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J Clin Pathol 1990;43:469-475

Bone marrow biopsy in monoclonalgammopathies: correlations between pathologicalfindings and clinical data

A Riccardi, G Ucci, R Luoni, A Castello, A Coci, U Magrini, E Ascari,for the Cooperative Group for Study and Treatment of Multiple Myeloma

AbstractBetween January 1987 and October 1989,561 consecutive untreated patientswith monoclonal gammopathy of un-determined clinical importance (MGUS)(n = 295) or with multiple myeloma(n = 266) were evaluated in a multicentretrial. Both bone marrow biopsy andaspiration (performed at differentanatomical sites) were required atpresentation. Bone marrow biopsy dataindicated that changes in bone marrowcomposition from MGUS to early multi-ple myeloma and to advanced multiplemyeloma followed a precise pattern, in-cluding an increased percentage of bonemarrow plasma cells (BMPC%), a shiftfrom plasmocytic to plasmoblastic cy-tology, an increase in bone marrowcellularity and fibrosis, a change in bonemarrow infiltration (becoming diffuserather than interstitial), a decrease inresidual haemopoiesis and an increase inosteoclasts. In multiple myeloma theBMPC% of biopsy specimens and as-pirate were closely related, although in5% of cases the difference between thetwo values was greater than 20%. Somehistological features were remarkablyassociated with each other. For example,BMPC% was higher in cases with plas-moblastic cytology, heavy fibrosis, orreduced residual haemopoiesis. Anaemiawas the clinical characteristic mostinfluenced by bone marrow histology.The BMPC% was the only histologicalvariable which affected the greatestnumber of clinical and laboratorycharacteristics, including, besideshaemoglobin concentration, erythrocytesedimentation rate, radiographic skeletalbone disease, and serum concentrationsof monoclonal component, calcium, #2-microglobulin and thymidine kinaseactivity. These data indicate that com-parative bone marrow histology in mono-clonal gammopathies has clinical impor-tance.

Multiple myeloma (MM) is a rather uniquemalignant disease in that the overall neoplasticburden can be calculated or, more simply,approximated from the serum or urine mono-clonal component.' How skeleton, kidney, andhaemopoietic marrow are affected is described

by a series of simple radiological and laboratorydata, including skeletal x-ray lesions, bloodurea and nitrogen concentrations or creatinineconcentration and Bence-Jones proteinuria,haemoglobin concentration, and percentage ofplasma cells infiltrating the bone marrow(BMPC0O) on bone marrow aspirate.2 Thesevariables have all been used for staging thedisease at diagnosis,35 which, in turn, definesprognosis. The ease with which multiplemyeloma can be studied justifies further at-tempts to improve the definition of diseaseactivity and associated changes.A bone marrow biopsy specimen offers a

better definition of bone marrow characteris-tics than bone marrow aspirate because itallows a greater number of variables to beobtained.6 Besides BMPCO I, the degree ofplasma cell anaplasia,79 and osteoclastactivation''" have been reported to be ofclinical relevance, but only recently Bartl et alretrospectively included bone marrow biopsyvariables into a multiple myeloma stagingsystem. 1`14 The drawbacks of this system,however, are that the proposed criteria fordefining these variables are rather complicatedand central reviewing of the slides is required.

In a prospective multicentre trial for thestudy and treatment of monoclonal gammo-pathies a bone marrow biopsy specimen show-ing >200% BMPC0o was one of threeprerequisites for diagnosing multiple myeloma(the two others were the presence of serum orurine monoclonal component and of multipleosteolytic lesions unexplained by other causes:two criteria out of the three had to be satisfied).A simple and (we believe) accurate protocol forevaluating histological variables in bonemarrow biopsy specimens was prepared andused by participating centres. In this paper wereport the feasibility of this attempt as well asthe differences in histological characteristicsobserved at diagnosis between monoclonalgammopathies of undetermined clinical im-portance (MGUS) and multiple myeloma, andamong multiple myeloma stages,3 and theassociation between histological and presentingfeatures in multiple myeloma.3

