LIPOBLASTIC AND MEGAKARYOCYTOID MULTIPLE MYELOMA
PETER A. HERBUT, M.D., AND LOWELL A. ERF, M.D.
Clinical Laboratories and the Division of Hematology, Department of Medicine, Charlotte
Drake Cardeza Foundation, Jefferson Medical College and Hospital,
Philadelphia, Pennsylvania
Although multiple myeloma can ordinarily be divided into plasma cell,
myelocytic, lymphocytic or erythrocytic types, one occasionally encounters
such tumors that defy exact classification. If it is true that this neoplasm is a
tumor of marrow cells, then, theoretically, one should encounter a great variety
of tumors starting with the most primitive cell—the reticulum cell, and ending
not only with the more mature cells of the plasmacytic, myelocytic, lymphocytic
and erythrocytic series but also with the cells of the megakaryocytic and lipocytic variety. Between these two extremes there should be many tumors
composed exclusively or almost exclusively of one cell type or another, or of
various combinations of the different cells. Practically, this is exactly what
is encountered.
While the variation in cellular composition can always be noted in routine
histologic sections, it is only the more mature cells that can be recognized with
any degree of certainty, whereas the remaining cells can at best be labelled
"primitive cells." As pointed out in a companion paper, the latter can, however,
in most instances be precisely identified from a study of aspirated marrow or
tumor stained with Wright's stain. It is because of the use of this latter method
that the identity of the following 2 unusual cases was first suspected, and only
later when the histologic sections were restudied was the final diagnosis established. The first case we believe is that of a lipoblastic type of multiple myeloma,
and the second that of a megakaryocytoid type.
R E P O R T O F CASES
Case 1. A white man 41 years old was well until 6 months before admission to the hospital when he gradually developed weakness, pallor, loss of 40 lbs. in weight, "bumps" on his
ribs and pains in the ribs, shoulder and back. Physical examination disclosed firm, fixed,
nontender tumors measuring about 3 cm. in diameter in the left 3rd and 8th ribs, the right
6th rib and the left frontal bone. Pallor, emaciation and slight lymphadenopathy were
present. Roentgenograms revealed a generalized demineralization of the bones with
areas of destruction in the ribs and vertebrae. The laboratory studies were as follows:
total plasma proteins 5 gm. per cent; blood calcium 12.5 mg. per 100 cc. of blood; blood
phosphorus 2.8 mg. per 100 cc. of blood; blood phosphatase 18.3 Bodansky units; hemoglobin
60 per cent; leukocytes 5,000 per c. mm.; and thrombocytopenia. There was no BenceJones proteinuria. Following diagnostic aspiration of the sternal marrow and removal of a
tumor from a rib, roentgen therapy was instituted with no beneficial effect. The patient
died one month after admission.
Aspiration of sternal marrow stained with Wright's stain revealed sheets
of tumor cells that contained an abundant amount of cytoplasm (fig. 1). Many
of the cell boundaries were indistinct and the cytoplasm tended to coalesce.
13
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P E T E R A. H E R B U T AND L O W E L L A. E R F
Often it was somewhat granular, light grey in color and contained few if any
vacuoles or phagocytosed particules. The nuclei were single, round or oval,
F I G . 1. Case 1. Smears of aspirated sternal marrow stained with Wright's stain showing
some cells w i t h distinct margins and others whose cytoplasm had coalesced. T h e nuclei
are identical with those of normal fat cells as illustrated in fig. 2 (X 900).
F I G . 2. Showing a normal fat cell in aspirated sternal marrow.
(Wright's stain X 900)
relatively small and were almost identical with these of normal marrow fat
cells (fig. 2). They possessed fine threadlike chromatin, small dark mucleoli
and stained a light blue.
M U L T I P L E MYELOMA
15
The surgically removed specimen consisted of a well circumscribed and
encapsulated tumor measuring 4.5 cm. across, and an attached portion of a
rib. The periosteum of the latter was continuous with the capsule over the
tumor. The neoplasm was nodular, moderately firm and on section presented
pink yellow to grey tissue in which there were numerous areas of hemorrhage.
