BONE FORMATION I N METASTASES O F OSTEOGENIC
SARCOMA
OF CASEWITH METASTASES
TO
REPORT
THE
BRAIN
WARREN 0.HARDING, 11, M.D., F.R.C.S. (Edin.), AND CYRIL B. COURVILLE, M.D.
(From the Department of Pathology, Los Angeles County Genaral Hospital, and Depurtment
of Neurology, College o f Medical Evangelists, Loo Angeles)
Occasionally one has an opportunity t o study the pathologic aspects
of cases which shed considerable light on current conceptions of
pathologic processes. The case here described is of double interest.
The metastatic nodules secondary to an osteogenic sarcoma of the
femur, though not always in contact with bone, were found to be capable of forming osteoid tissue and adult bone within their substance.
Furthermore, one of the metastatic nodules in the brain proved to be
radiographically visible, an observation hitherto unreported as f a r as
we have been able to learn.
Calcification within intracranial tumors has been recognized since
Virchow described psammoma bodies in so-called “dural endotheliomas” (meningiomas). I n a previous report from this hospital (1)
the statement was made that “calcareous deposits have been known to
occur in almost every variety of primary new-growths that compromise
the intracranial space.’’ The question of secondary growths was purposely omitted, in the belief that deposit of calcium in a metastatic
nodule was most unlikely. The unusually slow growth of metastatic
nodules within the brain substance in some instances would theoretically permit the deposit of calcium. As far as we know, however, this
bas not been described.
Actual bone formation in intracranial tumors is of much more rare
occurrence, and very few cases, not all of them unquestioned instances
of new growth, have been described in the literature. The process is
most commonly observed in meningiomas which have undergone regressive change. I t seems evident that bone formation in such tumors
is not necessarily due to their contact with pre-existing bone, for this
process occurs most frequently in meningiomas of the spinal canal,
where this situation does not exist.
Ossification may occur, in rare instances, in tumors of the glioma
group when for some reason o r other neoplastic activity has ceased.
Such an instance was described in the report previously referred to *
1 At the time this study was made, it was believed that the tumor in question, a small
circumscribed solid glioma of the genu of the corpus callosum, was of the type now known as a
spongioblastoma multiforme. This impression wa8 based ou the cellularity of the tumor,
the wide variation in the size a i d shape of the tumor ccll nuclei, arid the presence of uumarous
tumor giant cells. The growth is now considered to be an astrocytoma, having a tcndcncy
toward malignaiit change prior to the patieut’s death. This change is not infrequeritly
observed in astrocytomas found at autopsy.
787
FIQ.1. RADIOQRAPH
OF FEMUR
SHOWING
PRIMARY
TUNOR
FIQ.2. RADIOGRAPH
OF SKULLSHOWINQ
METASTASISIN OCCIPITALREUION
788
B O N E FORMATION IN METASTASES O F SARCOMA
789
(Case 1). It seems evident in these cases that bone is formed following degenerative changes in the tumor tissue after cessation of growth.
A different situation existed in the case of metastatic osteogenic
m o m a here in question. The cells forming the original tumor and
the metastatic nodules were of bony origin and the process of bone formation was evidence of biologic activity on their part.
REPORTOF CASE
History ( L . A . C. G . H . Case No. 232-245) :A thirty-eight-year-old Mexican lnborer
wm admitted to the hospital on Aug. 9, 1932, with a provisional diagnosis of osteomyelitis of the distal third of the left femur. Pain in the rcgion of the left knee had been
noticed for the first time six months previously and had been increasing in intensity in
the interim. The pain was boring in character and was of such severity two months after
onset that walking was impossible. The pain was worse a t night and interfered with
sleep. A mild febrile reaction had been present since the onset and, a t intervals, the
FIQ.3. NODULE
REMOVED
FROM RIQHTOCCIPITALLOBE,
SHOWING
ATTACHMENT
TO DmA
patient had noticed a n increase in the local temperature. He had lost twenty-flve pounds
in weight during the flve months before admission. There was no history of antecedent
trauma and the family history and past personal history revealed nothing relevant.
Physical Examination: The patient was inclined to be apprehensive, anticipating
extreme looal pain from the slightest movement of the affected limb. The abnormal
physiaal Andings were limited exclusively to the local lesion. The midportion of
the left thigh was diifusely swollen to a fusiform shape. The overlying skin was not
injected, and the superflcial venous channels were not dilated. The region of the swelling
was moderately edematous. An indistinct tumor intimately associated with the femur
was palpable. The normal movements of the hip joint and the knee joint were not
affected. Hyperextension of the knee joint elicited local pain a t both femoral supracondylar ridges. The inguinal lymph nodes were not palpable.
