-SAP in the spleen or liver or both. The autopsy data of patient 7 supported this hypothesis: ‘231-SPJ’uptake July 1996
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TABLE
III Comparison among Organ Involvement Using Clinical, Biological, or and 1231-SAP Scanning Imaging in the 24 Patients with Proven Amyloidosis Localization Suspected with Clinical, n = 24 Biological, or Histological Data Liver 8 (33%) Spleen (1 patient was splenectomized) 3 (13%) Kidney 13 (54%) Heart 13 (54%)
Histological Data Amyloidosis Abnormal Organ Uptake Observed with 1231-SAP Scanning 15 20 6 0
(60%) (87%) (25%) (0%)
TABLE Iv Characteristics
Patient Number 3 4 8
10
11 19 21 22 24 25 26 27
of the 12 Patients Who Had Two 1231-SAP Scintigraphy at Different Intervals Evolution of 24-Hour Interval Between Two Modification of 1231-SAP Tissue Retention Scintigraphies Uptake (Normal ~24%) Evolution 11 months Stable liver and spleen uptake, 72% to 75% Carpal tunnel syndrome disappearance of carpal required surgery, stable uptake condition, with VElMCP 12 months Stable (liver and spleen 68% to 85% Death from evolving amyloidosis uptake) 12 months Appearance of carpal uptake, 31%to49% Disappearance of nsephrotic stable kidney uptake syndrome, persistence of proteinuria cl,5 g/24 h, appearance of a cholestasis, stable condition with VBMCP 31 months Disappearance of kidney 76% to 68% Disappearance of nephrotic uptake, stable liver and syndrome, persistence of spleen uptake proteinuria cl,5 g/24 h with VAD 12 months Stable (liver, spleen and 53% to 56% Stable condition with VAD kidney uptake) 23 months Disappearance of gastric 22% to 0% Disappearance of signs of uptake malabsorption with MP; death from cerebral tumor Increase of kidney uptake, 34% to 50% Aggravation of nephrotic 17 months decrease of spleen and liver syndrome and appearance of uptake congestive heart failure 4 months Stable (liver and spleen 12% to 44% Death from congestive heart failure uptake) Stable condition 20 months Marked uptake of kidney, 8% to 24% appearance of liver and spleen uptake Disappearance of lung uptake, 37% to 46% Confirmation of diagnosis of 10 months persistence of cervical amyloidosis; stable condition with VMCP-VBAP uptake Complete remissiorl with VMCP10 months Disappearance of spleen, 40% to 14% kidney, lung and lumbar VBAP rachis uptake 35% to 52% Stable condition with 10 months Appearance of kidney and diphosphonates bone marrow uptake
MP = Melphalan/prednisone; VAD = vincristine/doxorubicin/dexamethasone; VBMCP = vincristine/BCNU/melphalan/cyclophosphamide/pre(lnisone; = vincristine/melphalan/cyclophosphamide/prednisone; VBAP = vincristine/BCNU/adriamycin/prednisone.
corresponded to organs with massive amyloid deposits (liver and spleen); kidneys, digestive tract, and myocardium had only perivascular deposits and no uptake was observed. This lack of visualization in some organs lead us to investigate the tissue retention activity, which may be correlated with the quantity or the rate of amyloid deposits.‘0,13 84
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VMCP
In normal subjects, 24 hours after the injection of the 1231-SAP,the tissue retention value was less than 24%, and no abnormal visceral uptake was found. In this present work, all of the 24 patients with biopsyproven AL amyloidosis had abnormal ‘231:-SAPscanning images or tissue retention or both (sensitivity and specificity of 100%when compared with our con-
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with the importance of amyloid deposits in our experience, AL amyloidosis without myelom;a seemsto l be more extensive than AL amyloidosis with mye80 --i TRGO% loma. It is remarquable to notice that patients withI-----I out renal fixation have higher 24-hour tissue reten-1 80 I-L-L-L&--L____ tion values (65.57% versus 45.66%, P = 0.05), I perhaps because of an important liver and spleen ‘231-S4Ptrapping. The latter organs generally have TRSO% far more amyloid in them, and presumably a much greater proportion of the tracer therefore localizes therein. I I Patients in group 3 are of particular interest. I I I I I These 6 patients with multiple myeloma were with50 10 20 30 40 out any clinical or biological signs of amyloidosis Time (months) at the moment of their first scintigraphy. Four of them had abnormal 24-hour tissue retention values Figure 2. Survival curves obtained in patients with 24-hour tissue retention greater than 50% (mean survival 11.3 months) and in pa- (Table V) . Hawkins et al 7 found normal scanning tients with less than or equal to 50% (mean survival 24.5 months). TR and normal ‘231-SAP clearance in 6 patients with = 24-hour tissue retention. monoclonal gammopathy, without any evidence of amyloidosis. Nevertheless, 1 of our patients sudtrol group). The 1231-SAP scanning is more sensitive denly developed 3 months after the first scintigrain the detection of amyloid deposits in the liver and phy an acute carpal tunnel syndrome that required spleen than clinical or biological data (60% versus surgery, and amyloidosis was confirmed by histo33% and 87% versus 13%, respectively) but less sen- logical study. In a second patient, a syst.ematic lasitive in kidney (25% versus 54%) and absolutely uu- bial salivary gland biopsy showed amyloidosis desensitive in the heart (0% versus 54%;Table V) . Most posits. This suggests the possibility of high of the patients (19 of 24) had abnormal tissue reten- frequency of asymptomatic amyloid deposits in pation within 24 hours with a mean of 55.66%for group tients with myelomas and also the possibility of 1 (without myeloma) and 34.37% for group 2 (with regression of amyloidosis with polychemotherapy myeloma; P = 0.005). If tissue retention is correlated (patient 26). Amyloidosis modified the prognosis, -i
--
z
TABLE
V
Patient Number 25
26
27 28 29 30 LSG = labial
1231-SAP Scintigraphy in Patients with Multiple Myeloma without Any Evidence of Amyloidosis at Time of Scintigraphy (Group 3) 24-Hour Tissue Durie and Retention Pathological Sites Gender and Age Salmon fg4yl 0 of 1231-SAP Uptake Evolution (Years) Classification 37% Acute carpal tunnel syndrome required M/58 Stage IIIlambda Lung, cervical surgery, confirmation of amyloid chains deposits; appearance of cardiac localization in spite of VMCP-VBAP but remission Presence of amyloid deposits in a Spleen, kidney, lung, 40% M/65 Stage Ill IgG lombar rachis systematic LSG biopsy but no signs lambda of amyloidosis 10 monthls later; remission with VMCP-VBAP Stable condition, diphosphonate None 35% M/56 Stage I IgG treatment only; normal LSG biopsy kappa 35% Normal LSG biopsy, VMCP-VBAP, bone Stage Ill IgG Lung M/59 marrow transplantation, partial karma response Normal LSG biopsy, VMCP-VBAP, bone None 23% F/50 Stage Ill IgG marrow transplantation kappa 17% Normal LSG biopsy, VMCP-VBAP, Stage Ill IgG Spleen F/54 remission kappa salivary
gland;
VMCP
= vincristine/melphalan/cyclophosphamide/prednisone;
VBAP = vincristine/BCNU/adriamycin/prednisone.