It contained no grossly demonstrable bone. Similar but larger tumors were
found at necropsy to involve most of the ribs, the left frontal bone and the
upper portion of the left ilium. There was also a complete and diffuse replacement of the marrow of the lower thoracic and all the lumbar vertebrae
with similar tumor tissue. The lower half of the right adrenal and one adjacent lymph node each contained a pinkish grey and hemorrhagic tumor that
measured 2.5 cm. in diameter. The prostate and the thyroid were grossly
normal. The remaining organs showed no noteworthy changes.
F I G . 3. Case 1. Section I'ruiii oiiu of ihe t u m o r s in a rib showing a diffuse arrangement
of t h e cells; several blood spaces and in t h e upper right hand corner a broad fibrous tissue
septum. (Hematoxylin and eosin X 100).
Microscopic sections of the surgically removed specimen disclosed compact
masses of tumor cells, often with foci of necrosis, supported by relatively broad
strands of dense fibrous tissue, and occasionally containing spicules of bone
(fig. 3.). The capsule was invaded by tumor cells. Examination with higher
power disclosed solid areas where the cell borders were indistinct and the cytoplasm tended to run together. These cells were rather uniform in appearance
and in some areas resembled liver cells. The cytoplasm was abundant and the
nuclei were relatively small, round, darkly stained and centrally placed. There
were other areas, however, where the cells were separated and sharply defined.
Whereas most of these were round or oval and resembled plasma cells, others
were spindle shaped, elongated or irregular and somewhat larger (fig. 4). As
before the cytoplasm in most of the cells was abundant and densely pink staining
although occasionally it was definitely foamy. Nuclei were round, dark and
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P E T E R A. H E R B U T AND L O W E L L A. E R F
central or eccentric in position. In none of the cells was the cytoplasm vacuolated. Mitoses were occasionally found. Examination with the oil immersion lens corroborated the above findings and in addition disclosed most of
the nuclei to be so dense that they resembled more those of primitive cells
rather than of plasma cells. When the chromatin was less compact it was
scattered irregularly throughout the nucleus and not in any definite cartwheellike manner. Nucleoli could not be recognized as such. Examination of
tissue obtained at autopsy disclosed essentially similar cells except that the
edges of some were frayed, and that the nuclei were more vesicular. As in the
previous section, however, the chromatin was irregulary distributed and nucleoli
were not recognized. There was in addition much hemorrhagic extravasation,
considerable necrosis and scattered golden brown pigment. The tumors in
F I G . 4. Case 1. Higher magnification of t h e section shown in fig. 3, showing many cells
t h a t closely resemble plasma cells a n d other cells with scanty or a b u n d a n t indistinct peripherally frayed cytoplasm. The nuclei are quite uniform and dark. (Hematoxylin and eosin
X 400).
the adrenal and lymph node were similar. The kidneys revealed no casts or
interstitial fibrosis. The entire prostate was sectioned but disclosed no carcinoma. The remaining organs showed no contributory changes. Some
sections of the tumor masses from the ribs stained with nile blue sulphate disclosed a peppering of minute blue to purple granules throughout the tumor
cells (Fig. 5). Simultaneously stained sections of two cases of plasmacytoma
and one case of monocytic leukemia were entirely free of fat granules.
Case 2. A man, 53 years old, was admitted to the hospital complaining of pallor, weakness and a "lung abscess." Physical examination was essentially normal. A roentgenogram of the skeleton revealed a generalized "demineralization" of the bones and equivocal
foci of erosion b u t no definite punched out areas of rarifaction or tumor masses. These
changes were interpreted by Dr. P . C. Swenson as compatible with a diffuse myelomatosis.
Roentgenograms of the chest disclosed a cavity measuring 2 cm. in diameter in the central
M U L T I P L E MYELOMA
17
portion of the left lower lobe. Other laboratory studies showed the following: total plasma
proteins 5.2 gm. per cent; blood calcium 8.9 mg. per 100 cc. of blood; blood phosphorus 2.9
mg. per 100 cc. of blood; blood phosphatase 7.7 Bodansky units; hemoglobin 45 per cent;
leukocytes 3000 per c. mm. of blood, no Bence-Jones proteinurea. Two sternal bone
marrow punctures, a sternal biopsy and a thoracotomy were performed. In spite of treatment with sulfadiazine the patient's health gradually failed and he died with severe hypopro teinemia 5 months after admission. Reexamination of the skull and long bones before
death revealed roentgenograph!c changes similar to those first observed. An autopsy was
not permitted.
