Aggressive fibromatosis involving the paramandibular soft tissues

oral pathology Editor: CHARLES E. TOMICH, D.D.S., M.S.D. American Academy of Oral Pathology Indiana University School of Dentistry 1121 West Michigan Street Indianapolis, Indiana 46202

Aggressive fibromatosis involving the paramandibular soft tissues A study with the aid of electron microscopy Brad Rodu, D.D.k,* Dwight R. Weathers, D.D.S., M.S.D.,** and Wallace G. Campbell, Jr., M.D., *** Birmingham, Ala. and Atlanta,

Ga.

The distinction at the level of light microscopy between aggressive fibromatosis and low-grade malignancies with fibroblastic features may be difficult. An electron microscopic study of four cases of aggressive fibromatosis of the mandibular soft tissue was undertaken to determine whether any ultrastructural characteristics could be identified that would aid in a more uniform distinction between these lesions. The pertinent findings include the identification of cells of fibroblastic derivation showing a range of organelle-podr to organelle-rich features, cytoplasmic microfibrils, and dilated rough endoplasmic reticulum profiles. These features are discussed in the light of previously published findings of other forms of aggressive fibromatosis and closely related lesions. The study reaffirms that although electron microscopy may be useful in confirming the cell of origin in these lesions, the accurate diagnosis of fibrous tumors still rests with the proper correlation of clinical and light microscopic features. Clinical follow-up of the cases supports both the diagnosis of aggressive fibromatosis and the recommended treatment of adequate local excision.

T he fibromatoses

are a group of fibrous connective tissue lesions that fall in the pathologic gray zone between categorically benign and malignant tumors.‘. * Since Stout’s initial definition of the fibromatoses in 19543 as a “term used without qualifying words for all of the fibrous growths that cannot be assigned to any other category,” the concept has been expanded to include a wide range of clinical and pathologic entities. The World

*Assistant Professor, Department of Pathology, University of Alabama School of Dentistry and School of Medicine, Birmingham. **Professor and Chairman, Department of Pathology, Emory University School of Dentistry, and Assistant Professor, Department of Pathology, Emory University School of Medicine, Atlanta, Ga. ***Professor of Pathology, Emory University School of Medicine. Atlanta.

0030-4220/81/100395

+ 09$00.90/00

1981 The C. V. Mosby

Co.

Health Organization4 lists under this category such diverse lesions as cicatricial fibromatosis, keloid, nodular fasciitis, irradiation fibromatosis, penile fibromatosis, fibromatosis colli, juvenile aponeurotic fibroma, nasopharyngeal fibroma, abdominal desmoid, extra-abdominal desmoid, congenital generalized fibromatosis, and palmar and plantar fibromatosis. Although the majority of fibromatoses involve the trunk or extremities, some cases may also be found in the head and neck area. Das Gupta and his colleagues5 and Kaufman and Stout6 found significant head and neck involvement in sizeable series of cases. Conley and his co-workers’ and Masson and Soule8 studied 40 and 34 cases, respectively, of head and neck fibromatoses, and various other case reports (including oral involvement) can be found.9-16 In 1958 Jaffe” first described what he considered 395

396 Rodu, Weathers, and Campbell

Oral Surg. October, 198 1

and clinical aspects that fulfill the criteria of aggressive fibromatosis to determine whether any ultrastructural features could aid in the characterization and diagnosis of these lesions. CLINICAL

Fig. 1. Rapidly

infiltrative, mandible (case 3).

destructive lesion of left

the intraosseous equivalent of an abdominal desmoid. Several have subsequently been reported in the the largest series of 16 cases was reviewed by Fisker and Philipsen in 1976.z3 These lesions are histologically well differentiated, with an aggressive local growth but a benign course. The principal problem in subclassifying some lesions of the fibromatosis group is distinguishing between those with a benign or nonaggressive natural history (e.g., palmar and plantar fibromatosis) and those with the potential for destruction or aggressive behavior (e.g., desmoids and extraabdominal desmoids). Many aggressive fibromatoses, especially those located outside the wellrecognized abdominal site, present a clinicopathologic dilemma because location and clinical presentation do not appreciably aid in the diagnosis. Only through a proper correlation of histologic and clinical parameters can these lesions be accurately diagnosed. They are manifested clinically by local aggressiveness and infiltration beyond palpable margins, 24thus simulating malignancy. Local recurrence rates are thus as high as 47% but metastases do not occur.7 A wide range of cellularity, collagen production, and inflammation is seen, but it is generally agreed that the mitotic index is low and cellular pleomorphism is not prominent.4x 25.26The latter criteria have served in large part to support the concept of benignity in regard to these lesions. Ambiguity has surrounded some aggressive fibromatoses, especially those occasional cases involving bones, as clearly definable clinicopathologic entities. We have studied by electron microscopy four cases involving the soft tissues of the mandible with secondary bone involvement exhibiting histologic jawsIS-'22;