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and its importance detected by the study of the 24hour tissue retention may potentially change the therapy, particularly when bone marrow transplantation is discussed. A study with a larger series must be done to confirm these results. The importance of the tissue retention study in addition to 12”I-SAPscanning is confirmed in our population. There is not a good correlation between amyloid deposits, localization, and scanning, particularly in the heart, kidney, and carpal tunnel. This may be directly related to the quantity or to the rate of the amyloid deposits. Concerning our experience, tissue retention might also be correlated with prognosis. Mean survival in patients with tissue retentions greater than 50% was 24.5 months versus 11.3 months in patients with less than or equal to 50%. These differences did not reach significance perhaps because of the few number of patients in the two groups. Nevertheless, sometimes few amyloid deposits may influence the survival rate when the heart is affected (patients 1, 17, and 22) in spite of low tissue retention values. A serial study of ‘231-SAPscintigraphy is essentially provided in secondary amyloidosis.‘4s’5 The authors of this study showed that visceral ““I-SAP fixation may vary in some treated patients, with a decrease in the body retention. This emphasizes the concept of a possible regression of amyloid deposits and encourages aggressive therapy of this lethal disease. We studied serially 9 patients with AL amyloidosis and 3 patients with multiple myeloma without signs of amyloidosis after their first scintigraphy (Table IV). In 7 of the 9 patients, clinical or biological data were in correlation with the data of the scintigraphy, particularly with 24-hour tissue retention (identical, diminution, or increase). In the 2 other patients there was a discordance: in patient 8 nephrotic syndrome disappeared despite increase in 24-hour tissue retention; in patient 24 the 24-hour tissue retention and the visceral uptake increased but no clinical nor biological signs of amyloidosis appeared, perhaps because of the small quantity of amyloid in the different organs as suggested by the small retention (8% and 24% between the two scintigraphies) . Concerning the serial study of the 3 patients with multiple myeloma without signs of amyloidosis at the time of the first scintigraphy, the high value of the retention in patient 25 suggests the presence of amyloid deposits that are secondarily confirmed; patient 27 remains at this time asymptomatic, and the diminution of the retention in patient 26 suggests that amyloidosis may regress with polychemotherapy. Indeed, all of the data put together suggest that regression of amyloidosis may be possible, that regression of amyloidosis may differ in different organs, and that there is little cor86
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relation between clinical findings and the amount of underlying amyloid. When heart localization exists, death may occur despite few amyloid deposits. In conclusion, “” I-SAP scanning protildes no correlation between the involvement of amyloid in the viscera and the imaging, particularly in heart, kidney, carpal tunnel, salivary glands and digestive tract. Echocardiographic study is more effective in the detection of cardiac involvement, which is dlirectly correlated with the prognosis. In contrast, the study of “‘I-SAP tissue retention is abnormal in all our patients and may be a diagnostic tool in asymptomatic patients. The ““I-SAP tissue retention may also be correlated with the prognosis, as most of t.he patients who died had more than 50%of ‘““I-SAP tissue retention values after 24 hours (exception made for heart localization because tissue retention was low, due to the absence of involvement of the other organ). The lX31-SAPtissue retention can help the clinical management of AL amyloidosis t,o guidle therapy, whereas some variations like proteinuria do not reflect the evolution of the amyloidosis.” The use of this technique for screening myeloma patients for amyloidosis, prior to bone marrow transplantation is most important.
ACKNOWLEDGMENT We are grateful to B. Hecquet Lllle, France, for the stabstical
of the Btostatistlcal Unit, Centre Oscar Lambret, analysis. We thank Prof. A. Janin for the hlsto-
pathological examination, J. Kerr-Conte of the Laboratolre de Culture Cellulalre, Facultb de Mddeclne Lllle, who made the English [grammar] translations, and Monlque Tomczak who carned out the typing of this manuscript.
REFERENCES 1. Glenner GG. Amyloid 1980;302:1283-1292, 2. Baltz ML, Caspi
deposits
and
amyloidosls:
the fl-fibrilloses.
NEJM.
1333-1343.
D, Evans DJ, et al. Circulating
serum
amyloid
P component
is the precursor of amylold P component In ttssue amyloid deposits. C/in Exp Immunol. 1986;66:691-700. 3. Saile R, Kandoussi A, Deveaux M, et al. Quanbtatlon of serum amylold P by enzyme IInked-immune-sorbent assay. Clrn Chem. 1991;37:1742-1745. 4. Gertz MA, Kyle RA, Grelpp PR. Response rates and survival In primary systemic amyloidosis. Blood. 1991;77:257-262. 5. Hachulla E, Janin A, Fkpo RM, et al. Labial salivary gland biopsy IS a reliable test for the diagnosis of primary clinical and immunohistologtc
and secondary study In 59
amyloidosis. A prospective patients. Aqhntrs Rheum.
1993;36:691-697. 6. Hawkins PN, Lavender JP, Myers HP, Pepys M. Diagnostic radlonuclide imaging of amyloid: biologlcal targettng by circulating human serum amylold P component. Lancet. 1988;i:143-148. 7. Hawkins PN, Lavender JP, Pepys MB. Evaluation of systemtc amyloidosis by sclntigraphy with 1Z31-labeled serum amyloid P component. NEJM. 1990;
323:508-513. 8. De Beer FC, Pepys MB. lsolabon of human C-reactive protein and serum amylold P component. J lmmunol Meth. 1982;50:17-31. 9. Horowitz B, Wlebe ME, Llppin A, Stryker MH. Inactivation of viruses In labile blood derivatives. I-DIsruption of lipid enveloped viruses by tri (n-butyl) phosphate detergent combination. Transfusion. 1985;25:516-522. 10. Stile R, Deveaux M, Hachulla E, et al. Slgnlficance of ‘*“l-labeled serum amyloid
P component
scintigraphy.
