Benign Fibrous Lesions and Langerhans Cell Histiocytosis

Lauren Zeitlinger, DO

William M. Parrish, MD, FAAOS

Neither of the following authors nor any immediate family member has received anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this chapter: Dr. Zeitlinger and Dr. Parrish.

ABSTRACT

Benign fibrous bone lesions are bone anomalies in which marrow and cancellous bone are replaced with abnormal fibrous tissue. More common in pediatric patients, these lesions are often found incidentally by imaging studies obtained for alternate indications. Treatment is usually nonsurgical, with clinical surveillance of lesions. Fibrous lesions may also be locally aggressive, causing deformity or fragility that warrants surgical intervention.

Langerhans cell histiocytosis is characterized by clonal proliferation of myeloid precursor cells and considered an inflammatory neoplasm. It presents as a continuum of disease, ranging from a solitary bone lesion to disseminated disease and end-organ dysfunction.

INTRODUCTION

Benign fibrous and histiocytic lesions of bone occur most commonly in children. These lesions are often diagnosed as incidental findings on plain radiographs obtained for other reasons. Plain radiographs can be diagnostic and preclude the need for biopsy for confirmation. Many of these entities are radiographic do-not-touch lesions and do not warrant additional intervention or investigation. Management often consists of observation, but when surgical intervention is required, the goal should be to restore structure and function.

NONOSSIFYING FIBROMA

Nonossifying fibroma (NOF) is a benign fibrous lesion most commonly found in the metaphysis of skeletally immature patients and occasionally in young adults. Eighty percent of NOFs occur in individuals younger than 20 years. Lesions found in older patients are often regressing. These lesions occur more commonly in males, with a ratio of 1.6:1.¹ The prevalence is estimated to be between 30% and 40% of children, but true incidence is unknown because of lack of symptoms and natural history of spontaneous involution.² These lesions are usually eccentrically located and are most commonly seen in the distal femur, proximal tibia, distal tibia, and proximal fibula.³

NOFs are most commonly identified as an incidental finding. They are generally asymptomatic unless associated with a pathologic fracture. Physical examination is generally normal.⁴ Pain in the area of a suspected NOF in the absence of a fracture or acute injury should raise suspicion of a more aggressive process.

There are several diagnostic terms for fibrous lesions, with relative interchangeability, including fibrous cortical defect, fibroxanthoma, NOFs of bone, and metaphyseal fibrous defect. Typically, fibrous cortical defect is reserved for smaller lesions.⁵

These lesions were thought to develop as a reactive process possibly secondary to the failure of normal subperiosteal membrane to ossify during development and instead fill in with fibrous tissue.³ However, recent DNA sequencing of NOFs has identified KRAS, FGFR1, and
NF1 mutations in most NOFs studied, suggesting that these are genetically driven true neoplasms involving activation of the RAS-MAPK pathway. The development of these lesions may be linked to a mutation in the MAPK (mitogen-activated protein kinase) pathway.²^,⁶ It is further speculated that spontaneous regression may be related to hormone signaling.⁶

Plain radiographs demonstrate well-defined geographic lesions that are typically eccentric in the metaphysis (Figure 1). As discussed in a 2021 study, there may be cortical expansion and thinning, but without cortical breach or soft-tissue extension.⁷ Fibrous cortical defects are generally between 1 and 3 cm in diameter. These may be intracortical and do not involve the medullary canal. NOFs are larger and are longer than they are wide. The outer edges are lobulated, and internal septation creates a bubbly appearance. A rind of sclerotic bone provides the margin, and the sclerosis progresses as the lesion matures. Bone scans may demonstrate faint uptake and do not contribute to the diagnosis. Cross-sectional imaging is seldom necessary to confirm the diagnosis. CT scans demonstrate thinning of the cortex. MRI studies are consistent with fibrous lesions on T2-weighted images, and T1-weighted images may show areas of hemosiderin deposits.¹^,⁴^,⁸

FIGURE 1 A, AP radiograph of the knee demonstrating a nonossifying fibroma in a 16-year-old patient. This is a common way for fibroxanthomas to be diagnosed. B, Lateral radiograph of the same fibroxanthoma in the same patient. The lesion demonstrates an eccentric lesion, with geographic borders and a sclerotic rim. On the lateral radiograph, sclerosis and remodeling of the lesion is evident at the inferior aspect.

