P myxomas (M) in 1948, the literature contained

Transcription

1 A COMPARATIVE STUDY INCLUDING ULTRASTRUCTURE OF INTRAMUSCULAR MYXOMA AND MYXOID LIPOSARCOMA PHILIP S. FELDMAN, MD* The clinicopathological data of ten intramuscular myxomas (IMM) and three myxoid liposarcomas (MLS) are presented with emphasis on their ultrastructure. Electron microscopy of three of the IMM demonstrated the principal cell of the IMM to be similar to a fibroblast with prominent R.E.R., welldeveloped Golgi apparatus and cytoplasmic filaments. Intracytoplasmic lipid droplets were very rare. The matrix was composed of finely granular material, collagen fibers, fibrils and few capillaries. In contrast with the IMM, the cytoplasm of the MLS contained extensive lipid droplets. Capillaries were very abundant and in close proximity to the lipoblasts. The distinction between an IMM and MLS is usually clear-cut by light microscopy. Dissimilar ultrastructural features provide additional data to separate these two tumors. Ultrastructure confirmed Enzinger s impression that the cell of origin of the IMM is similar to a fibroblast with features that support the hypothesis that these cells are the source of production of the excessive amount of mucopolysaccharides in the matrix. Cancer 43: , RIOR TO STOUT S comprehensive study of P myxomas (M) in 1948, the literature contained relatively few single case reports of this entity.2s Stout described his personal experience with 49 cases of M and 95 M (exclusive of M from the heart) collected from the literature. Twenty-five of his 49 M were located in the subcutaneous and aponeurotic tissues. He culled four examples of intramuscular myxoma (IMM) from the literature, and only one of his own M was intramuscular in location.2s In contrast, Enzinger reviewed the soft tissue M from the files of the Armed Forces Institute of Pathology and reported thirtyfour cases of IMM.5 He noted that almost one out of every six soft tissue M were located principally in muscle. Subsequently, several large series of IMM have been reported with emphasis on the clinical course, histochemistry, gross and light microscopic features. 13,16,23 From the Department of Pathology, University of Virginia, School of Medicine, Charlottesville, Virginia. * Associate Professor. Address for reprints: Philip S. Feldman, MD, Department of Pathology, University of Virginia. School of Medicine, Box 2 14, Charlottesville, VA The author thanks Dr. Lauren V. Ackerman and Dr. Walter C. Bauer for making pathological material available for this study and providing valuable suggestions. Accepted for publication April 28, )3-79/0200/05 12 $ American Cancer Society 512 Although the ultrastructural features of cardiac myxomas have been well documented, there has only been one ultrastructural report of soft tissue myxomas by Leung et al. and that was in the French literature. The present investigation reviews the findings of ten IMM with emphasis on the ultrastructural features of three cases. The distinction between IMM and myxoid variants of soft tissue sarcomas at times poses a diagnostic problem. MLS is the most frequent type of sarcoma confused with an IMM.5 I therefore examined three cases of MLS by EM and compared these findings with those of the IMM.6 In addition, tumor samples from 2 IMM and 2 MLS were retrieved from paraffin blocks and examined by electron microscopy to determine if ultrastructural features would enable separation of these tumors. MATERIALS AND METHODS Tissue for light microscopy was fixed in 10% neutral formalin. Paraffin embedded sections in all cases were stained by hematoxylin and eosin (H & E), periodic acid Schiff (PAS) with and without diastase, Gomori reticulin, alcian blue (ph 1.0 and 2.5), Mayer s mucicarmine, colloidal iron, Masson s trichrome and aldehyde fuchsin. In conjunction with the alcian blue and colloi-

