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Developing a population-based registry for patients with paraproteinemias or multiple myeloma
0895s4356/97/$17.00 PII SO8954356(97)00092-9
J Clin Epidemiol Vol. 50, No. 8, pp. 909-915, 1997 Copyright 0 1997 Elsevier Science Inc. ELSEVIER
Developing a Population-Based Registry for Patients with Paraproteinemias or Multiple Myeloma F. Ortg,’ J. Hennuns, ’ E. M. Noordijk,3 W. de Kieviet,4 I’. W. Wijermans,j P. J. Seelen, S. Snijder, 7, M. J. Oostindih-,7 and J. C. Kluin-Nelemunss~* ‘COMPREHENSIVE CANCER CENTER WEST, 23 16 XB LEIDEN, THE NETHERLANDS, ‘DEPARTMENT OF MEDICAL STATISTICS, UNIVERSITY OF LEIDEN, 2300 RC LEIDEN, THE NETHERLANDS, ‘DEPARTMENT OF CLINICAL ONCOLOGY, UNIVERCXTY MEDICAL CENTER, 2300 RC LEIDEN, THE NETHERLANDS, 4D~~~~~~~~~ OF CLINICAL CHEMISTRY, MUNICIPAL HOSPITAL LEYENBURG, 2504 LN THE HAGUE, THE NETHERLANDS, 5D~~~~~~~~~ OF HEMATOLOGY, MUNICIPAL HOSPITAL LEYENBURG, 2504 LN THE HAGUE, THE NETHERLANDS, 6D~~~~~~~~~ OF CLINICAL CHEMISTRY, WESTEINDE HOSPITAL, 2501 CK, THE HAGUE, THE NETHERLANDS, 7C~~~~~~~~~~~ CANCER CENTER WEST, 2316 XB LEIDEN, THE NETHERLANDS, *DEPARTMENT OF HEMATOLOGY, UNIVERSITY MEDICAL CENTER, 2300 RC LEIDEN, THE NETHERLANDS
ABSTRACT. The development of a population-based registry on paraproteinemia and multiple myeloma is described. A unique feature of this registry is the multidisciplinary approach to obtain and collect new cases. Clinical chemists, internists, hematologists, and pathologists could all enter patients. All patients newly diagnosed in the mid-western part of The Netherlands (1.7 million inhabitants in 1992) with a paraproteinemia or multiple myeloma in 1991, 1992, and 1993 were included. The project was composed of a registry of clinical and laboratory data extracted from the patient’s records, storage of 1 ml serum at diagnosis, and a yearly followup. A total of 1832 entries was received, of which 83% met the inclusion criteria. Comparison of this database with the Regional Cancer Registry showed that the paraprotein registry was successful as far as registration of myeloma patients was concerned. We conclude that the multidisciplinary approach used in this paraprotein registry is feasible and has resulted in a unique collection of patients for studying potential pre-malignant conditions such as paraproteinemia. J CLIN EPIDEMIOL 50;8:909-915, 1997. 0 1997 Elsevier Science Inc. KEY WORDS. Paraproteins, multiple myeloma, monoclonal lation-based registry
INTRODUCTION In population-based registries, all patients meeting certain pre-arranged criteria in a well-defined region are included in a uniform registry of items that are important to a specific disease. The true incidence of this disease can be calculated from such a registry, and possible risk factors for the occurrence of the disease can be evaluated. A comprehensive follow-up enables monitoring of survival. For this reason many countries have developed regional or national cancer registries [l]. The Comprehensive Cancer Centre West (CCCW) in The Netherlands has experience in establishing regional population-based registries [2,3]. Here we will describe the development of a registry for patients with ‘Address for correspondence: Dr. J. C. Kluin-Nelemans, Dept. of Hematology, University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. The current address of Dr. F. Ong is The Netherlands Cancer Institute, Department of Radiotherapy, 1066 CX Amsterdam, The Netherlands. The current addressof Dr. W. de Kieviet is the Department of Clinical Chemistry, St. Lucas Hospital 1061 AE Amsterdam, The Netherlands. Accepted for publication on 22 April 1997.
gammopathy of undetermined
significance, popu-
paraproteins and/or multiple myeloma in the CCCW region, which made use of multiple sources of information to ensure completeness. Paraproteins (monoclonal proteins) are produced by (a single clone of) plasma cells. They can be detected by protein electrophoresis and appear as an extra localized band or narrow spike. To confirm their monoclonal nature immunotyping can then be carried out, which will determine the paraprotein’s type of heavy (IgG, IgM, IgA, or IgD) and light chains (kappa or lambda). Being the direct product of plasma cells, they are considered to be an ideal tumor marker in multiple myeloma, a plasma cell malignancy [4,5]. Paraproteins may also occur in other hematological malignancies (mainly immunocytoma and other B-cell lymphoproliferations) and amyloidosis, as paraneoplastic phenomenon in solid tumors, and in autoimmune disorders or infections [4,6]. Often no cause is found: this is the so-called monoclonal gammopathy of undetermined significance (MGUS) [7]. After 20 to 35 years of follow-up, 16% of MGUS patients developed multiple myeloma [8]. In a retrospective study in a single center in The Netherlands, the
910
F. Ong et al.
cumulative incidence of malignant transformation was 11% in 14 years [9]. Patients with a paraprotein should therefore be checked regularly. In starting a population-based registry on paraproteinemias, a number of specific problems were encountered. A paraprotein is often unexpectedly found at a routine blood test when the patient presents with unrelated complaints. This means that physicians other than internists or hematologists also may be confronted with a patient with paraproteinemia, making it virtually impossible to have all patients reported. Clinical chemistry laboratories, on the other hand, will see all paraproteins with the possible exception of those very few multiple myeloma patients in whom no serum electrophoresis is carried out, or who did not have a paraprotein in serum or urine (non-secretory myeloma). Most paraproteins are not attributable to malignancies and will thus not be included in cancer registries. Furthermore, malignancies like multiple myeloma as well as other hematological malignancies are often diagnosed by cytology only, without the help of a pathologist, the latter being the main contributor to cancer registries in The Netherlands. We experienced that starting a population-based registry on patients with a paraproteinemia requires careful planning. However, even with limited means, a unique database can be established.
METHODS Aims of the Study In 1990, the Paraprotein Task Force of the Hemato-Oncological Working Party of the CCCW initiated a study on paraproteinemias. The eventual goal was to develop guidelines for physicians faced with a patient with a paraprotein, so that on one hand, patients with multiple myeloma or macroglobulinemia would not be missed, and on the other hand, patients with MGUS would be spared extensive tests or even unnecessary treatment. A population-based registry would not only provide information on frequency of paraproteinemias, but also on the physicians’ management of patients included in the registry, and through regular follow-up, gain information on the course of different paraproteinemias.