A radiograph of the femur showed a lesion centering at the junotion of the middle
and lower third of the shaft (Fig. 1). The bone was diffusely decalcified by a lesion
which appeared to be medullary in origin. The cortex was thinned, but appeared intact.
A moderate irregular ossifying periosteal reaction extended along the shaft f o r approximately 16 em. The rarefying bony lesion was apparently 10 om. in length. Radiographio examination of the lungs and the bones of the pelvis and head failed to demonstrate any secondary foci.
790
W A R R E N Q. HARDINO, 11, AND CYRIL
B. C O U R V I L I Z
Operation a d Surgical Pathology: A pathological fracture occurred thirty-six hours
before operation. The left femur was disartirulated at the hip joint by the Percy
cautery technir following B cauterg l>iopsg of the tumor. The biopsy was made following the appliration of an Esmarcli bandage proximal to the growth. A rapid frozen
section of the tissue was reported osteogenic sarcoma. The glands along the iliac vessels
wore not found to be enlarged. The immediate postoperative condition and course were
satisfactory.
The specimen consisted of the clisarticulated left leg. The cautery biopsy incision
extended down to a mass of hemorrhagic, spongy, gray h u e located between the two
fragments of the femur. The neoplastic tissue a t the site of the pathological fracture was
intermingled with fragments of bone which showed rarefaction. The ends of the femur
at !he fracture were eroded. The more extensive decalcification was situated in the
F I Q . 4.
BRAINSIIOWINQ NODULE
I N LEFTPARIETAL LOBE
The leptomeningcs are illtact over the tumor.
SECTION OF
medullary portion. The periosteum had been elevated from the bone f o r a distance of
6 em. from the site of frarture and showed a small amount of new bone formation.
Cozcrse: The postoperative course was uneventful f o r the Arst ten days. On the
tenth day the nurse reported a “local chill” of the right arm followed by a paralysis
of the right arm and leg. An examination made one hour later revealed no evidence of!
weakness on that side. On the thirteenth postoperative day the patient again suddenly
brcame p a r a l y i ~ don the right side. The paralysis was complete f o r approximately two
hours, with gradual improvement during the following twenty-four hours. The episode
was repeated on the fifteenth day following the operation, at which time the following
sequence of events was noted. A sensation of tingling followed by numbness was first
experienced in the right arm. This was followed by a similar occurrence in the right leg.
I n ahout five minutes a severe cramping pain occurred in the muscles of the right
shoulder girdle and persisted until the onset of convulsive contractions of all the muscles
of the arm and leg. A complete right hemiparesis persisted following the seizure. Examination of the optic fundi showed blurring of the upper segments of the optic discs.
The patient complained daily of right-sided headaches and numerous right-sided convulsive scizurcs were observed during the remainder of his illness. Metastatio nodules
being considered as a likely cause f o r the neurological manifestations, radiographs of
the skull were made, but were reported as negative. When these were re-studied in
light of the post-mortem findings, a calcified mass, approximately 3 cm. in diameter,
was seen in the right occipital region (Fig. 2).
BONE FORMATION IN METASTASES OF SARCOMA
791
Thirty-six days after the operation the patient was observed to be confused and
presented a n incomplete global aphasia. A bilateral choked disc was found with two to
three diopters swelling on the right and blurring of the nasal margin on the left. A
right spastio hemiplegia was presrnt. The patient became progressively worse and died
on the flfty-flfth postoperative day, approximately eight months following the onset of
symptoms.
Autopsy: A post-mortem examination was made by Dr. William Quinn, ten hours
after death. The lungs were increased in weight and presrnted numerous Arm nodules of
almost bone-like consistency, grayish white in color, and ranging from 0.5 to 1.5 om. in
diameter. The liver weighed 1080 grams and likewise revealed a number of hard, grayish
white nodules, measuring from 0.G to 2.5 em. in diameter. Aside from a slight cloudy
swelling of the kidneys, nothing worthy of note was observed in the abdomen.