Eur J Nucl Med.
1993;20:130-137.
SCINTIGRAPHY STUDY OF PRIMARY AMYLOIDOSIS/HACHULLA 11.
Durie
BGM.
Stagrng
and
kinetics
of multiple
myeloma.
Sem
Oncol.
1986;13:300-309. 12. Durie BGM, Salmon SE. A clinical staging system for multrple Correlatron of measured myeloma cell mass with presenting clinical response to treatment and survrval. Cancer. 1975;36:842-000. 13. Hachulla E, Wechsler B, Deveaux M, et al. Amylose localrsee
myeloma. features,
mique? Inter&t et lkmrtes de la scrntrgraphie au composant amyloide a I’iode 123, place de la biopsie de glandes salivaires accessoires. Interne. 1994;15:182-185.
P marque Rev Med
ou syste-
14. Hawkins PN, Rrchardson S, Vigustrn DM, et al. Serum amylord scintigraphy and turnover studies for diagnosis and quantitative
ET AL
P component lmonrtorrng of
AA amylordosrs in Juvenile rheumatoid arthritis. Arthntrs Rheum. 1!393;36:842851. 15. Hawkins PN, Richardson S, MacSweeney JE, et al. S#cintigraphic quantification and serial monitoring of human visceral amyloid deposits provide evrdence for turnover and regression. Q J Med. 1993;86:365-
374. 16.
Husby
G. Amyloidosis.
July 1996
Sem Arthritis
The American
Journal
Rheum.
1992;22:67-82.
of Medicinea
Volumle
101
87
with
E. Hachulla, MD, PhD, L. Maulin, MD, M. Deveaux, PhD, T. Facon, MD, Lifle, France, 0. B&y, MD, Paris, France, Ph. Vanhille, MD, Vafertciennes, France, B. Wechsler, MD, P. Godeau, MD, Paris, France, H. Levesque, MD, PhD, Rouen, France, P.Y. Hatron, MD, D. Huglo, MD, B. Devulder, MD, X. Marchandise, MD, Li/fe, France
OBJECTIVE: The purpose of this study was to assess the value of the serum amyloid P (SAP) component scintigraphy in patients with primary amyloidosis (AL). MATERIAL AND METHODS: Pure human SAP labeled with iodine-123 (1231-SAP) was given intravenously to 24 patients with biopsy-proven systemic amyloidosis (15 without multiple myeloma = group 1, and 9 with multiple myeloma = group 2) and to 6 patients with multiple myeloma without any clinical or biological signs of amyloidosis (group 3). Whole-body images as well as regional views and tissue retention levels were obtained after 24 hours. Our study was approved by the institutional review committee and all individuals gave informed consent and were prospectively studied (median 13 months, range 1 to 47 from the date of the scintigraphy to May 1995). RESULTS: Organ localization of 1231-SAP, indicating the presence of substantial visceral amyloid deposits, was observed in all patients in group 1 and 2. The organ uptake of 1231-SAP included the spleen (1 patient was splenectomized) in 20 of 23 cases (87%), the liver in 15 of 24 (60%), and the kidneys in 6 of 24 (25%). Myocardial 1231-SAP was never seen although 13 out of the 24 patients had clinical or echographic data for amyloidosis. Twentyfour hour tissue retention was significantly elevated in all patients (group 1 and group 2): 55.66% + 19.16% in group 1 and 34.37% +
From the Department of Internal Medicine, Hdpital Cl. Huriez (EH, LM, PYH, BD), Department of Nuclear Medicine IMD,.DH, XM), and Department of Hematology (TF) CHRU de Lille, France; Department of Internal Medrcine, Hopital Katie Salpetriere (OB, BW, PG) CHRU de Paris, France; Department of Nephrology, Hopital de Valenciennes (Pv), France; and De oartment of Internal Medicine (HL). CHRU de Rouen. France. Requests for reprints should be addressed to Eric Hachulla, MD, PhD, Department of Internal Medicine, Hopital Claude Huriez, Centre Hospitalier RegIonal, University of Lille, Place de Verdun, 59037 Lil e cedex, France. Manuscript submitted November 18, 1994, and accepted in revised form February 26, 1996.
01996 by Excerpta All rights reserved.
hledica,
Inc.
24.92% in group 2, as compared with normal levels ~24%. The sensitivity of the technique was 79% when only organ uptake was considered but reached 100% when tissue retention was also considered. The 24-hour tissue retention might be correlated with the severity of the amyloidosis: mean survival in patients with tissue retention greater than 50% was 11.3 months versus 24.5 months in patients with levels less or equal to 50%. Five of the 6 patients with multiple myeloma without evidence of amyloidosis had abnormal 1:Z31-SAP imaging and 24-hour tissue retention levels. In 2 of them, amyloidosis was secondly detected. In the 9 patients who had two scintigraphies, variations in 24-hour tissue retention values were in accordance with the clinical evaluation. CONCLUSIONS: Spleen and liver distribution of amyloidosis is mostly revealed by 1231-SAP scintigraphy in patients with AL amyloidosis. The uptake of 1231-SAP appeared in proportion to the quantity of amyloidosis present in ‘different tissues, and the relative quantity of amyloid deposits in the myocardium, carpal tunniel, digestive tract, and kidneys was often small and seldom visualized by 1231-SAP scintigraphy. In contrast 24-hour tissue retention levels were abnormal in all cases of known AL amyloidosis. This may be a positive argument for the diagnosis of amyloidosis when histopathological tests are normal. Tissue retention levels appear important as they may be correlated wit:h survival. Am .J Med. 1996;101:77-87. iagnosis of amyloidosis is usually made by the demonstration of apple-green birefringence in Congo red-stained tissue specimens examined with polarized microscopy. There are two main forms of acquired systemic amyloidosis: ’ Primary amyloidosis (AL) occurs in patients with plasma cell dyscrasia, in which fragments of monoclonal immunoglobulin light chains form amyloid fibrils; secondary amyloidosis (AA) occurs in patients with clhronic inflammatory conditions, in which the fibril protein is
D
0002-9343/96/$15.00 PII sooo2-9343(94)ooo54-x
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ET AL
derived from the serum amyloid A protein. In addition to the fibrils, all amyloid deposits contain amyloid P component, a nonfibrillar glycoprotein, derived from the serum amyloid P component (SAP), a normal circulating protein’s3 Both types of amyloidosis are usually fatal due to the accumulation of amyloid fibrils in the tissues, destroying normal structure and function. The median survival of patients with AL amyloidosis is estimated to be less than 15 months.4 Labial salivary gland biopsies using antibodies directed against the SAP component is a reliable test for the diagnosis of amyloidosis (sensitivity of 86%)) 5 but histologic examination provides very limited information about the distribution in tissues and the extent of diseaseprogression. Recently, it has been shown that iodine-labeled SAP can be used for locating foci of amyloidosis.fi,7 In addition, iodine-labeled SAP turnover may be valuable for monitoring systemic amyloidosis.7 We evaluated prospectively 24 patients with biopsy-proven systemic AL amyloidosis and 6 patients with multiple myeloma without any clinical or biological signs of amyloidosis. We discuss here i2”I-SAP scintigraphy in diagnosing amyloidosis, in identifying the distribution of amyloid deposits, and in determining the prognosis. The usefulness of this technique in serial study is equally discussed.
