The first and largest group of lesions involving the proliferation of fibrous tissue are best grouped under the term fibromatosis and include a wide range of clinical pathologic entities that predominantly involve the soft tissue and are nonmetastasizing but are of orthopaedic interest because of their anatomical location, occasional involvement of bone, and their tendency to invade locally and even recur after surgical excision. The group of fibromatoses may be multiple and familial and may even regress spontaneously, presenting a broad range of clinical variation. Because receptors for estrogen and/or progesterone may be present in fibrous lesions, increased growth rates during periods of high endogenous levels of sex steroid hormones are possible (1). Broadly speaking, the fibromatoses can be classified into those involving adults and those in a younger childhood population (2) (Table 8.1). Many fibroblastic lesions on light microscopy have been determined to be of myofibroblastic origin.

Fibrous metaphyseal defect (FMD) or nonossifying fibroma (NOF) and its smaller fibrous cortical defect counterparts have been considered the most common benign lesions of the skeletal system. Although the radiographic appearance of the classic NOF is pathognomonic, the proliferative spindle cell population, often in a matted, whorled, or storiform pattern with dispersed foam cells and benign multinucleated giant cells, mimics reactive and neoplastic conditions. There are now well-established clinical and anatomical facts associated with this lesion. In 1955, John Caffey (17), in reviewing the prevalence, natural course, and diagnostic significance of this lesion, concluded that they were extremely common in a developing child. In fact, radiographs in more than 200 normal boys and girls revealed that 33 percent had one or more fibrous cortical defects. Generally appearing in the age range of 4 to 8 years, none were noted before the age of 2 years, and they were subsequently seen with decreasing frequency in later teenage years. The consistent anatomic locations of these lesions are the metaphyseal region of long bones of the lower extremities, especially the distal end of the femur. They occur particularly at anatomic sites corresponding to the insertion of a tendon or ligament into the perichondrium of the epiphyseal growth plate. With skeletal maturation, they move into the diaphysis, supporting original concepts that muscular pull or periosteal injury may be important factors in their development (18) (Figs. 8.5 and 8.6). Indeed, the long axis of the roentgenographically evident lesion often parallels the long axis of the bone. With maturation, defects persisting over long periods usually become sclerotic and appear away from the growing end of the bone, again suggesting developmental contribution. More than 50 percent of the lesions are multiple (19,20), and their roentgenographic appearances are characteristic. Lesions are usually eccentrically located in the bone. This cortical location is often associated with thinning of the cortex with inner boundaries demarcated by sclerosis. Often ovoid and multilocular in appearance, there is great variation in their size (Fig. 8.7). As mentioned, most lesions are self-limited, with spontaneous regression in several years. Large lesions may lead to pathologic fracture, although surgical treatment should be minimal where appropriate.

Fracture is a definite risk once the NOF occupies more than 50 percent of the cross section of the bone. Both NOF and the fibrous cortical defects can become dense lesions as the patient matures.

Computed tomography (CT) scans demonstrate these lesions as well-defined lucencies, with density close to that of muscle. MRI scans show these lesions as areas of intermediate signal intensity in both T1-and T2-weighted images.

Multiple lesions may be associated with neurofibromatosis.

Grossly, FMDs are well circumscribed, and may be white, tan, or yellow depending on the amount of fibrous tissue, hemosiderin, and lipid accumulation, respectively (Fig. 8.8).

Nonossifying fibromas consist of a proliferative population of spindle cells, usually in a swirling pattern, often admixed with other cells including foam cells or lipophages, and benign, multinucleated giant cells (Fig. 8.9). Collagen production is rarely prominent. Hemosiderin is seen to a variable degree. In some instances, the proliferation of spindle cells may take on a cellular and even pleomorphic pattern, which could lead to misdiagnosis. Here, the classic roentgenographic appearance is extremely helpful to the pathologist in establishing the diagnosis. Because of their characteristic roentgenographic appearance, these lesions are commonly encountered and usually not biopsied.

A few cases of NOF with chromosome aberrations have been reported, all with near-diploid karyotypes and different structural rearrangements (21).

Nonossifying fibromas may be multiple in a large percentage of cases and, because of the occasional association with café-au-lait spots, may be confused with other entities, including polyostotic fibrous dysplasia and neurofibromatosis. Fibrous dysplasia characteristically has cutaneous pigmentation with a rugged or ragged border, so-called coast of Maine. In neurofibromatosis, café-au-lait spots are characterized by a smoother configuration, so-called coast of California. Nonossifying fibromas may be associated with either condition.