Selection
of Patients:
inclusion
and Exclusion
Criteria
The registry consisted of all patients newly diagnosed with either a paraprotein or multiple myeloma (non-secretory myeloma included). Also included were patients with light chains in serum or urine without a corresponding heavy chain. The paraprotein in serum or urine was detected by the investigation of the electrophoretic profile of the proteins, and had to be confirmed by immunotyping. The reasons for ordering the investigation were various and dependent on the treating physicians. A three-year time-period for accrual was decided upon (January 1991 through De-
cember 1993). The exclusion criteria were a paraprotein diagnosed before 1991 or the absence of confirmatory immunotyping of the paraprotein. Oligoclonal gammopathies (more than two different monoclonal bands) were also excluded, as well as multiple myeloma diagnosed at autopsy only. The registry was carried out in the region of the CCCW in the mid-western part of The Netherlands. In 1992, 1.7 million inhabitants (0.82 million males, 0.85 million females) lived in this region, which made up 11% of the Dutch population (15.1 million inhabitants); 9.5% was 70 years and older (this was 9.0% for the total Dutch population). All patients seen in any of the 15 hospital locations in the CCCW region fullfilling the entry criteria were eligible, even if they did not live in the region itself.
Procedure
for Reporting
Patients
Special permission for this registry was obtained from the management of all hospitals. Items to be included in the registry could be extracted from the patient’s hospital record according to the agreement made between CCCW and the hospitals for the Regional Cancer Registry. A unique feature of the paraprotein registry was the close cooperation with the clinical chemists. In order to include patients with non-secretory myeloma (no paraprotein detectable), internists, hematologists, and pathologists were also asked to contribute by entering patients with multiple myeloma or solitary plasmacytoma usually encountered during bone marrow or tumor examinations.
Determination
of the Items
to Be Registered
Information on presenting symptoms and signs, performance status, results of skeletal x-ray examinations, laboratory tests, and bone-marrow examination, comorbidity, and diagnosis and therapy with regard to the paraprotein was extracted from the patient’s hospital records. At the start of the project, an inventory was made of laboratory methods and normal values of the different tests in the different laboratories. Lactate dehydrogenase and alkaline phosphatase were entered as continuous variables, but were later dichotomized to correct for variations in normal values between institutions. Serum calcium was corrected for albumin concentration. If the paraprotein concentration was not reported, an estimation of the concentration in five categories (~5, 5-10, 10-20, 20-35, and 235 g/l) was made whenever possible, based on total gamma fraction and concentration of the immunoglobulins. The follow-up frequency was set to once yearly. For multiple myeloma, a follow-up form was filled in at least once yearly or at every change in therapeutic regimen. Items concerning laboratory, x-ray, and bone marrow examinations, any new diagnosis concerning the paraproteinemia, and information on therapy were included.
Population-Based
Registry
on Paraproteinemia
911
and Myeloma
To assess future prognostic factors and for quality control, an archive of serum samples at entry was set up in conjunction with the population-based registry, with samples to be stored centrally at -80°C.
TABLE 2. Diagnoses
made
by the
treating
physician n
Multiple myeloma Plasmacytoma MGUS
%
204
16 1
12 283 141
Registration
oy;T;;~;~;~;;ve
A registration form was designed to facilitate the uniform registration of items from the hospital records. All information was converted into numerical codes and entered into a database (Data Entry, SPSS Inc, Chicago, IL). Regular checks on inconsistencies were made to minimize registration errors. In a preliminary study on the first 132 patients, the feasibility of the project was evaluated, entry criteria were adjusted, and some practical problems on data collection were solved. For this project, one person (F.O.) did all registrations, after collecting the entry forms in person, To coordinate and supervise the registration, representatives of all disciplines supplying information, supplemented by a radiation oncologist and a biostatistician participated in the Paraprotein Task Force.
Myeloproliferative Other/unclassified Internal disease Paraneoplastic Auto-immune disorder Infection Other/unclassified Provisional diagnosis No diagnosis made No action by physician Patient’s refusal Report not received Lost/died before diagnosis Other Total
22 11
110 21 10 199
16
98 32 61 8 36 396 273 23
3 31
51 27 22
1271
100
RESULTS
A total of 1832 entries was received, of which 519 entries were from 199 1,682 entries from 1992, and 63 1 entries from 1993 (Table 1). About 17% of the entries were discarded because they did not meet the inclusion criteria, mainly because a paraprotein had already been found (sometimes in another hospital) before 1991. This was especially true for one center that acts as referral hospital for the whole region, and for entries made by pathologists, as a patient had often harbored a paraprotein for years before the onset of multiple myeloma. Laboratories using agarose (at 7 of 14 laboratories) instead of celluloseacetate for protein electrophoresis tended to find more paraproteins. A four- to fivefold increase in the number of entries was observed in three hospitals after the switch to agarose was made, predominantly in the low concentration group (< 10 g/l). To date, all data from 1271 patients have been collected and included in the registry. Diagnoses made by the treating
TABLE resulting
I. Number number
of entries of patients”
from
the different 1991
467
Clinical chemist Pathologist Internist/hematologist
“A patient
can be entered
1993
and Total
636 103 27
598 84 20
1701 290 82
519
766 682
702 631
2073 1832
383
517
371
1271
103
35
Total number of entries Total number of patients Patients included in the registry by September 1995
1992
sources,
605
by more than one source.
physician are presented in Table 2. Only 17% of patients was diagnosed with multiple myeloma or plasmacytoma by the treating physician, but this percentage differed greatly between hospitals, varying between 10% and 71%. “Paraprotein e causa ignota (e.c.i.)” was coded in 31%, mostly because the physician did not consider it necessary to make and record a diagnosis (69% of cases with “paraprotein e.c.i.“). In some cases the patient refused further analysis, some died or were lost to follow-up before a diagnosis had been made, and in 51 cases the physician did not receive the laboratory report that a paraprotein had been found, either because a patient was discharged before the laboratory had finished the final analysis, or because of administrative errors. We used a separate variable to distinguish cases in which the paraprotein was not mentioned in the patient’s record or in the ensuing correspondence with the patient’s family physician, which consists of the following possibilities: (1) a diagnosis was made; (2) follow-up of the paraprotein was planned, though no diagnosis had been mentioned; and (3) the paraprotein was not mentioned at all. Also included in this last category were patients with paraproteins accompanying other diseases (malignancies, infections, autoimmune disorders), but whose physicians did not mention the paraprotein anywhere. In 461/1254 (37%) cases, a diagnosis was made; in 226 cases (18%) paraprotein-related follow-up was contemplated (without a specific diagnosis having been made); while in 567 cases (45%) no mention was made of the paraprotein (no information for 17 cases). Again, there were great differences between hospitals. Percentages varied from
5 to
68
for
“no
mention
of paraprotein,”
6 to
28
912
F.
132
138 -
Janmar
apr-jun
Ong
et al.
