MULTIPLE MYELOMA
LESIONS OF THE EXTRA-OSSEOUS HEMATOPOIETIC SYSTEM*
JACOB CHURG, M.D., AND ALVIN J. GORDON, M.D.
From the Laboratories, Division of Pathology, The Mount Sinai Hospital, New York, New York
It is the purpose of this paper to report upon the incidence, character and
significance of extra-osseous lesions in multiple myeloma.
Until recent years extra-osseous involvement in this disease, except by direct extension from bone lesions, was considered to be rare. A number of isolated
cases with visceral involvement can be found in the literature. 5 ' 7 In reviewing
the autopsy material in this hospital we have found that, contrary to previous
concepts, the occurrence of extramedullary lesions was the rule rather than the
exception.
Our material consisted of 30 consecutive cases of multiple myeloma which were
encountered from 1933 to 1948 among approximately 5400 postmortem examinations. In addition to sections of postmortem material and of surgical biopsies,
smears of bone marrow made during life were available in nearly eveiy case
through the courtesy of the Department of Hematology (Dr. N. Rosenthal)
and the Second Medical Service (Dr. I. Snapper). Inasmuch as about one-fifth
of the autopsies revealed malignant conditions including lymphomatous diseases, multiple myeloma constituted nearly 3 per cent of all such conditions encountered. This high incidence is partly explained by more frequent clinical recognition of the disease by means of marrow aspiration (Rosenthal and Vogel18).
Furthermore, the introduction of stilbamidine treatment by Snapper21 attracted
a number of patients with myeloma to this hospital.
It is well recognized that extra-medullary lesions in multiple myeloma most
commonly occur in the organs of the hematopoietic system (spleen, lymph nodes
and liver), although almost every other organ has been implicated in isolated
instances. In their extensive review of the literature up to 1928, Geschickter and
Copeland7 stated that in a total of 425 cases, the lymph nodes were involved in
14 cases, the liver in 10, the spleen in 9 and the tonsils in 2. Single instances of
metastases to other organs were cited. In the recent review of multiple myeloma
Lichtenstein and Jaffe observed two cases of visceral involvement among 18
coming to autopsy.12 Lowenhaupt, on the other hand, reported finding "plasma
cell" infiltration of spleen and lymph nodes in every one of her 12 cases.13 Similarly Salsberg and Goldman reported myelomatous involvement of lymph nodes
in all patients in whom these structures were studied.19
Undoubtedly many pathologists have observed plasma cells in lymph nodes
and spleen in some cases of multiple myeloma, but because plasma cells may
occur in these locations in association with malignant tumors, they may have
been loath to identify them with the neoplastic plasma cells found in the bone
marrow. Obviously, myeloma cells in these locations must be distinguished from
* Received for publication, May 3, 1950.
934
MULTIPLE MYELOMA
935
mature plasma cells of the Marschalko type. This is often difficult because the
former, like all marrow cells, are easily modified by postmortem changes, poor
fixation and by action of dehydrating and embedding agents, so that many of
their identifying characteristics are lost. The fundamental problem, then is to
establish morphologic criteria for myeloma cells which could be applied to identify the cells even in imperfect sections.
IDENTIFICATION OF MYELOMA CELLS
The literature is replete with excellent descriptions of the "typical" myeloma
cell, both in sections and in bone marrow smears, 2 ' 3 ' 6i 7 - 1 8 ' 2 5 so that there is
little need of repetition. Though the cells vary from patient to patient, they are
essentially the same, and can be fairly easily recognized as such, particularly in
smears. It is generally agreed that a myeloma cell is an abnormal and immature
("atypical", "dysplastic") plasma cell.1 •2 •20 In any given case the cells are usually
similar in different organs, though on occasion considerable variation may occur
in the extra-skeletal lesions.
In addition to the typical myeloma cell, there occurs in many cases a smaller
cell, about half its size, which resembles a lymphocyte, 4 ' 7 or even a small erythroblast.23 However, in good sections the nucleus of the small myeloma cell often exhibits the typical "spoke wheel" pattern of the plasma cell (Fig. -3). Small cells
were present to some extent in the majority of our 30 patients and were often
linked to the typical "large" cells by various transitional forms. In 4 instances
(Cases 3, 4, 11, 13) the small cells markedly predominated. These cases did not
present any unique clinical or anatomic features (see Table 1) though Case 11
was the only example of massive involvement of the lymph nodes.