MethodsBetween January 1987 and October 1989, 742consecutive patients with untreated mono-clonal gammopathies entered a cooperativeprotocol for the study and treatment of mul-tiple myeloma, referred to as "MM Protocol

Clinica Medica II edIstituto di AnatomiaPatologica, Universita'ed IRCCS, PoliclinicoSan Matteo, 27100Pavia, ItalyA RiccardiG UcciR LuoniA CastelloA CociU MagriniE AscariCorrespondence to:A RiccardiAccepted for publication23 January 1990

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Riccardi, Ucci, Luoni, Castello, Coci, Magrini, Ascari

Table 1 Bone marrow histological variables to beevaluated

1 Per cent of bone marrow plasma cell (BMPC)*2 Cytology

Predominantly plasma cells (= plasmocytic cytology)Predominantly plasmoblasts (= plasmoblastic cytology)

3 CellularityReduced = bone marrow: fat ratio of < 1:2Normal = bone marrow: fat ratio between 1:2 and 1:1Increased = bone marrow: fat ratio of > 1:1

4 Fibrosis (Gomori's stain)Absent = no evidenceLow = fine reticulin networkIntermediate = multifocal or diffuse non-confluent

fibrosisHeavy = severe, diffuse fibrosis, with or without areas of

collagenisation5 Type of BMPC infiltration

Interstitial (with preservation of bone marrow structure)Diffuse (with generalised or patchy changes in bonemarrow structure)

6 Residual haemopoiesistHypoplasticNormal

7 OsteoclastsAbsentPresent

*BMPC"O was determined as the differential of at least 2000nucleated bone marrow cells at x 480 magnification.tFor evaluating residual haemopoiesis, the overall cellularityand the aliquots of normal haemopoietic precursors andplasma cells had to be taken into account.

1987". It was coordinated by the Institutes ofClinica Medica II and Anatomia Patologica atthe University and IRCCS Policlinico SanMatteo, Pavia.

Diagnosis of multiple myeloma required thepresence of at least two of the following threefeatures: (a) serum or urine monoclonalcomponent; (b) BMPC% greater than 20,determined on trephine bone marrow biopsyspecimen (a bone marrow aspirate also had tobe taken from a different anatomical site);(c) osteolytic lesions on plain skeletal x-ray.Patients with a serum or urine monoclonalcomponent but neither of the other two criteriawere considered to have a monoclonalgammopathy of undetermined clinical impor-tance. For diagnosis of non-secretory multiplemyeloma-that is, patients fulfilling onlycriteria (b) and (c)-biopsy specimens of a lyticlesion showing plasma cell infiltration wasrequired. Other causes of increased marrowplasmocytosis, such as rheumatoid arthritis,chronic infections, collagen disease, carcinoma,lymphoma or leukaemia, aplastic anaemia, andof monoclonal gammopathy, such as serumsickness, tuberculosis, neoplasms, wereexcluded before multiple myeloma or MGUSwere diagnosed. Precise criteria were alsoestablished for the diagnosis of solitary osseousor extra-medullary plasmocytoma as well asprimary plasma cell leukaemia in a fewpatients.

EVALUATION OF BONE MARROW HISTOLOGYAs a bone marrow biopsy specimen wasrequired at diagnosis, a protocol for the com-plete evaluation of bone marrow histology wasprepared. Prerequisites for this protocol were,of course, that it should take into accountpublished procedures,'3 1516 but also that it besimple enough to be used in a multicentre trialwithout requiring central reviewing of slides.The protocol was first discussed at a slide

seminar and agreed on by all the pathologists

from the various institutions. Table 1 lists theseven established histological variables whichhad to be evaluated (in a semiquantitative way)to describe bone marrow. Figures a-d showsome representative patterns. A bone marrowspecimen had to measure at least 20 mm2 to beevaluable. Dehydration and plastic embeddingof core biopsy specimens was advised, andpathologists were asked to omit responses onindividual histological variables in "doubtful"cases.The reproducibility of bone marrow biopsy

