347

CLINICO-PATHOLOGICAL CONFER ENCE-No. 19

A case of myelomatosis with terminal uraemia

Westminster Hospital, Vincent Square Laboratory

Summary of the Clinical Findings (Dr.Rosemary Cooper)P.M. A female; aged 53; died, November 5,

1955; Index No. T.87o8. She is known to havehad Parkinsonism for ten years. For three to fouryears she had aching in her thighs, mainly atnight, associated with cramp in her calves. Thepain kept her awake at night. In December I954,her tremor and rigidity became worse followinginfluenza. In June I955, she developed acuteaching pain in the lower dorsal region whichimproved after two weeks but left her feelingshe had no strength in her back. She alsodeveloped vomiting which has continued onand off since. At this time her Parkinsonismbecame worse and has remained so. Otherwiseshe was symptomless apart from general weaknessand anorexia. On examination there was obviousParkinsonism with rigidity more marked thantremor. There was generalized weakness andwasting. She had a curved kyphosis maximal inthe lower dorsal region producing marked bowingof the trunk. The blood pressure was I 5/70. Adiagnosis of Parkinsonism was made together withmultiple myeloma. The latter was suggested bythe combination of pain in the back, kyphosis,collapsed vertebrae, heavy albuminuria and in-creased sedimentation rate. It was confirmed bythe investigations and in particular by her plasmaproteins which showed marked hyperglobulin-aemia (globulin 9.0 g. per cent., albumin 2.I6 g.per cent.); the electrophoretic pattern showed amarked increase in gamma globulin and herflocculations showed marked dissociation. Asternal puncture showed typical myeloma cellsin the bone marrow, probably associated withmyelomatosis causing collapse of the spine.The patient was given Artane for her Parkin-sonism, 2 mg. b.d.; this was increased to 2 mg.q.d.s. and then to 5 mg. t.d.s. This reduced herrigidity a little. In view of her age and poorgeneral condition it was decided not to attempttreatment with X-ray or chemo-therapy which areoften unsatisfactory in multiple myeloma, but to

give symptomatic treatment to maintain hercomfort. Whilst she was in hospital she had anintermittent fever which increased terminally;no cause for this was found. During the last sixhours before death her temperature was 106°.Investigations

September i6, I955: Hb., 44 per cent., 6.5 g.per cent. R.B.C., 1,900,000. C.I., 1.16. P.C.V.,i8 c.c. per cent. M.C.V., 94.7 c. microns. M.C.H.,34 micro-micro g. M.C.H.C., 36.1 per cent.E.S.R., 74 per cent. W.B.C., 5,000 normaldifferential.

Chest X-ray: Uniting fracture right eleventhrib. Some fibrosis right lower lobe. Left lungclear.

Skull X-ray: normal.Abdominal X-ray: normal.September 17, I955: Liver Function Tests:

Blood urea, 122 mg. per cent. Serum alkalinephosphatase, 3 units. Flocculations normal exceptZinc sulphate, 56 units; Serum Albumen, 2.16 g.per cent.; Globulin, 9.o g. per cent.; Total, 11.6 g.per cent.

Paper Electrophoresis showed presence of largeamounts of abnormal gamma globulin. Serumphosphate, 3.I mg. per cent. Serum calcium,I3.6 mg. per cent.

September I9, 1955: Spine X-ray: Showedgeneralized osteoporosis and osteophytosis.Wedging of bodies of D 9 and 12 and L i and 2.Barium meal: normal.Catheter specimen of urine: Sterile. Moderate

proteinurea.Serum electrolytes: normal.Blood urea: 121 mg. per cent.September 20, 1955: Hb., 44 per cent., 6.5 g.

per cent.Urine: Total protein, 700 mg. per cent. Heat

coagulable protein and proteose present but nonucleoprotein or Bence-Jones.

September 21, I955: F.T.M.: Some free acid.Normal.

September 22, 1955: Serum alkaline phosphatase:i unit; Serum acid phosphatase: 0.9 units.