In practice, identification of extra-skeletal lesions under the microscope consisted of finding nodules or aggregates of foreign-looking cells and comparing
them with marrow cells in the same case, searching particularly for prominent,
eosinophilic and pyroninophilic nucleoli (Figs. 1 and 2), peripheral arrangement
of the chromatin in the nuclei and basophilic vacuolated cytoplasm. In the absence of nodules, however, or because of technically imperfect sections, these
criteria were often not sufficient to permit absolute identification. When this
occurred, we were often able to find certain pathognomonic cellular details in
the bone marrow or biopsy section which, in conjunction with the general criteria, permitted identification of cells in visceral locations.
For example, in Case 14 we found that the nuclei exhibited an easily recognizable rod-shaped structure, apparently an inclusion body, in the center. Occasionally some of the nuclei were "dumbbell" shaped or "budding" (incomplete
amitotic division) (Figs. 4, 5). In two instances (Cases 9, 27) large eosinophilic
inclusions (Russell bodies) occurred in the nucleus. In three others (Cases 10, 15,
21), similar bodies, though usually multiple and varying in size, were seen in
the cytoplasm (Fig. 6). In several instances, following stilbamidine treatment,
basophilic granules described by Snapper22 were present in the cytoplasm (Fig. 7).
In two of the latter (Cases 15, 19), unusual macrophage-like cells filled with
granules occurred in various locations.
930
CHUEG AND GORDON
TABLE 1
POSTMORTEM D A T A I N 30 C A S E S O F M U L T I P L E M Y E L O M A
A
A
C
cC
c
Microscopic Infiltration
0 1475 0
1 2250 0
2 1600 0
0
0
0
(None examined)
Para-aortic
Para-aortic, hilar
200
160
275
150
320
80
1
0
0
3
1
3
0
0
0
0
0
0
0
0
0
0
0
2
0
0
0
?
0
0
Weight, Gm.
110 0
225 0
100 0
Gross Infiltration
Gross Microscopic
Location of Examined Nodes Infiltra- Infiltration
tion
Weight, Gm.
Microscopic Infiltration
4
5
6
7
8
9
c
A
A
LYMPH NODES
LIVER
Gross Infiltration
1
2
3
TYPE OF AUTOPSY
CASE NUMBEB
SPLEEN
1850
1280
1900
2325
1850
1660
10* R
650 4
4 1500 3
3
11
A
360 0
3 2300 0
3
12
13
c
c
c
c
c
C
215 0
550 4
0 1210 0
4 2000 2
0
3
225 0
3 1625 0
3
340 ?
1 1340 1
2
2 1720 0
3 1575 0
3 1925 2
0
2
3
14
15
16
17
18
A
110 ?
150 0
150 ?
19
A
300 0
0 1930 0
0
20
A
1000 4
4 3300 3
3
21
c
100 1
2 1030 0
1
22
C
45 0
0
780 0
0
23
24
cC
110 0
200 ?
1 1180 0
2 1250 0
1
1
INFILTRATION OF
OTHER ORGANS
n.d.
1
0
n.d.
2
1
Hilar
(Not s t a t e d )
(Not stated)
Periportal
Periportal
Para-aortic
0
0
0
?
?
?
0
0
0
n.d.
2
3
Para-aortic,
periportal,
peripancreatic
Periportal, peripancreatic
Hilar
Abdominal, axillary
2
3
4
4
0
0
0
1
0
1
0
2
3
0
0
0
1
0
2
3
?
3
0
?
3
?