FIO.5. PHOTOMICROGRAPH
OF PRIMARY FIG.6. PHOTOMICROQRAFT~
SHOWINQ
TUMORSHOWINGIRREGULAR
BONE
BONEFORMATION
I N METASTASIS
IN LIVER ( x 260)
FORMATION
( x 260)
Upon removing the brain from the cranial vault, a hard globular tumor mass,
4.2 )( 3.8 x 2.7 om. in size, remained adherent to the dura and bone in the right occipital
region (Fig. 3). The brain about the nodule was considerably softened. The tumor was
of a dark red-brown color, having a mottled appearance due to circumscribed grayish
nodules present in its substance.
The brain presented a more or less universal flattening of the convolutions, more
marked in the midportion of the dorsolateral surface of the left cerebral hemisphere. I n
the upper portion of the left posteentral gyrus, the surface extension of a second nodule
was observed. This area appeared grayivh in color and Arm in consistency, lying beneath
an intact pia-arachnoitl. On coronal section the white substance of the left cerebral
hemisphere was found to be more voluminous than the right. Beneath the cortex of the
upper left precentral and postcentral convolution was found a sharply circumscribed,
irregular, mottled reddish gray tumor mass. It was very hard and evidently contained
calcareous material. I t measured 3 X 1.7 em. in its greatest cross sectional diameters in
the A r s t and 2.7 X 2.6 em. in a second section (Fig. 4).
792
WAItIlEN G. HARDING, 11, A N D CYRIL B. C O U R V I L L E
Histoptholog?y: The microscopic structure of the primary tumor was characteristic
of a sarcoma of the osteolytic type (Fig. 5 ) . The entire growth was permeated hy
nunierous neoplasmic vascular spaces which had no endothelial lining, and whose wall3
consisted of closely packed, malignant tumor cells, resembling the so-called abortive
osteoblasts. The plunip spindle cells sliowecl considerable pleomorphism. Irregular
t,ypes of mitotic Aguit%swere prominent. The osteoblastic cells also showed a high degree
of anaplasia. Numerous tumor giant cells were found and stood out in marked contrast
to the few osteoclastie giant cells that could be identified. I n the areas in which the largo
round osteoblastic cells predominated, one found large depoqits of irregular, pale, granulsr,
osteoid tissue. An irregular, incomplete process of calciflcation had occurred in some of
the osteoid tissue found in the central portion of tho growth.
7. PHOTOMICROGRAPH SHOWINQ
O ~ T E O I TISSUE
D
IN METASTASIS
To LUNQ( x 260)
FIQ.
FIQ.8.
TO
OSTEoID
TISSIJEI N
METASTASIS
LEFTPARIETAL
LOBEOF BRAIN
( X 260)
The cellulai* arc+liitecluiw of the mctastntic deposits was identical in each locution.
The relative 'number of abortive osteoblasts compared to the plump spindle cells appeared
to he increased. The cell types found in the primary growth could be duplicated in all
of the seconclaiy foci. Osteoid tissue was present in all of the deposits examined, antl
areas of calcifictition were found in each, varying somewhat in extent. Irregular upieules
of bone, about which were clustered osteoblasts and '' osteoclastic giant cells," were found
in the tumor mass in the left parietal lobe of the brain. The metastases were definitely
less vascular than the primary growth. Neoplastic vascular spaces were seen, however,
and many of these contained malignant tumor cells. The adjacent tissue surrounding
the metastatic foci was intensely hypereniie. The histologic appearance of the secondary
tumors is shown in Figs. 6, 7, antl 8.
.
DISCTTSSION
Bone formation has evoked coiisidcrable discusYioii during the past
tcii years. Tlic controversy has ceiitered largely about the function of
BONE FORMATION I N METASTASES OF SARCOMA
793
the osteoblast in this process. Two general points of view have been
developed, one of which considers the osteoblast to be a specially endowed cell whose function is that of bone formation, and another,
ohampioned by Leriche and Policard ( 2 ) , which considers bone to be
simple connective tissue which has become calcified through some chemical process rather than as a result of cellular secretion.
The generally accepted theory of osteogenesis may be briefly summarized as follows: The connective-tissue cells in the region to be
ossified undergo certain important modifications, namely, swelling,
hypertrophy, and mitosis. I n this stage of increased activity the connective-tissue cells arc called osteoblasts. The osteoblast secretes a
clear, jelly-like fluid which completely surrounds it, and is known as the
preosseous substance. The functional activity decreases a t this stage
and the contracting osteoblast surrounded by its secretion, the preosseous substance, becomes the bone cell. The preosseous substance
becomes impregnated with calcium, derived from the blood stream as a
result of some indefinite secretory activity of the osteoblast, thus forming adult bone.