SUMMARY

The clinical data of all patients are summarized in Table I. All lesions were found in the mandibular soft tissues of young persons and exhibited rapid onset and local aggressiveness (Fig. 1). They were bulky, fleshy, ill-defined tumors presenting intraorally as soft tissue swellings. There was bone resorption, but the lesions did not appear to arise primarily within bone, thus differing from those lesions described as desmoplastic fibromas.“” All patients were disease-free at intervals ranging from 1 to 6 years after wide excision of the lesions. Although some were lost to follow-up, they were tumor-free at the last examination. MATERIALS

AND METHODS

Tumors from Patients 2, 3, and 4 had been previously fixed in formalin and embedded in paraffin. These tissues were then processed through a series of xylenes, alcohols, and water. They were secondarily fixed in 1.5 percent neutral buffered glutaraldehyde, then fixed in 1 percent osmium tetroxide, dehydrated in a series of alcohols (70, 95, 100 percent) and propylene dioxide. The processed tissues were embedded in Maraglas.27 Sections were cut on a Porter-Blum MT-l microtome with glass knives. Thick sections were cut at 1 pm, stained with Paragon2” and studied to select representative areas. Thin sections cut with diamond knives were picked up on uncoated 75/300 mesh copper grids, stained with lead citrate and lead citrate with uranyl acetate, and studied with an RCA EMU4C electron microscope. Tissue from Patient 1 was fixed directly in glutaraldehyde and then processed in a similar manner. RESULTS Light microscopy

All lesions histologically exhibited variable numbers of spindle-shaped cells arranged in fascicles of fibrous connective tissue (Fig. 2). A scattered inflammatory response was seen in some areas. Although the lesions microscopically infiltrated adjacent bone and soft tissue, the individual cells showed mild pleomorphism and could be separated into light- and dark-staining groups of cells (Fig. 3). Mitotic figures were rare.

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involving paramandibular

Fig. 2. Representative low-power view of lesion (case 3) showing spindle-shaped of fibrous connective tissue. (Hematoxylin and eosin; x 100.)

Table I. Summary

cells arranged

in fast:icles

of clinical data Tumor

Patient

Age CY~..)

Race/ Sex

Location

Case 1

B. R. W.

2

W/M

J. B.

22

B/M

Case 3

D. K.

11

W/F

Case 4

D. L.

16

W/F

Left posterior mandible soft tissue Right posterior mandible soft tissue Left posterior mandible soft tissue Mid-mandible soft tissue

Case 2

NED

soft tissues 3%

Duration

I

T

Follow. -UP yr., NED

2 wk.

6

1 mo.

2%

2

mo.

Last few months

yr., NED

2

yr., NED

3

yr., NED

= no evidence of disease

Electron microscopy

Considering the previous paraffin impregnation, preservation of detail in the reprocessed tissue was acceptable for ultrastructural evaluation. However, illustrations have been drawn almost entirely from Patient 1 since those were of much better quality. Nevertheless, identical features were seen in all four patients. Generally the tumor cells were thin and elongated. At lower magnifications a pattern of organelle-rich to organelle-poor cells was observed. The plasma membranes were best evaluated in Patient 1, and examination revealed that they were usually smooth throughout; only occasional pinocy-

totic vesicles were present (Fig. 4). No microvilli or pseudopodia-like projections were noted (Fig. 4). Specialized cell junctions were not seen where two or more cells were in close proximity. Extracellular basement membrane material was not identified. The organelle-rich cells previously alluded to contained abundant rough endoplasmic reticulum (RER). A common feature was marked dilatation of the RER cisternae by electron-dense granular material that showed areas of denser condensations (Fig. 5). Mitochondria were easily identified in most cells (Fig. 6) but often were swollen and distorted due to autolysis. Golgi apparatuses were often multiple and showed disorganization of the lamellar structure

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Fig. 3. Representativehigher-powerview of lesion(case3) showingrelatively bland light-staining(L) and dark-staining(0) spindlecells.(Hematoxylin and eosin; x 450.)