F1

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348 POSTGRADUATE MEDICAL JOURNAL July 1956I'' !i: :.?"

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September 23, I955: Occult blood in steols.September 27, I955: Blood urea: I28 mg. per

cent.Bone marrow: Showed a sheet of classical

myelomatous cells.Hb., 43 per cent., 6.4 g. per cent.October 6, 1955: Serum BI2 concentration I5o

,u,g. per ml. (low normal).October Io, I955: Hb., 37 per cent., 5.5 g. per

cent.October 13, I955: Liver Function Tests: Little

change. Total proteins, Io.o2 g. per cent.Globulin, 8.0 g. per cent.November 2, I955: Hb., 33 per cent., 4.9 g. per

cent.

Relevant Autopsy Findings (Dr. George Lumb)(P.M. 223/55)

For the purpose of this meeting I propose toignore the fact that this patient had Parkinsonismand to concentrate entirely on the findings relatedto myelomatosis. Bony lesions were found in thesternum, ribs and vertebral column. In themanubrium sterni there was a large soft whitetumour measuring 5 cm. in diameter, destroyingthe bone and extending posteriorly into themediastinum. In the eleventh rib on the rightside in the mid-axillary line there was a smalltumour associated with an area of fracture. This

tumour was about a centimetre in diameter, softin consistency and was rather more red than thetumour in the sternum. The vertebral columnwas removed from the mid-cervical to the lowerlumbar region and, on cutting, it showed a diffuseinfiltration of the bone by plum coloured material.Some of the vertebrae were somewhat com-pressed but there was no evidence of completecollapse. The cut surface of the sternum alsoshowed replacement of the marrow by plumcoloured material showing irregular greyish fleckson its cut surface.

The kidneys were normal in size but extremelypale in colour. The capsules stripped readily andon the external surface of the very pale cortexcould be seen irregular spidery haemorrhagicsplashes. On cut surface the kidneys showed awell-defined cortico-medullary outline but theextreme pallor of the cortex with the irregularhaemorrhagic splashes was again to be seen.Both lungs showed a diffuse bronchopneumonia,

more marked at the bases than elsewhere. Therewas a considerable amount of mucopus in thebronchi and bronchioles but there was no evidenceof any tumour formation.The mediastinal glands were normal in size.The heart was normal except for considerable

pallor of the myocardium which was also veryfriable and showed evidence of fatty degeneration.

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July I956 Clinico-Pathological Conference 349

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FIG. 2.-Section of the cortex of kidney shewing dilated convoluted tubules filled with amorphouscasts of eosinophilic material. H. & E. x 220.

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FIG. 3.-Section of the cortex of kidney shewing a swollen glomerular tuft. H. & E. x 220.

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POSTGRADUATE MEDICAL JOURNAL July I956

Cause of Death. Terminal bronchopneumoniain the presence of multiple myelomatosis.

Histology from the tumour masses in thesternum, the rib and the vertebral column showessentially similar appearances. The normalstructure is replaced by a proliferation of darklystaining cells with intensely hyperchromaticnuclei showing a tendency to a 'clock face'arrangement (Fig. i). Many of the cells showa peri-nuclear halo and the nucleus is sometimeseccentric. The cytoplasm is basophilic. Thereis very little inter-cellular stroma and the cellstend to lie separated from each other. Wherestroma can be seen it tends to form a trabeculatedstructure. As the tissue had been fixed in formolsaline, no attempts were made to stain the cells withPyronin.The most striking changes in the kidneys are to

be seen in the tubules. Many of these are blockedwith amorphous casts of eosinophilic substancewhich, when stained by Lepehne's method forhaemoglobin using Benzidine and Prohydrol, gavenegative results. Tubular dilatation is not amarked feature although a number of convolutedtubules are dilated to the size of glomeruli (Fig. 2)Casts are found in the distal convoluted tubules,loops of Henle and collecting tubules. Many ofthese casts are seen to be surrounded by nucleigiving the appearance of giant cells. Glomeruliare for the most part within normal limits butsome show clubbing and an increase of reticulin(Fig. 3).

