Bone fibrous hyperplasia is a rare disease that occurs in adolescents, most patients are admitted without obvious symptoms but with pathological fractures as the first symptom, and the exact cause of the disease is so far unknown. The disease is highly aggressive, can severely damage bone, and is prone to recurrence, resulting in poor treatment outcomes. There is no uniform treatment at home and abroad.
In this paper, based on the review of the research and treatment progress of this disease at home and abroad, the origin, etiology, pathogenesis, clinical characteristics, treatment and basic theory of this disease are summarized systematically, hoping to provide relatively complete research data for clinical work.
1.Origin of fibrodysplasia
In 1921, Frangenheim was the first to discover and describe this disease, which was considered to be a special kind of hereditary fibrous osteitis. Subsequently, Kempson reported 2 cases involving the tibia in children and named it ossifying fibromatosis. Subsequently, the disease was discovered from time to time until 1981, when Campanacci and Laus unified the formal name of fibrodysplasia based on a study of 35 cases. This nomenclature has now been accepted by a wide range of medical practitioners.
2. Onset
The first onset of fibrodysplasia occurs mostly in children around 10 years of age, with a peak between 1 and 5 years of age. Neonatal onset has also been reported. To date, the oldest reported case is 39 years of age, and the age of onset varies from literature to literature, with Sweet and Ishida et al. reporting an average age greater than 10 years, while Komiya, Inoue, Ozak, Campanacci, and Laus reported younger than 10 years.
Although some of the literature reports a slightly higher incidence in males than in females, there is no significant gender difference in the overall trend of the disease. 16 of the 30 children reported by Sweet were male; 38 of the 80 patients reported by Park were male; the largest gender difference among all reports was reported in 35 children reported by Campanacci and Laus, of whom 21 were male. The largest gender difference among all reports was reported in the 35 children reported by Campanacci and Laus, of which 21 were male, accounting for 60% of the total, and this difference was not statistically significant.
3. Etiology
The etiology of the disease and the origin of the lesioned cells have not been conclusively established to date. Johnson believes that the disease has the same pathogenetic basis as enamel epithelioma, called fibrovascular defect. According to this theory, fibroheteroproliferative disorder originates from an abnormality of the haversian canal, and enamel epithelioma is secondary to this defect of the medullary tubular system.
Komiya and Inoue reported similar findings and identified this deficiency in intraperiosteal blood flow as one of the causes of fibrodysplasia.In their study of the cytogenesis of fibrodysplasia, Bridge et al. took separate tissue specimens from two male children and found a triplet of chromosome 12 in one of the 11-year-old children and chromosomes 7, 8 and 22 in the other. 8 and 22. The current study of enamel epithelioma suggests that it may be associated with chromosome 7 and 12 haplogroups. Thus, it is not difficult to assume that the two diseases are related in some sense. Similarly, this other chromosomal aberration is also present in the tissue specimens of this disease, but further studies have shown that these chromosomal aberrations are not pathogenic. The question of whether this chromosomal 3-ploidy aberration is responsible for the development of the disease remains to be further investigated.
4. Clinical manifestations
Most osteochondrodysplasias involve the tibial cortex, with the best site being the middle tibia and, to a lesser extent, the fibula.
Of the 30 children reported by Sweet, every case had tibial involvement and 5 cases had ipsilateral fibular lesions (17%). Similarly, in the 35 cases reported by Campanacci and Laus, there was tibial involvement in each case and ipsilateral fibular involvement in 4 cases (11%). Of these 35 cases, 22 lesions were located in the middle tibia, and 11 of the 12 cases in Ishida et al. had tibial involvement, mostly in the proximal diaphysis. These data are in general agreement with the statistical data of our hospital in the last 10 years.
Bilateral involvement of the tibia and ulna was rare in one of the five cases reported by Ozaki et al. The remaining four cases had tibial involvement and one case had ipsilateral fibular involvement. Radial and humeral lesions have also been reported in the literature.
The typical symptoms of this disease are painless hard swelling of the tibia and frequent involvement of the tibia producing a forward or lateral bending, with some patients being admitted with pathological fracture as the first symptom.
In a study of 80 children conducted by Park et al, 25% of the patients complained of pain, 12.5% had pathological fractures, 8.8% had swelling of the tibia as the first symptom, and 6.2% presented with limb deformity as the first symptom. In a study of 30 patients conducted by Sweet, 18 (60%) had pain, 13 (43%) had local swelling, 4 (13%) had limb deformity, and 1 was an incidental finding. similar results were reported by Komiya and Inoue.