Aspirations of sternal marrow showed in addition to the usual components
about 10 per cent typical plasma cells and many huge multinucleated giant
cells (fig. 6). Some of these contained as many as 22 nuclei. The latter were
FIG. 5. Case 1. Section from a tumor in a rib showing a peppering of fat granules throughout the tumor cells. Only the larger granules are seen in the photomicrograph. The cells
are indistinct because it was impossible to cut thin sections. (Nile sulphate blue stain
X400).
always uniform in shape and size and stained evenly. The cytoplasm was
abundant and hemogeneously light blue. The many nucleated cells resembled
megakaryocytes except that they did not posses the lobulated nuclei nor the
azurophilic granules characteristic of these cells.
The surgically removed tissue from the sternum consisted of four irregular
pieces containing spicules of bone and measuring as much as 6 mm. in diameter.
Microscopic sections disclosed a few bony trabeculae, areas of hemorrhage and
islands of greatly "hyperplastic" marrow that contained only a few adult fat
cells. Higher magnification of the marrow revealed mature and immature
myeloid cells, erythroblasts and normal megakaryocytes. There were present
also more immature cells that resembled plasma cells in that they showed round
or polygonal borders, abundant dense pink cytoplasm and round eccentric
lightly stained nuclei. In addition to these cells there were still others that were
considerably larger, round, possessed a scanty amount of pale, ill defined, almost
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P E T E R A. H E R B U T AND L O W E L L A. E R F
F I G 6 Case 2. Aspirated sternal marrow stained with Wright s stain showing single
a n d multinucleated plasma cells. Two of t h e l a t t e r closely resemble megakaryocytes.
(X 900 b u t two photographs have been further magnified).
F I G 7 Case 2. Section of a biopsy from t h e sternal marrow showing various elements
of the normal marrow together with m a n y single nucleated and several multinucleated
tumor cells. In t h e upper portion there is a normal megakaryocyte. (Hematoxylin and
eosin X 400).
M U L T I P L E MYELOMA
19
imperceptible cytoplasm and from 1 to 10 piled up nuclei (fig. 7). The latter
were larger than the nuclei in the cells just referred to. They were round,
lightly but evenly stained and showed a clumping of the chromatin at the
periphery. Examination with oil immersion lens showed the same characteristics together with centrally or slightly eccentrically placed nucleoli. The
nucleoli were better seen in the mononuclear cells than in the multinucleated
ones. The nuclei in these large cells differed from those of the mature megakaryocytes in that the latter were smaller, somewhat more irregular in outline
and contained more heavily stained and irregularly distributed chromatin.
DISCUSSION
It is well established that adult fat cells, lipomas and liposarcomas arise
from specialized perivascular mesenchymal cells which are probably related
to the reticulo-endothelial system.2-3 It has further been observed that in
liposarcoma the cellular composition is usually varied and that one type of
cell observed closely resembles the liver cell and another the plasma cell. While
ordinarily these two types 3 of cells are not found4 to the exclusion of cells which
contain granules, vacuoles or otherwise resemble adult fat cells, theoretically
there is no reason why on occasion the tumors cannot be composed entirely
of the undifferentiated lipoblasts. We believe that this is what occured in our
case 1. The identification of the cells as lipoblasts was first suspected from a
study of the sternal marrow stained with Wright's stain in which the nuclei of
the tumor cells appeared indentical with those of adult fat cells. Subsequently
many pieces of tissue removed from several tumors when stained with nile
sulfate blue disclosed a peppering of fat granules within the cytoplasm of the
cells. That all sections and all cells thus prepared did not take the positive
stain is not surprising because it is well known that as the cells become more
anaplastic the proportion of fat diminishes until it may be entirely absent. 5,3
In this connection we recently had an opportunity to study a surgically removed,
retroperitoneal liposarcoma whose cut surface presented a typical variegated
appearance of light brown, grey, pink and yellowish tumor nodules separated
by bands of myxomatous connective tissue. Microscopically all sections studied
resembled in some portions liver cells and in others plasma cells and so appeared
similar to those of the case under discussion. Some sections stained with
nile sulfate blue were negative for fat while others were peppered with minute
pink to blue granules.