2 ~~~ No. 2 IMMAND MLS Feldman 513 TABLE 1. Clinical Data of 10 Intramuscular Myxomas Case no. Age Sex Race Anatomic location Size Duration 1 31 F 2 66 M 3 55 M 4 59 F 5 35 M 6 44 M 7 62 F 8 74 M 9 51 M ~~ Caucasian (C) C C C C C C C F C Thigh, left Groin Finger, left Calf, right Thigh, right Distal upper arm, right Posterior neck, left Hand, thenar region, left Midback, left Thigh, right 5.5 x 4 x 3 cm (50 gm) 3.3 x 1.8 x 1.2 cm 2 x 1.5 x 1 cm 5x3cm 8 x 5 X 4.5 cm 3 ~ 2 x l c m 3 cm 1 month 2 months 2 months 2% years 10 years considerable period of time dal iron stains, sections were pretreated with bovine testicular hyaluronidase. Frozen-tissue sections were also made and stained with Oil Red 0 (ORO). Tissue for electron microscopy was fixed in 2.5% glutaraldehyde solution, postfixed in 1 % osmium tetroxide, dehydrated in graded ethanols, embedded in Epon 812 and cut on a Porter-Blum MT-2 Microtome. Sections were stained with uranyl acetate and lead citrate and studied with a Philips 300 and Hitachi HU-IIE-S electron microscopes. Tumor samples from 2 IMM and 2 MLS were retrieved from paraffin blocks by softening the blocks in the oven at 60 C for 5-10 minutes and then cutting out the areas of interest. The paraffin was then dissolved out in xylene and tissue passed through graded ethanols and finally water. The tissue was then fixed in 2.5% glutaraldehyde solution overnight and then processed in the same manner described above for fine structural studies. The clinical record of each patient was reviewed and follow-up data were obtained. RESULTS Intramuscular Myxomas Clinical Data: Pertinent clinical information is summarized in Table 1. Age, Sex and Race: At the time of histologic diagnosis, the ten IMM were in adults between 31 and 74 years with a mean of 52.7 years. Of the ten IMM, six occurred in men and four in women. Nine of the patients were Caucasian and the race was unknown in the tenth case. Signs and Symptoms: The clinical manifestations were not specific and in none of these IMM was the tumor correctly diagnosed prior to histologic examination. The majority of these patients presented with a painless palpable mass as the major symptom. The interval from apparent clinical detection and excision varied considerably, ranging from one month to ten years. In several patients, the duration of the IMM was unknown. There was no relation between the size of the IMM and its duration, e.g., one of the tumors noticed only one month before excision measured 5.5 cm, whereas another IMM present for ten years measured only 3 cm. Anatomic Site: Table 2 summarizes the anatomic distribution of the ten IMM. In the majority of cases the tumor originated in the thigh (3) or upper extremity (2 hand, 1 arm) with isolated cases in other sites. Gross Findings: The gross appearance was very similar in all ten IMM. The tumors were oval or spherical masses with a glistening mucoid appearance and were surrounded by skeletal muscle (Fig. 1). They were white to translucent grey and composed of gelatinous material. They were all well-circumscribed but closer inspection demonstrated an incomplete fibrous capsule with infiltration of the adjacent muscle. There was, therefore, a false TABLE 2. Anatomic Distribution of Intramuscular Myxomas ~~ ~ Location No. of cases Thigh 3* Hand 2* Neck 1 Calf 1 Upper arm 1 Back 1* Groin 1 TOTAL 10 * Studied by electron microscopy

3 514 CANCER February 1979 VOl. 43 Frc. 1. Gross appearance two IMM (A-arm, B-thigh) which on section were gelatinous, grey-white and mucinous. impression that these tumors were encapsulated. On cut section small cystic spaces filled with sticky slimy material were present in three egises. 'There were no areas of calcification, necrosis, or hemorrhage. The size varied and ranged from 2.0 cm to 8.0 cm in greatest dimension (Table 1). Light Microscopic Findings: The ten IMM were histologically similar varying primarily in the proportion of the two major components, cells and intercellular mucoid stroma. This ratio was not qnly different in different IMM but also in different regions of the same tumor. The H SC E stained sections of the ten IMM showed a predominance of an amorphous acidophilic stronia which was the most striking microscopic feature of these tumors. Enmeshed within this myxoid stroma were scattered tumor cells (Fig. 2). The cellular elements consisted of scattered stellate, round or spindle shaped cells. There was no tendency for these cells to arrange in groups. The nuclei were infrequently vacuolated and devoid of mitotic figures or nucleoli. The cytoplasmic boundaries were indistinct and poorly outlined. Cytoplasmic processes were prominent and appeared to run along adjacent reticulin fibers. Although the cytoplasm in occasional cells was vacuolated, no inclusion bodies were found. Intracytoplasmic staining of these vacuoles by alcian blue was seen focally and was prevented by pretreatment TABLE 3. Ultrastructural Findings of Intramuscular Myxomas and Myxoid Liposarcomas Intramuscular myxomas Myxoid liposarcomas Ultrastructural findings J.Y. B.B J.D. B.S. U.S. M.L. Nucleus Elongated, Elongated, Elongated, Irregular shape and comirregular irregular irregular pressed by lipid vacuoles Nucleoli t Rough endoplasmic reticulum Centrioles Smooth E.R Free ribosomes Filaments i Lysosome-like bodies i Glycogen Lipid droplets Pinocytotic vesicles Secretory vesicles i Golgi complex Mitochondria Basement membrane Junctional complex Matrix: Finely distributed electron dense granules Collagen fibersifibrils Vessels '' i absent; -few; ++-moderate; +++-abundant; ++++-very numerous.

