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THE POSSIBLE RELATIONSHIP BETWEEN PRIMARY CUTANEOUS XANTHOMAS AND THE MELANOMAS N. CHANDLER FOOT, M.D. (From the Department of Surgical Pathology of Cornell University Medical College and New York Hospital, New York) There has been considerable confusion concerning the nature of the large group of tumors and tumor-like structures known as “ xanthomas.” Some of them appear to be,que tumors, others doubtfully so, while still others are manifestly to be;cqqsidered as granulomas with many lipid-laden phagocytes imparting a xanthcfmatous appearance. In spite of a good deal of study, the matter has never been settled and it will not be until we answer the question: “ Are all these growths of similar, or of dissimilar histogenesis? ” The subject was taken up in extenso by Gruenfeld and Seelig (1) in a critical review En 1934, asd the conclusion was reached that the so-called tumors were really granulomas‘ and an expression of hypercholesterinemia. The attention of these investigators was focussed upon the type cell, known as the ‘‘ foam ” or ‘‘ Touton ” cell, the stroma being left out of the reckoning. They argued that these cells were nothing more than histiocytic phagocytes. The reader is re- ferred to their excellent review for a discussion of this subject and a generous bibliography. Haagensen (2), in a paper reporting a case of xanthoma of the breast, viewed the matter in much the same light, dividing these tumors into two classes : (a) primary xanthomas and (b) secondary xanthomatoid deposits of lipid-containing histiocytes in connection with inflammatory or degenerative processes. There are five subclasses in his first group, the last of which is the solitary xanthoma. It is with this that we have to deal in this paper, although the tumor we are discussing may be multiple, just as the melanoma or neuro- fibroma may be. It is my opinion that the cutaneous xanthoma may be removed from the general group of xanthomas and set more or less by itself in a separate cate- gory. Such tumors are frequently noted in the skin, causing a local swelling and forming a hard, globular, rather fixed mass just in or beneath it. There may also be a spot of brownish pigmentation in the epidermis overlying the mass, not readily distinguishable from the ordinary deep-seated melanoma. On bisecting such tumors one finds that they are usually 0.5-1.0 cm. in diam- eter, sometimes much larger. They are sharply delimited by a fibrous capsule that sets them off distinctly from the surrounding areolar and adipose tissue. Their section surfaces are usually homogeneous and putty-like in appearance and of a striking ochraceous-orange color. Those of the overlying skin may show a spot of brownish pigmentation. Microscopically, the tumors are seen to be composed of vacuolated cells of irregular outline occupying the meshes of a dense, curled, radiating rete of 425 42 6 N. CHANDLER FOOT collagenous connective tissue. The cells may be elliptical like those of the other (( xanthomas,” but they are more often elongated, fusiform, stellate, or branching. Sometimes they exhibit an arrowhead morphology. They are crowded into more or less narrow spaces and do not lie as loosely distributed as do those of the xanthelasma or the xanthoma of internal organs. There is, in short, nothing granulomatous about their appearance. The dense radiat- ing collagenous stroma, with its ‘(curly ” appearance, suggests a neurogenic origin, though the presence of vacuolated cells in the meshes of this rete has apparently diverted our attention from this similarity. FIG.1. NERVEFIERIL-S COURSING IN A TRABECULAOF A XANTECJMA Modified Ramon y Cajal silver impregnation. X 590 Struck by this fact, I subjected several of these tumors to a modification of the Ramon y Cajal silver method of block impregnation, superimposing a Masson-Goldner trichrome stain upon this in the paraffin sections (Foot, 3). The results seemingly justify the experiment, for it was found that non-medul- lated neurofibrils are readily demonstrable. They course in the trabeculae of the stroma either singly or in bundles (Figs. 1-3). They are almost invari- ably devoid of myelin sheaths. Occasionally they appear to enter the cell nests, there to be lost without forming definite bulbs, loops, or other endings. There are usually several large trunks of myelinated nerves at the base of the tumor, which penetrate the trabeculae, lose their sheaths, and continue along the septa toward the skin, where they ramify beneath the epidermis and be- come sparsely distributed. In one tumor examined (Fig. 4) there was found, overlying the xanthom- atous lesion, a well developed melanoma, which did not differ materially FIG. 2. Two BUNDLES OF SIMILARFIBRILS IN TRABECULAEOF ANOTHER XANTHOMA One, seen at the top of the picture, is cut transversely; the other, below and to the right, is cut longitudinally and is less clearly distinguishable from the stroma. Both are marked with arrows. Modified Ramon y Cajal technic. X 110 FIG. 3. A V-SHAPED BRANCHINGBUNDLE OF NEUROFIBRILSIN THE