Patients We studied 24 patients with biopsy-proven AL systemic amyloidosis group 1 was 15 patients without multiple myeloma; group 2 was 9 patients with multiple myeloma; and group 3 consisted of 6 patients with multiple myeloma without any clinical or biological signs of amyloidosis. The diagnosisof multiple myeloma was performed using the SWOG criteria and the staging according to Durie and Salmon.11’12 Nine of the patients with AL amyloidosis had two ‘23I-SAP scintigraphies within an interval of 4 to 31 months. Three patients in group 3 had two ‘?-SAP scintigraphies at U&month intervals. From the time of the scintigraphy to May 1995, all patients were prospectively studlied (median 13 months, range 1 to 47) with clinical assessment, serological and urine analysis, and sometimes echocardiography. Six healthy subjects were studied to establish normal data
Scanning
Protocol
Patients with a history of adverse reactions to iodine or intravenous radiological contrast media were excluded. Prior to injection, thyroid uptake of free iodine was blocked by lug01 2 days be:fore the imaging procedure, and by potassium perchlorate administered orally on the day of injection. Intravenous injection consisted of approximately 150 MBq containing 400 yg ‘231-SAP.The effective dose equivalent MATERIALS AND METHODS was 3.5mSv.7 Anterior and posterior whole-body imPreparation of Radiolabeling of SAP ages and regional views were acquired after 3 and 24 Component hours. Whole-body data were acquired with a Sera from regular blood donors were collected in a gamma-camera equipped with a large rectangular blood transfusion center (CRTS) and the SAP com- field (DSX Sopha Medical, But, France) using a meponent was isolated according to the method de- dium-energy high-resolution collimator. Scan speed scribed by De Beer and Pepys’ with several modiflca- was 12 cm/minute. For regional views, a circular tions. The SAP component was purified by field gamma-camera (DS7 Sopha Medical) equipped immunoaffinity chromatography, obtaining a purity of with a medium-energy high-resolution collimator more than 99%. Virus inactivation was performed ac- was used. Preset time was 600 s. All pictures were cording to the technique described by Horowitz et al9 displayed on x-ray film. All first scans were interNo contaminating bands were detected in 4% to 30?! preted without knowledge of clinical data. Then the gradient non-denaturing gels or with SDS-PAGE. Pu- results were considered in relation to clinical data. rified SAP was iodinated by a modified iodogen’s Discrepancies such as heart localization are evoked method. Briefly, to 500 ,ug SAP in 0.5 mL of 0.1 M PBS in the discussion section. (pH 7.4), 10 PL of 0.8 mM KI and 185 MBq of 1231 (I123LAB-B, CIS Bio International, Gifsur, Yvette, Clearance of 1231-SAP Component and Tissue France) were added. This suspension was transferred Retention Activity Venous samples were obtained at 5, 15, and 30 to a vial containing iodogen previously solubilized in dichloromethane. Each time labeling yield was mea- minutes, and at 1, 2, 3, 4, 24 and 48 hours after insured, it was greater than 97%.Electrophoretic and im- jection. All urine samples were collecte’d separately munoelectrophoretic controls did not indicate that la- within 2 days. One mL of each plasma sample, and beling of the purified SAP component caused 5 mL of the urine samples were each counted toalteration of the molecule. Furthermore, functional in- gether with an aliquot of the injected material in 1 tegrity of labeled SAP component was confirmed, since mL and 5 mL, respectively. As no other significant it retained its calcium-dependent binding to sepharose excretion route exists for SAP, whole-body retention and to amyloid fibrils in vitr~.~~~’Final preparation of was calculated at 24 hours, by subtracting the cumulative activity excreted in the urine from the total ‘?-SAP was sterile and nonpyrogenic. 78
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injected dose. In all patients the remaining tissue retention activity was evaluated at 24 hours after injection, by subtracting plasma activity from wholebody retention values. The analysis of variance (ANOVA or Kruskal-Wallis depending on the data) was used to compare groups. The chi-square test was used for the comparison of percentages. Survival analysis was performed using the Kaplan-Meier method for representation and the Mantel-Menszel test for comparison of groups. Multifactoral analysis of survival was performed by the Cox model. The study was approved by the institutional review committee and all individuals gave informed consent.