The lungs show widespread bronchopneumoniawith some super-added oedema.

Comment on PathologyDR. LUMB: The interest of this case from the

pathological point of view is the renal abnormality.Kidney changes in multiple myelomatosis havebeen noted by numerous authors and Bell'saccount in I933 is probably the most compre-hensive as he describes eleven cases.

I have seen two other examples apart from thisone and all cases seem to show similar appearancesto those we have seen this evening.There has been some debate as to the method of

formation of the giant cells around the eosinophilicplugs in the tubules. Bell believes that theyrepresent a true macrophage reaction but my ownfeeling is that the apparent giant cells are formedas a result of tubular epithelial proliferation.This can be demonstrated by serial sections andthis view has been confirmed by Morison, whowrote about a similar case in I941. With thisdegree of renal involvement it is quite possiblethat the terminal events in this case were broughtabout by uraemia. The increased oedema in the

lungs and the rising blood urea seemed to bear outthis view.

DR. D. MARRACK: These paper strips on whichthis patient's serum and urine were subjected toelectrophoresis show an excess of gamma globulinin the serum and a protein with an even lowermobility in the urine. These components pose thequestions of whether they are an abnormal proteinor whether in this disease they represent anaccentuation or over-production of a componentnormally present. It is worth noticing that thereis no clinical evidence that these patients everimmunize themselves against this abnormalprotein. In 1941, Gutman pointed out that theserum protein patterns in this disease could beclassified into three groups:

(a) Those with no qualitative or quantitativeabnormality detected; this occurs inpossibly a tenth of all cases.

(b) ' Gamma type' where there is an excess ofprotein with the mobility of a gammaglobulin.

(c) 'Beta and M types' where the mobility isthat of a beta globulin or lying betweenthe beta and gamma components.

Griffiths in I953 published data of anotheradditional group, the' alpha type.' In the 20 caseshe studied i were gamma; four beta; and fouralpha in type, and there was one with a normalpattern.No published case with an abnormal serum

protein pattern seems to have changed its typeduring the course of the disease.

In the literature then on I2 cases of myelo-matosis whose unusual serum protein componenthas been subjected to amino acid analysis (Smith),the samples studied had a wide range of electro-phoretic mobilities and isoelectric points, and theyshowed differences both one from another andfrom human pooled gamma globulin, in theamino-acids borne at the free ends of the poly-peptide chains. Yet their total amino-acid com-positions, whilst differing a little one from another,were all very similar to the pooled gamma globulin.The beta mobility proteins distinguished them-selves by their high carbohydrate content and thislatter probably accounts for their higher mobility.A technique which depends not only on the

species of amino-acids present but their spatialarrangement-quantitative precipitin tests-againshows that these unusual proteins are not identicalbut that they are related and have groupingssimilar to those found in pooled gamma globulin.The evidence then so far as it goes to date is

that these unusual serum protein components aremembers of a family of normal protein moleculesfound in the gamma globulin fraction, and in thisdisease state one member is present in excess.

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July 1956 Clinico-Pathological Conference 351

Turning to the urinary proteins one findsalbuminuria quite frequently, presumably due toglomerular change. Other proteins are sometimesfound either in addition or instead of albumin andthese latter have electrophoretic mobilities rangingfrom that corresponding to a beta globulin to thatof a gamma or even slower globulin. Occasionallythe mobility is that of an alpha globulin. Immuno-logically they are related to gamma globulin(Deutsch). Amongst these non-albumin pro-teinurias are found a few where the protein insteadof precipitating irreversibly on boiling at abouta pH. of 5.5, flocculates at under 6o0C., and thenredissolves on boiling and further reprecipitates oncooling the solution. This unusual behaviourwas first noted by Dr. Bence-Jones.Of 17 cases of myelomatosis with Bence-Jones