Fig. 4. Portionsof three stromalcellssetin collagen(C). Note rare pinocytotic vesicleformation (PV) in

the otherwisesmoothplasmamembranes,the mildly convoluted nuclei (N), abundantrough endoplasmic reticulum (ER), and collectionsof microfibrils (MF). (X 6,330.)

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Aggressive jibromatosis

(Figs. 6 and 7)., Collections of microfibrils beneath the plasma membrane were seen in many cells (Fig. 6) but were usually not a very prominent feature, and these collections did not show any dense condensations. The other cell type was organelle-poor (Fig. 8). These cells usually showed features similar to those of the organelle-rich cells, but cytoplasmic organelles were less numerous. Occasional cells showed almost no cytoplasmic organelles. Cells containing intermediate numbers of organelles were also readily identified (Fig. 9)-a spectrum conceivably reflecting an alteration in the functional state of the tumor cells. Microtubules and dense bodies were also rarely noted in all cell types. The nuclei of all cell types were fairly similar (Figs. 4, 7, and 8). They usually contained one or two nucleoli and showed slightly to moderately convoluted nuclear membranes. The chromatin appeared fairly evenly dispersed, with some condensation along the nuclear membranes. Spherical granular and filamentous intranuclear bodies (Fig. 7) similar to those described by Sapp and Brookez9 in herpetiform ulcers and of the type II as described by Bouteille and co-workerP were seen. Collagen fibers were readily identified in close apposition to many cells, but none were seen intracellularly (Fig. 9). No evidence of basement membrane production was noted along the plasma membranes. DISCUSSION

Although the histopathology of these cases supports the diagnosis of aggressive fibromatosis, there is still some question as to the exact location of origin. By their presentation we believe they arose in the paramandibular soft tissues, but origin from periosteum or even as a central desmoplastic fibroma with peripheral extensiorP cannot be completely ruled out. The cytoplasmic characteristics of the cells comprising the tumors of the presently reported cases, i.e., the extensive RER, prominent Golgi apparatus, the presence of scattered mitochondria, collections of microfibrils beneath the plasma membranes, and the nuclear morphology, are all consistent with the ultrastructure of fibroblasts31 In addition, a range of organelle-poor to organelle-rich cells is demonstrated. It had been previously noted that these lesions contained light- and dark-staining cells by light microscopy. These two cell types were observed on thin sections as well, which served to correlate the ultrastructural findings with the light microscopy findings in this regard. WilliamP has

involving paramandibular

soft tissues 399

Fig. 5. Fibroblast showing dilatation of rough endoplasmic reticulum (RERJ by electron-dense granular material. N, Nucleus. (x 5,520.)

found that an increase in the activity of fibroblasts in healing wounds is reflected in increased numbers of cell organelles, especially RER. The findings of a variety of cellular organizations suggest a range of activity among the cells in the present tumors, the organelle-poor cells apparently being the most inactive. All our lesions demonstrated intracellular collections of microfibrils. Although collections of microfibrils may be seen in fibroblasts, they are characteristically situated beneath the plasma membrane in myofibroblasts, cells with features of both fibroblasts and smooth muscle cells, first fully characterized by Gabbiani and associates,“3‘ 34 Majno and co-workers,“5 and Ryan and associates.3G The morphologic criteria set forth for a myofibroblast include (1) nuclear indentations or folds, (2) bundles of intracytoplasmic microfilaments arranged parallel to the long axis of the cell and showing multiple areas of condensation (dense bodies) similar to those present in smooth muscle cells, (3) surface differentiation in the form of desmosome-like intercellular connections, (4) basal lamina-like material surrounding cells, (5) abundant RER, and (6) prominent Golgi apparatuses.“3. 36It is clear that the cells in our cases fulfill some but not all of these criteria and therefore cannot be considered fully developed myofibroblasts. Some features of myogenous differentiation in the fibroblastic cells in our cases, nevertheless, is indicated. Recently several reported lesions of the fibromatosis category have been shown to contain myofibroblasts: Dupwytren’s contracture,“’ desmoid fibromatosis,“8 circumscribed fibromatosis,39 nodular

400 Rodu, Weathers, and Campbell

Fig. 6. Portion of modified fibroblast showing swollen mitochondria microfibrils (MF), disorganized Golgi apparatus (G), and smooth endoplasmic reticulum (RER). (X 10,600.)

