Giant-cell reactions in the connective tissue septa of ameloblastomas Jochanan DEPARTMENTS PITTSBURGH
II. ROSS, M.D.,’ OF SCHOOL
Pittsburgh,
PATHOLOGY,
E.
H.
Pa. i!lAGE:E
HOSI’ITAL
AND
1:SIVERSITY
OF
OF MEDICIXE
I
n recent years many intriguing problems involving the odontogcnic tumors have been solved.l-’ The most frequently encountered neoplasm of this group is the ameloblastoma. Although there are a number of histologic variations in its pattern, the one characteristic feature common to the vast majority of cases is the palisading of the outer cells and the loose arrangement of the inner cells of the tumor sheets, nests, and strands. Foreign-body giant-cell reactions in the supporting connective tissue of an ameloblastoma” and of craniopharyngiomas!’ have been described. Since then we have observed two addit,ional cases of giantcell reactions in ameloblastomas. It, is the purpose of this article to report on this process and to discuss its biologic implications. CASE MATERIAL Case
1t
An ameloblastoma, measuring 2 by 1 s by 1 cm., wax csriscd from the right of a 13.year-old boy. One and one-half years after the operation the tumor recurred, round monocystic mass about 1.0 cm. in diannker was rm~oved. Case 2 A 5%year-old right. mandible. was excised.
At
man was admitted with a large swelling operation, a whitish, firm, solid mass,
Case 3 A 63-year-old man had undergone curring amelohlastoma. On examination, formed hy numerous partly confluent Supported in part by Public Health *Research Instructor, Department Medicine. tThis ease was previously reported
70
of many manuring
maxilla and a
years’ duration in the 41/1_, l>y 31/2 by 2 cm.
several operations for removal of an obstinately rcthe left lower half of the face vvas found to he demasses extending from the mandible to ahout three Service Grant of Pathology, in detail
#H-6991. University
elsewhere.8
of
Pittshurgh
School
of
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Fig. 1. Case 1. “Ghost cells” engulfed by foreign-body giant cells. contain the shadows of nuclei. (Hematoxylin and eosin stain. Magnification, l/lo.) (From Boss, J. H.: A. M. A. Arch. Path., September, 1959.)
fingerbreadths graphically, noted. The the involved
The
71
“ghost rells” x.360; reduced
above the clavicle. Small subcutaneous nodules were also palpated. Roentgenoextensive bone destruction of the left mandible and a pathologic fracture were left. mandible was resected, together with the extraosseous tumor masses and skin.
HISTOLOGIC FEATURES The diagnosis of ameloblastoma in each of these cases was based on the pathognomonic histologic findings of this neoplasm : epithelial sheets, nests, and strands composed of a central core of loosely arranged cells in a reticulated pattern and a peripheral layer of palisading cuboidal to columnar cells (Figs. 2 and 3). In Case 2 adenomatoid and microcystic formations were scattered in large numbers within the reticulated epithelium; the lumina were partly empty and partly filled with an amorphous eosinophilic material. In Cases 1 and 2 there was abundant transformation of neoplastic cells of the reticulated epithelium into so-called “ghost cells.” The latter appeared as lightly eosinophilic, finely granulated, and distinctly bordered clods, each containing the shadow of a nucleus. They were grouped into aggregates, some consisting of only two or three “ghost cells” (Fig. l), while others were comprised of a multitude of such cells, often revealing concentric layering suggestive of growth by peripheral apposition (Figs. 2 and 3). A few “ghost cells” were calcified, as demonstrated by a hematoxyphilic, von Kossa-posit,ive granulation. With the peracetic acid-azure-eosin technique for keratin,l’ the “ghost cells” were stained bluish violet with sparing of unstained small round areas corresponding with the shadows of the nuclei; the reaction was not abolished by methylation. In many places the “ghost cell” aggregates were denuded of the surrounding reticulated epithelium, so that they came into direct contact with the connective
Fig.
3.
Pig. 8’. Case 2. A vaseularized connective tissue septum separating two sheets of t UIIIOI'. Note the palisading of the peripheral columnar cells and the reticulated pattern of the more central cells. Adenomatoid and microcystic formations are present within the reticc dated epithelium. Tn t,he upper half of the photograph are two large aggregates of “ghost ( :ells,” a few of which are calcified. (Hcmatoxplin and eosin stain. Magnification, x80; reduced l/o. ) Fig. 3. Case 2. Histiocytic and giant-cell reaction around an aggregate of “ghost ( dls.” There is a tendency toward concentric layering of the “ghost cells.” (Hematoxylin and eosin stain. Magnification, x190; reduced I,&.)
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Fig. 4. Case 3. Giant-cell stroma adjacent to ameloblastic tissue (lower right-hand porl iion of photograph). The giant cells are scattered among spindle-shaped to ovoid stromal cc3llS. Nc )te the close spatial relationship of the giant cells to the thin-walled blood vessels and the exl travasated red blood cells. (Hematoxylin and eosin stain. Magnification x190; reduced 4 $0.) Fig. 5. Case 3. Undifferentiated amelohlastic tissue (lower half of photograph) and I new in the adjacent connective tissue septum. The hone spicules are surroun ded b0 ne formation (Hematoxylin and eosin stain. Magnification, x40; reduced l/lo.) l)Y osteoclasts.