4 No. 2 IMM AND MIS. Feldnim 515 c FIG. 2. IMM composed of stellate, round or spindle shaped cells enmeshed within a myxoid stroma with rare blood vessels (X 1,000). * * t 0 u c r 0 with hyaluronidase. An irregular meshwork of delicate reticulin fibers was spread in the matrix with no particular relationship to the cells. A zonal structure of the IMM was not present as described by Glazunov and P~chkov.~ The matrix of all ten IMM stained positively with alcian blue and colloidal iron. The reaction was almost completely prevented by pretreatment with hyaluronidase. The intensity of these stains varied slightly from case to case and within different regions of the same tumor. The aldehyde-fuchsin and OR0 stains yielded negative results. At the periphery of the tumor were scattered muscle giant cells and atrophic muscle fibers. No skeletal muscle fibers were present within the substance of the IMM. The vascular component of these tumors was minimal and small blood vessels were widely scattered in the stroma. Electron Microdcopic Findingd: The ultrastructural features in the 3 IMM studies were similar (Table 3). The tumors were composed largely of amorphous material of low electron density with scattered fine granules of high electron density. Focally there were numerous fibrils and fibers exhibiting morphologic characteristics of collagen with 640 A cross- banding. Vessels were few in number and difficult to find. Tumor cells were arranged singly or in small groups but not closely apposed (Fig. 3). The nuclei were oval or elongated and irregular with a moderate number of nucleoli. The cytoplasmic organelles were unevenly distributed. The rough surfaced endoplasmic reticulum (RER) was abundant and frequently dilated (Figs, 3-5). Smooth surfaced endoplasmic reticulum profiles were not identified. Mitochondria were present in small numbers. The Golgi complexes were well developed (Fig. 5). Numerous cytoplasmic microfilaments were the most striking feature in all three cases. They were usually arranged in parallel bundles in a wavy pattern and did not show periodicity (Figs. 4, 6). An interesting feature was that many of these filaments were essentially identical with the stroma fibrils which frequently were in close juxtaposition to the cells (Fig. 7). In addition, fibers exhibiting the same morphologic characteristics of stromal collagen were noted in a few cells. Dense bodies were not present in these cells. Pinocytotic vesicles were numerous in all three cases. Centrioles (Fig. 5) were abundant in the three IMM and a solitary cilium was present in one

5 516 CANCER F~hruary 1979 Vol. 43 FIG. 3. Elongated hl cells with abundant K.E.R. in an amorphouh matrix of low electron density and scattered collagen fibers (X 1,950). Insct: Cilium with basal body and central filwils (~38,000). case. This cilium did not appear to be rudimentary since central and peripheral fibrils were present (Fig. 3). Intermediate stages in the fashioning of a cilium from a centriole were not encountered. The tumor cells were not delineated by a basement membrane. Treatment and Folloui-up: The extent of excision of the 10 IMM varied from enucleation to simple or wide local excision with a margin of the surrounding skeletal muscle. The following are the results of treatment: 1) 4 patients have been followed 5 years or longer with no recurrences; 2) 6 patients have been followed for less than 5 years (2 patients-4 years, 2 patients-3 years, 2 patients-2 years) with no recurrences. Myxoid Liposarcoma Clinirnl Findings: The three MLS were in Caucasian males of 19 years, 25 years and 30 years of age at the time of histologic diagnosis. The MLS originated in the thigh in 2 cases and popliteal fossa in one case. All three MLS presented with the chief complaint of a painless mass. The interval from clinical detection to surgery ranged from 1 month to 3 months.