Oral Surg. October, 198 1

(M), bundles of peripherally placed endoplasmic reticulum and rough

Fig. 7. Organelle-rich cell showing altered Golgi apparatus (G), abundant RER, and mildly convoluted nucleus with prominent nucleolus (Nu). B, Granular and filamentous intranuclear body; C, collagen. (X 7,500.)

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Fig. 8. Organelle-poor cell showing occasional RER cisternae and occasional pinocytotic vesicles (arrowheads). PM, Plasma membrane; N, nucleus; Nu, nucleolus; B, granular and filamentous intranuclear body. ( x 9,700.)

fasciitis,‘” desmoplastic fibromas of bone,41 and a low-grade spindle cell sarcoma (the histologic differential diagnosis included fibromatosis).42 Some studies have suggested that the presence of myofibroblasts in fibroblastic tumors indicates a favorable prognosis,34’ 36.43 but this conclusion is based on a limited number of cases available for review. Similar cells have been described in several cases of fibrosarcoma4’-46; however, the features have not been noted in some ultrastructural reports of fibromatoses47-49 and other fibrosarcomas?* 51 The presence of fibroblasts, tissue histiocytes, and myofibroblasts in fibrous histiocytomas’” suggests that these cells may in part represent simply varying expressions of a single cell line, myofibroblasts being by no means limited exclusively to fibrous tumors.51-61 Another interesting feature in this study was the consistent finding of large, dilated, saclike structures of RER tilled with a granular, electron-dense material. At least three other references to this type of structure were found: that of Allegra and Broderick” in a desmoid fibroblastoma, of Cracker and Murad44 in a fibrosarcoma of the male breast, and

of Lagace and co-workers4’ in desmoplastic fibromas of bone. Studies on the biosynthesis of collaiFf* IS may provide some insight into this finding. Procollagen, the protein precursor of collagen, is synthesized in the RER. The procollagen chains undergo a series of reactions, including hydroxylation and formation of interchain disulfide bonds that lead to triple helix formation and secretion from the cell. The hydroxylation process is accomplished by enzymes prolyl hydroxylase and lysyl hydroxylase and has been shown to be most important to subsequent helix formation. Experimentally, if fibroblasts are incubated under conditions in which intercellular iron, oxygen, or ascorbate is deficient, hydroxylation will not occur. Nonhelical procollagen accumulates in the RER and is subsequently secreted very slowly as a nonfunctional protein. Quite possibly, local factors result in a similar situation in the present tumors, and the electron-dense material in the RER represents an accumulated nonfunctional product. We did not find intracytoplasmic collagen in our cases. On the other hand, Welsh and MeyeF* demonstrated intracellular collagen fibers in some,

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Fig. 9. Cell of intermediate organellecompositionembeddedin a densecollagenousmatrix (‘C). PM,

Plasmamembrane;arrowhead,pinocytotic vesicle; N, nucleus.(X 5,150.)

but not all, mesenchymal tumors they examined (including keloids, desmoids, and fibrosarcomas). Allegra and Broderick”’ found intracellular collagen in their desmoid fibroblastoma, as did Welsh’” in a desmoid fibromatosis and Lagace and co-workers41 in desmoplastic fibromas of bone. Whether these findings represent intracellular collagen production, phagocytosis of extracellular collagen, and/or ultrastructural artifact is open to question, especially in view of recent concepts of collagen biosynthesis62,63 as discussed in the previous paragraph, whereby only procollagen is formed within the cell to be subsequently secreted and transformed into collagen extracellularly. In summary, the data accumulated thus far indicate that although electron microscopy can delineate the cell of origin in some sarcomas,“’ a problem of defining criteria of malignancy or cell of origin for fibrous tumors remains. Although fibrosarcomas generally show more nuclear abnormalities than fibromatoses,44, 45.So,51 other parameters such as RRR profiles and myofibroblastic differentiation have not as yet contributed definitively to the resolution of the subclassification and malignant potential of fibroblastic tumors. It appears that the accurate diagnosis of fibromatoses is dependent on a critical evaluation of clinical and histologic parameters, with electron microscopy being of supportive rather than definitive diagnostic importance. The authorsthank Mr. Willie Thomasfor his technical assistancein the preparation of this manuscript. This

material was presented in part before the American Academy of Oral Pathology on May 13, 1980. REFERENCES