examination was checked (in December, 1989)in two ways: First, we directly determined the Kindex.'7 Pathologists participating in the studywere independently given the slides of threerepresentative cases prepared at the co-ordinating institution. Agreement ofindividualresponses with those given on the same cases bythe proposing pathologists (AC, AC, and UM)was determined so as to eliminate the pro-portion of agreement among observers due tochance. In fact, the K index represents the ratiobetween the actual agreement beyond chanceand the potential agreement beyond chance. Aperfect agreement is reached when the index is> 8000, and a satisfactory agreement when it is>40%.Second, we compared the bone marrow

biopsy data obtained at the coordinating centre(and analysed by the pathologists who hadproposed the protocol) (45% of patients) withthose obtained at the affiliated centres (55%o ofpatients). This was aimed at ascertaining majordifferences in the distribution of histologicalfeatures due to uneven interpretation of bonemarrow morphology.

Basic data such as skeletal x-ray picture,haemoglobin concentration, serum or urinemonoclonal component, calcium and creatinineconcentration, as well as several additionallaboratory variables, including erythrocytesedimentation rate (ESR), white cell andplatelet counts, serum concentrations ofalbumin, ,B2-microglobulin, and thymidinekinase'8 were collected at diagnosis for bothpatients with multiple myeloma or MGUS.

Differences between patient groups in the

Table 2 Clinicalfeatures at diagnosis ofpatientsincluded in this study

No ofpatients

MultipleMGUS myeloma Total

Patients studied 295 266 561M/F 163/132 134/132 297/264Age in years (median) 64 68 66IgG 228 173 401IgA 43 60 103IgD 7 7IgM 24 24Light chain only 22 22Non-secreting 4 4Light chain type

h' 170 164 334A 125 102 227

Stage I 56Stage II 77Stage III 133

MGUS = monoclonal gammopathies of undeterminedimportance; multiple myeloma was staged according to Durieand Salmon3.

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471Bone marrow biopsy in monoclonalgammopathies

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Representative patterns of bone marrow disease in multiple myeloma, as classified in the protocolfor evaluation ofbone marrow biopsy specimens inthis study. (a) Interstitial pattern of infiltration with atypical bone marrow plasma cells (BMPC) representing 20% of total nucleated bone marrowcells (plasmacytic myeloma); cellularity and residual haemopoiesis are within normal range (Giemsa). (b) Same as in (a) but with predominantundifferentiated BMPC (plasmoblastic myeloma). (c) Diffuse infiltration by well differentiated BMPC (90%), withfew binucleated cells.Cellularity is increased but residual haemopoiesis hypoplastic (Giemsa). (d) Same as in (c) with undifferentiated (plasmoblastic) cytology.(e) Intermediate degree offibrosis (Gomori). (f) Diffuse pattern ofBMPC infiltration with numerous osteoclasts on residual bone trabeculae(Giemsa).

distribution of BMPC% (which is the onlycontinuous variable we examined) were testedby the two-tailed Student's t test. For otherhistological variables (which are non-continuous) Fisher's exact test or Yates'corrected x2 test were used. Correlations amongthe different histological variables were inves-tigated by the Pearson correlation procedure.

Differences in the distribution of clinical andlaboratory data among groups of patients withdifferent histological characteristics weretested using the two-tailed Student's t test.Testing for BMPC% was accomplished bydividing patients in two groups-those withhigher and lower BMPC% than the medianBMPC% .

ResultsWhen this evaluation was carried out(December, 1989), the records of 561 of the742 patients with monoclonal gammopathiesrecruited into the "MM Protocol 1987" be-tween January 1987 and October 1989 wereevaluable. Diagnosis was MGUS in 295 of 561(5269o) and multiple myeloma in 266 of 561(47.4%). The general characteristics of thesepatients are listed in table 2. The remaining 181are not included in this report because theirrecords had not yet reached the coordinatingcentre (n = 146), or the data were unsatisfac-tory for diagnosis (n = 30), or the diagnosis wassolitary osseous (n = 3) or extra-medullaryplasmocytoma (n = 2).



