The Role of the Spleen in the Hemolytic Anemia of Cancer Patients* JOHNE.ULTMANN

(Department of Medicine, Columbia University Collegeof Physw.iana and Surgeons and the Medical Services, Fraw Delaf&C1dandPresbyterian Hoapi@als,New York, N.Y.)

With the demonstration that the anemia of scintillation probe (NRD Model 53) with an aperture of ap many patients with disseminated cancer is largely proximately 25 mm. was used. The body surface projections due to an increased rate of erythrocyte destruc of the heart, spleen, and liver were determined by physical examination and the centers marked with skin pencil. The tion (4), it became of interest to study the im scintillation counter surface was placed over the center of each portance of the spleen in this process. Jandl et al. organ at such an angle as to be approximately parallel with (5) and others (3, 7) reported the feasibility of the organ surface. Each of these angles was measured and re determining red cell sequestration in various organ corded for every patient, permitting exact duplication of physical factors at subsequent scanning. The body surface sites with Cr@'-labeled eiythrocytes. By this counts thus obtained were expressed as the ratio of radioactiv technic, patients with essentially normal red cell ity over the spleen or liver to that over the heart (spleen/ life spans, patients with clearly defined hemolytic heart—Sp/H; liver/heart—L/H). anemias, and patients with disseminated cancer Clinical material.—Thirty-eight patients from the wards of and hemolysis were studied. the Francis Delafield Hospital and Presbyterian Hospital were selected for the study of sed cell survival and body surface counting. MATERIALS AND METHODS Coomba testing.—Coombs tests were performed on all RESULTS AND DISCUSSION patients with commercial Coombs serum (Department of Compaiiion of surface counts before and after Health, City of New York) and 2 drops of saline-washed cells in 9 per cent suspension and 2 drops of Coombs serum. The death—Hughes, Jones, and Szur (3) have sum @ mixture was incubated for hour at 39°C. and read after 2 manized the major sources from which surface minutes of centrifuging. counts may be derived. Twenty minutes after in Labeling erythrocytes with Cr@'.—Red-celllabeling with jection of Cr@'-labeled red blood cells, surface radioactive chromium was performed by adding SO ml. of heparinized whole blood to 150 @zc.of Na2Cr―04 of high counts over an organ are due to labeled red cells specific activity (25.0—40.8pc/mg, diluted with normal saline in transit through the organ, red cells in the over-@ to a concentration of 30 @cCr@'/ml).The mixture was gently lying tissues, or scatter from other sites. During agitated for about 10 minutes, and the red cells were then al the course of study, counts due to red cells in lowed to settle for about 1—14hours. The supernatant plasma transit through an organ being scanned fall with was then drawn off. The residual red cells with any trapped plasma were administered to the patient. Twenty-four hours the decrease of radioactivity of the whole blood. later, and at appropriate intervals thereafter (usually every Jandl et al. (5) have shown that, with the injec week), samples of venous blood were drawn for determination tion of Cn51-labeled hemoglobin, there is a marked of hematocrit and red cell Cr@'activity. The radioactivity of the elevation of radioactivity over the liver, while blood was determined by counting 2-ml. aliquots of packed red injected Cr@'Cl3 is largely removed via the unine cells in a well-type scintillation counter. Counts were corrected for background and physical decay. No correction for elution An increase of radioactivity over the spleen, of Cr@'from the red cells was made. The data so obtained were or any other site, other than the liver, occurring expressed as a percentage of the radioactivity at 24 hours. concomitant with a fall of blood radioactivity as Surface scintillation couniing.—Bodysurface counting was approximated by counting over the heart, must done 20 minutes after the injection of labeled erythrocytes. Subsequently, each patient was scanned at the time of sample then be assumed to be due to sequestration of red collection for the Cr'1 red cell survival study. An uncollimated blood cells in that organ. Jandi et at. (5) showed that labeled sensitized red cells disappeared a Presented in part at the annual meeting of the American Association for Cancer Reserch, Philadelphia, Pennsylvania, abruptly from the circulation and that radio April 11, 1958. activity appeared promptly over the spleen. Al This work was supported in part by a grant (C 2332) from though this does not prove that intact red cells are the National Cancer Institute of the National Institutes of sequestrated in the spleen, it is highly probable Health, United States Public Health Service. that this is the case. Received for publication May 5, 1938. Summary table.—Table 1 summarizes the vital 959