Although primary liposarcoma has been reported most frequently in extraskeletal tissue and organs, we have been able to find 9 cases that have been
recorded as originating in bone. Most of these tumors had certain common
characteristics in that 6 • 7 • 8 • 9 •6 (1) they arose as a single tumor that was localized
for even several years before it produced metastasis and death, (2) that they
were as a rule radiosensitive and roentgen therapy controlled them for varied
intervals and, (3) that histologically they disclosed much pleomorphism varying
from lipoblasts, to bizarre giant cells, granular cells, vacuolated cells and adult
fat cells. Our case, on the other hand, differs from these in that (1) the tumors
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P E T E R A. HERBTJT AND L O W E L L A. E R F
arose simultaneously in many ribs, and were accompanied by pains not only in
the ribs but also in the shoulders and back, thus suggesting that the disease
was generalized from the start, (2) that irradiation had neither any local effect
in diminishing the size of the tumors nor did it prolong life, for the patient died
7 months after the onset of the illness and (3) that the microscopic appearance
although showing some variation in shape and size of the cells was remarkably
constant. Large bizzare giant cells, vacuolated cells or adult fat cells were not
seen. For these reasons we believe that our case deserves the title of multiple
myeloma of a lipoblastic type rather than of liposarcoma.
Because we were unable to perform an autopsy on our case 2 its designation
as multiple myeloma is not too secure. Such a diagnosis was based upon the
following facts (1) a generalized "demineralization" of the bones with suggestable foci of erosion in a man 53 years old exhibiting no other obvious or demonstrable disease to account for such changes (2) the finding of large mononuclear and multinuclear "tumor" cells both in aspirated and surgically biopsied
sternal marrow (3) refractive anemia in spite of the "active" bone marrow
and (4) the short duration of the illness. Although tumefactions or punched
out areas of erosion of the various bones are almost always present in multiple
myeloma it is nevertheless possible to encounter widespread diffuse infiltration
of the marrow without roentgen evidence of such changes. For instance, in
case 1 of this report tumors were seen only in the ribs and vertebrae and only
general demineralization in the remaining bones. Yet the sternal marrow,
as demonstrated by aspiration, was filled with tumor cells. Secondly, in the
cases of multiple myeloma reported in the companion paper, tumor cells were
found not only in the areas of tumefaction seen roentgenographically but also
in the areas that showed only "demineralization". Thirdly it is a common
experience to find at necropsy widespread metastatic carcinoma in the marrow
particularly of the vertebral bodies and yet even upon reviewing the roentgenograms one finds no evidence of metastasis. We therefore believe that in case 2
the marrow was probably generally invaded by tumor cells in spite of the relatively negative roentgenograms and that the case should be classed as a multiple myeloma.
The exact nature of the tumor cells in case 2 became apparent only from a
study of smears of the sternal marrow stained with Wright's stain. These
disclosed many typical single nucleated plasma cells and all transitions from
these to cells containing 2 to 22 nuclei. In all the binuclear or multinuclear
cells both the cytoplasm and the nuclei were identical with those containing
single nuclei. They were thus actually plasma cells but in many instances
because they were so large and because they contained so many nuclei they
resembled megakaryocytes. They were however not true megakaryocytes
because they did not contain the lobulated nuclei nor the azurophilic cytoplasmic
granules so characteristic of these cells. We therefore use the term megakaryocytoid rather than megakaryocytic multiple myeloma. It is of interest to
note that Gunn and Mahle under the title "megakaryoblastic myeloma" described a case similar to our case 210. In a personal communication Gunn
M U L T I P L E MYELOMA
21
stated that "only a small percentage (of the multinucleated cells) showed azurophilic granules." High power photomicrographs of the multinucleated cells
in their case appear identical with those of the case reported here.
SUMMARY
Although 4 types of multiple myeloma, namely, plasmacytic, myelocytic,
lymphocytic and erythrocytic, are ordinarily recognized it is thought that
the remaining parent cells of the marrow might also at times give rise to true
multiple primary tumors. In this respect we have presented a case of lipoblastic and a case of megakaryocytoid multiple myeloma. The latter has
been so designated because the cells although steming from plasma cells have
partially differentiated into and resemble megakaryocytes.
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