3
Lung, diaphragm,
epicardium, s u b cutaneous tissue,
skeletal muscles
0
0
0
0
0
2
2
3
0
0
Abdominal,
hilar,
axillary
Abdominal,
hilar,
superficial
P a r a - a o r t i c , hilar
Para-aortic
Para-aortic,
periportal
Para-aortic,
periportal, hilar
Retroperitoneal,
hilar, mesenteric,
inguinal
Para-aortic,
periportal,
peripancreatic
Periportal,
hilar,
superficial
(Not stated)
Periportal, inguinal, axillary
0
0
Pleura,
kidney,
para-aortic fat
0
0
0
0
0
Kidney
(capillaries)
0
Kidney
ies)
(capillar0
Kidney
ies)
(capillar-
0
Tonsil
Kidney, colon
MULTIPLE MYELOMA
937
T A B L E 1— Continued
>
a
o
j
c
o
CASE NUMBER
OH
LIVER
O
s
O
25
20
A
C
75 0
200 ?
0 1860 0
3 1300 0
27
C
2000 4
4 3300 4
B
<
En
O
w
s
o
-c
.5?
S
c
hH
'•?
O
E
o
ba
*C
:>
<s
c
o
O
LYMPH NODES
Microscopic Infiltration
SPLEEN
0
Gross Microscopic
Location of Examined Nodes Infiltra- Infiltration
tion
Abdominal, hilar
Abdominal, hilar
0
0
0
2
Abdominal,
hilar,
axillary, supraclavicular
Para-aortic,
periportal
Para-aortic, hilar
Peripancreatic, hilar
3
4
?
0
I
4
28
29
30
A
290 0
0 1800 0
0
INFILTRATION OF
OTHER ORGANS
0
Kidney
(capillaries), lung (capillaries)
Pleura, lung, peritoneum,
testes,
periadrcnal fat
0
0
0
0
0
0
0
0
0
C, complete; A, abdominal incision only; R, rectal incision only.
0, absent; ?, doubtful; n.d., no d a t a available; 1, 2, 3, 4, degrees of involvement.
* T h i s case has been previously reported (reference 5).
C
C
125 0
295 0
0 1300 0
1 1975 0
EXTENT AND CHARACTER OF VISCERAL INVOLVEMENT
We could definitely establish involvement of the organs of the extra-osseous
hematopoietic system in 22 cases (73 per cent). In 10 of these, the involvement
was apparent grossly as nodular infiltration; in 5 of the latter the infiltration
was striking and extensive. In 6 of the 22 cases myelomatous infiltration of the
spleen or lymph nodes could have been suspected on gross examination because
of moderate enlargement and increased consistency of the organ, loss of normal
markings and disappearance of the follicles. The significance of these changes
was not realized until the present study was well under way. The presence of
lesions in this group, as well as in 6 other cases showing no obvious gross changes,
was established only by microscopic examination. Most frequently all three
organs, the spleen, liver and lymph nodes, were'involved though not necessarily
to the same degree. Less often the spleen and lymph nodes showed infiltration
but not the liver; sometimes only the spleen and sometimes only the lymph
nodes were involved. Other organs were invaded occasionally.
In 8 of the 30 cases (27 per cent) examination revealed no visceral involvement. In some of these it was considered that there was no involvement at all;
in the others the nature of suspicious-looking cells could not be definitely established or only rare scattered cells could be recognized.
938
CHTJRG AND GORDON
Spleen
Myeloma cells were found in 21 of 30 spleens. In general, in this series about
one-half of the spleens were increased in size, some being greatly increased.
Moderate enlargement (200 to 400 Gm.) sometimes occurred in the absence of
myeloma infiltration, but marked enlargement (500 to 2000 Gm.) always indicated the presence of myelomatous lesions. On the other hand, many of the
spleens of average or less than average weight contained myeloma infiltrations,
and in one such case (Case 21) there were grossly visible nodules. The gross appearance of the involved organ was not characteristic. Most commonly the
spleen was firmer than usual, the cut surface homogeneous and the follicles not
visible. The three largest spleens were more or less similar in that they were
filled with pinkish gray or grayish areas of varying size and sharpness of outline.
In addition, two of them (Cases 20, 27) contained small sharply outlined grayish
white nodules.