50%
25%
0% I jan-mar
1991 FIGURE 1. the fraction up), while from 1991 have been
apr-Jun
~ulaep
oot-dec
luI*ep
oct-dec
1992
Paraprotein mentioned in patient’s records or correspondence of paraproteins mentioned by the treating physician (either as the white columns represent the fraction of paraproteins not to the third quarter of 1993. Onlv a few cases from the fourth excluded from this analysis.
for “follow-up contemplated,” and 15 to 81 for “diagnosis made.” From the second quarter of 1992 onward, a gradual decrease of paraproteins that were not mentioned in the patient’s records or correspondence was observed (Fig. 1). Apart from the method used for protein electrophoresis, the policy for doing immunotyping accounted for differences in the number of patients being entered into the registry, and for the distribution of diagnosis among institutions. Immunotyping is generally done whenever an extra spike is detected during protein electrophoresis. To mention two extremes: in one institution this was only done at the explicit request of the physician (in practice only when myeloma was suspected). This policy resulted in myeloma being present in 71% of all paraproteinemias detected in this hospital. In only 5% of cases, the paraprotein was not mentioned in the patient’s records by the treating physician. In another hospital, protein electrophoresis was routinely performed in all patients admitted to an internal medicine ward. Here, myeloma constituted only 10% of all paraproteinemias, whereas the percentage of paraproteins not mentioned in the patient’s records was very high with 52%.
lanmar
apr-Jun
Jul-rep
1993
Completeness
to family physician. The black columns represent a firm diagnosis or mentioned as worthy of followmentioned at all. Data are given for each quarter quarter of 1993 have as yet been registered; they
of
the Registy
The majority of entries (82%) was supplied by the clinical chemists. It was apparent from the start that the number of entries from internists and hematologists would be incomplete. Several pathology laboratories reported not only multiple myeloma patients, but also patients with immunocytoma, and with monoclonal gammopathies without multiple myeloma. In 15 out of 322 patients (5%) reported by pathologist, internists, and hematologists the entry had erroneously not been made by the clinical chemist. In 75/ 198 cases (38%) a paraprotein caused by multiple myeloma was reported by the clinical chemist but not by the pathologist, internist, or hematologist. Serum from 867/1701 (51%) patients entered by clinical chemists was available for storage in the paraprotein serum archive. One hospital (supplying 8 1 entries) did not participate in the serum archive. The percentage of patients with a full analysis focusing on the presence or absence of multiple myeloma (consisting of laboratory, x-ray, and bone marrow examinations) increased with the concentration of the paraprotein (Table 3). Laboratory analysis was considered complete when all
Population-Based
Registry on Paraproteinemia
TABLE relation
913
and Myeloma
3. Number of patients meeting to paraprotein concentration
minimal requirements and diagnosis Bone
n Paraprotein concentration Cl0 g/l 10-20 g/l 20-35 g/l 235 g/l Light chain/non-seer. Unknown Overall Diagnosis Multiple myeloma Plasmacytoma MGUS Other hematological Internal disease Provisional diagnosis No diagnosis made Overall
marrow
n (%)
of pamprotein
X-ray
Lab.
n (%)
tests
n WI
analysis
in
All requirements
n W)
(g/l) 702 171 79 93 17
209
(30) (52) (77) (94) (88)
121 59 52 83 15 53 383
(17) (35) (66) (89) (88) (25j (30)
475 118 67 86 15 126 887
(68) (69) (85) (93) (88) (60) (70)
68 40 43 76 14
201 (99) 11 (92) 179 (63) 107 (76) 20 (10) 14 (39)
187 10 89 29 22 14 32 383
(92) (83) (31) (21) (11) (39) (8, (30)
190 11 219 99 138 25 205 887
(93) (92) (77) (72) (69) (69) (52) (70)
173 9 56 16 5 9
209 89 61 87 15
1271
204 12 283 141 199 36 396 1271
(10)
(23) (54) (82) (82)
(85) (75) (20) (11) (3) (25)
Abbreviation: non-seer. = non-secretory multiple my&ma. Full laboratory analysis (lab tests) was composed of all laboratory tests necessary for diagnosing and staging of MM (hemoglobin, creatinine, and corrected serum calcium levels). X-ray examination was considered done when at least two parts of the spinal column together with at least one other part of the skeleton were photographed. When a full laboratory analysis in combination with x-ray and bone marrow examinations were performed, minimal requirements for a correct diagnosis of the paraprotein have been met.
tests necessary for diagnosing and staging of multiple myeloma were done: hemoglobin, creatinine, serum calcium, and albumin (for correction of serum calcium) [lO,l 11. Either bone marrow cytology or histology was considered sufficient for analysis, even though in some cases no exact percentage of plasma cells was reported. For skeletal x-ray examinations, at least two parts of the spinal column with at least one other part of the skeleton had to be photographed. In 731/1271 (58%) a quantitative analysis of the paraprotein concentration was missing, but in 84% at least a semi-quantitative estimation could be made. When multiple myeloma was diagnosed, the analysis was generally complete, but when the clinical diagnosis was a non-malignant paraprotein or the diagnosis was not made the reverse was true (Table 3).
Comparison with Cancer
Registry
the Regimal of the CCCW
The number of multiple myeloma patients in this population-based registry on paraproteinemia was compared with the Regional Cancer Registry. This registry enters all patients with newly diagnosed malignancies living in the CCCW region reported by the pathology laboratories. The hospital registry of the discharge diagnoses of all clinical patients is used to supplement the entries by the pathological laboratories [12]. Of 270 patients with multiple myeloma or solitary plasmacytoma included in the Regional Cancer
Registry in 1991, 1992, and 1993, 218 had also been included in the paraprotein registry, while two cases turned out to be accidentally registered twice. Of these 218 cases, nine had already been included at an earlier time in the paraprotein registry because of paraproteinemia occurring before multiple myeloma was diagnosed. A total of 38 patients did not meet the entry criteria for the paraprotein registry, either because the paraprotein was discovered before 1991 (n = 29), a plasmacytoma did not have an accompanying paraprotein (n = 6), or the diagnosis multiple my eloma had been made at autopsy only (n = 3). Six patients had not been diagnosed as having myeloma in the paraprotein database (physician maintained the differential diagnosis of stage I multiple myeloma or MGUS) and should therefore not have been included in the Regional Cancer Registry. Ten patients included in the Regional Cancer Registry were missed by the paraprotein registry. Six of these came from one hospital that experienced some problems in entering patients due to personnel changes. Forty-four patients with multiple myeloma included in the paraprotein registry were not included in the Regional Cancer Registry (11 in 1991, 19 in 1992, and 14 in 1993; Table 4). An important reason for this was that no histology was available (n = 13), occurring most often in hospitals where bone marrow cytology was examined by the hematologist and not sent to the pathology laboratory. Thirteen patients were not included in the Regional Cancer Registry because they did not meet the entry criteria: twelve patients with multiple
914
F. Ong
TABLE
4. Myeloma
patients
(n = 44) not included
No bone marrow histology Missed by cancer registry, reason unknown Histology: no myeloma, clinical/cytological Diagnosis treating physician: no myeloma’ Patient not living in CCCW region Total
by the Regional
Cancer
Registry
1991
1992
1993
Total
4 3 2 2
4 2 5 7 &
5 3 3 3
13 8
diagnosis myeloma 3
11
“Although the treating physician did not make a diagnosis multiple criteria according to Durie and Salmon [13] were applied, which multiple myeloma.