dosis (nephrotic syndrome or g1omeruk-x proteinuria) and only 6 out of the 13 patients had a,bnormal kidney ‘231-SAPfixations. The mean 24-hour tissue retention was 45.66% -C 15.83% in the patients with kidney fixation (6 of 13) versus 65.57% t 17.17 in the patients without kidney fixation (7 of 13; P = 0.05). Myocardial 1231-SAP fixation was never seen, although 13 out of the 24 patients had clinical or echography data of amyloidosis. Twenty-four hour tissue retention was elevated in 19 of 24 patients with proven amyloidosis: 55.66% ? 19.16%in group 1 and 34.37% ? 24.92%in group 2 (P = 0.005). This gave a sensitivity of 79%, a specificity and a. positive predictive value of lOO%,and a negative predictive value of 54%.But when organ uptake was considered RESULTS with the 24-hour tissue retention (abnormdl >24%), Healthy Subjects the ‘231-SAPscintigraphy was abnormal in all 24 paAbnormal 1231-SAF’ uptake was never observed in tients with proven amyloidosis; the specificity and the 6 normal subjects. The 24-hour tissue retention the negative predictive value reached lOO%.. values were 2%, 5%, 6%, 8%, 13%,and 24%. Nine of the patients with proven amyloidosis had two ‘?-SAF’ scintigraphies at different interlrals (TaPatients with Proven AL Amyloidosis ble IV). A concordance between stable or diminishing There were 15 patients in group 1 (6 men and 9 24hour tissue retention values and a stabilization or women), age (mean t SD) 56.8 2 10.9 years; and 9 improvement of clinical or biological data was noticed patients in group 2 (7 men and 2 women), age 58.5 t- in patient number 3, 10, 11, and 19. In patient number 8.6. No statistically significant difference was found be- 4, 21, and 22, the augmentation in the 24hour tissue tween the two groups concerning ageand gender. Clin- retention value was associated with the degradation of ical, pathological, and laboratory flndings are summa- clinical data The results observed in patient 8 and 24 rized in Table I and Table II. Results of ‘?SAP scans are controversial: in the first one, the nephrotic synand the values of ‘231-SAF’tissue retention at 24 hours drome disappeared despite an enhancement in the 24 are expressed in these same tables. Uptake into thy- hour tissue retention (31% to 49%) ; in the sec’ondcase, roid, salivary glands or gastrointestinal tract must be a stable condition (no deterioration in organ function) considered with caution due to the possible concen- was associated with an increase in the 24hour tissue tration of free iodine in these tissues. Figure 1 shows retention (8% to 24%) coupled with the apparition of whole-body scans obtained in a control and in two pa- liver and spleen uptake. The median follow-up in this study was 13 tients with amyloidosis. Histological proven amyloidosis was demon- months (range 1 to 47) from the first scintigraphy. strated in 18 of 22 patients via a minor salivary gland The 24-hour tissue retention is important .asit may biopsy, in 4 of 6 with an abdominal fat biopsy, in 5 be correlated with the severity of the amyloidosis: of 7 with a rectal submucosa biopsy, and in 7 of 8 15 patients died during the period of study, 9 had with a renal biopsy. Organ localization of 1231-SAP, more than 50% 24-hour tissue retention. Figure 2 indicating the presence of substantial visceral amy- shows the Kaplan-Meier survival curves after the scintigraphy, dividing the patients into two groups, loid deposits, was observed in all patients. Table III shows the involvement of different organs compared greater than and less than or equal to 50% retenwith scanning imaging. The organ uptake of ‘“31-SAP tion. The adjusted relative risks derived from the Cox regression model included the variables age, included the spleen in 20 of 23 cases (87%; 1 patient was splenectomized) , the liver in 15 of 24 (60%)) and multiple myeloma, congestive heart failure, and the kidneys in 6 of 24 (25%). All patients with clini- tissue retention. Only congestive heart failure sigcally or biologically suspected liver amyloidosis (he- nificantly influenced the survival (P = 0.04). Mean patomegalia or cholestasis, n = 8), had abnormal survival for the patients with less than or equal to ‘231-SAPcomponent fixation in the liver (5 of 8 had 50% retention was 24.5 months (the mesdian surpositive a liver biopsy, the 3 others did not have a vivan was not reached), mean survival for the patients with more than 50% retention was 11.3 liver biopsy done). In 7 out of the 24 patients without suspected liver amyloidosis, an abnormal liver lz31- months (median 4.5) but this did not reach a sigSAP fixation was found. In contrast, 13 out of the 24 nificant level in the Cox regression model (P = patients had biologically suspected kidney amyloi- 0.08). July 1996
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TABLE I Characteristics
Patient Number
of 15 Patients with AL Amyloidosis without Multiple Myeloma (Group 1). Results of 1231-SAP Component Scans and 9-SAP Component Tissue Retention
Gender and Age (Years)
1
F/71
2
M/54
3
F/62
4
M/42
5
F/5 1
6
M/69
7
M/47
8
F/61
9
F/80
Clinical, Biological or Echographic Data at Time of Scintigraphy
IgG kappa Proteinura 6 g/24 h and renal insufficiency Congestive heart failure IgG lambda Congestive heart failure Splenomegaly Purpura Neuropathy Urinary light lambda chains Congestive heart failure Carpal tunnel syndrome Orthostatic hypotension Nephrotic syndrome Urinary light lambda chains Congestive heart failure Splenomegaly Cholestasis Nephrotic syndrome Orthostatic hypotension Gastric bleeding Urinary light lambda chains Purpura Myocardial hypertrophia Goiter Urinary light lambda chains Macroglossia Congestive heart failure Urinary light lambda chains Purpura Hepatomegaly Cholestasis Neuropathy Nephrotic syndrome Renal insufficiency IgA lambda and IgG lambda Neuropathy Nephrotic syndrome No detectable light chains Hepatomegalia Cholestasis Renal insufficiency
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M-Hour Tissue Retention (Normal <24%)
Biopsy-proven Amyloidosis
Pathological Sites of lz31SAP Uptake
Labial salivary gland
Spleen
28%
21 months Colchicine and VAD: death from congestive heart failure
Skin Spleen Negative labial salivary Orbitar gland and abdominal fat biopsy
51%
5 months VMCP: death from congestive heart failure
Labial salivary gland Abdominal fat Liver
Spleen Liver Carpal
72%
26 months VBMCP: decrease of proteinuria, heart condition stable
Bone marrow Gastric Kidney Negative rectal submucosa and labial salivary gland biopsy
Spleen Liver
68%
15 months Colchicine and V&MCP: increase of proteinuria, death from evolutive amyloidosis
Thyroid Labial salivary gland
Spleen Thyroid
54%
3 months VAD: death from congestive heart failure