Microscopically, 21 cases showed unequivocal involvement, and in an additional 3 cases, there were a few scattered myeloma cells. The pattern' of splenic
infiltration was essentially similar in all cases, whether markedly or slightly involved. Myeloma cells in various-sized aggregations were found both in the
sinusoids and the intersinusoidal cords. In the sinusoids they either lay in close
approximation to the lining endothelium or filled the lumen. In the cords they
were intermingled with other cellular constituents, often congregating around
the small arterioles and the trabeculae. The disturbance of the general architecture was roughly proportional to the degree of involvement. The normal pattern became progressively obscured, while the follicles decreased in size and
number, and finally disappeared. Distribution of the myeloma cells was often
uneven, producing the previously mentioned gray areas. However, when infiltration was diffuse and even, the appearance of the organ was very similar to that
seen in leukemia (Fig. 8). Where sharply defined nodules were grossly visible
there was destruction of splenic tissue with invasion of the capusle.
Lymph ATodes
In our experience the more lymph nodes that are taken for microscopic examination, the more commonly is myelomatous infiltration found. Infiltration
occurs most frequently in the retroperitoneal nodes (para-aortic, portal, panF I G . 1. Myeloma cells in a smear of sternal aspiration, showing prominent nucleoli. Case
20. May-Gruenwald-Giemsa. X1S00.
F I G . 2. Myeloma cells in a section of spleen, showing prominent nucleoli. Case 20. Methyl
green-pyronin. X1S00.
F I G . 3. " S m a l l " mveloma cells in a section of bone marrow. Note spoke-wheel nuclei.
Case 4. H . and E . X1S00.
F I G . 4. Myeoloma cell with a " d u m b b e l l " nucleus in a lymph node. Case 8. H. and E.
X1200.
F I G . 5. Multinucleated myeloma cell in a smear of sternal aspiration. Case 14. MayGruenwald-Giemsa. X1200.
F I G . - 6 . Russell bodies in the cytoplasm of a myeloma cell. Section of spleen. Case 21.
H . and E . X900.
F I G . 7. " S t i l b a m i d i n e " granules in myeloma cells. Section of a lymph node. Case 19.
Methyl green-pyronin. X1200.
>
->
F i a s . 1-7
939
940
CHUEG AND GORDON
creatic,- paravertebral). Hilar nodes are implicated less often, perhaps because
chronic inflammatory changes make the recognition of myeloma cells difficult.
The same explanation may be given for the relatively infrequent involvement
of superficial lymph nodes, though in a few cases an inguinal node, and in one,
an axillary node, contained myeloma cells. Because axillary and cervical nodes
were rarely examined, we are unable to make a categorical statement about them.
Superficial adenopathy was infrequent during life.
Of the 28 subjects from whom lymph nodes were available, 18 showed myelomatous infiltration. In general there were no characteristic changes grossly,
but the involved lymph nodes were usually discrete, enlarged to a moderate
degree (up to 3 cm. in the largest diameter) and-often firmer than normal. On
cut section the}' exhibited uniform grayish white or pinkish white tissue. However, even lymph nodes of normal size and appearance occasionally showed
myeloma infiltration. In one instance all lymph nodes, including the small ones,
were hard; fibrosis was found microscopically (Case 27). In another unusual
case (Case 11), there was striking enlargement of lymph nodes with fusion into
huge masses and destruction of adjoining organs (pancreas).
Microscopic changes in the lymph nodes were analogous to those in the spleen.
The architectural pattern was at first preserved, but there was marked diminution or disappearance of the germinal centers. Under high power, myeloma cells
could be seen scattered within the medullary cords and interfollicular areas, as
if they replaced individual lymphocytes and were intermingled with them. In
places there were small loose groups of cells of varying size and density and, finally, true nodules composed only of myeloma cells and lying in the sinusoids or
replacing lymphatic tissue (Fig. 9). Often these sinusoidal nodules were particularly striking under low magnification. As the degree of involvement progressed, lymphocytes disappeared and sinusoids became compressed or obliterated. The process ended in a complete replacement of leukemic type. In a few
instances the capsule was invaded (Cases 11, 19).
^
Liver
Fourteen of the livers were infiltrated. In most instances, the liver was normal
in size but occasionally it was moderately enlarged. There were two instances
(Cases 20, 27) of marked enlargement, both associated with massive and widespread myelomatous infiltration of viscera. With these exceptions, there was no
correlation between the size of the organ and the presence of myeloma cells. The
liver was never involved alone but in combination either with the spleen or lymph
nodes or both.