Allen, P. W.: The Fibromatoses: A Clinicopathologic Classification Based on 140 Cases. Part I, Am. J. Surg. Pathol. 1: 255-210, 1977. 2. Allen, P. W.: The Fibromatoses: A Clinicopathologic Classification Based on 140 Cases. Part II, Am. J. Surg. Pathol. 1: 305-321, 1977. 3. Stout, A. P.: Juvenile Fibromatoses, Cancer 7: 953-978, 1954. 4. Histological Typing of Soft Tissue Tumors, Geneva, 1969, World Health Organization. 5. Das Gupta, T. K., Brasfield, R. D., and O’Hara, J.: ExtraAbdominal Desmoids: A Clinicopathological Study, Ann. Surg. 170: 109-121, 1969. 6. Kaufman, S. L., and Stout, A. P.: Congenital Mesenchymal Tumors, Cancer IS: 460-476, 1965. 7. Conlev. J.. Healev. W. V.. and Stout. A. P.: Fibromatosis of the H&d and Neck Am.‘J. Sur li2* 609-614 1966 8. Masson J K and’soule E. I-!: Desmoid Tumors’of the Head ahd’Ne:k, Am. J. Surg. 11;: 615-622, 1966. 9. Smith, J. F.: Nodular Fasciitis of the Buccal Pad, Arch. Otolaryngol. 86: 217-218, 1967. 10. Connolly, N. K.: Juvenile Fibromatosis, Arch. Dis. Child. 36: 171-175, 1961. 11. Larsson, A., and Bidrlin, G.: Aggressive Fibrous Lesions of the Oral Cavity, J.-Oral Pathol-3: 241-251, 1976. 12. Wilkins. S. A.. Jr.. Waldron. C. A., Mathews, W. H., and Droulias, C. A.: Aggressive Fibromatosis of the Head and Neck, Am. J. Surg. 130: 412-415, 1975. 13. Shapiro, W., and Go&r, L. B.: Fibromatosis: A Case Involving the Mandible, Laryngoscope 78: 78-88, 1968. 14. Peede, L. E., Jr., and Epker, B. N.: Aggressive Juvenile Fibromatosis Involving the Mandible: Surgical Excision with Immediate Reconstruction, ORAL SURG. 43: 651-657, 1977. 15. Henefer, E. P., Bishop, H. C., and Brown, A.: Juvenile Fibromatosis With Invasion of the Mandible: Report of TWO Cases, J. Oral Surg. 36: 965-970, 1978. 16. Melrose, R. J., and Abrams, A. M.: Juvenile Fibromatosis Affecting the Jaws, ORAL SURG. 49: 317-324, 1980. 1.