Labial salivary gland Abdominal fat Bone marrow Rectal submucosa Ocular conjonctive Labial salivary gland Bone marrow Rectal submucosa Kidney
Spleen
64%
4 months VAD: death from congestive heart failure
Spleen Liver
65%
13 months VBMCP: death from congestive heart failure
Labial salivary gland Abdominal fat Kidney Vesical
Kidney Salivary glands Lombar rachis
31%
Kidney with positive anti-kappa staining Negative abdominal fat biopsy
Spleen Liver Salivary glands Thyroid Digestive tract
67%
25 months Colchicine and VBMCP: disappearance of the nephrotic syndrome, persistence of proteinuria <1,5 g/24 h 3 months Absence of treatment, death of unknown origin
Only one autopsy had to be done, making it possible to compare the quantity of amyloid deposits in different organs with the SAP scans (patient 7, 80
ET AL
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Follow-up Evolution
Study and after Scintigraphy
only liver and spleen showed ‘231-SAP uptake): Massive amyloid deposits were found in spleen, liver, and adrenal gland, whereas only perivascular
SCINTIGRAPHY STUDY OF PRIMARY AMYLOIDOSIS/HACHULLA TABLE
ET AL
I Continued
Patient Number
Gender and Age (Years)
10
F/54
11
M/44
12
M/54
13
F/59
14
F/44
15
F/61
Clinical, Biological or Echographic Data at Time of Scintigraphy
IgG kappa Hepatomegalia Nephrotic syndrome IgG lambda Nephrotic syndrome Urinary light lambda chains Hepatomegalia Cholestasis Neuropathy Nephrotic syndrome No detectable light chains Hepatomegalia Cholestasis Congestive heart failure No detectable light chains Arthropathy Nephrotic syndrome Renal insufficiency No detectable light chains Macroglossia
VAD = vincristine/doxorubicin/dexamethasone;
VBMCP
Pathological Sites of lz31SAP Uptake
Biopsy-proven Amyloidosis
Labial salivary gland Kidney Kidney
Labial salivary gland Liver Spleen Rectal submucosa Labial salivary gland with anti-kappa staining Gastric with anti-kappa staining Labial salivary gland with anti-kappa staining Kidney with anti-kappa staining Negative rectal submucosa biopsy Labial salivary gland with anti-lambda staining Liver Rectal submucosa
24-Hour Tissue Retention (Normal <24%)
Spleen Liver Kidney Spleen Liver Kidney Adrenal glands Liver (splenectomy)
72% 53%
Follow-up Evolution
Study and after Scintigraphy
42 months VAD: disappearance of the nephrotic syndrome 16 months Colchicine and VAD: stabilization
69%
4 months VAD: death from liver and kidney failure
Spleen Liver Bone marrow
40%
7 months VAD: death from liver failure
Spleen
75%
12 months VAD: stabilization
Spleen Liver
14%
39 months VBMCP: stabilization
= vincristlne~CNU/melphalan/cyclophosphamide/prednisone.
deposits were observed in myocardium, digestive tract, kidneys, and lungs. This confirms that in patients with massive amyloidosis deposits in the liver or spleen, a major percentage of the injected lz31-SAP was concentrated rapidly in these areas after injection.
acute carpal tunnel syndrome, which required surgery. Histopathological study confirmed the diagnosis of amyloidosis. At the time of the second scintigraphy, cardiac localization was found after echography and the retention raised froim 37% to 46%. In patient 26, 24-hour tissue retention value was 40%. A systematic labial salivary gland biopsy Multiple Myeloma Patients Without Evidence of revealed asymptomatic amyloid deposits. This patient had a severe myeloma that required polyAL Amyloidosis Among the 6 patients with myeloma without ev- chemotherapy. The second 24-hour tissue retenidence of amyloidosis, 3 had serial 1231-SAPscintig- tion 10 months later was less than 14% and no signs of amyloidosis appeared. Patients 27 and 28 raphies at lo-month intervals (Table IV and Table V ). Four of the 6 patients had high 24-hour tissue had abnormal 24-hour tissue retention levels but retention values, with a mean value of 31.16% L 9% no signs of amyloidosis appeared after more than 1 year of follow-up. with occasional abnormal visceral visualization. One patient had normal imaging and normal 24hour tissue retention values; the other had normal DISCUSSION There is no gold standard for the evalluation of 24-hour tissue retention but had pathological spleen uptake values. Patient 25 had a high 24-hour amyloidosis. Various treatments have been attissue retention (37%). Three months after the first tempted guided by biological and echographic data4 scintigraphy patient 25 suddenly developed an Repeated biopsies are often impractical, and the July 1996
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rABLE II Characteristics
‘atient lumber 16
17
18
19
20
21
22
23
24
of 9 Patients with AL Amyloidosis and Multiple Myeloma (Group 2). Results of 1231-SAP Compcbnent Scans and ‘*‘I-SAP Component Tissue Retention 24-Hour Tissue Clinical, Pathological RetenDurie and Biological or BiopsySites of 1231- tion Gender and Salmon Echographic proven SAP (Normal Follow-up Study and Age (years) Classification Data Amyloidosis Fixation ~24%) Evolution F/48 Stage III Urinary light kappa Labial salivary Spleen 34% 3 months chains gland Kidney VAD: stabilization; death from Skin Lombar spine septic process Purpura Proteinuria Negative kidney biopsy 14% 23 months M/56 Stage I IgG lambda Labial salivary Spleen Congestive heart gland Colchicine and VMCP-VBAP: failure death from congestive heart Diarrhea failure M/62 Stage I IgA kappa Labial salivary Spleen 59% 3 months Liver Diarrhea gland VMCP-VBAP: death from Occlusion Gastric tract Left lung occlusive syndrome and and colic cachexia Liver Rectal submucosa Digestive tract Gastric 15% 47 months M/58 Stage I IgA kappa MP: stabilization of Malabsorption Negative labial Lungs amyloidosis; death from salivary cerebral tumor gland biopsy Labial salivary Spleen 50% 28 months M/64 Stage I IgG lambda Liver MPC: stabilization of Congestive heart gland Kidney neuropathy, but increase of failure nephrotic syndrome and Nephrotic syndrome onset of orthostatic hypotension Neuropathy Skin Spleen 34% 32 months M/72 Stage I IgA lambda Colchicine and MP: Macroglossia Negative labial Liver aggravation of nephrotic Purpura salivary Kidney Nephrotic gland biopsy syndrome and appearance of congestive heart failure syndrome 12% 10 months M/51 Stage I IgG lambda Labial salivary Spleen Purpura gland Liver VBMCP: death from congestive heart failure Congestive heart Skin Salivary glands failure 76% 1 month Stage Ill IgG kappa Labial salivary Spleen F/68 VMCP: death from digestive Submaxillar gland gland Liver hemorrhage and cardiac Gastric hypertrophy Bone marrow failure Macroglossia Myocardial hypertrophy Digestive hemorrhage 8% 34 months M/48 Stage I IgM kappa Labial salivary Kidney Shoulder Chloraminophene: stabilization Arthropathy gland Neuropathy Skin Lungs Bone marrow
MP = Melphalan/prednisone; phalan/cyclophosphamtde/predisone; sone.