Gross examination of an NOF demonstrates soft fibrous tissue with brownish-tan tissue and foci of hemorrhage. Histologically, the NOF demonstrates monotonous fibroblastic cells with little atypia and few mitoses.⁹

In most cases, management of fibrous cortical defects and NOF is with serial radiographs as needed to establish the diagnosis and monitor the progression, and ultimate regression, of the lesion. These lesions will ossify and mineralize coincidentally with skeletal maturity. Although most of these lesions are managed nonsurgically, those that become quite large can cause pain because of mechanical insufficiency and place the patient at risk for fracture. Curettage and bone grafting are indicated in these situations, with prophylactic fixation if needed. Calcium sulfate has also been used for management of large defects, as discussed in a 2022 study.¹⁰ In cases where structural support is needed, vascularized fibula graft has been described, particularly for femoral neck pathologic fractures, in a 2020 study.¹¹ Recurrence of these lesions is rare after surgical intervention.⁸

DESMOPLASTIC FIBROMA

Desmoplastic fibroma is an exceptionally rare benign but aggressive lesion of bone that shows similarity with
soft-tissue fibromatosis. The lesion is composed of dense fibrous tissue that infiltrates the local bone but does not have the ability to metastasize. Desmoplastic fibroma occurs most commonly between the ages of 15 and 40 years and is more common in women than men. More than 50% of these lesions occur in the femur, tibia, and pelvis. The mandible is also a common site.¹²^,¹³^,¹⁴

Pain lasting several months is the most common presenting symptom. Of affected patients, 15% to 20% may have an initial presentation with a pathologic fracture. On examination, findings are nonspecific in the absence of a fracture, but there can be some subtle swelling about the affected bone.

Radiographically, desmoplastic fibroma is characterized by osteolytic defects with slight to moderate expansile remodeling of the bone and lobulated margins (Figure 2). The tumor can break through the cortex and appear loculated and may contain a soft-tissue component.¹⁵ Periosteal reaction is rare unless a fracture has occurred. Bone scans demonstrate increased uptake. CT can be valuable to assess the extent of bony involvement.¹⁵ On MRI, the lesion is characteristically low signal on T1- and T2-weighted images, as discussed in a 2022 study.¹⁶

FIGURE 2 A, AP radiograph of the hip demonstrating a ground glass pattern in fibrous dysplasia. Normal trabecular pattern of bone is less prominent and rimmed by a sclerotic border of host bone. There is a noted pathologic fracture through the lesion B, Lateral radiograph of the hip demonstrating the similar appearing, eccentric lesion with a sclerotic border. C, T2-weighted magnetic resonance image demonstrating high signal characteristic of fibrous dysplasia. D, T1-weighted magnetic resonance image demonstrating the marrow-replacing lesion, with a geographic border.

Desmoplastic fibroma is grossly a firm intramedullary tissue and is histologically similar to an aggressive soft-tissue fibromatosis. It is relatively hypocellular with well-differentiated fibroblasts seen in a mature collagen matrix. Contrary to fibrosarcoma, pleomorphism and atypical mitoses are absent.¹⁷ Genetic abnormalities have been observed. Loss of 5q21-22 gene location has been reported.

Treatment varies based on location and degree of bone involvement, from aggressive intralesional curettage to wide en bloc resection and reconstruction, in cases involving extensive bone loss. Local recurrence rates of up to 40% have been reported.¹⁸ The recurrence rate decreases with en bloc resection rather than excision and curettage. Therefore, according to a 2022 study, resection and reconstruction is the favored treatment method.¹⁷

FIBROUS DYSPLASIA

Fibrous dysplasia is a developmental anomaly of bone in which the normal bone marrow and cancellous bone are replaced with abnormal fibrous and fibro-osseous tissue. Fibrous dysplasia can be isolated to one bone or may be diffuse, causing substantial deformity and disability. Fibrous dysplasia can be classified clinically as monostotic (involving one bone) or polyostotic (involving more than one bone). McCune-Albright syndrome and Mazabraud syndrome are also associated with fibrous dysplasia.¹³ McCune-Albright syndrome is associated with precocious puberty and café au lait spots, whereas Mazabraud syndrome is associated with soft-tissue myxomas.