I n the theory advocated by Leriche and Policard, the coiicept of bone
as the secretory product of a specific cell is abandoned and it is considered to bc produced in the following manner. The connective tissue
in the region to be ossified becomes edematous probably as a result of
lymph stasis depending upon vasculariaation. This edema is not an
ordinary fluid infiltration but is a colloidal change characteristic of
connective tissue. The so-called osteoblasts, or modified connectivetissue cells, become surrounded by this preosseous substance and a
process of degeneration begins which transforms the osteoblast into the
adult bone cell. The degeneration of these cells may liberate certain
substances o r ferments which impreFnate the surrounding substance
and thus influence its subsequent activity, probably through their influence upon the circulation. The calcification of this medium is dependent upon circulatory phenomena following closely the general law
that tissue which has become functionally inactive becomes the site of
calcification. The deposit of calcium transforms the preosseous substance into bone by some colloidal chemical change as yet not understood, Bone formation in tumors as a result of degenerative change
seems t o answer the requirements of this theory.
To those accepting the osteoblastic theory of bone formation, the
finding of bone in metastatic deposits of a sarcoma such as we have
described is nothing unusual. Greig ( 3 ) , on the other hand, has written: “It is significant that no professional pathologist, even of wide
experience, with whom I have discussed the matter can recall from his
own experience a single case in which even one metastasis from a
periosteal or endostcal ‘ostcogenctic’ sarcoma contained bone.” He
reports ( 4 ) that hc has not found any instance of this in the extensive
collection of specimens in the museum of the Royal College of Surgeons
of Edinburgh. He argues that, if the sarcoma cells are bone-forming,
the metastases should be osseous and if osseous in one organ they ought
794
WARREN 0. HARDINO, 11, AND CYRIL
B. COURVILLE
to be osseous in all. Greig does not deny that on rare occasions bone
formation is found in an isolated metastasis in the lung, liver, spleen, or
lymph node, but he logically explains this by the facts that the sarcomatous tissue is an embryonic connective tissue capable of dedifferentiation into the preosseous substance and that deposits of calcium are
frequently found in such organs, thus furnishing the essential conditions for bone formation.
The case here reported is of interest in that all of the metastatic foci
of osteogenic sarcoma contained bone in a developmental o r adult form.
In the liver and lung some portions of this osteoid tissue were heavily
impregnated with calcium, either regularly distributed, as in the case
of adult bone, or irregularly deposited in excess, as is common in abnormal calcification. The nodule in the occipital lobe, which had been
radiographically visible, contained an abundance of calcium. The
nodule in the left central region, separated from the bone by an intact
dura and pia-arachnoid, revealed only the earliest evideiiceB of calcium
deposit, although osteoid tissue was more or less evenly and abundantly
distributed throughout the entire mass. The greater abundance of
calcium in the nodule in contact with dura and bone would seem to favor
Qrieg’s view to the extent that a local source of calcium facilitates the
process of adult bone formation eveii though it is not entirely necessary.
This nodule was slightly larger in size and was probably the older of
the two.
STJMMARY
The occurrence of calcium in intracranial tumors is not rare, although bone formation in growths so situated is most unusual, For the
most part, as in the case of ossified meningiomas, the presence of bone
is evidence of an advanced regressive change in such tumors. Probably because of their comparatively rapid evolution, metastatic tumor
nodules in the brain have not been known to contain calcium. The cage
here reported is unique in that all of the secondary foci of an osteogenic
sarcoma, primary in the femur, including two large nodules in the brain,
contained osteoid tissue with variable amounts of calcium deposit. The
nodule situated in the right occipital pole contained so much calcium a s
to be radiographically demonstrable. This observation seems to favor
the theory of specific activity on the part of the osteoblast. At least the
metastatic tumor cells demonstrated a biologic activity in the direction
of adult bone formation.
REIPERENCES
1. COURVILLE,
c. B., AND ADELSTEIN,L. J.: Intracranial calcification, with particular
reference to that occurring in the gliomas, Arch. Burg. 21: 803 (Nov.), 1930.
2. LERICRE,R., AND POLICARD,A . : The Normal and Pathological Physiology of Bone,
C. V. Moshy Co., 8t. Louis, 1928.
3. GREIG,D. M . : Clinical Observations on the Surgical Pathology of Bone, Oliver and
Boyd, Edinburgh, 1931. p. 238.
4. GREIG,D. M. : Personal communication.