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Table 3 Distribution of bone marrow histological characteristics in multiple myeloma and MGUS and in multiplemyeloma stages

Multiple myeloma stageNo ofpatients Multiplewith variable MGUS myeloma p Value I II III p Value

Median BMPC0o 8-3 46 0 0001 23 41 58 0 0001Cytology

Plasmocytic 143 146 0-0001 38 45 63 0 005Plasmoblastic 2 62 0 016 16 40 00

CellularityReduced 18 27 5 11 11Normal 102 86 0-0005 24 25 37 0-2Increased 21 56 10 14 32

FibrosisLow 136 127 0-0134 40 53 000Heavy 6 52 00001 3 13 36 00009

Type of infiltrateInterstitial 90 98 0.0133 32 33 0.0001Diffuse 22 90 00001 7 22 61

Residual haemopoiesisHypoplastic 23 93 0-0001 10 29 54 0-02Normal 127 93 oo 32 25 3602

OsteoclastsAbsent 102 91 0-0001 24 28 39 0 06Present 13 56 00110 14 3206

A bone marrow biopsy specimen was ob-tained at presentation in 382 of 561 (68 0%)patients, more often in multiple myeloma (217of 266, 82 0%) than in MGUS (165 of 295,55 9%). A bone marrow aspirate (at an ana-

tomical site different from that of the bonemarrow biopsy) was obtained in 499 of 561(88 9%) patients-namely, in 239 of 266(90-1 %) with multiple myeloma and in 260 of295 (8833%) with MGUS. Physicians oftenpreferred a bone marrow aspirate to biopsyspecimen when the diagnosis of multiplemyeloma was regarded as unlikely on clinicalgrounds, and therefore histological data are

absent in several patients with MGUS. In mostof the 49 patients with multiple myeloma whodid not undergo bone marrow biopsy thediagnosis had already been ascertained by thesimultaneous presence of serum or urinemonoclonal component and multiple osteolyticlesions.

Seven variables had to be evaluated in bonemarrow biopsy specimens (table 1). TheBMPC% was determined in all cases. Plasmacell cytology, cellularity, fibrosis, type ofBMPC infiltration, presence of osteoclasts andresidual haemopoiesis were evaluated, indecreasing order (in 96-67% of patients withmultiple myeloma and in 88-68% of patientswith MGUS).

Overall results of the bone marrow histologyare reported in table 3. Due to the diagnosticcriteria, the BMPC% was much greater inmultiple myeloma (median value = 46%,range = 5 8-98%) than in MGUS (medianvalue = 8-3%, range = 2-5-19-5%). Withrespect to MGUS, multiple myeloma also had a

greater incidence of plasmoblastic cytology,increased cellularity and fibrosis, diffuse typeof plasma cell infiltration, hypoplastic residualhaemopoiesis and osteoclasts.

In 218 patients (82 0%) with multiplemyeloma the BMPC% was determined on thefindings of both bone marrow biopsy andimprint. Median BMPC% values were similarin biopsy specimens (46 2%) and aspirates(44 5%), and paired values were also closelyrelated (p < 0 000003). The overall dispersion

around the correlation line, however, was quitewide (r2 = 0-49), and in 11 (4 6%) cases thedifference in BMPC% between the two bonemarrow sampling procedures was greater than20% (21-90%). In 24 (7 4%) patients only oneofthe two procedures gave aBMPC% diagnos-tic for multiple myeloma-that is, a BMPC%greater than 20%. In these cases the highestBMPC count was the accepted value for diag-nosis.The pattern of histological changes from

stage I to stage III multiple myeloma was verysimilar to that seen from MGUS to multiplemyeloma (table 3). With respect to earlymultiple myeloma, in advanced multiplemyeloma the BMPC% was higher, cytologywas more often plasmoblastic, cellularity wasincreased, plasma cell infiltration was morediffuse, fibrosis heavier, residual haemopoiesisscantier and osteoclasts were more common.No significant difference in histological

characteristics was detected between MGUSand stage I multiple myeloma.The reproducibility of data collected at the

different centres by the individual pathologistswas good. The K indexes were between 45 and75%O for the seven histological variables con-sidered (table 1). The two groups of patients-that is, those from the coordinating centre andthose from the affiliates-were similar forclinical stage and the other main clinicalcharacteristics. No difference in the distribu-tion of any histological feature could beattributed to uneven interpretation criteria.