MPC = melphalan/prednisone/cyclophosphamide; VBAP = vincristine/BCNU/adriamycln/prednisone;
clinical evaluation remains the sole criteria for continued treatment with mainly alkylating agents. A few years ago, Hawkins et al6,7developed a diagnos82
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VAD = vincristine/doxorubicin/dexamethasone; VMCP VBMCP = vincristine/BCNU/melphalan/cyclophos(,hamide/predn
= vincristine/mel
tic tool for amyloidosis, using ‘231-SAPscintigraphy. It was rapidly considered to be a technique that localized amyloid deposits with the gamma camera in
SCINTIGRAPHY STUDY OF PRIMARY AMYLOIDOSIS/HACHULLA
FA
C
24
H
ET AL
FP
‘.
Figure 1. Whole-body scan obtained in a control patient (A), in a patient with liver and spleen uptake (B), and in patient with spleen, kidney, and adrenal gland uptake (Cl.
patients with systemic and localized amyloidosis.6 Moreover, the uptake of ‘231-SAPis proportional to the quantity of amyloid deposits appearing in particuIar tissues7 The myocardium could not be adequately visualized; the relative quantity appearing in the heart was often rather small. The lack of uptake
in some organs such as kidney, heart, bone marrow, salivary glands, carpal regions, and digestive tract, in cases of proven amyloidosis may have been due to the accumulation of a major part of the ‘231-SAP in the spleen or liver or both. The autopsy data of patient 7 supported this hypothesis: ‘231-SPJ’uptake July 1996
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TABLE
III Comparison among Organ Involvement Using Clinical, Biological, or and 1231-SAP Scanning Imaging in the 24 Patients with Proven Amyloidosis Localization Suspected with Clinical, n = 24 Biological, or Histological Data Liver 8 (33%) Spleen (1 patient was splenectomized) 3 (13%) Kidney 13 (54%) Heart 13 (54%)
Histological Data Amyloidosis Abnormal Organ Uptake Observed with 1231-SAP Scanning 15 20 6 0
(60%) (87%) (25%) (0%)
TABLE Iv Characteristics
Patient Number 3 4 8
10
11 19 21 22 24 25 26 27
of the 12 Patients Who Had Two 1231-SAP Scintigraphy at Different Intervals Evolution of 24-Hour Interval Between Two Modification of 1231-SAP Tissue Retention Scintigraphies Uptake (Normal ~24%) Evolution 11 months Stable liver and spleen uptake, 72% to 75% Carpal tunnel syndrome disappearance of carpal required surgery, stable uptake condition, with VElMCP 12 months Stable (liver and spleen 68% to 85% Death from evolving amyloidosis uptake) 12 months Appearance of carpal uptake, 31%to49% Disappearance of nsephrotic stable kidney uptake syndrome, persistence of proteinuria cl,5 g/24 h, appearance of a cholestasis, stable condition with VBMCP 31 months Disappearance of kidney 76% to 68% Disappearance of nephrotic uptake, stable liver and syndrome, persistence of spleen uptake proteinuria cl,5 g/24 h with VAD 12 months Stable (liver, spleen and 53% to 56% Stable condition with VAD kidney uptake) 23 months Disappearance of gastric 22% to 0% Disappearance of signs of uptake malabsorption with MP; death from cerebral tumor Increase of kidney uptake, 34% to 50% Aggravation of nephrotic 17 months decrease of spleen and liver syndrome and appearance of uptake congestive heart failure 4 months Stable (liver and spleen 12% to 44% Death from congestive heart failure uptake) Stable condition 20 months Marked uptake of kidney, 8% to 24% appearance of liver and spleen uptake Disappearance of lung uptake, 37% to 46% Confirmation of diagnosis of 10 months persistence of cervical amyloidosis; stable condition with VMCP-VBAP uptake Complete remissiorl with VMCP10 months Disappearance of spleen, 40% to 14% kidney, lung and lumbar VBAP rachis uptake 35% to 52% Stable condition with 10 months Appearance of kidney and diphosphonates bone marrow uptake
MP = Melphalan/prednisone; VAD = vincristine/doxorubicin/dexamethasone; VBMCP = vincristine/BCNU/melphalan/cyclophosphamide/pre(lnisone; = vincristine/melphalan/cyclophosphamide/prednisone; VBAP = vincristine/BCNU/adriamycin/prednisone.