myeloma according to the criteria by Durie and Salmon [13], were not diagnosed as such by their physicians, and one patient was excluded in the Regional Cancer Registry because he did not live in the CCCW region. DISCUSSION In three years, due to the excellent participation of clinical chemists in particular, a surprisingly high number of patients with paraproteins was entered into the registry. Clinical chemists had thus far never participated in this kind of large scale registry in the CCCW region. Among other things, by comparison with the Regional Cancer Registry, it turned out that this paraprotein registry was successful in registering patients with multiple myeloma. The Regional Cancer Registry did not include several myeloma patients, in some cases because their bone marrow cytology was examined by the hematologist instead of the pathologist. Some of these patients will be registered at a later time when a patient is admitted to hospital since the hospital’s registry of discharge diagnoses is made available to the Regional Cancer Registry. Moreover, most Cancer Registries tend to be a bit behind, and will collect cases during update procedures. The frequency of newly discovered cases of paraproteinemia in 1992 calculated from our data was 31/100,000 inhabitants, and 189/100,000 for people above 70 years of age. The frequency of multiple myeloma was 4.5/100,000 for females and 4.8/100,000 for males, which was slightly higher than the 4.1 for females, and 4.6 for males reported by the Netherlands Cancer Registry in 1992 [12]. The actual incidence will be still higher, since in the paraprotein registry all multiple myeloma patients who had been diagnosed with MGUS before 1991 were excluded. For the frequency calculations in the paraprotein registry all patients diagnosed in the hospitals located in the region were used, including those not actually living here. In the Regional Cancer Registry, these patients are excluded and the data are given to the Regional Cancer Center to which the patient actually belongs. Conversely, patients living in the “West” region who are diagnosed somewhere else, will be registered in the CCCW registry. Since the paraprotein registry is unique to
2 14
et al.
10
12 -i 44
myeloma, for the paraprotein registry the after all resulted in a definitive diagnosis
the CCCW, we used all registered patients for frequency calculations to compensate for this fact. The prevalence of paraproteins is reported to be 3% for people over 70 years of age, and between 1% and 2% for people aged 50 and older [14-161. However, most of these reports date from the 1960s and 197Os, when protein electrophoresis was not as sensitive as nowadays. The frequency of newly discovered cases has to our knowledge not been reported yet. One report on indence of monoclonal proteins actually reported plevaknce [15]. The advantage of our population-based registry was that, although the number of paraproteinemia and multiple myeloma cases differed greatly between hospitals, the figures for the total of all hospitals gave an accurate description of the overall frequency in this region. It is evident that this is not the true incidence in the general population, as the patients sought medical help for a diversity of problems for which the determination of a protein electrophoresis was deemed necessary. Also, being a population-based registry intending only to observe, many different policies of physicians and laboratories accounted for large differences in the number of entries and the distribution of diagnoses, which makes the development of uniform guidelines essential. However, we wanted to provide physicians with practical figures on the number of patients encountered in their day-to-day practice and not conduct a systematic search to discover all patients harboring a paraproteinemia. Moreover, we felt it necessary to observe the different policies first before developing these guidelines. The percentages of multiple myeloma and solitary plasmacytoma (17%), and other hematological malignancies (11%) reported here match the numbers reported by Kyle (18% and lo%, respectively), the only exception being that Kyle found primary amyloidosis in 9% ofpatients with a paraproteinemia, which was extremely rare in our registry [8]. The first year of the registry (1991) was considered a starting year in which problems had to be solved, and participants had to get used to the entry forms. We assume that the registry is not complete for that year apart from the entries made by the pathologists, who employ an automated registry of all pathological diagnosis made. Personal contact with participants and publicity given to the project (by
Population-Based
Registry
on Paraproteinemia
915
and Myeloma
and presentations to the hemato-oncological meetings of the CCCW) helped to maintain interest in the project, and ensured that entry forms were completed on a regular basis. We conclude that the establishment of a reliable paraprotein registry is feasible. It has additional value above already annual
reports,
existing
regional
journal
articles,
cancer
registries.
A multi-disciplinary
ap-
proach is required to make a paraprotein registry as complete as possible. We observed that apart from being a descriptive registry, this project may also have had some favorable influence on hospital policy concerning the detection and follow-up of patients with a paraproteinemia. Finally, the assumption was proven to be correct that many patients with hematological malignancies diagnosed by blood and bone marrow cytology only may be missed by the Regional
Cancer
Registries
who
mainly
pathology departments, and will lead of the incidence of these diseases. This
work
was funded
by the Dutch
employ
entries
6.
7. 8. 9.
from
to an underestimation
Praeventiefonds,
5.
grant no.
10.
11.
2821620. 12.
References 1. Parkin DM, Sanghvi LD. Cancer registration in developing countries. In: Jensen OM, Parkin DM, MacLennan R, Muir CS, Skeet RG, Eds. Cancer Registration: Principles and Methods. IARC Scientific Publications No 95. Oxford, UK: Oxford University Press: 1991, pp. 185-207. 2. Otter R. Non-Hodgkin’s Lymphoma in a population-based registry. Thesis, 1989. 3. Coebergh JWW, Oostindier MJ, Tersmette AC, van Westering RP, Eds. Lustrumrapportage Regionale Kankerregistratie 1986-1990. Leiden, The Netherlands: Comprehensive Cancer Centre West; 1994. 4. Kyle RA. Plasma cell proliferative disorders. In: Hoffmann R,
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Benz EJ, Shattil SJ, Furie B, Cohen HJ, Silberstein LE, Eds. Hematology: Basic Principles and Practice, 2nd edition. New York: Churchil Livingstone; 1995, pp. 1354-1375, 2nd ed. Salmon SE, Cassady JR. Plasma cell neoplasms. In: DeVita VT Jr, Hellman S, Rosenberg SA, Eds. Cancer: Principles and Practice of Oncology. Philadelphia: Lippincott; 1989; 1853-1888. Duggan DB, Schattner A. Unusual manifestations of monoclonal gammopathies: Autoimmune and idiopathic syndromes. Am J Med 1986; 81: 864-870. Kyle RA, Lust JA. Monoclonal gammopathies of undetermined significance. Semin Haematol 1989; 26: 176. Kyle RA. “Benign” monoclonal gammopathy-after 20 to 35 years of follow-up. Mayo Clin Proc 1993; 68: 26-36. van de Poe1 MHW, Coebergh JWW, Hillen HFP. Malignant transformation of monoclonal gammopathy of undetermined significance among out-patients of a community hospital in SoutheasternNetherlands. Br J Haematol 1995; 91: 121-125. Lymphoma Tumor Group. Plasma cell disorders. In: Cancer Treatment Policies. Vancouver, B.C., Canada: British Columbia Cancer Agency; 1992: 4-6. Durie BMG, Salmon SE. A clinical staging system for myeloma: Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer 1975; 36: 842-854. Visser 0, Coebergh JWW, Schouten LJ, Eds. Incidence of Cancer in The Netherlands 1992. Utrecht, The Netherlands: SIG Health Care Information; 1995. Durie BGM. Staging and kinetics of multiple myeloma. Semin Oncol 1986; 13: 300-309. Axelsson U, Bachmann R, Hall&r J. Frequency of pathological proteins (M-components) in 6,995 sera from an adult population. Acta Med &and 1966; 179: 235-237. Kyle RA, Finkelstein S, Elveback LR, Kurland LT. Incidence of monoclonal proteins in a Minnesota community with a cluster of multiple myeloma. Blood 1972; 40: 719-724. Saleun JP, Vicariot M, Deroff P, Morin JF. Monoclonal gammopathies in the adult population of Finis&e, France. J Clin Path01 1982; 35: 63-68.