6 No. 2 IMM AND MIAS * Feldmnn 517 FIG. 4. M cell with prominent R.E.R., filaments arid well-developed Golgi complex (X20.000). Inset: illustrates filaments under higher magnification ( x 38,000).

7 518 CANCER February 1979 Vol. 43 FIG. 5. M cell with well developed Golgi complexes, R.E.R. and centrioles (X 16,000) Gross Findings: The gross appearance was similar in the three MLS. The size varied and ranged from 3.0 cm to 8.0 cm in greatest dimension. On section, the MLS were glistening, mucoid, grey-white and gelatinous (Fig. 8). Small satellite nodules adjacent to the main tumor mass were present in one case and proved the initial impression of encapsulation to be false. Light Microscopic Findings: The three MLS presented a uniform histologic appearance and were composed of three elements: 1) lipoblasts; 2) capillaries with a prominent plexiform arrangement; and 3) a myxoid matrix (Fig. 9). The rich vascular network was easily seen with H & E section and was further emphasized by a Gomori reticulin stain. The matrix stained strongly with the alcian blue stain; this reaction was almost completely prevented by pretreatment with hyaluronidase. Thus, all 3 MLS contained large amounts of an acid mucopolysaccharide (AMP). The AMP was largely located extracellularly, but was focally present in the cytoplasm of lipoblasts. In focal regions the extracellular material formed lakes between cells and gave the tumor a lacelike pattern. The lipoblasts were stellate to irregular in shape with indistinct cell boundaries; however, the reticulin stain demonstrated fine argyrophilic processes producing a pseudosyncytial arrangement of these cells. Lipid droplets were focally present in the cytoplasm and displaced the nuclei to the periphery of the cell. An OR0 stain on frozen sections helped demonstrate abundant intracytoplasmic lipid. Large multivacuolated lipoblasts, giant cells and mitoses were not seen. No capsule separated the MLS from the adjacent soft tissue. Electron Microscopic Findings: The ultrastructural features in the three MLS were similar (Table 3). The three most striking fea-

8 No. 2 IMM AND MLS Feldman 5 19 FIG. 6. Numerous cytoplasmic filaments arranged in parallel bundles with a wavy pattern (~8,000). tures were 1) prominent lipid droplets within the lipoblasts; 2) the vascular component; and 3) the abundant matrix. Lipid droplets occupied most of the cytoplasm and were homogeneously opaque and frequently bound by a limiting membrane. Occasionally no membrane was present separating the droplets from the other cytoplasmic organelles (Fig. 10). The lipid droplets varied in size and compressed the peripherally positioned nucleus into irregular shapes (Fig. 10). Nucleoli were occasionally evident. Cytoplasmic organelles in the thin rim of cytoplasm not occupied by the lipid droplets consisted of glycogen, mitochondria, and smooth endoplasmic reticulum. Pinocytotic vesicles, Golgi apparatus and lysosomes were rare. Free ribosomes were occasionally present. Cytoplasmic filaments were rare and present in only one of the three MLS. Junctional complexes and basal lamina material were absent. Lipoblasts were frequently found in juxtaposition to capillaries which were numerous (Fig. ll). There was no evidence of intracellular viral particles. The matrix consisted of amorphous material of low electron density within which were scant microfibrils, collagen fibers and small granules of high electron density. Treatment and Follow-up: One MLS was treated by wide excision and has not developed a local recurrence or metastases six years following surgery. One was treated by local excision and three years after surgery developed metastatic MLS in bone and the extradural region about T4 with a complete block on the myelogram. He presented at our hospital with lower extremity numbness and had nearly complete bilateral loss of motor and sensory functions in his lower extremities. The other patient with a MLS was treated initially by enucleation. Since the MLS involved the surgical margin, additional surgery with wide excision was performed and he has not yet developed a recurrence, but the follow-up since surgery is only 26 months. DISCUSSION In 1863, Virchow used the term myxomata to describe a group of tumors which histologically resembled the structure of the