proteinuria Rundles noted that in nine, there wasan unusual serum component with the sameelectrophoretic mobility as the patient's urineprotein. In eight others they were different.Other observers have claimed, as one mightanticipate, an inverse relation between the con-ceritrations of the urine and serum componentswith the same mobility. In other words thehigher the renal clearance of the protein the lessthere is in the serum. Bence-Jones proteinmolecules are one-third to one-eighth the sizeof gamma globulin molecules and never seem to bealike and often they lack methionine, a state ofaffairs not known in serum proteins. Isotopicstudies by Putnam with 13c and 15N labelledglycine, show that Bence-Jones protein issynthesized from the amino-acid pool and is not abreakdown product of tissue protein and that it israpidly excreted; and further its synthesis is unre-lated to that of the abnormal plasma protein present.

PROFESSOR PULVERTAFT: During the last fiveyears we have been making slide cultures ofmyeloma cells whenever cases were available in thehospital. Their appearance as seen by phasecontrast microscopy differs from their appearancein stained preparations.The tumour cells also differ somewhat from the

plasma cells normally found in the bone marrow.They have enormously thick mitochondria. Theylook like twigs as opposed to matches. It iscommon to see an area round the nucleus inwhich mitochondria are never found. Plasma cellsnever move and apart from the nucleated red cellsthey are the only cells in the bone marrow whichhave no motility. Small particles from theirsurface become detached and it is my own viewthat the abnormal proteins found in the serum andin the urine may be derived from these detachedcellular particles. Recently I have been interestedin the possibility of analysing the substances inplasma cells by means of the interferencemicroscope.

DR. LUMB: Can the clinicians tell us anythingabout the treatment of these patients ?

DR. BREWIN: Urethane has been reported togive successes but its use has been largely given upin the radiotherapy department here. It has anunpleasant side effect in that it tends to makepatients very sick. I think high voltage X-raysare very useful sometimes for relieving pain butunfortunately the disease is often widespread andmultiple fractures tend to occur so that it may bedifficult to take the patient to the radiotherapydepartment without aggravating his pain.DR. LUMB: I remember a case in the wards in

Westminster some eight or nine years ago thatseemed to be improved following the use ofStilboestrol.MR. ROBERT Cox: Patients are still treated with

this drug and successes are reported. I thinkthere are enough examples of improvements ofsymptoms following hormonal treatment to excludethe possibility of mistaken diagnosis. I refer ofcourse to the bony metastases from a carcinoma ofthe prostate being mistaken for myelomatosis.

PROFESSOR PULVERTAFT: I attended a patho-logical meeting in Southampton recently whereseven cases of myelomatosis treated with Stil-boestrol were reported in which dramatic improve-ment had been produced. It must be rememberedof course that pain may spontaneously improvewhilst the general condition deteriorates.

DR. IAIN MACDOUGALL: Can you tell mewhether one would expect to find such a lowserum alkaline phosphatase as there was in thiscase and is it of any importance ?

PROFESSOR N. F. MACLAGAN: I think that thelow serum alkaline phosphatase is rather typicalof myelomatosis. If this phosphatase is raised itrepresents attempts at bony repair by osteoblasts,a process which seems to be vefy ineffective in thisdisease.

I would like to make a general point here aboutthe abnormal proteins which occur in myelo-matosis. It is important to demonstrate theseabnormalities as simply as possible. Firstly, theserum globulin may be raised and Bence-Jonesprotein or proteose may be found in the urine.In addition, there are two methods for testingwhich overlap to some extent. One is serumelectrophoresis and the other is the flocculationtests. It is typical of myeloma that one or moreof the flocculation tests may be strongly positivewhile others are completely negative. This rarelyhappens in any other condition.We were unusually fortunate in the case under

discussion, since nearly all of these changes werepresent simultaneously. This is by no meansalways the case and in general one cannot tell whichtest will prove the most useful in any particularpatient.