J Clin Epidemiol Vol. 50, No. 8, pp. 909-915, 1997 Copyright 0 1997 Elsevier Science Inc. ELSEVIER
Developing a Population-Based Registry for Patients with Paraproteinemias or Multiple Myeloma F. Ortg,’ J. Hennuns, ’ E. M. Noordijk,3 W. de Kieviet,4 I’. W. Wijermans,j P. J. Seelen, S. Snijder, 7, M. J. Oostindih-,7 and J. C. Kluin-Nelemunss~* ‘COMPREHENSIVE CANCER CENTER WEST, 23 16 XB LEIDEN, THE NETHERLANDS, ‘DEPARTMENT OF MEDICAL STATISTICS, UNIVERSITY OF LEIDEN, 2300 RC LEIDEN, THE NETHERLANDS, ‘DEPARTMENT OF CLINICAL ONCOLOGY, UNIVERCXTY MEDICAL CENTER, 2300 RC LEIDEN, THE NETHERLANDS, 4D~~~~~~~~~ OF CLINICAL CHEMISTRY, MUNICIPAL HOSPITAL LEYENBURG, 2504 LN THE HAGUE, THE NETHERLANDS, 5D~~~~~~~~~ OF HEMATOLOGY, MUNICIPAL HOSPITAL LEYENBURG, 2504 LN THE HAGUE, THE NETHERLANDS, 6D~~~~~~~~~ OF CLINICAL CHEMISTRY, WESTEINDE HOSPITAL, 2501 CK, THE HAGUE, THE NETHERLANDS, 7C~~~~~~~~~~~ CANCER CENTER WEST, 2316 XB LEIDEN, THE NETHERLANDS, *DEPARTMENT OF HEMATOLOGY, UNIVERSITY MEDICAL CENTER, 2300 RC LEIDEN, THE NETHERLANDS
ABSTRACT. The development of a population-based registry on paraproteinemia and multiple myeloma is described. A unique feature of this registry is the multidisciplinary approach to obtain and collect new cases. Clinical chemists, internists, hematologists, and pathologists could all enter patients. All patients newly diagnosed in the mid-western part of The Netherlands (1.7 million inhabitants in 1992) with a paraproteinemia or multiple myeloma in 1991, 1992, and 1993 were included. The project was composed of a registry of clinical and laboratory data extracted from the patient’s records, storage of 1 ml serum at diagnosis, and a yearly followup. A total of 1832 entries was received, of which 83% met the inclusion criteria. Comparison of this database with the Regional Cancer Registry showed that the paraprotein registry was successful as far as registration of myeloma patients was concerned. We conclude that the multidisciplinary approach used in this paraprotein registry is feasible and has resulted in a unique collection of patients for studying potential pre-malignant conditions such as paraproteinemia. J CLIN EPIDEMIOL 50;8:909-915, 1997. 0 1997 Elsevier Science Inc. KEY WORDS. Paraproteins, multiple myeloma, monoclonal lation-based registry
INTRODUCTION In population-based registries, all patients meeting certain pre-arranged criteria in a well-defined region are included in a uniform registry of items that are important to a specific disease. The true incidence of this disease can be calculated from such a registry, and possible risk factors for the occurrence of the disease can be evaluated. A comprehensive follow-up enables monitoring of survival. For this reason many countries have developed regional or national cancer registries [l]. The Comprehensive Cancer Centre West (CCCW) in The Netherlands has experience in establishing regional population-based registries [2,3]. Here we will describe the development of a registry for patients with ‘Address for correspondence: Dr. J. C. Kluin-Nelemans, Dept. of Hematology, University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. The current address of Dr. F. Ong is The Netherlands Cancer Institute, Department of Radiotherapy, 1066 CX Amsterdam, The Netherlands. The current addressof Dr. W. de Kieviet is the Department of Clinical Chemistry, St. Lucas Hospital 1061 AE Amsterdam, The Netherlands. Accepted for publication on 22 April 1997.
gammopathy of undetermined
significance, popu-
paraproteins and/or multiple myeloma in the CCCW region, which made use of multiple sources of information to ensure completeness. Paraproteins (monoclonal proteins) are produced by (a single clone of) plasma cells. They can be detected by protein electrophoresis and appear as an extra localized band or narrow spike. To confirm their monoclonal nature immunotyping can then be carried out, which will determine the paraprotein’s type of heavy (IgG, IgM, IgA, or IgD) and light chains (kappa or lambda). Being the direct product of plasma cells, they are considered to be an ideal tumor marker in multiple myeloma, a plasma cell malignancy [4,5]. Paraproteins may also occur in other hematological malignancies (mainly immunocytoma and other B-cell lymphoproliferations) and amyloidosis, as paraneoplastic phenomenon in solid tumors, and in autoimmune disorders or infections [4,6]. Often no cause is found: this is the so-called monoclonal gammopathy of undetermined significance (MGUS) [7]. After 20 to 35 years of follow-up, 16% of MGUS patients developed multiple myeloma [8]. In a retrospective study in a single center in The Netherlands, the
910
F. Ong et al.
cumulative incidence of malignant transformation was 11% in 14 years [9]. Patients with a paraprotein should therefore be checked regularly. In starting a population-based registry on paraproteinemias, a number of specific problems were encountered. A paraprotein is often unexpectedly found at a routine blood test when the patient presents with unrelated complaints. This means that physicians other than internists or hematologists also may be confronted with a patient with paraproteinemia, making it virtually impossible to have all patients reported. Clinical chemistry laboratories, on the other hand, will see all paraproteins with the possible exception of those very few multiple myeloma patients in whom no serum electrophoresis is carried out, or who did not have a paraprotein in serum or urine (non-secretory myeloma). Most paraproteins are not attributable to malignancies and will thus not be included in cancer registries. Furthermore, malignancies like multiple myeloma as well as other hematological malignancies are often diagnosed by cytology only, without the help of a pathologist, the latter being the main contributor to cancer registries in The Netherlands. We experienced that starting a population-based registry on patients with a paraproteinemia requires careful planning. However, even with limited means, a unique database can be established.
METHODS Aims of the Study In 1990, the Paraprotein Task Force of the Hemato-Oncological Working Party of the CCCW initiated a study on paraproteinemias. The eventual goal was to develop guidelines for physicians faced with a patient with a paraprotein, so that on one hand, patients with multiple myeloma or macroglobulinemia would not be missed, and on the other hand, patients with MGUS would be spared extensive tests or even unnecessary treatment. A population-based registry would not only provide information on frequency of paraproteinemias, but also on the physicians’ management of patients included in the registry, and through regular follow-up, gain information on the course of different paraproteinemias.
