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Fibroblasts in Health and Disease
- 2. • Introduction • Embryogenesis, Anatomy, Physiology • Fibroblast in health • Organ specific functions • Organogenesis • Fibroblasts in disease • Wound healing, inflammation, Fibrosis • Tumour progression • Fibroblasts neoplasms 2
- 3. Introduction • Mesenchymal cells that form the stroma or framework of tissues • Amazing similarity in morphology, function and biochemical repertoire regardless of their location. • Phenotypic and functional heterogeneity. • Take part in growth, development & repair of normal tissue as well as in diseases affecting many different organs • Location next to epithelial or parenchymal cells, - "juxtaparenchymal cells" 3
- 5. Anatomy 5
- 6. Histology • Large spindle-shaped, often stellate with long cytoplasmic extentions and distinct acidophilic and fibrillar cytoplasm. • Nuclei are indented or show strangulations of nuclear segments. • Connected to each other by adherens and gap junctions • Myofibroblasts : display prominent cytoplasmic actin microfilaments (stress fibers) • Fibronexus - Transmembrane complex made up of intracellular contractile microfilaments and the ECM protein - fibronectin. 6
- 7. Ultrastructural Features of Myofibroblasts Compared with Fibroblasts and Smooth Muscle Cells 7
- 8. EM picture 8
- 9. RECEPTORS EXPRESSED 1. CYTOKINES • IL-1R, TNF- α R, IL-6 R, IL-8 R, IL-4 R 2. GROWTH FACTORS • TGF-/EGFR, PDGF- R, BFGF-R, IGF-IR, FGFR-II 3. INFLAMMATORY MEDIATORS • Prostaglandins 4. NEUROTRANSMITTERS & PARACRINE MEDIATORS • Acetylcholine, Histamine, Serotonin, Bradykinin, Endothelin, Atrial Natriuretic Factor Aldosterone Or Angiotensin II 5. ADHESION PROTEINS • ICAM-1, VCAM-1, NCAM, MCP-1, Integrin 9
- 10. SECRETED BY FIBROBLASTS 1. CYTOKINES • IL-1, IL-6, TNF-α , IL-10. 2. GROWTH FACTORS – • CSF-1, GM-CSF, PDGF, βFGF, EGF, TGF-β 3. CHEMOKINES – • IL-8, Lymphotaxin • MCP-1(monocyte chemo-attractant protein), • MIP-1(macrophage inflammatory protein), MIP-2, • RANTES (regulated and normal T cell expressed and secreted) 4. INFLAMMATORY MEDIATORS – • Phospholipase A2 Activating Protein , • PGE2, PAF, NO, CO, H2O2 • Prostacyclin, 10
- 11. Fibroblast functions • Organ specific functions • Organogenesis 11
- 12. Organ specific functions SITE HEALTH DISEASE SKIN- Papillary, Reticular dermal fibroblasts • Epithelial growth differentiation, • wound repair, Granulation tissue • Scleroderma; • Keloid, • Dupuytren's Contracture • Psoriasis EYE- orbital fibroblasts corneal fibroblast lens fibroblast Orbital fibroblast - glycosaminoglycan secretion for cushion in eye in orbit Corneal myo-fibroblast Lens formation Angiogenesis and wound healing Exophthalmos Of Grave's Disease Anterior Capsular Cataract Proliferative Vitreoretinopathy Diabetic Micro-aneurysm 12
- 13. Organ specific functions SITE HEALTH DISEASE MOUTH Periodontal ligament - attachment of teeth Gingival myofibroblasts • structure of gum • Palatal mucosa - structure of palate Gingival Hypertrophy Secondary To Drugs BRAIN - Astrocyte Substrate pathways for neural growth • Formation of blood-brain barrier • Secrete mitogens and growth factor for neurons Produce glial scar tissue HIV-associated cognitive motor disease, Spongiform encephalopathy 13
- 14. Organ specific functions SITE HEALTH DISEASE BREAST Stromal fibroblast • Epithelial growth and differentiation • Contraction & expulsion of milk fibrocystic disease, desmoplastic reaction to breast cancer LUNG Interstitial cell - alveolus formation Pulmonary Interstitial Fibrosis, Idiopathic And Drug-induced, Sarcoidosis, Emphysema Diffuse Alveolar Damage Pulmonary Hypertension HEART AND PERICARDIUM Structure of cardiac valve Atherosclerosis & Re–stenosis, Hypertension Micro-aneurysms, Edema, And Hemorrhage Repair after myocardial infarction 14