9 520 CANCER February 1979 Vol. 43 FIG. 7. Cytoplasmic filaments closely resembled strornal fibrils which were in close juxtaposition to the cells (X 14,500). human umbilical Although he noted variations in the patterns of these tumors, he recognized one type that remained a definite entity and did not differentiate into any other histologic variety. Unfortunately, Virchow s concept of M as an independent tumor was lost because diverse mesenchymal tumors which contain myxoid elements were erroneously diagnosed as M and vice versa. The necessity of establishing diagnostic criteria for M was recognized by Stout, who presented the first extensive review of M in He defined M as true neoplasms of mesenchymal origin composed of stellate cells in a loose mucoid stroma which closely resembled primitive mesenchyme.... there must be no recognizable differentiated elements, e.g., rhabdomyoblasts, etc. 28 Stout s definition of M is widely accepted and used and has helped clarify the previously chaotic situation amongst clinicians and pathologists concerning the nature of M. Stout and Enzinger pointed out that the difficulty in diagnosing M resided in the confusion caused by myxomatous degeneration present in mesenchymal tumors of diverse histologic type (e.g., MLS, extraskeletal myxoid chondrosarcoma, myxoid variant of malignant fibrous histiocytoma, etc.) which could be mistaken for a M.5*28,31 This question is of more than academic importance, for the diagnosis has considerable bearing on the choice of treatment. This problem is exemplified in eight of the 34 IMM in Enzinger s series. All eight were initially regarded as malignant, and four treated by radical ~urgery.~ Conversely, sarcomas have been mistaken for myxomas.2, 6 Kindbloni el al. noted 2 MLS that were earlier misinterpreted as M.16 Canalis et (11. reviewed myxornatous lesions at UCLA Medical Center and also found six sarcomas that were initially diagnosed as M. The distinction between an IMM and MLS, which is the most common type of sarcoma con-

10 No. 2 IMM AND MLS * Feldman 52 1 fused with a M,5 at times still poses a diagnostic problem. For example, five of our ten IMM were submitted to Dr. Lauren V. Ackerman and Barnes Hospital for consultation and two of the referring pathologists favored the diagnosis of MLS. Angiography is the greatest single aid in the preoperative diagnosis of an IMM since it demonstrates a poorly vascularized tumor in contrast with the high vascularity found in MLS.16 But an accurate preoperative diagnosis is infrequently made because clinical features of IMM and MLS, such as age range and sex, are similar and nonspecific with considerable overlap. Both MLS and IMM are tumors of adult life and are exceedingly rare in ~hildren.~,~,~,'~ The IMM have a wide age range but are most frequent between years.13 Several series of IMM show the mean age to vary from 42.8 to 57.5 years.i3 The mean age in our 10 IMM was 52.7 years. The MLS tend to occur in younger people than the IMM. One-half of the patients with MLS in the lower extremity observed by Enzinger were less than 42 years of age with a median of 39 years4 MLS are slightly more prevalent in male^.'^*^^ However, the FIG. 8. Gross appearance of a MLS (Thigh) which on section was glistening, gelatinous and grey-white. sex predilection in IMM is less clear although several studies note that IMM are slightly more frequent in females.5*10~16~23 Our series demonstrated no significant sex predilection with 6 IMM in men and 4 in women. The most frequent symptom in both IMM and MLS is a painless palpable mass. Therefore, this symptom is not useful in differentiating these two neoplasm^.^*^*'^^'^^^^ The anatomic distribution in soft tissue in FIG. 9. MLS composed of lipoblasts, myxoid matrix and plexiform capillary pattern ( x 1,000).