Eponyms associated with NOF and café-au-lait spots include one coined by Mirra (22), termed Jaffe-Campanacci syndrome, a syndrome that includes multiple NOFs of the mandible, café-au-lait spots, endocrine disorders, mental retardation, ocular anomalies, and cardiovascular malformations (23). The diagnosis of Jaffe-Campanacci syndrome, usually made in the peripuberty years, can be made by identifying smooth-bordered (coast of California) café-au-lait spots and axillary freckling in association with multiple NOFs without any evidence of neurofibromas (23). “Fibrous cortical defects,” a term used by radiologists, is thought to be the same lesion as NOF, and is distinguished by its smaller size and frequent spontaneous sclerosis earlier in childhood than NOF.

Asymptomatic FMDs do not need to be treated. Large lesions with imminent fracture may require curettage and bone grafting.

Although benign fibrous histiocytoma (BFH) is a tumor that is well described in the soft tissue, it less commonly involves bone and, where encountered, bears a striking resemblance in its histologic appearance to the developmental abnormality FMD. It is distinguished from FMD by the atypical location in bone (not limited to metaphysis), more frequent occurrence outside the lower extremity, and occurrence in older patients. The majority of BFHs of bone involve long tubular bones, but they may also occur in other sites such as the spine, pelvis, and ribs, distinctly unusual locations for FMDs (24) (Fig. 8.10). Radiographically, BFH is a well-defined, lytic expansile lesion with little periosteal reaction. Internal trabeculations and sclerotic margins may be seen (Fig. 8.10). Bone scintigraphy has been reported mildly positive, and MRI images reveal a T1-weighted signal similar to skeletal muscle (25).

BFH occurs in adults between the third and sixth decades. It is characterized histologically by the proliferation of fibroblasts and histiocytes, usually in a swirling or storiform pattern, often admixed with foam cells, lipophages, and multinucleated giant cells. The foam cells may be prominent, giving a yellow gross appearance to the tumor. The lesions may be painful. Because of its distinct clinical differences, BFH is considered a benign tumor that can be locally aggressive and can even recur following curettage.

Of note in discussing the differentiation between BFH, considered a tumor of bone, and NOF, considered a developmental problem, is the recognition in tissue pathology of a broad range of disorders that may be characterized by the same heterogeneous population of cells. For example, histiocytes may be of metabolic (as in Gaucher disease), inflammatory, reactive, or neoplastic origin. The spectrum of change and clinical possibilities requires careful clinical, roentgenographic, and pathologic correlation.

BFH is considered a true neoplasm and may behave aggressively at the local site of involvement. Because recurrence may follow curettage, a margin of normal bone should be removed to avoid recurrence (26).

Initially described by Cappell in 1935 in the fibula as an endosteal fibroma, Jaffe popularized the term “desmoplastic fibroma” a quarter of a century later for benign fibrous lesions arising within the bone with histologic characteristics of the extraosseous desmoid tumors. Desmoplastic fibroma has been considered to be the bony counterpart of the more common desmoid-type fibromatosis of soft tissue based on its characteristic long-sweeping blandly cellular fascicles of myofibroblastic cells. Recent genetic studies, however, question this association (vida infra).This rare, locally aggressive benign lesion may be extremely difficult to differentiate histologically from desmoids and low-grade fibrosarcomas and even fibrous histiocytoma, but combined characteristic pathologic and roentgenographic features can distinguish this lesion.

Desmoplastic fibroma is a rare, locally aggressive solitary tumor with a reported incidence of 0.06 percent to 0.11 percent of primary bone tumors (27).

It tends to be diagnosed in the first three decades of life, with no sexual predilection, and most commonly presenting in the ilium, long bones, and mandible (Fig. 8.11). Any flat bone may be involved, including the scapula, rib, and clavicle. Because of its insidious onset, the lesion is usually large at the time of clinical diagnosis, with only slight pain on occasion. Rarely, a pathologic