corresponded to organs with massive amyloid deposits (liver and spleen); kidneys, digestive tract, and myocardium had only perivascular deposits and no uptake was observed. This lack of visualization in some organs lead us to investigate the tissue retention activity, which may be correlated with the quantity or the rate of amyloid deposits.‘0,13 84
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VMCP
In normal subjects, 24 hours after the injection of the 1231-SAP,the tissue retention value was less than 24%, and no abnormal visceral uptake was found. In this present work, all of the 24 patients with biopsyproven AL amyloidosis had abnormal ‘231:-SAPscanning images or tissue retention or both (sensitivity and specificity of 100%when compared with our con-
SCINTIGRAPHY STUDY OF PRIMARY AMYLOIDOSIS/HACHULLA
ET AL
with the importance of amyloid deposits in our experience, AL amyloidosis without myelom;a seemsto l be more extensive than AL amyloidosis with mye80 --i TRGO% loma. It is remarquable to notice that patients withI-----I out renal fixation have higher 24-hour tissue reten-1 80 I-L-L-L&--L____ tion values (65.57% versus 45.66%, P = 0.05), I perhaps because of an important liver and spleen ‘231-S4Ptrapping. The latter organs generally have TRSO% far more amyloid in them, and presumably a much greater proportion of the tracer therefore localizes therein. I I Patients in group 3 are of particular interest. I I I I I These 6 patients with multiple myeloma were with50 10 20 30 40 out any clinical or biological signs of amyloidosis Time (months) at the moment of their first scintigraphy. Four of them had abnormal 24-hour tissue retention values Figure 2. Survival curves obtained in patients with 24-hour tissue retention greater than 50% (mean survival 11.3 months) and in pa- (Table V) . Hawkins et al 7 found normal scanning tients with less than or equal to 50% (mean survival 24.5 months). TR and normal ‘231-SAP clearance in 6 patients with = 24-hour tissue retention. monoclonal gammopathy, without any evidence of amyloidosis. Nevertheless, 1 of our patients sudtrol group). The 1231-SAP scanning is more sensitive denly developed 3 months after the first scintigrain the detection of amyloid deposits in the liver and phy an acute carpal tunnel syndrome that required spleen than clinical or biological data (60% versus surgery, and amyloidosis was confirmed by histo33% and 87% versus 13%, respectively) but less sen- logical study. In a second patient, a syst.ematic lasitive in kidney (25% versus 54%) and absolutely uu- bial salivary gland biopsy showed amyloidosis desensitive in the heart (0% versus 54%;Table V) . Most posits. This suggests the possibility of high of the patients (19 of 24) had abnormal tissue reten- frequency of asymptomatic amyloid deposits in pation within 24 hours with a mean of 55.66%for group tients with myelomas and also the possibility of 1 (without myeloma) and 34.37% for group 2 (with regression of amyloidosis with polychemotherapy myeloma; P = 0.005). If tissue retention is correlated (patient 26). Amyloidosis modified the prognosis, -i
--
z
TABLE
V
Patient Number 25
26
27 28 29 30 LSG = labial
1231-SAP Scintigraphy in Patients with Multiple Myeloma without Any Evidence of Amyloidosis at Time of Scintigraphy (Group 3) 24-Hour Tissue Durie and Retention Pathological Sites Gender and Age Salmon fg4yl 0 of 1231-SAP Uptake Evolution (Years) Classification 37% Acute carpal tunnel syndrome required M/58 Stage IIIlambda Lung, cervical surgery, confirmation of amyloid chains deposits; appearance of cardiac localization in spite of VMCP-VBAP but remission Presence of amyloid deposits in a Spleen, kidney, lung, 40% M/65 Stage Ill IgG lombar rachis systematic LSG biopsy but no signs lambda of amyloidosis 10 monthls later; remission with VMCP-VBAP Stable condition, diphosphonate None 35% M/56 Stage I IgG treatment only; normal LSG biopsy kappa 35% Normal LSG biopsy, VMCP-VBAP, bone Stage Ill IgG Lung M/59 marrow transplantation, partial karma response Normal LSG biopsy, VMCP-VBAP, bone None 23% F/50 Stage Ill IgG marrow transplantation kappa 17% Normal LSG biopsy, VMCP-VBAP, Stage Ill IgG Spleen F/54 remission kappa salivary
gland;
VMCP
= vincristine/melphalan/cyclophosphamide/prednisone;
VBAP = vincristine/BCNU/adriamycin/prednisone.
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and its importance detected by the study of the 24hour tissue retention may potentially change the therapy, particularly when bone marrow transplantation is discussed. A study with a larger series must be done to confirm these results. The importance of the tissue retention study in addition to 12”I-SAPscanning is confirmed in our population. There is not a good correlation between amyloid deposits, localization, and scanning, particularly in the heart, kidney, and carpal tunnel. This may be directly related to the quantity or to the rate of the amyloid deposits. Concerning our experience, tissue retention might also be correlated with prognosis. Mean survival in patients with tissue retentions greater than 50% was 24.5 months versus 11.3 months in patients with less than or equal to 50%. These differences did not reach significance perhaps because of the few number of patients in the two groups. Nevertheless, sometimes few amyloid deposits may influence the survival rate when the heart is affected (patients 1, 17, and 22) in spite of low tissue retention values. A serial study of ‘231-SAPscintigraphy is essentially provided in secondary amyloidosis.‘4s’5 The authors of this study showed that visceral ““I-SAP fixation may vary in some treated patients, with a decrease in the body retention. This emphasizes the concept of a possible regression of amyloid deposits and encourages aggressive therapy of this lethal disease. We studied serially 9 patients with AL amyloidosis and 3 patients with multiple myeloma without signs of amyloidosis after their first scintigraphy (Table IV). In 7 of the 9 patients, clinical or biological data were in correlation with the data of the scintigraphy, particularly with 24-hour tissue retention (identical, diminution, or increase). In the 2 other patients there was a discordance: in patient 8 nephrotic syndrome disappeared despite increase in 24-hour tissue retention; in patient 24 the 24-hour tissue retention and the visceral uptake increased but no clinical nor biological signs of amyloidosis appeared, perhaps because of the small quantity of amyloid in the different organs as suggested by the small retention (8% and 24% between the two scintigraphies) . Concerning the serial study of the 3 patients with multiple myeloma without signs of amyloidosis at the time of the first scintigraphy, the high value of the retention in patient 25 suggests the presence of amyloid deposits that are secondarily confirmed; patient 27 remains at this time asymptomatic, and the diminution of the retention in patient 26 suggests that amyloidosis may regress with polychemotherapy. Indeed, all of the data put together suggest that regression of amyloidosis may be possible, that regression of amyloidosis may differ in different organs, and that there is little cor86
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ET AL
relation between clinical findings and the amount of underlying amyloid. When heart localization exists, death may occur despite few amyloid deposits. In conclusion, “” I-SAP scanning protildes no correlation between the involvement of amyloid in the viscera and the imaging, particularly in heart, kidney, carpal tunnel, salivary glands and digestive tract. Echocardiographic study is more effective in the detection of cardiac involvement, which is dlirectly correlated with the prognosis. In contrast, the study of “‘I-SAP tissue retention is abnormal in all our patients and may be a diagnostic tool in asymptomatic patients. The ““I-SAP tissue retention may also be correlated with the prognosis, as most of t.he patients who died had more than 50%of ‘““I-SAP tissue retention values after 24 hours (exception made for heart localization because tissue retention was low, due to the absence of involvement of the other organ). The lX31-SAPtissue retention can help the clinical management of AL amyloidosis t,o guidle therapy, whereas some variations like proteinuria do not reflect the evolution of the amyloidosis.” The use of this technique for screening myeloma patients for amyloidosis, prior to bone marrow transplantation is most important.
ACKNOWLEDGMENT We are grateful to B. Hecquet Lllle, France, for the stabstical
of the Btostatistlcal Unit, Centre Oscar Lambret, analysis. We thank Prof. A. Janin for the hlsto-
pathological examination, J. Kerr-Conte of the Laboratolre de Culture Cellulalre, Facultb de Mddeclne Lllle, who made the English [grammar] translations, and Monlque Tomczak who carned out the typing of this manuscript.
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