The gross involvement was characterized by the presence of discrete, white,
sharply circumscribed nodules beneath the capsule or in the parenchyma. They
FIG. S. "Leukemic" infiltration of spleen by myeloma cells. Case 13. H. and E. X450.
FIG. 9. Myelomatous nodule in a lymph node. Case 2. H. and E. X225.
FIG. 10. Myelomatous tumor (upper half of figure) and sinusoidal infiltration of the liver
with destruction of liver cells'. Case 20. H and E. X100.
FIG. 11. Nests of myeloma cells in liver sinusoids. Case 9. H. and E.
FIG. 12. Myelomatous nodule in the lung. Case 20. H. and E. X9.
FIG. 13. Myelomatous nodule in a striated muscle. Case 20. H. and E. X300.
<
^
r/
'IS*'-
942
CHURG AND GORDON
were usually few in number; occasionally only a single lesion was found grossly
in the entire liver. Characteristically they were small, from pinhead size to 1 cm.
in diameter. Some livers also showed diffuse grayish streaking, sometimes extensive enough to obscure the lobular pattern (Cases 15, 20).
Microscopically, in cases with minimal involvement, myeloma cells were found
in the sinusoids, lying singly and in small clumps (Fig. 11). More advanced
lesions were characterized by expansion of these sinusoidal aggregates with compression of liver cords and formation, in places, of large masses of cells. In such
cases the periportal fields showed varying, sometimes considerable infiltration
by myeloma cells. Occasionally the infiltration was purely periportal. In two instances (Cases 20, 27) destruction of liver tissue was diffuse and extreme (Fig.
10).
Other Organs
Involvement of other viscera was rare compared with that of the lymph nodes,
spleen and liver8 (see Table 1). It was never observed without the involvement of
the latter organs though in Case 3 it could be recognized grossly, while spleen
and lymph nodes showed only microscopic lesions.
DISCUSSION
As already demonstrated, extra-medullary lesions in multiple myeloma are of
three types: (1) vascular, (2) diffuse and (3) discrete.
In the first, the occurrence of single or small groups of cells in circulatory
spaces such as capillaries of the kidney or sinusoids of the liver, suggests that
the cells were brought there by the blood. This is in conformity with the wellrecognized presence of myeloma cells in the circulation, which occurs in a considerable percentage of cases. 6 ' 16 In our own series "plasma cells" were reported
in the peripheral blood in 14 of 30 cases. The highest percentage was 33, but in
the majority the percentage was from 1 to 3. We could examine personally only
11 smears of peripheral blood and found myeloma cells in 5.
The second and most common type of visceral involvement is diffuse proliferation of myeloma cells with more or less pronounced tendency to nodular
aggregates. This is essentially the same process that is seen in the bone marrow;
in'the latter there is also the basic pattern of diffuse infiltration with local accumulation of myeloma cells. This myelomatous proliferation occurs almost exclusively at the site of potential hematopoiesis and characteristically leads to
the enlargement of the organ concerned with obliteration of the architecture,
similar to that seen in leukemia. Since involvement of the organs of the extraosseous hematopoietic system is rarely as extensive as in that disease, recognition at the autopsy table is difficult except in instances in which localized collections of cells form gross nodules.
No sharp line of demarcation can be drawn between the vascular and the
diffuse involvement, because in the latter the sinusoids of the liver and spleen
are characteristically filled with myeloma cells. One might even claim that the
difference is merely quantitative and that the diffuse type represents migration
MULTIPLE MYELOMA
943
of neoplastic cells from the vessels into the surrounding tissue. On the other hand,
it is at least equally probable that myeloma cells originate locally in the tissues
and filter through into the vascular spaces. This is the old problem, of "colonization" from the marrow versus autochthonous origin, that held the attention of
students of leukemia. In leukemia the consensus is in favor of the latter possibility,10 and the same reasoning can be applied to multiple myeloma. Certainly,
the histologic picture in myeloma, particularly in the lymph nodes, with its
gradual replacement of normal elements by myeloma cells, suggests local proliferation. If we assume a multicentric origin of lesions in the bone marrow, then
similarity of the pattern of involvement in other hematopoietic organs suggests
additional foci of origin rather than metastases.
