Non-ossifying Fibroma Research Articles

The Epidemiology of Benign Proliferative Processes of the Skeletal System in Children.

A suspicion of a proliferative bone lesion in a child seems to be a major diagnostic problem for clinicians. There are no diagnostic and treatment algorithms described in the literature and no reliable cohort epidemiological data. Our study was conducted among 289 paediatric patients (0–18 years old) with an initial diagnosis of a bone tumour or tumour-like lesion. The study comprised a retrospective epidemiological analysis, an assessment of the concordance of the initial diagnoses with the histopathological diagnoses and an analysis of the specific locations of the various bone lesions. The results obtained have made it possible to formulate the following conclusions. (1) The most common proliferative bone lesion in children is osteochondroma; also common are fibrous dysplasia, non-ossifying fibromas and bone cysts. (2) Verifying the initial diagnosis by means of biopsy is essential. (3) Osteochondromas are typically located in the metaphyses of long bones, fibrous dysplasia in the femur and skull, cyst-like lesions in the proximal humerus and non-osteochondral fibromas exclusively in the lower limbs. What could improve the quality of treatment for children with primary proliferative bone diseases is the establishment of centres of paediatric orthopaedic oncology skilled in early diagnosis and prompt management.

An Epidemiological Study of Primary Bone Tumors of the Fibula.

Relatively low incidence has led to an under-rating of fibula tumors. This study aimed to evaluate fibula tumors as a whole and to give detailed information based on histological types according to the anatomic location of the tumors in the fibula. Evaluation was made of all the primary bone tumors of the fibula recorded in our bone tumor registry and institute of pathology from 2007 to 2018. Of these, 62 cases were identified. Analysis included assessment of age, gender, tumor localization, the presenting symptoms, the duration of symptoms, and treatment methods. There were 48 (77.4%%) benign and 14 (22.6%) malignant tumors. The most commonly found benign tumors were non-ossifying fibroma (12/48; 25%) and aneurysmal bone cyst (12/48; 25%), and the malignant tumors were chondrosarcoma (3/14; 21.4%) and chondroblastic osteosarcoma (3/14; 21.4%). The most common location for both benign and malignant tumors (58.3%, 71.4%) are the proximal fibula, followed by the distal fibula (27.1%, 28.6%) and the diaphysis (14.6%, 0%). Six (9.7%) patients presented with pathological fibula fractures. Fibular tumors are rarely encountered in clinical practice but are mostly benign, with malignancy determined in approximately a quarter of patients. However, as most benign tumors are asymptomatic, and therefore remain undetected, the actual proportion of malignant tumors will be much lower.

Giant cell tumor of bone in an eighteenth-century Italian mummy

Giant cell tumor (GCT) of the bone is a locally aggressive and rarely metastasizing neoplasm. It is composed of neoplastic mononuclear stromal cells with a monotonous appearance admixed with macrophages and osteoclast-like giant cells. In a small subset of cases, GCT is malignant. Terminology previously related to this entity, and which is no longer supported by the World Health Organization, includes osteoclastoma and benign fibrous histiocytoma (BFH). Giant cells occur in numerous other pathologic conditions of the bone, which accounts for the misrepresentation of these non-GCT tumors in the early literature. Non-ossifying fibroma (NOF), aneurysmal bone cyst, and chondroblastoma have been erroneously labeled GCT for this reason. A single description of an ancient GCT was reported by Brothwell and Sandison and subsequently mentioned by Aufderheide and Rodrìguez-Martìn who were astonished that more of these tumors had not been identified in archaeological cases. To the best of our knowledge, no other cases of ancient GCT have been cited in the paleopathology literature. The study of this type of neoplasm in antiquity can be used as a means to better understand its characteristics and behavior and to expand the depth of time of the etiology of these lesions. We report a case of GCT of the left femur observed following the total body CT imaging of a partially mummified adult female, dating to eighteenth century.

Pathological fracture in paediatric bone tumours and tumour-like lesions: A predictor of benign lesions?

To determine the incidence and causes of pathological fractures in paediatric bone tumours and tumour-like lesions, and to determine if they are predictive of benign lesions. Retrospective review of children with suspected bone tumours referred to a specialist musculoskeletal oncology service between September 2019 and August 2020. Data recorded included patient age and gender, lesion location, the presence of a pathological fracture on the initial plain radiograph, and the final diagnosis made either by image-guided biopsy/curettage or based on typical imaging features. 231 patients were included with 233 lesions (138 males and 93 females with mean age 10.5 years, range 3 months-18 years). Final diagnosis was based on histology in 85 (36.5%) cases and imaging in 148 (63.5%) cases, 52 (22.3%) lesions classed as non-neoplastic, 139 (59.7%) as benign and 42 (18%) as malignant. Pathological fractures were seen in 41 cases (17.6%) at presentation, involving the humerus in 19 (46.3%), the femur in 14 (34.1%), the tibia in 3 (7.3%), the fibula and radius in two each (4.9%) and the second toe proximal phalanx in 1 (2.4%) (p < 0.001). The commonest underlying lesions included simple bone cyst (n = 17; 41.5%) and non-ossifying fibroma (n = 10; 24.4%). Only 4 cases (9.75%) were malignant, one case each of osteosarcoma, Ewing sarcoma, leukaemia and BCOR undifferentiated round cell sarcoma. Pathological fracture occurred in 27.7% of non-malignant lesions and 9.5% of malignant lesions, this difference being statistically significant (p < 0.001). Pathological fractures were seen in 17.6% of paediatric bone tumours, tumour-like lesions, being significantly associated with humeral location and non-malignant diagnosis. Demonstrates the frequency, location and underlying diagnosis of pathological fractures in paediatric bone tumour and tumour-like lesions.