Eleven of the 12 children reported by Ishida et al. were between the ages of 2 months and 5 years, with a mean age of 14 months. One of them was asymptomatic, and two of the three neonates with tibial osteochondrodysplasia had a first presentation with local swelling and one with a pathological fracture.
In general, the clinical manifestations of this disease are relatively insidious, and most patients with non-pathological fractures are diagnosed late, which hinders the timely diagnosis and treatment of the disease.
Usually, this disease can be divided into 3 types.
(1) solitary type of fibrous heteroplasmosis
The lesion process is benign, and it is most common to occur in a single bone. It can be divided into limited and extensive types according to the extent of bone destruction. The clinical symptoms are mild, often with localized discomfort, soreness, and mild pain, and are often seen for local swelling or pathological fractures.
(2) Multiple fibrous heteroplasia
The onset of symptoms is related to the severity and extent of the lesion. The lesions invade most of the bones throughout the body, often favoring one limb, with bilateral involvement being asymmetric and producing various deformities. Multiple lesions are more extensive, and pathological fractures occur in 85% of cases. Multiple pathological fractures may occur in the same area, and sometimes skin pigmentation may be seen.
(3) Albright syndrome
It is overwhelmingly female and rare. There are 3 main features.
(a) Skin pigmentation spots: brown or brownish-yellow in color with irregular edges and poorly defined, mostly located on the back.
(b) Precocious puberty: irregular vaginal bleeding, but not menstruation, early appearance of secondary sexual characteristics and early development of sexual organs in females, and enlarged genital organs in males.
(c) Bone changes with multiple fibrous heterogeneous proliferation. The disease affects skeletal development. In childhood, due to endocrine changes, skeletal development is faster than normal children, so the stature is slightly taller, but because the epiphysis closes earlier than normal children, the stature in adulthood is shorter than normal. Occasionally, there is mental retardation, and the combination of other endocrine symptoms is rare. The development of the disease is faster before maturity and slower and more stable in adulthood.
5.Differential diagnosis
The disease should be differentiated from monostotic fibrous dysplasia, non-ossifying fibroma, and enamel epithelioma. In general, these diseases are more common in children over 10 years of age and are more likely to invade the femur and ribs than fibrous heteroplasia, which does not resolve on its own.
On imaging, the intramedullary lesions in fibrodysplasia have a typical hairy glass appearance. In long bones, the lesions are mostly located in the medullary cavity and cortex and progress toward the epiphysis, where they may form a fan shape within the periosteum from an intact, thin cortex. CT shows the inner part of the lesion, without soft tissue components, with autolysis of the bone, sclerotic destruction of the lesion edges, cortical destruction and swelling of the surrounding soft tissue. T2 high signal.
Histologically, the lesion is not surrounded by actively growing osteoblasts and is cytokeratin-negative (Figure 4).
Cytogenetics showed that the disease was associated with chromosome 3 and 5 abnormalities.
Non-ossifying fibromas differ from this disease in that they are mainly caused by mesenchymal defects. The lesion tissue is mostly composed of spindled cells and multinucleated giant cells, which also do not have an active osteoblastic border and are cytokeratin negative.
The more difficult differentiation is between fibrous heteroplasia and enamel epithelioma. An exact differential diagnosis is particularly important for the diagnosis and treatment of both diseases. Both have similar sites of predilection, and there are no significant differences in imaging and histological examination. The difference between the two is that the latter is often combined by swelling of the soft tissues with intramedullary involvement, and in the absence of pathologic fracture occurring, the latter often has a periosteal reaction and histological examination reveals darker stained epithelial cell islands. In most cases, pain is more severe in patients with enamel epithelioma than in patients with fibrous heterogeneous proliferative disease.
6.Treatment
Due to the high recurrence rate of this disease, most scholars believe that the disease should be treated conservatively until skeletal maturity. Scraping and bone grafting can be performed at this time without increasing the risk of recurrence. For children of any age, corrective surgery for associated deformities can be performed. If the lesion is considered progressive, or if the child has multiple pathological fractures, aggressive surgical treatment is indicated.
6.1 Conservative treatment
The more popular view is that the disease should be treated conservatively until skeletal maturity. Recurrent pathological fractures are a serious problem in active children. Tibial braces applied to patients with tibial pseudarthrosis can reduce the likelihood of pathologic fracture episodes in the conservative management of this disease. A laced leather boot can be used to protect the area between the patient’s knee and ankle. Most of the case fractures associated with this disease are non-displaced, although the fracture healing process is slower than normal and most patients heal with plaster immobilization alone. Radiotherapy is contraindicated in patients with this disease, as this treatment tends to induce deterioration of the disease.