The incidence of fibrous dysplasia is equal between males and females. Monostotic fibrous dysplasia is
usually diagnosed before age 30 years and most commonly identified during childhood or adolescence as an incidental finding. Monostotic disease accounts for approximately 70% of patients with fibrous dysplasia. Polyostotic fibrous dysplasia is more often diagnosed at a younger age, with a mean age at diagnosis of 8 years, and often presents with pain or pathologic fracture. The proximal femur is the most common site for disease.¹⁹

The etiology of fibrous dysplasia is not fully understood but thought to be a postzygotic mutation affecting the cell membrane-bound protein G. Both monostotic and polyostotic forms of fibrous dysplasia exhibit an abnormal proliferation of mesenchymal osteoblastic precursor cells with this mutation. Chromosome 12 has been postulated as the location of this mutation. Patients with McCune-Albright syndrome exhibit an increased level of interleukin 6 that may be responsible for increased bone resorption secondary to increased activity of osteoclasts.¹³

Fibrous dysplasia is often first discovered as an incidental radiographic finding.³^,⁴^,²⁰ Alternatively, patients can present with vague symptoms, including swelling or tenderness, or a stress fracture. Seventy percent of patients with fibrous dysplasia report bone pain. Deformity can develop as a result of repetitive stress that causes fractures to heal and then remodel. Bones most commonly affected by fibrous dysplasia include the femur (91%), the tibia (81%), the pelvis (78%), bones in the foot (73%), and craniofacial bones (50%).¹³ Chronic fracture and remodeling of the proximal femur in this condition can lead to the classic shepherd’s crook deformity. Craniofacial involvement can lead to proptosis and blindness in rare cases. Extraskeletal manifestations associated with fibrous dysplasia can be substantial (Table 1).

Table 1 Extraosseous Findings in Fibrous Dysplasia

± Café au lait areas with coast of Maine irregular contour

50% occurrence in polyostotic disease and proportional to skeletal involvement

Most commonly located on the dorsal neck, lower lumbar region, face, lips, and oral mucosa

Solitary and multiple myxomas (predilection for the right side) especially with polyostotic form (Mazabraud syndrome). The myxomas may originate from primitive mesenchymal cells that differentiate to fibroblasts that lose the ability to produce collagen, but instead produce hyaluronic acid

Precocious puberty (females > males) (McCune-Albright syndrome) may present as vaginal bleeding within the first few months of life

Albright triad: multiple bone lesions (predominantly unilateral), precocious puberty, café au lait spots (tend to be unilateral and may be overlying involved bone)

Myriad endocrine abnormalities are possible

Most common single entity causing oncogenic osteomalacia, from renal phosphate wasting caused by fibroblast growth factor 23

Reproduced from Pitcher JD Jr, Weber KL: Benign fibrous and histiocytic lesions, in Schwartz HS, ed: Orthopaedic Knowledge Update^®: Musculoskeletal Tumors 2. American Academy of Orthopaedic Surgeons, 2007, pp 121-132.

Most cases of fibrous dysplasia can be diagnosed with plain radiography.³^,⁴^,¹³^,²⁰ The diaphysis or metaphysis of long bones is the most common location (Figure 2). The normal trabecular pattern of bone is replaced by woven bone and fibrous tissue, producing the classic ground glass appearance. The radiographic interface between the tumor and normal intramedullary bone exhibits a sharp geographic border consistent with a benign process. Periosteal elevation can be seen in the case of healing stress fractures. Shepherd’s crook deformity or bowing of the tibia can be evident on plain radiographs.¹³ Other changes, such as islands of mineralized cartilage or a secondary aneurysmal bone cyst, may also be seen. Technetium bone scans demonstrate mild to moderate uptake. MRI shows decreased signal intensity on T1-weighted images and increased signal intensity on T2-weighted images²⁰ (Figure 2, C and D).

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