- 15. Organ specific functions SITE HEALTH DISEASE BLOOD VESSEL Pericyte - Angiogenesis; regulation of local blood flow Myocardial Fibrosis STOMACH AND INTESTINE • Interstitial cell of cajal - regulation of motility, "pacemaker" activity • Sub-epithelial myo-fibroblast • Epithelial growth and differentiation • Contraction of gastric glands and intestinal villi • Regulation of intestinal absorption and secretion • Abnormal Intestinal Motility; • Hypertrophic Pyloric Stenosis; • Hirschsprung's Disease, Idiopathic Pseudo-obstruction • Collagenous Colitis; • Villous Atrophy And Crypt Hyperplasia; • Polyp Formation, • Fibrosis Of Crohn's Disease, • Healing Gastric Ulcer 15
- 16. Organ specific functions SITE HEALTH DISEASE LIVER Peri-sinusoidal stellate cell (ito cell) • endothelial and sinusoid structure and function; • regulation of blood flow; • vitamin A storage Fibrosis And Cirrhosis Ischemia-reperfusion Injury Of Hepatic Transplantation PANCREAS Periacinar stellate cell - growth development of the acinus Pancreatic Fibrosis BONE MARROW Stromal cell - nurture stem cells and promote hematopoiesis Fibrosis in myelodysplasia Neoplastic diseases 16
- 17. Organ specific functions SITE HEALTH DISEASE KIDNEYS Mesangial cell - glomerular growth and differentiation; regulation of glomerular blood flow Interstitial cell - tubule growth and differentiation Proliferative And Sclerosing Glomerulonephritis. Absence Of Glomerular Structure Renal Tubulo-interstitial Fibrosis UTERUS Endometrial myofibroblasts - regeneration of endometrium after menses placental myofibroblasts - structure of placental stem villus 17
- 18. Organ specific functions SITE HEALTH DISEASE OVARY Theca cells -meiosis and ovulation Tumours-fibroma PROSTATE Stromal cells - growth and differentiation of prostate gland BPH TESTIS Peri-tubular myoid cells • growth and differentiation of seminiferous tubules • contraction and expulsion of sperm Leydig cells - androgen secretion Capsule cells - contraction of capsule 18
- 19. Organogenesis Mesenchymal-epithelial interactions – growth and differentiation of the tissue or organ through • Secretion of soluble growth factors. • Expression of their receptors • Secretion & formation of interstitial matrix and/or basement membrane molecules • Proliferation & differentiation of epithelial (or parenchymal), vascular and neurogenic elements 19
- 20. Organogenesis 20
- 21. Role of fibroblasts in disease • Tissue repair • Inflammation • Fibrosis- inflammation and tissue repair, organ related • In tumour progression • Tumours arising from fibroblasts 21
- 23. 23
- 24. TISSUE REPAIR- Wound healing • WOUND HEALING WITH MINIMAL SCAR • DEFICIENT SCAR FORMATION • Wound dehiscence • Ulceration • EXCESSIVE FORMATION OF GRANULATION TISSUE • Keloid • Exuberant granulation • CONTRACTION • Contractures 24
- 25. Inflammation 25
- 26. ROLE IN FIBROSIS • FIbrogenic Cytokines : IL-1, IL-6, PDGF, TGF, IGF-I, βFGF • Potential abnormalities in matrix secretion • Degradation of matrix by MMPS • Inhibition of MMPS by TIMPS - Fibrosis. 1. Formation of new blood vessels (angiogenesis) 2. Migration and proliferation of fibroblasts 3. Deposition of extracellular matrix 4. Maturation and organization of fibrous tissue (remodeling) 26
- 27. Fibrosis 27
- 31. TUMOUR PROMOTION • Myofibroblasts promote tumour development, and act in concert with neoplastic cells. • Early idea that abundant matrix synthesized by the myofibroblast formed a physical barrier inhibiting tumour cell movement and amounted to a protective measure for the host . 31
- 32. Cancer Associated Fibroblasts (CAF) What makes them different !!!!!!! • Secreted growth factor - Granulin (GRN) • Alpha SMA & FSP – 1 & FAP • VIMENTIN • PDGF beta and alpha IL-1beta ,IL- 6, COX-2, TGF beta • Myofibroblasts • Epithelial-to-mesenchymal transition (EMT), • Wnt1 overexpression • Fibroblast core serum response • Altered PG2 receptors • Senescent fibroblasts -osteopontin-dependent- progression of pre-neoplastic epithelium to malignancy 32
- 33. 33 LOX induced cross linked collagen Fibroblasts caveolin-1
- 34. TUMOUR AND TUMOUR LIKE LESIONS OF FIBROBLASTS 34
- 35. Benign Fibroblastic/Myofibroblastic Proliferations • Nodular Fasciitis • Proliferative Fasciitis • Ischemic Fasciitis (Atypical Decubital Fibroplasia) • Keloid • Desmoplastic Fibroblastoma (Collagenous Fibroma) • Angiofibroma of Soft Tissue • Superficial Fibromatoses • Palmar Fibromatosis • Plantar Fibromatosis • Penile Fibromatosis (Peyronie Disease) 35