Selection
of Patients:
inclusion
and Exclusion
Criteria
The registry consisted of all patients newly diagnosed with either a paraprotein or multiple myeloma (non-secretory myeloma included). Also included were patients with light chains in serum or urine without a corresponding heavy chain. The paraprotein in serum or urine was detected by the investigation of the electrophoretic profile of the proteins, and had to be confirmed by immunotyping. The reasons for ordering the investigation were various and dependent on the treating physicians. A three-year time-period for accrual was decided upon (January 1991 through De-
cember 1993). The exclusion criteria were a paraprotein diagnosed before 1991 or the absence of confirmatory immunotyping of the paraprotein. Oligoclonal gammopathies (more than two different monoclonal bands) were also excluded, as well as multiple myeloma diagnosed at autopsy only. The registry was carried out in the region of the CCCW in the mid-western part of The Netherlands. In 1992, 1.7 million inhabitants (0.82 million males, 0.85 million females) lived in this region, which made up 11% of the Dutch population (15.1 million inhabitants); 9.5% was 70 years and older (this was 9.0% for the total Dutch population). All patients seen in any of the 15 hospital locations in the CCCW region fullfilling the entry criteria were eligible, even if they did not live in the region itself.
Procedure
for Reporting
Patients
Special permission for this registry was obtained from the management of all hospitals. Items to be included in the registry could be extracted from the patient’s hospital record according to the agreement made between CCCW and the hospitals for the Regional Cancer Registry. A unique feature of the paraprotein registry was the close cooperation with the clinical chemists. In order to include patients with non-secretory myeloma (no paraprotein detectable), internists, hematologists, and pathologists were also asked to contribute by entering patients with multiple myeloma or solitary plasmacytoma usually encountered during bone marrow or tumor examinations.
Determination
of the Items
to Be Registered
Information on presenting symptoms and signs, performance status, results of skeletal x-ray examinations, laboratory tests, and bone-marrow examination, comorbidity, and diagnosis and therapy with regard to the paraprotein was extracted from the patient’s hospital records. At the start of the project, an inventory was made of laboratory methods and normal values of the different tests in the different laboratories. Lactate dehydrogenase and alkaline phosphatase were entered as continuous variables, but were later dichotomized to correct for variations in normal values between institutions. Serum calcium was corrected for albumin concentration. If the paraprotein concentration was not reported, an estimation of the concentration in five categories (~5, 5-10, 10-20, 20-35, and 235 g/l) was made whenever possible, based on total gamma fraction and concentration of the immunoglobulins. The follow-up frequency was set to once yearly. For multiple myeloma, a follow-up form was filled in at least once yearly or at every change in therapeutic regimen. Items concerning laboratory, x-ray, and bone marrow examinations, any new diagnosis concerning the paraproteinemia, and information on therapy were included.
Population-Based
Registry
on Paraproteinemia
911
and Myeloma
To assess future prognostic factors and for quality control, an archive of serum samples at entry was set up in conjunction with the population-based registry, with samples to be stored centrally at -80°C.
TABLE 2. Diagnoses
made
by the
treating
physician n
Multiple myeloma Plasmacytoma MGUS
%
204
16 1
12 283 141
Registration
oy;T;;~;~;~;;ve
A registration form was designed to facilitate the uniform registration of items from the hospital records. All information was converted into numerical codes and entered into a database (Data Entry, SPSS Inc, Chicago, IL). Regular checks on inconsistencies were made to minimize registration errors. In a preliminary study on the first 132 patients, the feasibility of the project was evaluated, entry criteria were adjusted, and some practical problems on data collection were solved. For this project, one person (F.O.) did all registrations, after collecting the entry forms in person, To coordinate and supervise the registration, representatives of all disciplines supplying information, supplemented by a radiation oncologist and a biostatistician participated in the Paraprotein Task Force.
Myeloproliferative Other/unclassified Internal disease Paraneoplastic Auto-immune disorder Infection Other/unclassified Provisional diagnosis No diagnosis made No action by physician Patient’s refusal Report not received Lost/died before diagnosis Other Total
22 11
110 21 10 199
16
98 32 61 8 36 396 273 23
3 31
51 27 22
1271
100
RESULTS
A total of 1832 entries was received, of which 519 entries were from 199 1,682 entries from 1992, and 63 1 entries from 1993 (Table 1). About 17% of the entries were discarded because they did not meet the inclusion criteria, mainly because a paraprotein had already been found (sometimes in another hospital) before 1991. This was especially true for one center that acts as referral hospital for the whole region, and for entries made by pathologists, as a patient had often harbored a paraprotein for years before the onset of multiple myeloma. Laboratories using agarose (at 7 of 14 laboratories) instead of celluloseacetate for protein electrophoresis tended to find more paraproteins. A four- to fivefold increase in the number of entries was observed in three hospitals after the switch to agarose was made, predominantly in the low concentration group (< 10 g/l). To date, all data from 1271 patients have been collected and included in the registry. Diagnoses made by the treating
TABLE resulting
I. Number number
of entries of patients”
from
the different 1991
467
Clinical chemist Pathologist Internist/hematologist
“A patient
can be entered
1993
and Total
636 103 27
598 84 20
1701 290 82
519
766 682
702 631
2073 1832
383
517
371
1271
103
35
Total number of entries Total number of patients Patients included in the registry by September 1995
1992
sources,
605
by more than one source.
physician are presented in Table 2. Only 17% of patients was diagnosed with multiple myeloma or plasmacytoma by the treating physician, but this percentage differed greatly between hospitals, varying between 10% and 71%. “Paraprotein e causa ignota (e.c.i.)” was coded in 31%, mostly because the physician did not consider it necessary to make and record a diagnosis (69% of cases with “paraprotein e.c.i.“). In some cases the patient refused further analysis, some died or were lost to follow-up before a diagnosis had been made, and in 51 cases the physician did not receive the laboratory report that a paraprotein had been found, either because a patient was discharged before the laboratory had finished the final analysis, or because of administrative errors. We used a separate variable to distinguish cases in which the paraprotein was not mentioned in the patient’s record or in the ensuing correspondence with the patient’s family physician, which consists of the following possibilities: (1) a diagnosis was made; (2) follow-up of the paraprotein was planned, though no diagnosis had been mentioned; and (3) the paraprotein was not mentioned at all. Also included in this last category were patients with paraproteins accompanying other diseases (malignancies, infections, autoimmune disorders), but whose physicians did not mention the paraprotein anywhere. In 461/1254 (37%) cases, a diagnosis was made; in 226 cases (18%) paraprotein-related follow-up was contemplated (without a specific diagnosis having been made); while in 567 cases (45%) no mention was made of the paraprotein (no information for 17 cases). Again, there were great differences between hospitals. Percentages varied from
5 to
68
for
“no
mention
of paraprotein,”
6 to
28
912
F.
132
138 -
Janmar
apr-jun
Ong
et al.