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IJLTMANN—HemOlytw Anemia of Cancer Patients 961

@@ .@‘ statistics, diagnosis, hematologic data, and results

@@@ .@ .@ .@ a p.. of the present study for each subject. Except

@@@@@ $@ ‘@ s@ where specifically stated, each patient was given

@@@ .@ .@ .@ t Cr@'-labeled autogenous enythrocytes. For pur @@@@@ c@ @3 poses of this study, the patients with malignant

@ .@ .@ r@ tumors were arbitrarily divided into two groups.

5@ 5@ 0-@ C1@ c!@ Those patients who had a 50 per cent erythrocyte survival beyond 925days were considered to have

@@@@ ‘00 0 0 0 no evidence of hemoly-tic anemia. All patients with

@@@@ 0 0 ‘.@‘•@ 0@ 50 per cent erythrocyte survival of 925 days or less were considered to have frank hemolytic @ 0 55 t.. 55 t@ *0 anemia. No patients with evidence of external

@ 5@ 5@ 5@ ,.@ 5@ 5, — — blood loss, uremia, or infection were included in M I the study. The body surface counts of each patient are also recorded in Table 1. In the column @ a ‘SCOt- t@ — . @@@@ “@ 0 T0 are listed the Sp/H and L/li ratios at the beginning of the study—i.e., 920minutes after in

@@@@ 0 55 55 55 0 jection of Cr@'-labeled erythrocytes. In the column

@@@ — ,- ,-@ “@ ,@ “Tmaj. Sp. are shown the Sp/H and LIlT ratios ;54 that were obtained at a time when the Sp/H ratio

Cl) Q@ was maximal. In a number of patients, the maxi @ U) @ U) — .@— 0 ‘0 t@. mal increase in radioactivity over the spleen oc

I-' a — 55 — — — — — curred after the time of red cell half-life. This is in @ z contrast to patients with intrinsic red cell defects, in which high splenic activity is apparent early. I- @@@ ‘u@ 0 X 55 0• 0@ Control subjects.—Patients with normal red @ 0 hI'@@ @@@ .E — 0 55 55 0 — cell survival and no neoplastic disease served as control subjects. There were three patients in this @ C@) @@@@@ IZ &@lgi @i @1 group (Table 1, patients 1—3).Chart 1 depicts a @ — representative result in one of the subjects. The cross-hatched area shown in the upper portions of @ z U) 5, 5, 0 0 0 0 the figures represents the range of the red cell life 0 span values in six normal volunteers, given a I- smaller amount of Cr@' (50 sc.) than used in the present study. In the subjects without neoplastic @@@@@@@@@ 0 disease and with nearly normal red cell survival, the ratios of spleen/heart and of liver/heart counts at zero time are less than one, and neither ratio in @@@@@ creases significantly above one with time. The ap

@ U) ça4 ç54rz4 proximate range of Sp/[I and L/H ratios as ob tamed in these three patients is shown schemati cally in cross-hatched areas in the lower portions of all subsequent figures.