- 38. Ischemic fasciitis and atypical decubital fibroplasia 38
- 39. Pleomorphic fibroma of the skin. 39
- 40. angiofibroma 40
- 41. keloid 41
- 44. Fibrous Tumors of Infancy and Childhood • Fibrous Hamartoma of Infancy • Infantile Digital Fibromatosis • Fibromatosis Colli • Infantile Fibromatosis (Lipofibromatosis) • Congenital and Acquired Muscular Fibrosis 44
- 45. Fibrous Hamartoma of Infancy 45
- 48. Borderline and Malignant Fibroblastic Tumors • Deep Fibromatoses • Congenital/Infantile Fibrosarcoma • Inflammatory Myofibroblastic Tumor • Adult-Type Fibrosarcoma • Fibrosarcoma Variants 48
- 49. Deep (desmoid type)fibromatosis 1. Extra-abdominal fibromatosis - musculo-aponeurotic fibromatosis - affects the muscles of the shoulder, pelvic girdle, and thigh of adolescents and young adults. 2. Abdominal fibromatosis - occur in women of childbearing age during - musculoaponeurotic structures of the abdominal wall, especially muscles 3. Intra-Abdominal Fibromatosis - distinguished by the clinical setting and location. 49
- 52. Fibrosarcoma Classification of Fibrosarcoma • Adult-type fibrosarcoma • Myxoid type (myxofibrosarcoma) • Fibromyxoid type (low-grade fibromyxoid • sarcoma/hyalinizing spindle cell tumor with • giant rosettes) • Sclerosing epithelioid type • Juvenile/infantile fibrosarcoma 52
- 54. FIBROSARCOMA 54
- 55. 55
- 56. Treatment options • DNA based anti- fibroblast growth factor vaccine • Genetically engineered FSP-1 • Vaccine of VEGF and consequences • Vascular promotion to enhance chemotherapy • Modification of ECM by reducing oxidative stress • Contact guidance model and use of TGF beta 1,2,3 for scar minimalisation • Dermal and skin equivalents for skin replacement • Decorin + TGFβ = profibrotic – inhibits bleomycin induced pulmonary fibrosis 56
- 57. • Endostatin has anti fibrotic and anti angiogenesis effects • Vitamin D3 inhibits collagen 1, which is profibrotic • Wnt – βcatenin – fibroblast to myofibroblasts • MMPs/MMP inhibitors (MMPIs). • Hepatocyte growth factor , Bone morphogenic factor-7 and Relaxin inhibit fibroblasts through TGFβ1 activity 57
- 58. References • Ieda M, et al. (2010) Direct reprogramming of fibroblasts into functional cardiomyocytes • by defined factors. Cell 142(3):375–386. • Inagawa K, Ieda M (2013) Direct reprogramming of mouse fibroblasts into cardiac myocytes. J Cardiovasc Transl Res 6(1):37–45. • Han DW, et al. (2012) Direct reprogramming of fibroblasts into neural stem cells by defined factors. Cell Stem Cell 10(4):465–472. • Kim J, Ambasudhan R, Ding S (2012) Direct lineage reprogramming to neural cells. Curr Opin Neurobiol 22(5):778–784. • Thier M, et al. (2012) Direct conversion of fibroblasts into stably expandable neural stem cells. Cell Stem Cell 10(4):473–479. • Hiramatsu K, et al. (2011) Generation of hyaline cartilaginous tissue from mouse adult dermal fibroblast culture by defined factors. J Clin Invest 121(2):640–657. 58
- 59. • Marsh, T., Pietras, K., & McAllister, S. S. (2013). Fibroblasts as architects of cancer pathogenesis. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1832(7), 1070-1078. • Huschtscha LI, et al. (2012) Enhanced isolation of fibroblasts from human skin explants. Biotechniques 53(4):239–244 • Abe,M., Ho,C.H., Kamm,K.E., and Grinnell,F. (2003) Different molecular • motors mediate platelet-derived growth factor and lysophosphatidic acidstimulated • floating collagen matrix contraction. J. Biol Chem. 278, 47707- • 47712. • Abe,R., Donnelly,S.C., Peng,T., Bucala,R., and Metz,C.N. (2001) Peripheral • blood fibrocytes: differentiation pathway and migration to wound sites. J. • Immunol. 166, 7556-7562. • Abercrombie,M., Flint,M.H., and James,D.W. (1954) Collagen formation and • wound contraction during repair of small excised wounds in the skin of rats. J. • Embryol. Exp. Morphol. 2, 264-274. 59
- 60. • Bayreuther K, Rodemann HP, Francz PI, Maier K (1988) Differentiation of fibroblast stem cells.J Cell Sci Suppl 10:115–130 60
Editor's Notes
- - ECM by focal contacts