fracture may be the presenting symptom. Roentgenographically, these lesions are usually distinct, expansile, lucent lesions with well-defined margins (Fig. 8.12). Cortical erosion with pathologic fracture may be seen. CT scans may show evidence of soft tissue invasion where involved. Desmoplastic fibroma appears well defined on MR images, revealing a low signal intensity on T1. T2-weighted images show low to intermediate signal. The clear separation of intraosseous tumor from normal bone marrow and extent of soft tissue involvement makes MRI extremely valuable in planning surgery. Histologically, the lesions are essentially identical to that of the desmoid tumor and are characterized by dense, collagenized tissue within which are uniform-appearing, benign fibroblasts. Although cellularity may vary within the lesion, the cells are almost always small and regular with bland nuclei and little hyperchromasia and mitotic activity. There are usually no giant cells. On microscopy alone, the distinction between a desmoplastic fibroma and desmoids, low-grade fibrosarcoma, and even fibrous histiocytoma may be very difficult. Special flow cytometric and histologic techniques have revealed diploid DNA ploidy, averaged 23 mean proliferative cell indices. Mitoses are rare. Mast cells may be seen.

Immunohistochemically, there is a variable degree of staining for smooth muscle actin, pan muscle actin, desmin, and cyclin D1. Nuclear β-catenin is occasionally present, but this is generally in less than 10 percent of the cells. Immunoexpression of MDM2 and CDK4 is also negative, in distinct contrast to low-grade central osteosarcoma.

The clinical course is that of local aggression with recurrence in up to 72 percent after nonresection procedures, 17 percent with resections, and 0 percent when resected with a wide surgical margin (27). Therefore, recurrence may be avoided by a good surgical margin. Metastases have been reported after local recurrence in 3 of 184 cases (1.6 percent) reported in the literature. Recurrences range from 9 months to 11 years (average, 2.7 years). It is recommended that 3 years be the minimum follow-up period for evaluation of the efficacy of therapy (27). Recurrences in the extremities have led to amputations in 25 percent of cases (27).

The involvement of the APC/β catenin pathway in various fibromatoses has raised questions regarding whether desmoplastic fibroma shares these alterations. However, whereas nuclear β-catenin expression appears relatively specific for fibromatosis (nuclear overexpression of β-catenin protein is seen in more than 90 percent of fibromatoses), comparable degrees of these APC gene mutations have not been observed in desmoplastic fibroma (28,29).

In contrast to desmoid-type fibromatosis of soft tissue, no mutations are found in exon 3 of CTNNB1, encoding β-catenin. Thus, genetically there is little evidence to consider desmoplastic fibroma as the intraosseous counterpart of desmoid-type fibromatosis. Some cases show a trisomy of 8 and 20.

Fibrous tumors of both soft tissue and bone may reveal focal “myxoid” histologic features characterized by stellate-shaped cells in a loose clear, gelatinous, or myxoid connective matrix background. The significance of this component is unclear, but has nonetheless lent itself to additional classifications of lesions including fibromyxoma of bone (30,31), which is similar to chondromyxoid fibroma of bone. In “fibromyxoma,” there is usually a distinct lytic lesion, which, although contained by the periosteum, may erode the cortex. These tumors tend to have light gray color with rubbery consistency, and histologically show proliferation of bland fibrous tissues and areas characterized by clear stellate cells in a myxoid stroma, thus giving rise to the term. Hemorrhage and necrosis may be seen, but not the lobulated pattern that is typical of chondromyxoid fibroma, which also contains large areas of cartilage. Other variants on this lesion have been described, including ossifying fibromyxoid tumor of soft parts (32).

First described by Albright in 1937 in a child with precocious puberty and café-au-lait spots, fibrous dysplasia is a frequently observed developmental abnormality of the skeleton, which has several well-described clinical pathologic variants (Table 8.2). The hallmark of fibrous dysplasia is replacement of normal bone and marrow by tissue composed of fibrous tissue and irregular minute spicules of woven bone. The most common type of fibrous dysplasia is a monostotic form involving one bone. It affects more females than males, and presentation is usually in the first few decades of life. Polyostotic forms tend to be monomelic or hemisomic in distribution and have been broadly classified as oligostotic, diffuse, or associated with Albright syndrome (33) (Table 8.2). Other variations include those affecting the bones of the skull and facial bones often with dramatic clinical characteristics, sometimes described as “cherubism” or “leontiasis ossea.” The café-au-lait spots seen in the classic Albright syndrome occur mainly in a unilateral distribution, often on the back, and may be reminiscent of the café-au-lait spots seen in neurofibromatosis.

Tissue from FD may produce excess FGF-23 with its resultant hypophosphatemia and osteomalacia (Chapter 3).