.@ This confirms the results in normaLs as pre I .@ sented by others (3, 5, 7). These findings in the @ @; control subjects suggest that in the destruction of @@@ I normallyagingredcellsneitherthe spleennorthe

@@ .@ .@ liver are particularly selective in retaining red @ @1, @‘ cells, although the spleen appears a little more

@ .@ .@‘ active per unit weight of organ than the liver (3). @ ;@ @: Congenital hemolytic anemia.—A patient with @@@ an intracorpuscular defect was studied. This pa @ tient (Table 1, patient 4) with congenital hemo lytic anemia (hereditary spherocytosis) showed a

. shortened red cell life span and selective retention

0- of labeled red cells in her spleen. Jandl and associ @@@@ ;@ :i @; ates (5), as well as Schloesser and associates (7) in

Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1958 American Association for Cancer Research. 96@ Cancer Research Vol. 18, September, 1958 their more extensive series, obtained similar re Schloesser et al. (7) show similar findings. Jandl sults. They also demonstrated that a normal et al. (6) have discussed the sequestration of red spleen will “pickup―Cr@-labeled spherocytes as cells altered by inimune mechanisms. readily as the patient's spleen, whereas neither Hemolytie anemia with nega@tiveCoomb@te@itand normal nor patient's spleen will sequestrate nor aplenomegaly.—When the Coombs test is negative, ma! red cells. Previous work employing different yet when clinical evidence is unequivocal that technics had shown that the spherocyte is selec hemolysis is present, the mechanism ofjthe tively removed by the normal or pathologic hemolysis is more difficult to delineate. There may spleen (8). be a defect of the red blood cell which'is even more

I00

90 CHRONICPULMONARYDISEASE

b 80 50% RBC Survival : 26 days

70

60

50

40

30

SPLEEN' NOT

.@ 5 PALPABLE

4

3

2

0 10 20 30 40 50 60 Days

Caawr 1.—Resultin one of three control subjects. The red course of study. In seventeen patients with carcinoma or cell life span is normal. The ratios of spleen/heart and liver! lymphoma and no hemolytic anemia, similar results were heart counts do not increase significantly above 1 during the obtained.

Coonths-positive hemolytie anemia.—In acute, elusive than when anti-globulin coating can be acquired idiopathic hemolytic anemia with a demonstrated or the splenomegaly per se may re strongly positive Coombs test, the red cell defect suit in red cell sequestration and hemolysis. The is more subtle than in the cells with intracor increase in counts over the spleen may give evi puscular defects. The red cell has a “coating―of dence of squestration of labeled red cells and serve antibody globulin. Results of the study of one as an in vivo measure of an increase in splenic patient (Table 1, patient 5) with a strongly posi selectivity for red cells. Four patients in this cate tive Coombs test are shown in Chart @.The gory were studied. One patient with agnogenic patient showed a shortened red cell life span and a myeloid metaplasia (Table 1, patient 6) and a marked sequestration of autogenous red cells in his shortened red cell life span had a marked increase enlarged spleen. Data of Jand! et d. (5) and of of radioactivity over the spleen with time. In a

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ULmx@—Hemolytie Anemia of Cancer Patients 968

patient with Laennec's cirrhosis (Table 1, patient splenism, was also studied. The patient's own Cr@' 7), the findingswereessentiallythesame.Ofpar labeled erythrocytes were sequestrated in the ticular interest is a woman with biopsy-proved spleen in significant amount. hemochromatosis (Table 1, patient 8). This pa The aforementioned results with intracorpuscu tient had evidence of hypersplenism with severe lar and extracorpuscular hemolytic anemia con leukopenia (1500 wbc/cu mm) and marked throm firm the findings of others and serve as a back bopenia (50,000 platelets/cu mm), but no anemia. ground for an interpretation of results in patients Red cell life-span studies showed only moderately with neoplastic disease. shortened erythrocyte survival. Nevertheless, the Patients with various neoplastic di.eases.—

IDIOPATHICHEMOLYTIC ANEMIA CoombsTest StronglyPositive 90 50% RBC Survival : 16 Days