- The proposed sources of hepatic myofibroblasts: Resident cells (hepatic stellate cells and portal fibroblasts); bone marrow-derived mesenchymal cells, and EMT from hepatocytes and cholangiocytes. Different insults initiate inflammation and then cause hepatocyte stellate cells activation and hepatocyte and biliary cell damage, necrosis and EMT. Continuous insults will shift those EMT-like cells to complete EMT cells and finally myofibroblasts, the main producer of extracellular matrix, which may be one of the main causes of an early loss of regenerative capacity. A similar process also occurs in biliary cells. Some cytokines play an important role to affect the adjacent cells and promote EMTs, such as TGF-β1 (B); B: Schematic presentation of the major intracellular signal transduction pathways of TGF-β1 in liver fibrosis. TGF-β1 is a chief inducer of the EMT process, and p-Smad2/3, p38 MAPK and ILK function as mediators of the intracellular signaling pathway. TGF-β1 signals via heteromeric transmembrane complexes of type I and type II receptors that are endowed with intrinsic serine/threonine kinase activity (ALK activin receptor-like kinase). Upon type-II-mediated phosphorylation of the type I receptor, the activated type I receptor initiates intracellular signalling by phosphorylating receptor regulated-Smad2 and Smad3. Activated Smads form heteromeric complexes with Smad4 and these complexes accumulate in the nucleus where they mediate transcriptional responses. p-Smad2/3: Phosphorylated-Smad2/3; MAPK: Mitogen-activated protein kinase; GSK-3β: Glycogen synthase kinase-3β; ILK: Integrin-linked kinase; TCF/LEF-1 complex: T cell factor/lymphoid enhancer-binding factor-1 complex; EMT: Epithelial-mesenchymal transition; TGF: Transforming growth factor. Formal pathogenesis of liver fibrosis (fibrogenesis). The "canonical principle" of fibrogenesis starts with necrosis or apoptosis of hepatocytes and inflammation-connected activation of hepatic stellate cells (HSC triggering), their transdifferentiation to myofibroblasts with enhanced expression and secretion of extracellular matrix and matrix deposition (fibrosis). The latter is a precondition for cirrhosis. New pathogenetic mechanisms concern the influx of bone marrow-derived cells (fibrocytes) and of circulating monocytes and their TGF-β driven differentiation to fibroblasts in the damaged liver tissue. A further new mechanism is epithelial-mesenchymal transition (EMT) of bile duct epithelial cells and potentially of hepatocytes. All three complementary mechanisms enlarge the pool of matrix-synthesizing (myo-)fibroblasts in the damaged liver. The most important fibrogenic mediators are transforming growth factor (TGF)-β, platelet-derived growth factor (PDGF), insulin-like growth factor 1 (IGF-1), endothelin-1 (ET-1), and reactive oxygen species (ROS including hydroxyl radicals, superoxid anions). Abbreviations: ASH - alcoholic steatohepatitis; NAFLD - non-alcoholic fatty liver disease. Inset shows an electron micrograph of HSC with numerous lipid droplets indenting the nucleus.
- Under normal conditions, insult to healthy tissue activates transient mechanisms that repair the damaged tissue. Chronic or repetitive insult can lead to the onset of tissue fibrosis through persistent activation of myofibroblasts. These activated myofibroblasts remodel the surrounding ECM, generating a high linearized collagen-containing microenvironment with increased biomechanical stiffness as a result of increased ECM deposition and posttranslational modification. Concomitantly, the release of several growth factors and cytokines drives changes in angiogenesis and cell growth within the affected tissue. These changes lead to the generation of prometastatic microenvironments that support the colonization of circulating tumor cells, and also activation of already resident dormant tumor cells. At the primary tumor, similar mechanisms of stromal cell recruitment and activation lead to the development of tumor-associated desmoplasia facilitating tumor initiation and progression to metastasis. Finally, the active remodeling at secondary premetastatic sites mimics tissue fibrosis mechanisms, albeit at a microscopic scale, and acts to enhance tumor cell colonization and growth.