6.2 Surgical treatment
The disease is characterized by a high recurrence rate after scraping or excision, so most scholars believe that surgical treatment after skeletal maturation is a reasonable option. This does not increase the likelihood of recurrence. Campanacci and Laus suggest that extensive resection with bone grafting should be performed in children with rapidly progressive disease that results in significant bone destruction or multiple morbid fractures, even though the skeleton is not yet mature. The prophylactic use of intramedullary pins is also a good option for children with frequent pathological fractures, which is somewhat similar to the treatment of children with osteogenesis imperfecta. It is not usually considered advisable to perform a major lesion resection, as this procedure only increases the risk of pathologic fractures without any real impact on the treatment of the disease.
Depending on the location and extent of the lesion, the current procedures can be broadly classified as follows.
(4) Mass scraping with autologous iliac bone graft
(5) Mass scraping with bone cement or allograft bone graft
(6) Mass removal with fibula or rib grafting
Of particular interest is the recent introduction of mass scraping with allogeneic cancellous bone + BMP grafting. It is suitable for cases with a small lesion. After thorough scraping of the lesion, the implantation of allogeneic bone avoids the concomitant deformity due to the extraction of autologous bone, the amount of filled bone can be relatively large, and the occurrence of recurrence due to the underlying lesion tissue at the extraction site is prevented. The BMP protein contained in the implant can effectively induce regeneration of normal bone tissue around the lesion. Compared with traditional bone cement or autologous iliac bone graft, it is simple and easy to perform, with excellent results and no increase in recurrence rate.
7. Complications
7.1 Recurrence
A major feature of this disease is the high recurrence rate after scraping or resection. According to current reports, the recurrence rate ranges from 64% to 100%, and Goergen et al. reported multiple recurrences in a 3-year-old child and a 6-month-old child after resection, and Wang et al. reported similarly for this disease after surgery, and Campanacci and Laus concluded that recurrence is basically guaranteed in children over 10 years of age.
7.2 Malignancy
Although malignant transformation is rare, it has been reported in the literature, and one of the few cases of malignant transformation to date has been reported by Ben Arush et al. This child, a 14-year-old male, was found to have fibrodysplasia at around 4 years of age. Subsequently, an ipsilateral gastrocnemius synovial sarcoma was found at the age of 14 years, and CT showed multiple pulmonary metastases at the time of detection.
8. Prognosis
The course of fibrodysplasia is difficult to predict, the growth rate of the lesion varies, and it is possible for the lesion to disappear on its own. campanacci and Laus broadly classified the prognosis into 3 categories.
(1) Moderate rate of progression, with most lesions appearing one after another within 5 to 10 years of detection.
(2) High rate of progression with rapid deformity and functional impairment of the limb.
(3) Self-absorption and disappearance.
In most cases, the lesions continue to grow during the immature skeletal stage, with the growth rate being faster in children younger than 10 years of age. The prognosis of this disease is more common in the first case until skeletal maturity.
9. Outlook
Fibrous heteroplasia is very similar to enamel epithelioma in terms of pathology, clinical presentation, and imaging. Although the latter sometimes presents as a hypodifferentiated osteosarcoma, fibrous anaplastic proliferation of bone does not have any histologic features of deterioration.
Studies have shown some association with enamel epithelioma. Czerniak and Springfield et al. have found that fibrodysplasia-like enamel epithelioma can progress to enamel epithelioma, and this fibrodysplasia-like enamel epithelioma is considered by many to be an intermediate stage between fibrodysplasia and enamel epithelioma. This hypothesis is further supported by the similar findings of Hazelbag et al.
Firstly, they found that the epithelial cells of fibroblastic proliferative disorders can gradually transform into primitive tumor-like epithelium, just like the epithelial cells of enamel epithelial tumors. Second, both patients with fibrous heteroplasia and patients with fibrous heteroplasia-like enamel epithelioma were diagnosed at an age younger than that of enamel epithelioma. Third, the imaging presentations of the two were very similar. Fourth, both of the 2 patients they studied showed a progression from fibrous heteroplasia to enamel epithelioma at the time of local recurrence after surgery. There is no uniform answer as to whether this process is reversible, and further trials are needed to confirm it. And regardless of its outcome, there will be important guidance for clinicians in their work.