11 80 I.) .@% @70

60 ‘I,. 0 50

‘.5 ¼

30

20 SPLEEN: 3cm BELOW .@ :@:‘ COSTALMARGIN

SPLEEN

SPLEEN LIVER

0 10 20 30 Days CHART 2.—This patient with idiopathic hemolytic anemia Remission occurred when prednisone was increased from 10 and a strongly positive Coombs test had a shortened red cell mg. to 40 mg. daily on the 10th day of the study. life span and marked sequestration of red cells in his spleen.

initial spleen count was above 1.0, compatible Twenty-nine patients with various neoplastic with the splenomegaly found on physical examina diseases were studied. In none of these patients tion, and splenic counts rose significantly with could a positive Coombs test be demonstrated. time, indicating red cell sequestration greater than Nine patients with carcinomas and eight pa normal. All clinical evidence of hypersplenism dis tients with lymphomas or lymphatic leukemia appeared following splenectomy. A patient with (Table 1, patients 10—@6)hadmostly local disease sarcoidosis (Table 1, patient 9), no anemia or or were in clinical remission. In these patients, shortened red cell life span, but leukopenia and there was either no hemolytic anemia or only a thrombopenia presumably on the basis of hyper slightly shortened red cell life span (50 per cent

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erythrocyte survival greater than @5days). In no palpable spleen. In six cases a moderate to this group of patients, the spleen/heart and liver/ marked increase in splenic activity was found. In heart ratios initially, and during the course of the a patient with documented Hodgkin's disease study, were entirely within normal limits. It may (Table 1, patient 35) the mild anemia, but con be inferred from this that, in patients with proved siderable hemolysis and splenic uptake of labeled neoplastic disease where there is little or no activ erythrocytes, was the only evidence of disease ity of disease process, there is little or no effect on activity. There was no splenomegaly in this the red cell life span, nor is splenic sequestration patient. demonstrable. Greenfield and Price (@) reported experiments

CARCINOMATOSIS 50% RBCSurvival ±10Days

‘I •0

50

40

30

a0 SPLEEN: NOT PALPABLE 5

@iI 4

3 s,__ø__s___._._.__sSPLEEN 2

@ NORMAL SPLEEN @ i/i//I/I NORMAL LIVER

@ 0 20 30 40 50 Days

CHART 3.—Result in one of three patients with carcinomatosis and severe hemolytic anemia. There was marked sequestra tion of red@cells in the spleen.

In three of four patients with disseminated car on red cell survival in animals bearing various cinoma (Table 1, patients @7—@9)andno palpable tumors. They indicated that in some instances spleen, there was demonstrated a moderate to there was significant hemorrhage into the tumor marked hemolytic anemia and a significant in and surrounding tissues, accounting largely for the crease in radioactivity over the splenic area (see shortened red cell life span. This finding was con Chart 3). The results in the fourth patient will be firmed by us for rats bearing Walker sarcoma or presented below (patient 37). Yoshida ascites tumor (1). In previous studies of Seven patients with lymphoma or chronic iym the red cell life span in tumor patients, done in this phatic leukemia (Table 1, patients 30—36)had laboratory (4), post mortem examination in ap significant hemolysis. Some of these patients had proximately half of the patients studied failed to

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reveal evidence of significant hemorrhage into dence of red cell sequestration in a tumor mass was and around tumor masses. a 30-year-old man (Table 1, patient 38) diagnosed In the present series, two patients showed evi as multiple plasmacytomas. On examination, he dence of increasing radioactivity over tumor had multiple large masses over bones (forehead, masses. One patient (Table 1, patient 37), illus left clavicle, sternum) and intra-abdominally. The trated in Chart 4, is a 75-year-old woman who spleen and liver could not be felt. Sedimentation had a right nephrectomy for hypernephroma in rate was above 100 mm., and a serum protein 1946. When observed by us, she had a large fixed electrophoresis showed a spike compatible with mass, 15 cm. in diameter, in the right lower ab multiple myeloma; biopsy of the clavicular mass