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352 POSTGRADUATE MEDICAL JOURNAL July 1956

DR. LUMB: Could I just clarify one point formyself here,? In interpreting the flocculationtests is it true to say that any one of them may beraised in different cases ?PROFESSOR MACLAGAN: Yes, but those which

most commonly show gross abnormality are thezinc and ammonium sulphate tests.

PROFESSOR PULVERTAFT: So far we have dis-cussed tumour deposits in bone only. In whatother organs have you personally found deposits ?DR. LUMB: In a few cases one has seen plasma

cell proliferations in liver and spleen and lymphnodes. In other words when the proliferationsbecome generalized they tend to involve thereticuloendothelial system. It is my own personalview that these conditions are in fact a tumour ofthe reticuloendothelial system most commonly

localized in bone. Occasionally, as you know,examples of plasma cell leukaemia are found.Another site for soft tissue tumours is in the naso-pharynx. These cases most commonly pursue abenign course and are not associated with bonylesion but occasional examples are recorded wheremultiple bone deposits appear.

BIBLIOGRAPHYDEUTSCH, H. F., KRATOCHVIL, C. H., and REIF, A. E. (I955),

J. Biol. Chen., 216, I03.GRIFFITHS, L. L., and BREWS, V. A. L. (1953), J. Clin. Path.,

6, I87.GUTMAN, A. B., MOORE, D. H., GUTMAN, E. B.,

McCLELLAN, V., and KABAT, E. A. (1941), J. Clin. Invest.,20, 765.

MORISON, J. E., J. Path. Bact., 53, 403.PUTNAM, F. W., and HARDY, S. (955), J. Biol. Chem., 212,

36I, 37I.SMITH, E. S., BROWN, D. M., McFADDEN, M. L.,

BUETTNER-JANUSCH, V., and JAGER, B. V. (1955),Ibid., 216, 6oi.

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Bibliograbhv continued from bpae 346. S. Fazlullah, M.B.(Osm.), D.T.M. & H. (Eng.)BRAIN, R., and STRAUSS, E. B. (I955), Rec. Adv. Neurol.

Psychiat., 44-54.CHANG HSIANG-TUNG (I953), J. Neuro. Physiol., i6, I7.CLARK, W. E. LEGROS, and BOGGON, R. H. (i935), Phil.

Trans., 224B, 313.COHN, R. (I948), J. Neurol Physiol., II, I93-I97.COHN, R. (195I), Neurology, I, 119.COHN, R. (I95I),J. Neur. & Ment. Dis., 113, 47I.CRITCHLEY, M. (I95I), Proc. Roy. Soc. Med., 44, 337.CRITCHLEY, M. (1953), Fifth Int. Neurol. Conference,

I53-I67.CRITCHLEY, M. (I953), 'Parietal Lobes,' Arnold & Co., London,

144, 203, 225, 256, 326, 356.CRITCHLEY, M. (I949), Brain, Ixxii, 538-56I.

DENNY-BROWN, D. (1953), Fifth Int. Neurol. Conference,pp. 215-216.

HANS HOFF (I953), Ibid., 195-2I1.HENSON, R. A. (I949), Brain, lxxii, 576, 598.HEAD, H., and HOLMES, G. (I9II), Brain, 34, 102-254.HOLMES, G. (1918), British J. Ophthalmology, 2.OPPENHEIM, H. (I885), Neurol. Centralb., 4, 529-532.OPPENHEIM, H. (19gx), Textbook of Nervous Diseases, i, 5x.

Fifth Edition. Trans., A. Bruce Edinburgh and T. N. Foulis.PEELE, T. L. (I942), Jour. Comp. Neurol., 77, 693.POTZL, O. (1924), Ztschr. f. d. ges. Neuro . u. Psych., 93.POTZL, O. (I953), referred by H. Hoff.ROTHFIELD, J. (1932), Nervenartz, 5, 528-532.SHAPIRO, M. F., and DANIELS, F. (1952), Neurology, 2, 509-5I3.ZIEGLER, D. K. (1952), Ibid., 2, 50I-508.

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