- FOXD1-lineage fibroblasts and pericytes in the interstitial space or attached to endothelium, respectively, respond to signals of endothelial or epithelial injury in a bidirectional manner, including PDGFR-β and -α engagement, which triggers detachment, spreading, migration, and differentiation to myofibroblasts. This process can resolve, but the extent of reversion or other mechanisms of myofibroblast disappearance remain unclear. Some studies propose that a circulating leukocyte also contributes to myofibroblasts, but it remains poorly characterized. Myofibroblasts respond to growth factors, plasma factors, and environmental cues to proliferate, deposit fibrillar matrix, and contract. Expression of metalloproteinases, including ADAMTS family members and their regulators, coordinates detachment, migration, formation of collagen fibrils; factors regulating matrix turnover and degradation including FAP and CTHRC1 favor matrix accumulation. Myofibroblasts are a potent source of cytokines and chemokines and metabolic products, which regulate the inflammatory response. As injury persists, myofibroblasts undergo transcriptional and miRNA reprogramming that contributes to their persistence in an activated state. A subpopulation of myofibroblasts may utilize Endo180 to degrade and resorb pathological matrix, which promotes resolution. The fate of myofibroblasts is currently unclear, but resolution of fibrosis may involve reversion, cell death, or possibly senescence.
- Nodular fasciitis with plump, randomly oriented spindle cells surrounded by myxoid stroma. Note the mitotic activity and extravasated red blood cells Nodular fasciitis is a pseudosarcomatous, self-limiting reactive process composed of fibroblasts and myofibroblasts Intravascular fascitis Movat stain of intravascular fasciitis outlining intravascular growth of the spindle-cell proliferation. 17. Nodular fasciitis with diffuse smooth muscle actin immunoreactivity.
- large, basophilic ganglion-like cells with one or two vesicular nuclei and prominent nucleoli.The cells have abundant basophilic, slightly granular cytoplasm but lack cross-striations typical of rhabdomyoblasts
- Ischemic fasciitis and atypical decubital fibroplasia are synonyms for a pseudosarcomatous fibroblastic/myofibroblasticproliferation that predominantly involves soft tissues overlying bony prominences and often (but not always) occurs in elderly and physically debilitated or immobilized patients. Microscopically, ischemic fasciitis has a zonal pattern, often with a central zone of liquefactive or focally coagulative necrosis surrounded by a fringe of proliferating vessels and fibroblasts/myofibroblasts (Figs. 8-32 and 8-33). The peripheral vessels are usually small, thin-walled, and ectatic; they are lined by prominent, occasionally atypical, endothelial cells (Fig. 8-34). In addition, a proliferation of plump cells formperivascular clusters or merge imperceptibly with the peripheral vessels; these cells may be cytologically atypical, with large, eccentric, often smudgy hyperchromatic nuclei, prominent nucleoli, and abundant basophilic cytoplasm.
- sparsely cellular and composed predominantly of thick, haphazardly arranged collagen. The characteristic feature is the presence of scattered spindle-shaped or stellate cells, including multinucleated giant cells with large pleomorphic, hyperchromatic nuclei and small nucleoli (Fig. 8-37). Mitotic figures are rare, but occasionally an atypical mitotic figure is seen.96 The stroma may show focal or (rarely) diffuse myxoid change.99,100 Adnexal structures are generally not found, and there may be a sparse intralesional lymphoplasmacytic infiltrate. Immunohistochemically, the cells show variable immunoreactivity for smooth muscle and muscle-specific actin, suggesting myofibroblastic differentiation.97 Some also stain for CD34 and CD99,101 but immunostains for S-100 protein, desmin, and cytokeratin are negative.