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tissue of the tumor septa. Here the “ghost cells” were surrounded by hist,iocytes and giant cells. Occasionally giant ~011sclngulfed a small group of ‘ *ghost cells” (Fig. 1). Where larger “ghost ~11” conglomerates had been formed, the giant cells were found only at the periphery of the aggregates (Fig. 3). In Cases 2 and 3, in which the ameloblastoma had caused extensive bone destruction, a different kind of giant-cell reaction from t,hat just described had taken place. Whereas, generally, the septa of an ameloblastoma consist of vascularized connective tissue (Fig. 2), in each of these two cases the latter was replaced by a giant-cell stro1na.l” This was characterized by the admixture of spindle-shaped to ovoid stromal cells” and multinucleated giant cells, the latter often showing a conspicuous spatial relationship to sinusoidal blood vessels (Fig. 4). The nuclei of both stromal and giant cells were round to oval and vesicular, and they often contained distinct nucleoli. The abundant cytoplasm of the giant cells was opaque, and their nuclei tended t,o crowd centrally. In some places extravasated red blood cells were present among the stromal cells. It seemedsignificant that in Case 3 this type of giant-cell reaction was strictly limited to the intramandibular tumor portion, while the extraosseous portion of the tumor revealed the usual picture of connective tissue septa. Case 3 exemplifies the semimalignant course which amelobastomas occasionally take. Whereas the cxtramandibular tumor tissue exhibited the typical features of ameloblastoma, some intramandibular tumor she&s and nests were composed of undifferentiated cells. In the latter localization only, there was also moderate mitotic activity. In the intramandibular portion, osteoid and immature bone were laid down within the connective tissue septa in proximity to, as well as away from, the tumor tissue (Fig. 5). Ostcoclasts were present around many of these bone spicules. Cytologically, the osteoclasts and the multinucleated cells of the giant-cell stroma, as illustrated in Fig. 4, were indistinguishable. It was only their relationship to t,he bony spiculcs or their admixture with the stromal cells that made such a distinction possible. DISCUSSION
Three different types of giant-cell reaction occurring in the septal connective tissue of ameloblastomas have been described. As will be elaborated, these were a foreign-body, a reparative-granulomatous, and an osteoclastic reaction. The occurrence of “ghost cells, ” with and without, calcification, in ameloblastomas has been mentioned previously by Thoma and Goldman’ and by Robinson.13 The morphologic features, tinctorial behavior, and dystrophic calcification of these cells make it highly probable that they arc the product of a special form of aberrant keratinization of the neoplastic epithelial cclls.S Apparently, the “ghost cells” are biologically a “foreign” element, and the process which they elicit (that is, the histiocytic and giant-cell reaction) seemsto represent a foreign-body reaction. The second type of giant,-cell reaction, which is characterized by the admixture of the multinucleated cells and the so-called stromal cells,‘” corresponds histologically and functionally with the central reparative granuloma of bonc.14 This is elicited by various lesions causing bone damage; in the cases described
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here, it was brought about by the invasion of bone substance by the ameloblastoma. The derivation of the multinucleated cells of the giant-cell reparative granuloma, as well as those of the giant-cell tumor of bone (osteoclastoma) and the epulis, is unknown. Five hypotheses can be put forward : (1) The giant cells are an integral part of the lesion, developing through fusion of a number of stromal cells. (2) The giant cells differentiate from multipotent endosteal or periosteal cells stimulated to proliferation by as yet poorly understood irritative processes. (3) The giant cells are of endothelial origin; hence, their close relation to blood vessels. (4) The giant cells are reactive to the interstitial hemorrhages which are commonly seen in these lesions. (5) The giant cells are osteoclasts. The third giant-cell type is the osteoclast, as is apparent from its relationship to the bony spicules. The osteoclast is cytologically indistinguishable from the multinucleated cells of the three giant-cell lesions mentioned above. The long-continued polemic about the identity or nonidentity of the osteoclasts on the one hand and the giant cells of the reparative granuloma, epulis, and giantcell tumor on the other hand is well known. Because of the morphologic and histochemical similarities of these cells, Peplerl” concluded that the epulis is the peripheral counterpart of the osteoclastoma. Our studies, however, led us to believe -that the epulis is reparative-granulomatous in nature.” Kegardless of this more academic controversy over the classification and origin of these giant cells, it seems advantageous for the time being to separate them on the basis of histologic rather than cytologic characteristics as osteoclasts or as an integral part of a reparative granuloma or giant-cell tumor of bone. There are a number of neoplastic and nonneoplastic conditions of bone in which giant cells of different biologic significance are a characteristic finding.” Among these, the reparative granuloma is apparently a specific reactive process of the bone caused by many different lesions associated with bone destruction. Its development has even been reported after extraction of a tooth or in association with an impacted tooth.16 In the present Cases 2 and 3 it is believed that a reactive process, whereby the stroma is transformed into a reparative-granulomatous tissue, has taken place secondary to bone damage by the ameloblastoma. We have observed this phenomenon of reparative-granulomatous transformation of the tumor septa in a benign lymphangioma of the hard palate and in a metastatic adenocarcinoma of the mandible. I1 The term giant-cell stroma is most aptly applied to the supporting connective tissue of a tumor thus transformed. New bone formation and, at the same time, marked osteoclastic activity are not uncommonly associated with bone destruction resulting from a primary or metastatic lesion. This process, observed in Case 3, is well illustrated in Fig. 5. SUMMARY Three cases of ameloblastoma in which three biologically different types of giant cell were present in the connective tissue stroma are described : (1) foreignbody giant cells reactive to aberrant keratinization of neoplastic cells forming so-called “ghost cells”; (2) giant cells as an integral component of a reparativegranulomatous transformation of the connective tissue septa; and (3) osteoclasts resorbing bone spicules newly formed in the connective tissue stroma.
76 noss
O.S., O.M. .Tnly,
& O.P. 1964
Am.
.J. Path.
22:
Ortar,
Msu.
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