11 522 CANCER February 1979 Vol. 43 FIG. 10. Lipoblasts \\hose cytoplasm was occupied mostly by lipid droplets which compressed the peripherally placed nucleus into irregular shapes (X 7,800). both MLS and IMM is similar; both occur most frequently in the thigh.4,5,16,23 Separation of a M from a MLS by the gross appearance is fraught with error since they share many features: frequent location in the thigh, grey-white, mucoid and glistening cut surface. Yet notable differences exist. The MLS not infrequently have areas of normal yellow fat interspersed among the sarcomatous masses and may be focally hemorrhagic as a result of increased vascularity or hemor- rhage.27these features are absent in an IMM. Both the IMM and MIS may have more than one nodule, but multiple nodules are more frequent in MLS." Histologically, the IMM and MLS have distinct differences which allow these tumors to be separated. IMM are characterized by a paucity of vessels and are devoid of a plexiform capillary network, whereas MLS are richly vascular with a characteristic plexiform capillary att tern.^,^ The presence of multivacuolated lipoblasts which contain lipid demonstrable by the OR0 stain further aids in the distinction between a MLS and IMM since M cells give a negative reaction with this stain. Moreover, the cellular elements in an IMM consist of scattered stellate, round or spindle shaped cells which are infrequently vacuolated. The matrix of both the IMM and MLS stains positively with alcian blue and this reaction is completely altered by pretreatment with hyaluronidase. Thus the staining characteristics of the matrix in the MLS and IMM are similar and do not help differentiate these tumors. While the distinction between an IMM and MLS is usually clearcut by light microscopy, the ultrastructural features are also very dissimilar (Table 3), and provide additional evidence to help identify the lesion. Ultrastructurally the IMM were characterized by a scarcity of vessels and were largely composed of an amorphous material of low electron density within which were widely scattered tumor cells. The cytoplasm contained abundant R.E.R., a well-developed Golgi complex and numerous cytoplasm filaments. Lipid droplets were very rare in one case and absent in the other two. In contrast with the IMM, the cytoplasm of the MLS contained extensive lipid droplets which compressed the

12 No. 2 IMM AND MLS. Feldman 523 FIG. 11. Lipoblasts (L) in close juxtaposition to capillaries (C) with red blood cells ( x 1,950). nuclei into irregular shapes. Cytoplasmic organelles in the thin rim of cytoplasm not occupied by the lipid droplets were scanty. Capillaries were very abundant and in close proximity to the lipoblasts. The amorphous matrix of the MLS was similar to that of IMM except that there were fewer fibrils and collagen fibers in the MLS. Centrioles were numerous in the IMM but were not observed in the MLS. A solitary cilium was identified in one IMM. The presence of this cilium in a cell interpreted to be a fibroblast was initially perplexing. However, Sorokin and Schuster noted the formation of rudimentary cilia which lacked the two central fibrils in fibroblast~.~~,~~ They concluded that these cilia were nonmotile and perhaps had a sensory function. The fact that the cilium observed in our case appeared to contain the normal compliment of fibrils further complicates the question of the role of these rare cilia, and their function remains obscure. The tumor cells in the IMM resemble the principal cells in CM.7 Both of these tumors are characterized by cells enmeshed within abundant stroma composed of fine electron dense granules with scattered collagen fibers and fibrils. In CM the cells are tightly conjugated in small groups with interdigitating cytoplasmic processes which are not present in IMM. The cytoplasmic organelles are similar with numerous filaments, abundant R.E.R., well-developed Golgi complexes and pinocytotic vesicles present in both CM and IMM. On the other hand, centrioles, rare in CM, are abundant in IMM; and focal filamentous dense bodies are present in CM which are absent in IMM.7 Tumor samples from two IMM retrieved from paraffin blocks demonstrated preserved fine structural features with prominent R.E.R., numerous cytoplasmic filaments and paucity of vessels. The tumor samples from the MLS demonstrated little identifiable fat which has been dissolved out of the tissue in the prior processing for paraffin. However, the nuclei were irregular in shape and the spaces adjacent were consistent with the re-