In multiple myeloma, some histologicalvariables were related to each other. BMPC%was greater in patients with plasmoblastic thanin those with plasmocytic cytology (62 com-pared with 38%; p < 0-0001), with heavyrather than low fibrosis (59 compared with40%; p < 0-002), with diffuse rather thaninterstitial infiltration (62 compared with 31%;p < 0-0001), and in those with poor rather thannormal or increased residual haemopoiesis (57compared with 33%; p < 0-0001). In indi-vidual cases bone marrow areas more heavilyinfiltrated by plasma cells also had morefibrosis, or osteoclasts, or both. Severe fibrosis

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Table 4 Distribution of bone marrow histological characteristics according to some laboratory variables in multiplemyeloma

Monoclonal Serum f2Haemoglobin component calcium microglobulin Serum thymidine

Variable ESR (g/dl) (gldl) (mg/dl) (pg/ml) kinase (Ulul)

BMPC <460o 69 120 3-1 95 6-2 770-0001 0-0001 0-0001 0-001 ns 0-05

>460 100 9-8 4-5 10-2 7-8 14-7Cytology

Plasmocytic 81 11-4 3-6 9-6 6-5 7-0ns 0002 ns ns ns 0-02

Plasmoblastic 99 10-2 3-7 9 7 7-6 16 3CellularityReduced 91 10-8 3-7 9 5 5-4 6-6Normal 76 ns 12-1 0-02 3-4 ns 9-5 0-04 7-1 0-001 9 5 0-003Increased 86 10-5 3 7 9 9 6-3 14-2

Type of infiltrateInterstitial 78 11-7 3-3 9-5 64 6-9

0-05 0-001 0-006 0-05 0-05 0-05Diffuse 91 10-7 4-1 9-8 7-2 14-7

FibrosisAbsent/low 79 11-6 3-4 9-6 5-2 7-1

0.01 0-0001 0-003 ns 0-02 0-05Intermediate/heavy 99 9-7 4-3 9.9 10-0 14-8

Residual haemopoiesisHypoplastic 94 10-3 4-0 9-7 6-6 14-6

0 001 0-0001 0-006 ns ns 0-05Normal 71 12-1 3-2 9-5 6-8 7-7

OsteoclastsAbsent 82 11-5 3-4 9-6 5-8 10-0

ns 0-05 ns ns ns nsPresent 88 10-8 3-6 9.7 5-3 12-8

was also more often found in patients withplasmoblastic cytology (p < 0-02). Residualhaemopoiesis was especially poor in patientswith increased cellularity and diffuse type ofinfiltration (p < 0-0001).

Overall correlations between histology andclinical characteristics are summarised in table4. The haemoglobin concentration was thelaboratory variable most profoundly influ-enced by bone marrow histology in multiplemyeloma. Anaemia was, in fact, more severein patients with a BMPC% of >46 or withplasmoblastic cytology, abnormally poor or

abnormally increased bone marrow cellularity,heavy fibrosis, interstitial infiltrate, poorresidual haemopoiesis and the presence ofosteoclasts. On the contrary, white cell andplatelet counts were not related to histology.The degree of bone marrow infiltration by

plasma cells was the single histological featurewhich influenced the greatest number ofclinical and laboratory variables. TheBMPC%changed according to the severity ofx-ray bonedisease. BMPC% was 34% in patients with nolesions or osteoporosis, 49% in those with lessthan three osteolytic lesions in different sites ofthe skeleton, and 55% in those with moreextensive bone disease (p < 0-002). Patientswith a BMPC% of >46 also had higher serumcalcium than those with lower BMPC% (table4). No other histological variable was related tox-ray bone disease and serum calcium.Additional laboratory variables which were

higher in patients with aBMPC% of > 46 thanin those with lower bone marrow infiltrationwere ESR and serum concentrations of mono-clonal component, f2-microglobulin, andthymidine kinase.A few other correlations between histology

and laboratory variables in multiple myelomaare shown in table 4. There were no significantdifferences among histological characteristicsdepending on sex, age, heavy or light chainsubtype, presence or absence of Bence-Jonesproteinuria, or serum concentrations of al-

bumin, blood urea and nitrogen concentrationsand creatinine and alkaline phosphataseactivity.