50%
25%
0% I jan-mar
1991 FIGURE 1. the fraction up), while from 1991 have been
apr-Jun
~ulaep
oot-dec
luI*ep
oct-dec
1992
Paraprotein mentioned in patient’s records or correspondence of paraproteins mentioned by the treating physician (either as the white columns represent the fraction of paraproteins not to the third quarter of 1993. Onlv a few cases from the fourth excluded from this analysis.
for “follow-up contemplated,” and 15 to 81 for “diagnosis made.” From the second quarter of 1992 onward, a gradual decrease of paraproteins that were not mentioned in the patient’s records or correspondence was observed (Fig. 1). Apart from the method used for protein electrophoresis, the policy for doing immunotyping accounted for differences in the number of patients being entered into the registry, and for the distribution of diagnosis among institutions. Immunotyping is generally done whenever an extra spike is detected during protein electrophoresis. To mention two extremes: in one institution this was only done at the explicit request of the physician (in practice only when myeloma was suspected). This policy resulted in myeloma being present in 71% of all paraproteinemias detected in this hospital. In only 5% of cases, the paraprotein was not mentioned in the patient’s records by the treating physician. In another hospital, protein electrophoresis was routinely performed in all patients admitted to an internal medicine ward. Here, myeloma constituted only 10% of all paraproteinemias, whereas the percentage of paraproteins not mentioned in the patient’s records was very high with 52%.
lanmar
apr-Jun
Jul-rep
1993
Completeness
to family physician. The black columns represent a firm diagnosis or mentioned as worthy of followmentioned at all. Data are given for each quarter quarter of 1993 have as yet been registered; they
of
the Registy
The majority of entries (82%) was supplied by the clinical chemists. It was apparent from the start that the number of entries from internists and hematologists would be incomplete. Several pathology laboratories reported not only multiple myeloma patients, but also patients with immunocytoma, and with monoclonal gammopathies without multiple myeloma. In 15 out of 322 patients (5%) reported by pathologist, internists, and hematologists the entry had erroneously not been made by the clinical chemist. In 75/ 198 cases (38%) a paraprotein caused by multiple myeloma was reported by the clinical chemist but not by the pathologist, internist, or hematologist. Serum from 867/1701 (51%) patients entered by clinical chemists was available for storage in the paraprotein serum archive. One hospital (supplying 8 1 entries) did not participate in the serum archive. The percentage of patients with a full analysis focusing on the presence or absence of multiple myeloma (consisting of laboratory, x-ray, and bone marrow examinations) increased with the concentration of the paraprotein (Table 3). Laboratory analysis was considered complete when all
Population-Based
Registry on Paraproteinemia
TABLE relation
913
and Myeloma
3. Number of patients meeting to paraprotein concentration
minimal requirements and diagnosis Bone
n Paraprotein concentration Cl0 g/l 10-20 g/l 20-35 g/l 235 g/l Light chain/non-seer. Unknown Overall Diagnosis Multiple myeloma Plasmacytoma MGUS Other hematological Internal disease Provisional diagnosis No diagnosis made Overall
marrow
n (%)
of pamprotein
X-ray
Lab.
n (%)
tests
n WI
analysis
in
All requirements
n W)
(g/l) 702 171 79 93 17
209
(30) (52) (77) (94) (88)
121 59 52 83 15 53 383
(17) (35) (66) (89) (88) (25j (30)
475 118 67 86 15 126 887
(68) (69) (85) (93) (88) (60) (70)
68 40 43 76 14
201 (99) 11 (92) 179 (63) 107 (76) 20 (10) 14 (39)
187 10 89 29 22 14 32 383
(92) (83) (31) (21) (11) (39) (8, (30)
190 11 219 99 138 25 205 887
(93) (92) (77) (72) (69) (69) (52) (70)
173 9 56 16 5 9
209 89 61 87 15
1271
204 12 283 141 199 36 396 1271
(10)
(23) (54) (82) (82)
(85) (75) (20) (11) (3) (25)
Abbreviation: non-seer. = non-secretory multiple my&ma. Full laboratory analysis (lab tests) was composed of all laboratory tests necessary for diagnosing and staging of MM (hemoglobin, creatinine, and corrected serum calcium levels). X-ray examination was considered done when at least two parts of the spinal column together with at least one other part of the skeleton were photographed. When a full laboratory analysis in combination with x-ray and bone marrow examinations were performed, minimal requirements for a correct diagnosis of the paraprotein have been met.
tests necessary for diagnosing and staging of multiple myeloma were done: hemoglobin, creatinine, serum calcium, and albumin (for correction of serum calcium) [lO,l 11. Either bone marrow cytology or histology was considered sufficient for analysis, even though in some cases no exact percentage of plasma cells was reported. For skeletal x-ray examinations, at least two parts of the spinal column with at least one other part of the skeleton had to be photographed. In 731/1271 (58%) a quantitative analysis of the paraprotein concentration was missing, but in 84% at least a semi-quantitative estimation could be made. When multiple myeloma was diagnosed, the analysis was generally complete, but when the clinical diagnosis was a non-malignant paraprotein or the diagnosis was not made the reverse was true (Table 3).
Comparison with Cancer
Registry
the Regimal of the CCCW
The number of multiple myeloma patients in this population-based registry on paraproteinemia was compared with the Regional Cancer Registry. This registry enters all patients with newly diagnosed malignancies living in the CCCW region reported by the pathology laboratories. The hospital registry of the discharge diagnoses of all clinical patients is used to supplement the entries by the pathological laboratories [12]. Of 270 patients with multiple myeloma or solitary plasmacytoma included in the Regional Cancer
Registry in 1991, 1992, and 1993, 218 had also been included in the paraprotein registry, while two cases turned out to be accidentally registered twice. Of these 218 cases, nine had already been included at an earlier time in the paraprotein registry because of paraproteinemia occurring before multiple myeloma was diagnosed. A total of 38 patients did not meet the entry criteria for the paraprotein registry, either because the paraprotein was discovered before 1991 (n = 29), a plasmacytoma did not have an accompanying paraprotein (n = 6), or the diagnosis multiple my eloma had been made at autopsy only (n = 3). Six patients had not been diagnosed as having myeloma in the paraprotein database (physician maintained the differential diagnosis of stage I multiple myeloma or MGUS) and should therefore not have been included in the Regional Cancer Registry. Ten patients included in the Regional Cancer Registry were missed by the paraprotein registry. Six of these came from one hospital that experienced some problems in entering patients due to personnel changes. Forty-four patients with multiple myeloma included in the paraprotein registry were not included in the Regional Cancer Registry (11 in 1991, 19 in 1992, and 14 in 1993; Table 4). An important reason for this was that no histology was available (n = 13), occurring most often in hospitals where bone marrow cytology was examined by the hematologist and not sent to the pathology laboratory. Thirteen patients were not included in the Regional Cancer Registry because they did not meet the entry criteria: twelve patients with multiple
914
F. Ong
TABLE
4. Myeloma
patients
(n = 44) not included
No bone marrow histology Missed by cancer registry, reason unknown Histology: no myeloma, clinical/cytological Diagnosis treating physician: no myeloma’ Patient not living in CCCW region Total
by the Regional
Cancer
Registry
1991
1992
1993
Total
4 3 2 2
4 2 5 7 &
5 3 3 3
13 8
diagnosis myeloma 3
11
“Although the treating physician did not make a diagnosis multiple criteria according to Durie and Salmon [13] were applied, which multiple myeloma.