13 524 CANCER February 1979 Vol. 43 gions of prior localization of the lipid droplets. There were very few filaments and R.E.R. in the cytoplasm. Capillaries were easily found in the stroma. These ultrastructural differences between the IMM and MLS were interpreted to be diagnostic, and it is therefore felt that in cases of diagnostic difficulty ultrastructure is indicated even if the only tissue available has been fixed in formaldehyde and embedded in paraffin. Separation of IMM from other benign mesenchymal tumors may at times be difficult, but is of less practical significance. Accumulation of acid mucopolysaccharides in benign lesions such as ganglia, neurofibromas, nodular fasciitis and lipoma may closely simulate the structure of a M and lead to diagnostic err01-s.~ Follow-up of our ten IMM demonstrated a benign clinical course with no recurrence. However, the follow-up was less than five years in six cases. The lack of recurrences and absence of metastases in our IMM substantiates the finding of a low rate of recurrence in earlier and negates the prediction by Stout of a high rate of recurrence with M.28,29 In striking contrast, M of the jaw, in some series, have a recurrence rate of approximately 25%.32,35 This aggressive feature, in addition to ultrastructural studies that demonstrated epithelial islands which possibly had developed from odontogenic epithelial rests, strongly suggests that M of the jaws is odontogenic in origin and distinct from soft tissue h1." This would also explain the high frequency of this intraosseous tumor in the jaw and the extraordinary rarity of myxomatous tumors of bone outside the facial ~keleton.~~.~~ Although the clinical, gross and light microscopic features of IMM are now recognized, the etiology of IMM is unknown. An infectious origin was suggested by Glazunov and Puckov who postulated a viral origin on the basis of demonstrated nuclear and cytoplasmic inclusions reminiscent of those seen in Shope's infectious fibroma and Sanarelli's infectious myxomato~is.~ However, all subsequent studies of IMM have failed to demon- sequently devel~ped.~.'~ However, the majority of patients reported denied or made no mention of antecedent tra~ma.~*'~*~~ There was no history of previous trauma in our 10 IMM. Although there is no evidence of an hereditary or familial pattern in IMM, a review of the literature by Wirth et al. revealed 9 cases of IMh4 associated with polyostotic fibrous dysplasia (FD) which raised the question of a genetic relationship between these 2 lesions.33 They described 2 cases of their own and noted that, although the histogenesis of these 2 conditions was obscure, their association was more than a mere coincidence. They thus favored a common histogenesis, and proposed that a basic error in tissue metabolism was responsible for these 2 condition^.^^ Similarly, some basic genetic defect arising at an early stage of embryogenesis has been postulated as responsible for Albright's syndrome with its multisystem involvement including FD.' A search for evidence of bone disease in our cases was unrewarding. This is not surprising, because 1) FD usually occurs considerably earlier than IMMI3a3l and, therefore, we would have expected FD to already be manifest, and 2) IMM associated with FD are usually m~ltiple.~' The diagnosis of lesions of bone and soft tissue, however, is sometimes made c~ncurrently,'~,'~ and Wirth et al. noted one case of solitary IMM associated with Fll.31 It is therefore imperative to look for evidence of bone lesions regardless of the number of IMM or previously known bone disease. Stout considered M to originate from cells that closely resembled primitive mesenchyme.26 Enzinger suggested that "the M cell is an altered fibroblast that produces an excess of mucopolysaccharides and is incapable of as- sembling mature ~ollagen."~ Our findings confirm both Stout's and Enzinger's impression. Our ultrastructure studies demonstrated that the cell responsible for M is a primitive mesenchymal cell with features characteristic of a fibroblast. The extensive R.E.R., welldeveloped Golgi apparatus, and pinocytosis are not only indicative of the cell of origin but strate intracellular inclusi~ns.~j~~~~j~~~~ Simi- suggest a secretory function. These features larly we found no virus particles or inclusions would support the hypothesis that these fibroin our 10 IMM. Trauma has also been con- blasts were the source of production of the sidered as a possible etiologic factor since mucopolysaccharides and scattered collagen some patients with IMM noted a previous his- fibers in the matrix. Leung et al. also noted tory of trauma the region where an IMM sub- the fibroblastic nature of the M cells by ultra-