DiscussionIn a multicentre trial the feasibility of examin-ing bone marrow histology was evaluated toascertain the histological characteristics ofMGUS and multiple myeloma and multiplemyeloma stages, as well as their influence on

the clinical and laboratory presenting featuresof patients with multiple myeloma. A bonemarrow biopsy study protocol was used thatwas thought to fulfil reported require-ments6-13 1516 and be simple enough to be usedwithout requiring a central review ofthe slides.The first step was to obtain, in addition to a

bone marrow aspirate, a bone marrow biopsyspecimen, which is not a standard procedurefor diagnosing and staging monoclonalgammopathies. Bone marrow biopsy was

avoided in almost half the patients who were

later diagnosed with MGUS (where multiplemyeloma was considered to be unlikely on thebasis of presenting clinical features). On theother hand, biopsy was performed almost as

often as aspiration in patients with multiplemyeloma (in 82% and 90% of cases, respec-tively), where, as a rule, it was avoided whenthe diagnosis had already been ascertained bythe presence ofa serum monoclonal componentand osteolyses. This indicates that bonemarrow biopsy is acceptable as a diagnosticprocedure when a serious disease is suspected.

Despite the fact that the BMPC% frombiopsy specimens and aspirates (taken fromdifferent anatomical sites in 218 patients withmultiple myeloma) were closely related, thepattern of plasma cell infiltration in multiplemyeloma can be patchy. In fact, the dispersionof paired biopsy and aspirate BMPC% valuesaround the correlation line was quite wide and,specifically, in about 5% of cases the differencebetween the two values was greater than 20%,

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and in about 80% of cases only one value wasgreater than 20% (which was the level requiredfor diagnosing multiple myeloma in this study).In patients without monoclonal component orosteolysis, or both, where the BMPC% value isa prerequisite for diagnosis, obtaining two bonemarrow samples is therefore probably advis-able.The BMPC% was determined on all bone

marrow biopsy specimens, and other histo-logical variables-that is, plasma cell cytology,bone marrow cellularity and fibrosis, type ofBMPC infiltration, presence of osteoclasts andresidual haemopoiesis-were established, indecreasing order, in 92-68% of the cases(pathologists were specifically asked to omitresponses in doubtful cases). Data were re-producible as the K index'7 was quite high andthe distribution of histological characteristicswas similar in the two clinically comparablegroups of patients (the one examined at thecoordinating institute and the other at theparticipating centres). This indicates that theprotocol is generally suitable for use in amulticentre trial without requiring centralsupervision. Further exercise will improve thealready good collection of data.Changes in bone marrow composition from

MGUS to multiple myeloma and from early toadvanced multiple myeloma followed anidentical pattern which included increasingBMPC%, a shift from plasmocytic to plasmo-blastic cytology, an increase in bone marrowcellularity and fibrosis, bone marrow infiltra-tion becoming diffuse (rather than interstitial),a decrease in residual haemopoiesis and anincrease in the osteoclast number.This pattern of histological progression al-

ready suggests that there are interrelationsamong at least some of the histological vari-ables-that is, some of them are probablyinterdependent variables in multiple myeloma,and this was confirmed by direct statistics. Forexample, the greater the BMPC%, the morepronounced the fibrosis (and several patho-logists reported that the patchiness offibrosis isalso increased in the most heavily infiltratedareas, where osteoclasts are more frequentlyfound).6101619 Another example is that patientswith plasmoblastic cytology also have a highBMPC% as well as heavy fibrosis. An overallinterpretation of these data is difficult andperhaps unnecessary. The fact that both highBMPC%5OS4 and plasmoblastic cytology79 havealready been recognised as characteristics ofpatients with advanced or aggressive multiplemyeloma leads to the speculation that thesefeatures are mainly responsible for the otherchanges in bone marrow histology-that is, forthe increase in bone marrow cellularity, diffuseplasma cell infiltration, fibrosis, reduction ofnormal haemopoiesis and osteoclastic activa-tion.Apart from the overall condition of the

