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CONTRIBUTION TO THE PATHOGENESIS OF MULTIPLE HEREDITARY OSTEOCHONDROMATOSIS AN EXPERIMENTALSTUDY SHELDON A. JACOBSON, M.D. (From ?he Richard Morton KostPr Research Laboratory, Brooklyn, N. Y.) Since the cartilaginous exostoses whose multiple occurrence has been known under many names were first subjected to histologic study, dispute has waxed hot concerning their derivation. The various theories need not be discussed in detail here. Generally speaking, they fall into two categories. According to one group the lesions originate from the epiphyseal cartilage and bone; ac- cording to the other, from the coverings of the shaft and of the epiphyseal- metaphyseal junction. On first consideration, the architecture of the exostoses speaks strongly for an epiphyseal origin, since they exhibit a really remarkable mimicry of the normal growing end of an enchondrally formed bone. The failure to explain this resemblance on the part of those who reject such an origin has proved a serious handicap to acceptance of their postulates. The experiments to be recorded here would seem to offer a satisfactory explanation. A female dog weighing about twenty-five pounds was anesthetized with nembutal and the right tibia was saucerized on the anterior side at about the junction of the upper and middle thirds. A fracture through the remaining cortex was then easily produced. Thirty-two days later the animal was killed. Imperfect union had taken place with overriding of the fragments. Longi- tudinal section was made. Fig. 1, an area selected from the callus, shows a large mass of cartilage, the upper portion of which is comparable to the distal, relatively inactive part of an epiphyseal plate. Below this area the analogy is striking. The cartilage cells are seen to be actively proliferating. They have aligned themselves in parallel rows perpendicular to the plane of osteo-cartilaginous junction, which is represented by a distinct, if somewhat jagged line. Below this line tra- beculae of bone are seen, and from among them vascular spaces are eroding and interdigitating with the cartilaginous columns, which are being replaced by bone. The picture could readily masquerade as part of an epiphysis with delayed and irregular growth, as for example in early rickets. It certainly bears a closer resemblance to such a structure than do most cartilaginous exostoses. It has been shown by Huggins that if pieces of bladder mucosa are transplanted into the rectus muscle of a dog, they have the property of becom- ing cystic and of evoking a metaplastic ossification on the part of the adjacent host tissue. Huggins’ experiment was repeated by us on a female dog; thirty- five days after transplantation the graft and its surrounding structures were 220 PATHOGENESIS OF MULTIPLE HEREDITARY OSTEOCHONDROMATOSIS 22 1 FIG 1 FIGS.2 AND 3 For explanation of figures see text. excised. A cyst was found, lined by epithelium of the urinary type. Adja- cent to it were islands of bone and smaller ones of cartilage. Fig. 2 represents an area from this tissue, showing cartilage cells in the upper part. Although the architecture is less regular than that shown in Fig. 1, the cartilage cells are distinctly seen proliferating and aligning themselves in 222 SHELDON A. JACOBSON rows which are more or less perpendicular to the bone-cartilage interface. Marrow elements are again penetrating, eroding, and removing the degenerated and calcified cartilage cells nearest to them. Fig. 3 represents another area from the same specimen, showing similar properties. Ossification has thus been evoked by stimuli of two distinct types. In both instances cartilage has been formed in association with bone. Neither process is related to normal osteogenesis. Both are remote from an epiphysis; one, in fact, from any part of the skeleton. In each instance, nevertheless, the picture is strikingly similar to that of a growing epiphyseal plate. In other words, an epiphyseoid structure can be produced without any embryonic pre- FIG.4 For explanation see text. determination at the site of production. The inference is drawn that the architecture of the epiphysis is not specific to itself, but results from inherent qualities of bone and cartilage as such. The hypothesis is offered that when bone and cartilage, of whatever origin, are actively growing in close juxtaposition, the cartilage has a tendency to align and orientate itself with reference to the plane of junction, and that the bone in turn has a tendency to resorb, invade, and replace the cartilage. This, if true, would account for the mimicry of epiphyseal plates exhibited by carti- laginous exostoses, even if the origin of the two were distinct, as the writer believes it is. PATHOGENESIS OF MULTIPLE HEREDITARY OSTEOCHONDROMATOSIS 22 3 The question naturally arises as to why, if the above hypothesis be cor- rect, the characteristic architecture is not more frequently described in places where bone and cartilage occur remote from epiphyseal regions. The answer is not far to seek. A second female dog was subjected to the transplantation of bladder mucosa into the rectus muscle. Thirty-four days later the operative site was excised under nembutal anesthesia. Fig. 4 is a representative histologic field. The lower area represents fiber-bone. Above this are cartilage cells whose arrange- ment may at first glance seem to be a random one. A closer inspection reveals signs of a definite arrangement, and it appears possible that section through a more favorable plane would have shown the same architecture as described above. In order to reveal this characteristic structure two criteria must be satisfied. In the first place the spatial relationship of the bone and cartilage must be such that there is a definite and (for a given area) single plane of junction between them, so that each can exert upon the other the effects postulated above. This condition does not obtain in an ordinary callus. Islands of bone, cartilage, and fibrous connective tissue are scattered helter-skelter, and the ensuing mul- tiple polarity of many " fronts '' does not evoke a recognizable architectural response. In the second place, the plane of section must run perpendicularly to the osteochondral junction; otherwise the structure, even if it exists, will not be recognizable to the pathologist. It can readily be seen, therefore, that in only a minority of cases will an ectopic epiphyseoid structure occur; and that in only a fraction of these will the structure appear in recognizable form upon the microscopic slide. For another type of growth, Selye has shown that in very young rats, ampu- tation of the femur above the junction cartilage results at first in confused callus formation of the usual type. Thereafter, a reorientation of the osseous and chondral elements takes place, with the formation of a typical growth- cartilage line. It is conceivable that the law of growth suggested in this paper may apply not only to cartilaginous exostoses, but to the normal ontogenesis of all enchon- drally formed bones. At the present time, however, we lack sufficient basis for a development of this thesis. SUMMARY Experimental evidence is presented to demonstrate that wherever cartilage and bone, however formed, are growing together, a mutual polarity may result. By virtue of this an epiphysis-like structure is produced. This, if true, would adequately explain the epiphysis-like architecture of cartilaginous exostoses. REFERENCES HUGGINS,C. B.: Proc. SOC.Exper. Biol. & Med. 27: 349, 1929-30. SELYE,H.: J. Anat. 68: 289, 1934. .

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