14 No. 2 IMM AND MLS. Feldman 525 structure and felt that these cells showed evi- microfilaments were present which closely dence of secretory activity.ls Our ultrastruc- resembled fine fibrils in the extracellular tural studies were very similar, with this ex- space. This finding suggests the production of ception: in our cases, numerous cytoplasmic these fibrils by these cells. 1. Albright, F., Scoville, B., and Sulkowitch, H. W.: Syndrome characterized by osteitis fibrosis disseminata, areas of pigmentation, and a gonadal dysfunction. Further observations including the report of two more cases. Endocrinology 22: , Canalis, R. F., Smith, G. A,, and Konrad, H. R.: Myxomas of the head and neck. Arch. Otolaryngol. 102: , Enterline, H. T., Culherson, J. D., Rochlin, D. B., and Brady, L. W.: Liposarcoma-A clinical and pathologic study of 53 cases. Cnncrr 13: , Enzinger, F. M., and Winslow, D. J.: Liposarcoma- A study of 103 cases. Virchows Arch. Path. Anat. 335: , Enzinger, F. M.: Intramuscular myxoma. Am.J. Clin. Prithol. 43: , Feldman, P. S.: A comparative ultrastructural study of intramuscular myxoma and myxoid liposarcoma. Lab. Invest. 34:315, 1976 (Abstract). 7. Feldman, P. S., Horvath, E., and Kovdcs, K.: An ultrastructural study of seven cardiac myxomas. Cancrr 40: , Flenker, H.: Myxoid liposarcoma-light and electron microscopic investigation. Virchowv Arch. A. Path. Annt. Hi.stol. 371: , Fu, Y.-S., and Perzin, K. H.: Non-epithelial tumors of the nasal cavity, paranasal sinuses and nasopharynx: A clinicopathologic study. VII. Myxomas. Cancer 39: , Glazunov, M. F., and Puchknov, I. G.: On the socalled muscular myxomas and myxosarcomas with intracellular inclusions in the human. Vopr. Onko. 6: 11-27, Gould, V. E., Jao, W., Gould, N. S., and Soto, J. M.: Comparative ultrastructure of hibernomas and myxoid and pleomorphic liposarcomas. Lab. Invat. 34:316, 1976 (Abstract). 12. Harrison, J. D.: Odontogenic myxoma: Ultrastructural and histochemical studies. J. Clin. Pathol. 26: , Ireland, D. C. R., Soule, E. H., and Ivins, J. C.: Myxoma of somatic soft tissues. Mayo Clin. Proc. 48: , Kalderon, A. E., and Fethiere, W.: Fine structure of two liposarcomas. Lab. Invest. 28:60-69, REFERENCES 15. Kaufman, S. L., and Stout, A. P.: Lipohlastic tumors in children. Carmr 12: , Kindhlom, L.-G., Stener, B., and Angervdll, I,.: Intramuscular myxoma. Cancer 3 1 : , Kindhlom, L.-G.: Liposarcoma -A clinicopathologic, radiographic and prognostic study. Arta Pnthol. Microbiol. Scnnd. [A](Suppl. 253):l-71, Leung, T. K., Vauzelle,, J. L., Patricot, L. M., Lejeune, E., and Queneau, P.: Etude ultrastructurale et cytochimique d'un myxoma musculaire assock a une dysplasie fihreuse. Ann. And. Puthol., 16: , Lichtenstein, L., and Jaffe, H.: Fibrous dysplasia of hone. Arch. Pathol. 33: , Morton, D. L., Malmgren, R. A., Hall, W. T., and Schidlovsky, G.: Immunologic and virus studies with human sarcomas. Surgery 66: , Napolitano, I,.: The fine structure of adipose tissues. In Handbook of Physiology: Adipose Tissue. A. E. Renold, and G. F. Cahill, Eds. Baltimore, Williams and Wilkins, Razzuk, M. A,, Urschel, Jr., H. D., Race, G. J., Kingsley, W. B., and Paulso, D. L.: Liposarcoma of the mediastinurn.]. Thor. Cardiovasc. Surg. 6 1 : , Rosin, R. D.: Intramuscular myxomas. Br.J. Surg. 60: , Scarpelli, D. B., and Greider, M. H.: A correlative cytochemical and electron microscopic study of a liposarcoma. Cancer 15: , Schuster, F. L.: Ciliated fibroblast from a human brain tumor. Anat. Rec. 150: , Sorokin, S.: Centrioles and the formation of rudimentary cilia by fibroblasts and smooth muscle cells. J. Cell Bid. 15: , Stout, A. P.: Liposarcoma-The malignant tumor of lipoblasts. Ann. Surg. 119:86-107, Stout, A. P.: Myxoma: The tumor of primitive mesenchyme. Ann. Surg. 127: , Stout, A. P.: Myxoma. In Tumors of the Soft Tissues, Atlas of Tumor Pathology, 2nd ser. Fasc. l., Washington, D. C., Armed Forces Institute of Pathology, 1966; pp Virchow, R.: Cellular Pathology as Based upon Physiological and Pathological Histology. Philadelphia, J. B. Lippincott, 1863; pp