- The cells in the fibrous tissue are cytologically bland and may be spindle or stellate in shape with nuclei that lack hyperchromasia and have small nucleoli and little mitotic activity (Fig. 8-46). The dense, fibrous stromamay show hyalinization or focal myxoid change, often withcollagen fibers arranged in a parallel fashion. Mature fat entrapped within the lesion can occur but is unusual.158 Thevascular channels are slit-like or dilated and vary in number,configuration, and thickness. Some vessels are surrounded byfew, if any, smooth muscle cells, whereas others show focalpad-like thickenings.159 CD31 and CD34. The immediate perivascular cells show variable staining for smooth muscle actin,
- Keloids are characterized by a fibrocollagenous proliferation of the dermis with haphazardly arranged thick, glassy, deeply acidophilic collagen fibers (Fig. 8-49). During the early phase, the lesions tend to be vascular, particularly at their periphery, accounting for the clinical appearance of an erythematous lesion. Later, lesions show decreased vascularity and more prominent hyalinization, which may undergo focal calcification or osseous metaplasia. Bland spindle-shaped cells are scattered throughout this hypocellular lesion.
- Grossly, desmoplastic fibroblastoma is a well-circumscribed, firm mass with a white-to-gray cut surface, without hemorrhage or necrosis. Microscopically, the tumor is more or less circumscribed but not infrequently minimally infiltrates the surrounding soft tissues. The lesion is hypocellular and consists of widely spaced bland spindle- to stellate-shaped cells embedded in a collagenous or myxocollagenous stroma (Figs. 8-50 to 8-52). Mitotic figures are rare or absent, and necrosis is not present. Blood vessels are usually inconspicuous but may exhibit perivascular hyalinization. Immunohistochemically, most show focal staining for smooth muscle actin or muscle-specific actin, consistent with myofibroblastic differentiation,204,205 but stains for desmin, CD34, S-100 protein, and cytokeratins are typically negative.
- resembling a fibrolipoma. Fibrous hamartoma of infancy showing a characteristic organoid pattern composed of interlacing fibrous trabeculae, islands of loosely arranged spindle-shaped cells, and mature adipose tissue. CD34
- Fibromatosis colli has long been recognized as a peculiarbenign fibrous growth of the sternocleidomastoid muscle that usually appears during the first weeks of life and is often associatedwith muscular torticollis, or wryneck. It bears a closeresemblance to other forms of infantile fibromatosis Microscopic examination discloses partial replacement of the sternocleidomastoid muscle by a diffuse fibroblastic proliferation of varying cellularity (Figs. 9-23 and 9-24). The constituent cells lack nuclear hyperchromasia, pleomorphism, and mitotic activity. Scattered throughout the lesion are residual muscle fibers that have undergone atrophy or degeneration with swelling, loss of cross-striations, and proliferation of sarcolemmal nuclei. This intimate mixture of proliferated fibroblasts and residual atrophic skeletal muscle fibers is fully diagnostic of the lesion and should not be confused with the infiltrative growth of a malignant neoplasm.
- Infantile fibromatosis, diffuse type, removed from the trapezius muscle of a 5½-month-old girl. The absence of digital malformations helps distinguish it from an early nonossifying stage of fibrodysplasia ossificans progressiva. Replacement of muscle tissue by fibrous tissue and mature fat bearing a superficial resemblance to a lipomatous tumor. T
- deep fibromatoses show strong nuclear accumulation of β-catenin,
- lesion is poorly circumscribed and infiltratesthe surrounding tissue, usually skeletal muscle (Fig. 10-3). The proliferation consists of elongated, slender, spindle shapedcells of uniform appearance surrounded and separated from one another by collagen, with little or no cell-to-cell contact Identical to those described for extra-abdominal fibromatosis, except that the average tumor is smaller and behaves less destructively than those in extra-abdominal locations. Most tumors measure 3 to 10 cm in greatest dimension, and, when arising in the rectus muscle or its fascia, they usually remain at the site of origin and do not cross the abdominal midline
- Grossly, most lesions appear circumscribed, but like other forms of fibromatosis, there is microscopic infiltration into the surrounding soft tissues, including the bowel wall. Microscopically, the lesions are composed of cytologically bland spindle-shaped or stellate cells evenly deposited in a densely collagenous stroma. Typically, there is variable cellularity, with some areas showing almost complete replacement by dense fibrous tissue. In others, the stroma shows marked myxoid change. Scattered keloid-type collagen fibers may be present, including prominent dilated thin-walled veins and muscular hyperplasia of small arteries. Nodular lymphoid aggregates may be present at the advancing edge of the tumor.
- high-power view of immature appearing fibroblasts with a prominent lymphocytic infiltrate, characteristic of infantile fibrosarcoma. muscle-specific actin, smooth muscle actin, and caldesmon. 110,111 The more primitive-appearing ovoid cells tend not to express these muscle markers.