myeloma according to the criteria by Durie and Salmon [13], were not diagnosed as such by their physicians, and one patient was excluded in the Regional Cancer Registry because he did not live in the CCCW region. DISCUSSION In three years, due to the excellent participation of clinical chemists in particular, a surprisingly high number of patients with paraproteins was entered into the registry. Clinical chemists had thus far never participated in this kind of large scale registry in the CCCW region. Among other things, by comparison with the Regional Cancer Registry, it turned out that this paraprotein registry was successful in registering patients with multiple myeloma. The Regional Cancer Registry did not include several myeloma patients, in some cases because their bone marrow cytology was examined by the hematologist instead of the pathologist. Some of these patients will be registered at a later time when a patient is admitted to hospital since the hospital’s registry of discharge diagnoses is made available to the Regional Cancer Registry. Moreover, most Cancer Registries tend to be a bit behind, and will collect cases during update procedures. The frequency of newly discovered cases of paraproteinemia in 1992 calculated from our data was 31/100,000 inhabitants, and 189/100,000 for people above 70 years of age. The frequency of multiple myeloma was 4.5/100,000 for females and 4.8/100,000 for males, which was slightly higher than the 4.1 for females, and 4.6 for males reported by the Netherlands Cancer Registry in 1992 [12]. The actual incidence will be still higher, since in the paraprotein registry all multiple myeloma patients who had been diagnosed with MGUS before 1991 were excluded. For the frequency calculations in the paraprotein registry all patients diagnosed in the hospitals located in the region were used, including those not actually living here. In the Regional Cancer Registry, these patients are excluded and the data are given to the Regional Cancer Center to which the patient actually belongs. Conversely, patients living in the “West” region who are diagnosed somewhere else, will be registered in the CCCW registry. Since the paraprotein registry is unique to
2 14
et al.
10
12 -i 44
myeloma, for the paraprotein registry the after all resulted in a definitive diagnosis
the CCCW, we used all registered patients for frequency calculations to compensate for this fact. The prevalence of paraproteins is reported to be 3% for people over 70 years of age, and between 1% and 2% for people aged 50 and older [14-161. However, most of these reports date from the 1960s and 197Os, when protein electrophoresis was not as sensitive as nowadays. The frequency of newly discovered cases has to our knowledge not been reported yet. One report on indence of monoclonal proteins actually reported plevaknce [15]. The advantage of our population-based registry was that, although the number of paraproteinemia and multiple myeloma cases differed greatly between hospitals, the figures for the total of all hospitals gave an accurate description of the overall frequency in this region. It is evident that this is not the true incidence in the general population, as the patients sought medical help for a diversity of problems for which the determination of a protein electrophoresis was deemed necessary. Also, being a population-based registry intending only to observe, many different policies of physicians and laboratories accounted for large differences in the number of entries and the distribution of diagnoses, which makes the development of uniform guidelines essential. However, we wanted to provide physicians with practical figures on the number of patients encountered in their day-to-day practice and not conduct a systematic search to discover all patients harboring a paraproteinemia. Moreover, we felt it necessary to observe the different policies first before developing these guidelines. The percentages of multiple myeloma and solitary plasmacytoma (17%), and other hematological malignancies (11%) reported here match the numbers reported by Kyle (18% and lo%, respectively), the only exception being that Kyle found primary amyloidosis in 9% ofpatients with a paraproteinemia, which was extremely rare in our registry [8]. The first year of the registry (1991) was considered a starting year in which problems had to be solved, and participants had to get used to the entry forms. We assume that the registry is not complete for that year apart from the entries made by the pathologists, who employ an automated registry of all pathological diagnosis made. Personal contact with participants and publicity given to the project (by
Population-Based
Registry
on Paraproteinemia
915
and Myeloma
and presentations to the hemato-oncological meetings of the CCCW) helped to maintain interest in the project, and ensured that entry forms were completed on a regular basis. We conclude that the establishment of a reliable paraprotein registry is feasible. It has additional value above already annual
reports,
existing
regional
journal
articles,
cancer
registries.
A multi-disciplinary
ap-
proach is required to make a paraprotein registry as complete as possible. We observed that apart from being a descriptive registry, this project may also have had some favorable influence on hospital policy concerning the detection and follow-up of patients with a paraproteinemia. Finally, the assumption was proven to be correct that many patients with hematological malignancies diagnosed by blood and bone marrow cytology only may be missed by the Regional
Cancer
Registries
who
mainly
pathology departments, and will lead of the incidence of these diseases. This
work
was funded
by the Dutch
employ
entries
6.
7. 8. 9.
from
to an underestimation
Praeventiefonds,
5.
grant no.
10.
11.
2821620. 12.
References 1. Parkin DM, Sanghvi LD. Cancer registration in developing countries. In: Jensen OM, Parkin DM, MacLennan R, Muir CS, Skeet RG, Eds. Cancer Registration: Principles and Methods. IARC Scientific Publications No 95. Oxford, UK: Oxford University Press: 1991, pp. 185-207. 2. Otter R. Non-Hodgkin’s Lymphoma in a population-based registry. Thesis, 1989. 3. Coebergh JWW, Oostindier MJ, Tersmette AC, van Westering RP, Eds. Lustrumrapportage Regionale Kankerregistratie 1986-1990. Leiden, The Netherlands: Comprehensive Cancer Centre West; 1994. 4. Kyle RA. Plasma cell proliferative disorders. In: Hoffmann R,
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Benz EJ, Shattil SJ, Furie B, Cohen HJ, Silberstein LE, Eds. Hematology: Basic Principles and Practice, 2nd edition. New York: Churchil Livingstone; 1995, pp. 1354-1375, 2nd ed. Salmon SE, Cassady JR. Plasma cell neoplasms. In: DeVita VT Jr, Hellman S, Rosenberg SA, Eds. Cancer: Principles and Practice of Oncology. Philadelphia: Lippincott; 1989; 1853-1888. Duggan DB, Schattner A. Unusual manifestations of monoclonal gammopathies: Autoimmune and idiopathic syndromes. Am J Med 1986; 81: 864-870. Kyle RA, Lust JA. Monoclonal gammopathies of undetermined significance. Semin Haematol 1989; 26: 176. Kyle RA. “Benign” monoclonal gammopathy-after 20 to 35 years of follow-up. Mayo Clin Proc 1993; 68: 26-36. van de Poe1 MHW, Coebergh JWW, Hillen HFP. Malignant transformation of monoclonal gammopathy of undetermined significance among out-patients of a community hospital in SoutheasternNetherlands. Br J Haematol 1995; 91: 121-125. Lymphoma Tumor Group. Plasma cell disorders. In: Cancer Treatment Policies. Vancouver, B.C., Canada: British Columbia Cancer Agency; 1992: 4-6. Durie BMG, Salmon SE. A clinical staging system for myeloma: Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer 1975; 36: 842-854. Visser 0, Coebergh JWW, Schouten LJ, Eds. Incidence of Cancer in The Netherlands 1992. Utrecht, The Netherlands: SIG Health Care Information; 1995. Durie BGM. Staging and kinetics of multiple myeloma. Semin Oncol 1986; 13: 300-309. Axelsson U, Bachmann R, Hall&r J. Frequency of pathological proteins (M-components) in 6,995 sera from an adult population. Acta Med &and 1966; 179: 235-237. Kyle RA, Finkelstein S, Elveback LR, Kurland LT. Incidence of monoclonal proteins in a Minnesota community with a cluster of multiple myeloma. Blood 1972; 40: 719-724. Saleun JP, Vicariot M, Deroff P, Morin JF. Monoclonal gammopathies in the adult population of Finis&e, France. J Clin Path01 1982; 35: 63-68.