Nonossifying Fibroma of the Distal Tibia: Predictors of Fracture and Management Algorithm.

Nonossifying fibroma (NOF) is a common benign lesion in children and adolescents. This study investigated the risk of pathologic fracture in NOF lesions of the distal tibial based on anatomic location, clinical symptomatology, and imaging features, in order to propose an algorithm for the management of such lesions. In an IRB-approved retrospective case-control study, all patients diagnosed with NOF between 2010 and 2017 were extracted from our database. Patients below 18 years of age at the time of diagnosis and with lesions involving the distal tibia were included. Demographic data, the reason for visit, and the mechanism of injury were recorded. Radiographs were reviewed to record the size (absolute and relative to bone width) and location of each lesion. Computed tomography and magnetic resonance imaging examinations were also reviewed when available. Two authors graded all lesions using the Ritschl classification and determined the presence of 2 novel signs: the syndesmosis sign and the Pac-Man sign. A total of 84 patients were included in the final analysis, of which 25 were in the fracture group and 59 in the nonfracture group. None of the patients in the fracture group was previously diagnosed with NOF, but nine (36%) patients had symptoms for >6 months preceding the fracture. Ankle sprain was the most common reason for visit in the nonfracture group. The lateral location of the lesion in the distal tibia (P=0.001), size (P<0.001 for both absolute and relative values), Ritschl stage (P=0.003), syndesmosis sign (P=0.005), and the Pac-Man sign (P=0.002) were significant predictors of fracture. All measurements had almost-perfect to perfect inter-rater agreements. The most significant imaging risk factors for fracture are a larger size, Ritschl stage B, and the presence of cortical thinning on anteroposterior or lateral radiographs. We introduced 2 signs for these distal tibial NOFs, a scoring system, and a management algorithm that is based on radiographs alone but incorporates advanced imaging findings in equivocal cases. Therapeutic Level III-case-control study.

The Natural History of Benign Bone Tumors of the Extremities in Asymptomatic Children: A Longitudinal Radiographic Study.

Benign bone tumors are common incidental findings in the pediatric population during radiographic evaluation. Counseling these patients requires reassurance and raises questions about the natural history of these tumors over time. The purpose of this study was to estimate the prevalence and observe the behavior of benign childhood bone tumors in an asymptomatic population. A historical, longitudinal radiographic collection of healthy children was reviewed, which included comprehensive left-sided radiographs of the extremities at yearly intervals. In this study, 262 subjects with 25,555 radiographs were screened for benign bone tumors at a median age of 8 years (range, 0 to 18 years). All potential tumors were reviewed by a multidisciplinary panel, which confirmed the radiographic diagnosis of each lesion, the age at which the lesion first appeared, and the age at which it had resolved. Prevalence rates were calculated using the number of distinct subjects available for each radiographic location and age. Thirty-five tumors were identified in 33 subjects, including 19 nonossifying fibromas, 8 enostoses, 6 osteochondromas, and 2 enchondromas. The prevalence rate for all tumors combined increased with age and was 18.9% overall. The overall prevalence rates for specific tumor types were 7.5% for nonossifying fibromas, 5.2% for enostoses, 4.5% for osteochondromas, and 1.8% for enchondromas. Nonossifying fibromas demonstrated a bimodal distribution of prevalence, with a peak at 5 years (10.8%) and another after skeletal maturity (13.3%). The median age at the first appearance for all tumors combined was 9 years (range, 2 to 15 years), but varied by tumor type. Nonossifying fibromas often resolved (7 [37%] of 19), with further resolution possible beyond the last available radiograph. Enostoses, osteochondromas, and enchondromas persisted until the last available radiographs in all subjects. The prevalence of benign childhood bone tumors of the extremities was 18.9% in a historical asymptomatic population. Longitudinal radiographs allowed observation of the timing of the first appearance and the potential for resolution for each tumor type. These findings provide unique evidence to answer many commonly encountered questions when counseling patients and their families on benign bone tumors. Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Monostotic fibrous dysplasia of fibula: a rare case report