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17. Jaffe, H. L.: Tumors and Tumorous Conditions of the Bones and Joints, Philadelphia, 1958, Lea & Febiger, p. 298. 18. Marlette, R. H., and Gerhard, R. C.: Intraosseous “Fibroma” and “Fibromyxoma” of the Mandible, ORAL SURG. 25: 792-799, 1968. 19. Dehner, L. P.: Tumors of the Mandible and Maxilla in Children, Cancer 31: 364-384, 1973. 20. Cunningham, C. D., Smith, R. O., Emiquez, P., and Singleton, G. T.: Desmoplastic Fibroma of the Mandible: A Case Report, Ann. Otol. Rhinol. Laryngol. 84: 125-129, 1975. 21. Nussbaum, G. B., Terz, J. J., and Joy, E. D., Jr.: Desmoplastic Fibroma of the Mandible in a Three-Year-Old Child, J. Oral Sure. 34: 1117-1121. 1976. 22. Fregdman, P. D., Cardo, V. A., Kerpel, S. M., and Lumerman, H.: Desmoplastic Fibroma (Fibromatosis) of the Jawbones, ORAL SURG. 46: 386-395, 1978. 23. Fisker, A. V., and Philipsen, H. P.: Desmoplastic Fibroma of the Jaw Bones, Int. J. Oral Surg. 5: 285-291, 1976. 24. Hunt, R. T., Morgan, H. C., and Ackerman, L. V.: Principles in the Management of Extra-Abdominal Desmoids, Cancer 13: 825-836, 1960. 25. Mackenzie, D. H.: The Fibromatoses: A Clinicopathological Concent. Br. Med. J. 4: 277-281. 1972. 26. Stout, ‘A: P., and Lattes, R.: Tumors of the Soft Tissues, Atlas of Tumor Pathology. Washington, D.C., 1967, Armed Forces Institute of Pathology, second ser., fast. I, pp. 17-31. 27. Erlandson, R. A.: A New Maraglas, D. E. R. (R) 732, Embedment for Electron Microscopy, J. Cell. Biol. 22: 704-709, 1964. 28. Spurlock, B. O., Skinner, M. S., and Kattine, A. A.: A Simple Rauid Method for Staining Enoxv-Embedded Specimens for Light Microscopy With tithe‘PO&chromatic Stain Paragon1301, Am. J. Clin. Pathol. 46: 252-258, 1966. 29. Sapp, J. P., and Brooke, R. I.: Intranuclear Inclusion Bodies in Recurrent Aphthous Ulcers With a Herpetiform Pattern, ORAL SURG. 43: 416-421, 1977. 30. Bouteille, M., Kalifat, S. R., and Delarue, J.: Ultrastructural Variations of Nuclear Bodies in Human Diseases, J. Ultrastruct. Res. 19: 474-486, 1967. 31. Ross, R.: The Connective Tissue Fiber Forming Cell. In Gould, B. S., editor: Treatise on Collagen, New York, 1968, Academic Press, Inc., vol. 2, part A, pp. l-82. 32. Williams, G.: The Late Phases of Wound Healing: Histological and Ultrastructural Studies of Collagen and Elastic Tissue Formation, J. Pathol. 102: 61-68, 1970. 33. Gabbiani, G., Ryan, G. B., and Majno, G.: Presence of Modified Fibrobiasts in Granulation Tissue and Their Possible Role in Wound Contraction. Exoerientia 27: 549-550, 1971. 34. Gabbiani, G., Hirschel, B. J., Ryan, G. B., Statkov, P. R., and Majno, G.: Granulation Tissue as a Contractile Organ. A Study of Structure and Function, J. Exp. Med. 135: 719-734, 1972. 3s. Majno, G., Gabbiani, G., Hirschel, B. J., Ryan, G. B., and Statkov, P. R.: Contraction of Granulation Tissue in Vitro: Similarity With Smooth Muscle, Science 173: 548-550, 1971. 36. Ryan, G. B., Cliff, W. J., Gabbiani, G., Irle, C., Montandon, d., Statkov, P. R., and Majno, G.: Myofibroblasts in Human Granulation Tissue. Hum. Pathol. 5 55-67. 1974. 37. Gabbiani, G., and’ Majno, G.: Dupuytren’s Contracture: Fibroblast Contraction? An Ultrastructural Study, Am. J. Pathol. 66: 131-146, 1972. 38. Stiller, D., and Katenkamp, D.: Cellular Features in Desmoid Fibromatosis and Well-Differentiated Fibrosarcomas, Virchows Arch. [Pathol. Anat.] 369: 155-164, 1975. 39. Feiner, H., and Kaye, G. I.: Ultrastructural Evidence of Myofibroblasts in Circumscribed Fibromatosis, Arch. Pathol. Lab. Med. 10th 265-268, 1976. 40. Wirman, J. A.: Nodular Fasciitis, A Lesion of Myofibroblasts: An Ultrastructural Study, Cancer 38: 2378-2389, 1976. 41. Lagace, R., Delage, C., Bouchard, H., and Seemayer, T. A.: .I