The third and least common form of extra-medullary lesion is the discrete circumscribed nodule found outside the hematopoietic system, resembling malignant tumor metastasis. Similar discrete nodules are also known to occur in
leukemia.10
Histogenesis of myeloma and plasma cells has been recently discussed by
Bay id.2 There is an increasing tendency to ascribe their origin to the primitive
reticulum cell and we heartily agree with this concept. Lowenhaupt13 claims that
myeloma cells also arise from the endothelial lining of the splenic sinuosids. She
bases her conclusions on the tendency of plasma cells to arrange themselves
along the Avail of the sinusoids and "hang" into the blood stream singly or in
small clumps. However, in our material similar pictures were produced by cells
which partly penetrated the sinusoidal wall from the outside. At present, the
endothelial origin of myeloma cells cannot be considered as proven.
The earliest recognizable form of myeloma cell is a large rounded structure
with a large central nucleus, very fine chromatin pattern, large nucleolus and a
comparatively small amount of cytoplasm.11 When this cell predominates, as in
many of the metastatic nodules in Case 20, the microscopic appearance of the
tumor, is very similar to that of reticulum cell sarcoma. It resembles the early
precursors of the blood cells, and just like the latter, can be properly termed a
"stem cell". No doubt the various stem cells, including that of the myeloma, are
closely related, or perhaps even identical, as is maintained by the monophyletic
school of hematologists. A series of transitions leads from the stem cell to the
typical myeloma cell and thence to structures resembling mature plasma cells.
A similar cycle of development, from the primitive mesenchymal cell to a large
stem cell similar to a lymphoblast, to the typical Marschalko plasma cell, has
been observed by Miller14 in his study of inflammatory response to tuberculoprotein.
In addition, there is still another line of development which has not received
much attention in the recent literature. According to many authorities the plasma
cell may also arise from a small round cell, very similar to, if not identical with,
the small lymphocyte. A similar origin has also been postulated for the myeloma cell.9 From our experience we can state that young forms of the small
myeloma cell bear a general resemblance to the lymphocyte, and are also similar
to primitive cells of the marrow such as the "small reticulum cell" of Rohr17
944
CHURG AND GORDON
and the "hematogone",24 in having nucleoli, poorly defined cytoplasm and
tendency to occur in syncytial groups. Whether it is or is not identical with the
lymphocyte, it seems to us that a small stem cell, analogous to the large stem
cell, does exist in the marrow and probably in other mesenchymal tissues, and
that it can give rise to myeloma cells and plasma cells.
SUMMARY AND CONCLUSIONS
1. In 30 patients with multiple myeloma who came to autopsy, myelomatous
infiltration of the extra-osseous hematopoietic system (spleen, lymph nodes,
liver) was found in 22 (73 per cent). In 9 of the 22, other viscera were also involved.
2. In 10 instances involvement could be recognized on gross examination alone,
being massive and striking in 5 of this group; in 12 instances gross changes were
suggestive or nonspecific, requiring microscopic confirmation.
3. The usual pattern of visceral involvement consisted of scattered and diffuse
infiltration, with more or less tendency to nodular aggregates. This is, essentially,
the same pattern that prevails in the bone marrow.
4. The above findings support the idea that multiple myeloma is a disease of
the hematopoietic system closely allied to leukemia, though concerned with a
separate cell type, the plasma cell.
5. The origin of the myeloma cell is discussed. It is believed to develop from
a. primitive reticulum cell which becomes converted into a large or a small stem
cell.
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MULTIPLE MYELOMA
945
16. RICHTER, M . : Leucemia. In Downey, H . : Handbook of Hematology. New Y o r k : Paul
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17. R O I I R , K . : Das mensohliche Knochenmark. Leipzig: Georg Thieme, 1940, 2S6 p p .
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Addendum. Since completion of this study, 14 additional cases of multiple
myeloma were examined at autopsy in this laboratory. In 9 cases infiltration
was found in the spleen, lymph nodes and liver; in 4 of these, infiltration was
apparent on gross examination. In the entire series of 44 cases, involvement of
the extra-osseous hematopoetic system was found in 31 (70 per cent).