HYPERNEPHROMA

@ b 50% RBC Survival 15Days t .@‘

0

SPLEEN: NOT PALPABLE

.@ LARGE ABDOMINAL MASS

I' ‘MASS

¼

0 I0 20 30 40 50 Days

CHART4.—Resultsobtained in a patient with a large right strated a shortened red cell life span and a significant increase lower quadrant abdominal mass which appeared 11 years after of radioactivity over the mass. a right nephrectomy for hypernephroma. There was demon

domen. At this time, there was a moderate anemia provided histological confirmation. Chart 5 de but no hematuria, melena, or nitrogen retention. picts the results obtained in studying this patient. The red cell life span was shortened markedly. The red cell life span showed a significant shorten The surface scintillation counts over the non ing. There was moderate accumulation of radio palpable spleen or liver rose only slightly above activity over the spleen and over the predominant the normal range. On the other hand, there was a right lower abdominal mass. The marked uptake significant accumulation of radioactivity over the over the area of the liver, however, was very palpable metastatic mass. difficult to explain. One of the possibilities that The second patient in whom there was evi was considered was that destruction in many of

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the masses devoid of reticuloendothelial elements life span was normal (Table 1, patient 19) and in might load the liver with a large amount of two of whom it was moderately decreased (pa labeled hemoglobin. There was no evidence tients @7and 36), there was a normal Sp/H and clinically for hemoglobinemia or hemoglobinuria. L/H ratio until late in the study. In one of the When the patient expired and came to post mor patients, the spleen was palpable. These three pa tem examination, a large hemorrhagic mass 15 cm. tients showed late (days 67, 59, 58) normal L/H in diameter was found in the abdomen; in the ratios but had Sp/H ratios of p2.8, 8.6, and 5.1. upper pole of the right lobe of the liver, immedi This is in contrast to patients with normal red ately subjacent to the area counted previously, cell life spans who showed only a gradual rise in

I00 MULTIPLE MYELOMA 90 50% RBC Survival: 17days 80

70

60

50

40

30 BLOOD H@MAT'D@PT 20 SPLEEN:NOT PALPABLE 5 LARGEABDOMINALMASS .‘@

@ 5.) 4 L LIVER 3 ¼. MASS @ I SPLEEN 2 ______

SPLEEN0LIVER 0

10 20 30 40SC Days

CHART 5.—hi a patient with multiple myeloma, there was mass. At post mortem examination, the spleen was found to be found a shortened red celllifespan and accumulation of radio small. In the right lobe of the liver and in the abdominal mass, activity over the liver, spleen, and over a large abdominal extensive areas of hemorrhage were found.

there was also found a large (8 X 10 X 8 cm.) Sp/H and L/H ratios over the 60—75days of area of hemorrhage; the spleen was smaller than study. Furthermore, these ratios are also unlike normal. those in the patients with hemolysis who generally In the two cases cited, the mass of tissue in showed a rise in Sp/H ratio before day @Oor30. volved appears large enough to account for the Late in the study, the surface counts were lower disappearance rate of the Cr@'-labeled red cells. and became less reliable. Because of this, the pos It has not been possible to quantitate adequately sibility exists that an error may occur over the the amount of sequestration. area of the spleen due to significant scatter from In three patients, in one of whom the red cell the area of the heart. We believe, nevertheless,

Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1958 American Association for Cancer Research. ULmt@—Hemolytic Anemia of Cancer Patients 967 that these findings are real. Jandl et al. (5) have confirming the findings reported in the literature. reported that the rate of loss of Cr@'radioactivity In most patients with malignant tumors and from the spleen averages about 4 per cent per day. shortened red cell survival, but negative Coombs The findings in these three patients, as well as the tests, there was also found a moderate to marked fact that maximal splenic sequestration occurred increase of radioactivity over the spleen. It is well past the time of 50 per cent Cr@'red cell sur concluded that, in the hemolytic anemia of many viva! in many other patients, suggests that the patients with malignant tumors, the spleen plays data of Jandl and associates may not apply to an active role in the removal of red blood cells. some of these patients with malignant tumors. The interpretation of the data presented leads ACKNOWLEDGMENTh one to the following hypothesis. The spleen Se Mrs. Ana Tiburcio, Miss Alice Laughlin, and Mr. Anthony questrates not only intrinsically abnormal red R. Dente gave technical assistance. cells (i.e., congenital hemolytic anemia) or red The author wishes to thank Dr. Alfred Gelihorn for his advice and encouragement. cells obviously coated by globulin (as in Coombs positive hemolytic anemia), but also red cells REFERENCES which may be damaged more subtly. In many, but not all, patients with hemolytic anemia of ma 1. GELLHORN,A.; Hystai@r,G. A.; and ULTMANN,J. E. The Mechanism of the Anemia of Cancer. N.Y. Med., 13:614- lignancy, the spleen plays an active role in the 24, 1957. removal of red blood cells, their sequestration, and 2. GREENFIELD, R. E., and PRICE, V. E. Studies on the Fate of probably their ultimate destruction. The useful Erythrocytes in Tumor-bearing Animals. Proc. Am. Assoc. ness of this technic to select patients with malig Cancer Research,2:111—12,1956. 3. Huouas JONES, N. C., and Sztmi, L. Determination of the nant tumors and hemolytic anemia for splenec Sites of Red-Cell Destruction Using “Cr-labelled Cells. tomy will require further investigation. Brit. J. Haematol., 3:820—51, 1957. 4. HYMAN,G. A.; GELLHORN,A.;and Haitvay, J. L. Studies SUMMARY on the Anemia of Disseminated Malignant Neoplastic It has been demonstrated that hemolysis con Disease. 11. Study of the Life Span of the Erythrocyte. tributes significantly to the anemia of malignancy. Blood, 9:618—81, 1956. 5. JANDL, J. H. ; GREENBERG, M. S.; YONEMOTO, R. H. ; and The present study was undertaken to determine CASTLE, W. B. Clinical Determination of the Sites of Red the role of the spleen in this hemolytic process. Cell Sequestration in Hemolytic Anemias. J. Clin. Investi Following injection of Cr@'-labeled erythrocytes, gation, 35:842—67, 1956. the change in radioactivity, with time, above the 6. JANDL, J. H.; JONES, A. R.; and C@tsmn, W. B. The De struction of Red Cells by Antibodies in Man. I. Observa heart, spleen, and liver was determined by using a tions on the Sequestration and Lysis of Red Cells Altered by body-surface counting technic. Immune Mechanisms. J. Clin. Investigation, 36: 1428—59, In subjects with normal red cell survival, the 1957. ratios of spleen/heart (Sp/11) and of liver/heart 7. SCHLOESSER, L. L. ; KORST, D. R. ; CLATANOFF, D. V. ; and (L/H) counts at zero time are less than one, and SCHILLING, R. F. Radioactivity over the Spleen and Liver Following the Transfusion of Chromium―-Labelled Eryth neither ratio increases significantly above one with rocytes in Hemolytic Anemia. J. Clin. Investigation, 36: time. 1470—85,1957. In a patient with congenital spherocytic anemia 8. WEISMAN, R., JR.; Huai@y, T. H.; HARRIS, J. W.; and and in a patient with idiopathic Coombs-positive H@us,T. H. Studies of the Function of the Spleen in the Hemolysis of Red Cells in Hereditary Spherocytosis and hemolytic anemia, maximal Sp/H ratios were sig Sickle Cell Disorders. J. Lab. & Clin. Med., 42:965-66, nificantly greater than simultaneous L/II ratios, 1953.

Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1958 American Association for Cancer Research. The Role of the Spleen in the Hemolytic Anemia of Cancer Patients

John E. Ultmann

Cancer Res 1958;18:959-967.

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