patients (stage of disease), the haemoglobinconcentration was the clinical variable mostclosely associated with histological progres-sion, while the white cell and platelet countswere not influenced. This suggests that mye-loma cells affect erythropoiesis, but not

myelopoiesis or megakaryocytopoiesis, prob-ably by humoral factors. That physical dis-placement of haemopoietic cells can produceanaemia without causing leucopenia, andthrombocytopenia is unlikely, while theproduction of active lymphokines is a recog-nised ability of multiple myeloma cells.2>2'On the other hand, the BMPC% was the

only histological variable that affected (besideshaemoglobin concentration) the greatestnumber of clinical and laboratory characteris-tics. In fact, x-ray bone disease worsened andserum calcium increased the greater theBMPC%, which is in keeping with the fact thatplasma cells secrete a number of humoralfactors which stimulate locally osteoclastactivity (osteoclast activating factor).2"24 TheESR and serum concentrations of monoclonalcomponent, ,B2-microglobulin, and thymidinekinase (thought to be relevant prognosticfactors) 8 2527 were also strictly related toBMPC%. Osteoclasts (and fibrosis) were morefrequently found in patients with a highBMPC% and in more heavily infiltrated,patchy areas.In conclusion, this study indicates that it is

feasible to obtain data on monoclonal gammo-pathies from bone marrow histology in amulticentre trial, that these data haveclinical relevance and can be used for stagingmultiple myeloma. Up to now only BMPC%and plasma cell cytology5 1 had been proposedas staging variables (without being widely usedin practice), and the data presented here con-firm that they are useful. What other histo-logical variables may be relevant for survivalcannot be confirmed at present, as some ofthem could be mutually related and the followup of patients was quite short. More definiteinformation will come from an adequate followup and a multivariate analysis of pertinentclinical, laboratory, and histological data.

The following members participated in this study: EmatologiaFerrara (Professor G L Castoldi, Professor R Spanedda, DrA Cuneo); Patologia Medica V, Milan (Professor C Rugarli, DrE Bucci, Dr M Tresoldi); Semeiotica Medica, PoliclinicoGemelli, Roma (Professor B Bizzi, DrG Nicoletti); Ematologia,Parma (Professor V Rizzoli, Dr L Craviotto); Clinica Medica,Divisione Oncologia, Modena (ProfessorV Silingardi, ProfessorR Piccinini); Oncologia, Como (Dr C Epifani, Dr F Alberio);Ematologia Niguarda, Milan (Professor F De Cataldo, DrL Barbarano); Medicina II, Cremona (Professor E Bianchini,Dr S Morandi); Medicina I, Piacenza (ProfessorL Buscarini, DrM Di Stasi); Medicina II, Legnano (Professor E Cassi, DrA DePaoli); Medicina I, Magenta (Professor C Novi, Dr E Rinaldi);Medicina I, Melegnano (Professor U Visca, Dr M VenturaParadiso, Dr 0 Pica); Semeiotica Medica, l'Aquila (Professor DQuaglino, Dr A De Pasquale); Medicina B, Varese (Professor AVenco, Dr G Pinotti); Medicina C, Varese (Professor HSalmimi, Dr N Brumana); Medicina I, Gallarate (Professor LGhiringhelli, Dr A Ceriani); Ematologia, Pisa (Professor BGrassi, Dr M Petrini); Medicina I, Alessandria (Dr GMontanaro, Dr A Pagetto); Oncologia, Mantova (Dr E Aitini);Medicina, Biella (Professor S Fontana, Dr M Badone);Medicina, Voghera (Professor F Nicrosini, Dr P Cardellini);Medicina 1, Massa Carrara (Professor F Bechini, Dr EManeschi); Medicina, Somma Lombardo (Professor MMainardi, Dr A Daverio).

Research was supported by CNR (Consiglio Nazionale delleRicerche, Roma, Progetto Finalizzato Oncologia, grant No.88.00841.44), by AIRC (Associazione Italiana per la Ricerca sulCancro, Milano) and by IRCCS (Istituto di Ricovero e Cura aCarattere Scientifico Policlinico San Matteo, Pavia).

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