MORESUPERFICIAL PORTIONS OF A XANTHOMA,LYING JUST BENEATHTHE EPIDERMISAND ENCLOSINGIN THEIR SECTOR SEVERALFOAM CELLS, WITH WHICHTHEY ARE IN DIRECTCONTIGUITY Modified Ramon y Cajal technic. X 2,200 42 7 42 8 N. CHANDLER FOOT from the ordinary pigmented nevus. The cells of its deeper portions became merged with the vacuolated cells of the more deeply situated xanthoma. Not only do the xanthoma and melanoma show a similarity in the presence and distribution of neurofibrils, but it is also true that Meissner corpuscles cannot be demonstrated in either. Apparently the cells destined to form these are diverted from the derma to the tumor and never completely differentiate. Another point of similarity that should be stressed is the presence, in both groups, of pigmented melanophores, possibly also of melanoblasts. They are found wandering in the connective-tissue septa of the xanthomas and some- times sharing the rete spaces with the foam cells. Occasionally there are multinucleated giant cells, with or without contained pigment (Fig. 4). The presence of these melanophores may impart a distinctly brownish color to the integument overlying the tumor, in the total absence of any true melanomatous tissue. Such a xanthoma recently came under our observation. The clinical and gross pathological diagnosis was ‘‘ pigmented nevus ” until the sections were examined under the microscope, when it was found that the entire growth was composed of the coarse reticulated stroma and foam cells we have been discussing, plus many melanophores in the stroma. Block impregnations were made of cutaneous tumors of a number of other types : fibromas, angiornas, fibrosarcomas, hair-matrix or basal-cell carcino- mas, and neurogenic subcutaneous sarcomas. No considerable number of neurofibrils could be demonstrated in any of these save the last-named, which showed bundles and fibrils exactly similar to those just described (Fig. 5). The normal nerve fibers that might be expected in any piece of skin were naturally present, but only the xanthomas and neurogenic sarcomas showed these abundantly. It is therefore not amiss to suggest that, in this form of xanthoma, we are dealing with a tumor that has a philogenetic position intermediate between that of the melanoma, which is terminal on the nerves, and the lemmoma and neurofibroma, which may occur along their course. The xanthoma might be said to have a “ subterminal ” position on the peripheral nervous tree. With this hypothesis in view, the vacuolated cells of the growth immediately sug- gest units of the sheath of Schwann, which are normally vacuolated and con- tain lipids. They would then differ materially from mere “ lipophages ” or histiocytes, both in their origin and their morphology. That the latter is ma- terially different has already been indicated. The frequent association of xanthomas with melanomas and the gradual merging of the one into the other would then be readily comprehensible, as the type cell would, in each case, be a modified Schwann cell. The distribution of these cells along the perivascular spaces has misled at least one author into believing them to be embryonal fat cells, but this distribution is often seen in the case of melanomas and, with ap- propriate technic, they may be seen to follow nerve fibers that course along with the vessels. That such tumors have malignant analogues is indicated by such growths as that shown in Fig. 5. Here the vacuolated cells are replaced by less ma- ture fusiform components that resemble fibroblasts and may or may not show vacuolization. Thus the innocent members of the group show foam cells that lie in the meshes of a dense collagenous network, while the malignant varieties FIG.4. A FIELDSHOWING MELANOMATOUS AND XANTHOMATOUSFORMS OF GROWTH The small cells in the alveoli are pigmented and a pigmented giant cell is seen in the upper left corner. Note the stellate arrangement of the fibrous stroma, characteristic of fibroxanthoma. Masson-Goldner technic. X 110 FIG. 5. BUNDLEOF NEUROFIBRILLAEIN A NEUROGENICSARCOMA OF THE SKIN The apparent myelin sheaths are a result of the different focal planes, in reality other fibrils just out of focus. These are really non-myelinated fibrils. Modified Ramon y Cajal technic. X 530 429 430 N. CHANDLER FOOT have exactly the same general topography, though the type cells are denser and smaller, and tend to be fusiform. The less malignant lesions are usually slowly growing and may not show many mitotic figures. It is well known that these ‘‘ sarcomas ” tend to recur after removal and, with each recurrence, to assume more and more the characteristics of a true malignant sarcoma. Ap- parent transitions are sometimes seen from the non-malignant to the malignant form, with many bloated, irregular tumor giant-cell forms among the more typical foam cells. It should be understood that the presence of nerve fibrils in these tumors is taken to indicate their connection with nervous tissue; that these nerves are, however, a very active constituent of the neoplasm is questionable.

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