1

Desmoplastic Fibroma of Bone: An Ultrastructural Study, Am. J. Surg. Pathol. 3: 423-430, 1979. 42. Vasudev, K. S., and Harris, M.: A Sarcoma of Myofibroblasts, Arch. Pathol. Lab. Med. 102: 185-188, 1978. 43. Bhawan, J., Bacchetta, C., Joris, I., and Majno, G.: A Myofibroblastic Tumor: Infantile Digital Fibroma (Recurrent Digital Fibrous Tumor of Childhood), Am. J. Pathol. 94: 19-36, 1979. 44. Cracker, D. J., and Murad, T. M.: Ultrastructure of Fibrosarcoma in a Male Breast, Cancer 23: 891-899, 1969. 45. Churg, A. M., and Kahn, L. B.: Myofibroblasts and Related Cells in Malignant Fibrous and Fibrohistiocytic Tumors, Hum. Pathol. 8: 205-218, 1977. 46. Jakobiec, F. A., and Tannenbaum, M.: The Ultrastructure of Orbital Fibrosarcoma, Am. J. Ophthalmol. 77: 899-917, 1974. 47. Allegra, S. R., and Broderick, P. A.: Desmoid Fibroblastoma: Intracytoplasmic Collagenosynthesis in a Peculiar Fibroblastic Tumor: Light and Ultrastructural Study of a Case, Hum. Pathol. 4: 419-429, 1973. 48. Battifora, H., and Hines, J. R.: Recurrent Digital Fibromas of Childhood-An Electron Microscope Study, Cancer 27: 1530-1536, 1971. 49 Welsh, R. A.: Intracytoplasmic Collagen Formation in Desmoid Fibromatosis, Am. J. Pathol. 49: 515-535, 1966. 50. Causey, G., and Heyner, S.: The Electron Microscopic Examination of Normal and Neoplastic Fibroblasts Cultivated in Vitro, Br. J. Cancer 17: 454-459, 1964. 51. Stembridge, V. A., Luibel, F. J., and Ashworth, C. T.: Soft Tissue Sarcoma.-Electron Microscopic Approach to Histogenetic Classification, South. Med. J. 57: 772-779, 1964. 52. Geer, J. C.: Fine Structure of Human Aortic Intimal Thickening and Fatty Streaks, Lab. Invest. 14: 1764-1783, 1965. 53. Ghadially, F. N., and Mehta, P. N.: Multifunctional Mesenchymal Cells Resembling Smooth Muscle Cells in Ganglia of the Wrist, Ann. Rheum. Dis. 30: 31-42, 1971. 54. Bhathal, P. S.: Presence of Modified Fibroblasts in Cirrhotic Livers in Man, Pathology 4: 139-144, 1972. 55. Madden, J. W.: On the Contractile Fibroblast (Editorial), Plast. Reconstr. Surg. 52: 291-292, 1973. 56. Harris, M., and Ahmed, A.: The Ultrastructure of Tubular Carcinoma of the Breast, J. Pathol. 123: 79-83, 1977. 57. Moss, N. S., and Benditt, E. P.: Spontaneous and Experimentally Induced Arterial Lesions. I. An Ultrastructural Survey of the Normal Chicken Aorta, Lab. Invest. 22: 166-183, 1970. 58. Ryan, G. B., Cliff, W. J. Gabbiani, G., Irle, C., Statkov, P. R., and Majno, G.: Myofibroblasts in an Avascular Fibrous Tissue, Lab. Invest. 29~197-206, 1973. 59. Woyke, S., Domagala, W., Oleszewski, W., and Korabrec, M.: Pseudosarcoma of the Skin. Cancer 33: 970-980. 1974. 60. Weathers, D. R., and Campbell,‘W. G.: Ultrastructure of the Giant Cell Fibroma of the Oral Mucosa, ORAL SURG. 38: 550-561, 1974. 61. Baur, P. S., Larson, D. L., and Stacey, T. R.: The Observation of Myofibroblasts in Hypertrophic Scars, Surg. Gynecol. Obstet. 141: 22-26, 1975. 62. Prockop, D. J., Kivirikko, K. I., Tuderman, L., and Euzman, N. A.; The Biosynthesis of Collagen and Its Disorders, N. Engl. J. Med. 301: 13-23, 1979. 63. Prockop, D. J., Berg, R. A., Kivirikko, K. I., and Uitto, J.: Intracellular Steps in the Biosynthesis of Collagen. In Ramachandran. G. N.. and Reddi. A. H.. editors: Biochemistrv of Collagen,‘New York, 1976, Plenum Press, pp. 163-273. ’ 64. Welsh, R. A., and Meyer, A. T.: Intracellular Collagen Fibers in Human Mesenchymal Tumors and Inflammatory States, Arch. Pathol. 84:354-362, 1967. Reprint

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