&lt;p&gt;Fibrous dysplasia is a developmental anomaly of bone formation that may exist in monostotic or polyostotic form. Monostotic fibrous dysplasia of fibula is a rare case with unusual site and most common sites being facial bones, ribs, proximal femur and tibia. We report a case of 10-year-old boy attended our hospital with occasional pain in left leg while having strenuous activity. On clinical examination there was no obvious swelling with normal appearing skin. Radiographic examination revealed lesion with both radiopaque and radiolucent features showing a “ground-glass” appearing lesion in proximal one third of fibula. Differential diagnosis considered are simple bone cyst, non-ossifying fibroma, osteo-fibrous dysplasia, adamantinoma. As a definitive treatment curettage was done and biopsy sent for histopathological examination, which confirmed he diagnosis. Follow up after 10 months shows normal bone growth as evidenced radiologically and patient is asymptomatic. Case in detail and recent review of literature has been discussed. From our case, we have shown that it is possible to treat uncomplicated fibrous dysplasia with minimally invasive approach of simple curettage. Patient is symptomatically relieved within 2 months without any complications.&lt;/p&gt;

The Clinical and Radiological Outcome of Stages 1 and 2 Enneking Benign Bone Lesions with Pathological Fracture

BackgroundPresentation of benign lesions with a pathological fracture may be confusing to general orthopedic surgeons regarding missing a fracture in a pathological bone, the need for special care for these lesions, and the potential for healing of these fractures. The objective of this work was to evaluate the clinical and radiological outcomes of the treatment of patients with stages 1 and 2 Enneking benign bone-tumors presented with pathological fractures. MethodsThis retrospective study included 66 patients who presented with a pathological fracture through stage 1 or 2 Enneking benign bone lesions and were received at the emergency unit of the orthopedic department between 2014 and 2018. Demographic data and patient's evaluation were collected. Lesion-size (length, width, and depth) was calculated from the X-ray. Surgical intervention was planned in 28 patients. The indication for surgery was either fracture fixation or curettage of the lesion with or without augmentation. There were no repeated surgeries or local recurrences. The filling of the cavity was classified according to modified Neer's classification. ResultsSixty-six patients, 45 males, and 21 females were included. Forty-two affections were right while 24 were left. The mean age was 14.9 ± 8.6 (range, 3-40) years. The most common radiological diagnoses were simple bone-cysts 43.9% (n = 29), followed by non-ossifying fibroma 27.3% (n =18). The mean length of the lesions was 4.4 ± 2.6 (range, 1 - 12) cm, width was 1.6 ± 0.8 (range, 0.3- 4.5) cm, and depth was 1.8 ± 0.9 (range, 0.3 - 5) cm. The mean follow-up was 24.15 ± 18.7 months. Minor complications occurred in 7 patients (10.6%). Fifty-four out of 65 lesions (83%) showed either almost complete or partial filling of the lesions. There was no significant difference regarding the filling of the lesions according to the modified Neer's classification between those who were treated conservatively and those who underwent surgical intervention P-value = 0.783. ConclusionCareful diagnosis of a pathological fracture through stages 1 and 2 Enneking benign bone tumors is essential before initiating treatment. These fractures have good potential for bone healing and a low incidence of complications even with conservative treatment. Special surgical care of the lesion is not mandatory in all situations and should be individualized.Level of evidence: Level III, retrospective.

Utility of P63 in Differentiating Giant Cell Tumor from Other Giant Cell-Containing Lesions.

To assess P63 expression in giant cell-containing lesions of the bone (GCLB) and to determine its utility in differentiating giant cell tumor of the bone (GCTB) from other GCLBs. Cases diagnosed as GCLB on histopathology were included in the study. P63 immunohistochemistry was performed in all the cases. The percentage of cells showing nuclear positivity was assessed in the non-giant cell component. Statistical analysis was performed using the Mann-Whitney U test. Of the total 53 cases studied, the majority were GCTBs (23), followed by 12 cases of chondroblastomas (CBL) and 18 other giant cell lesions (GCLs). All giant cell-containing lesions except one case of CBL and brown tumor of hyperparathyroidism (BTH) showed P63 staining in the non-giant cell component. However, the mean P63 labeling of GCT (52.6%) was higher compared to CBL (28.3%), aneurysmal bone cyst (ABC) (15.2%), non-ossifying fibroma (NOF) (24.5%), giant cell lesion of small bones (GCLSB) (11%), BTH (6.8%) and chondromyxoid fibroma (CMF) (12.3%), with a p-value of < 0.001. Although p63 was present in majority of the GCLBs, its percentage positivity was significantly higher in GCTB compared to the other GCLBs. The diagnosis of GCTB is likely if cut-off value of > 50% is applied.

Displaced distal femur metaphyseal fractures: clinical and radiographic outcome in children aged 6–16 years treated by elastic stable intramedullary nailing

Fractures of the distal femur metaphysis (DFM) are rare. The main objective of this study was to retrospectively evaluate the clinical and radiographic outcomes of displaced DFM fractures in children treated by elastic stable intramedullary nailing (ESIN). We retrospectively reviewed 24 DFM fractures, including five pathological fractures secondary to non-ossifying fibroma (mean age, 10.9 years; range, 6-16) who underwent surgical treatment by ESIN. The patients were followed radiographically and clinically on a regular basis. Sixteen boys and eight girls were included in the study. Radiographically, all fractures healed, but five healed with complications. Most of the DFM fractures were transverse (n = 18, 75%), and all patients but two (91.7%) underwent closed reduction and stabilization of the fracture. All the patients were pain-free at their last follow-up. All regained full normal activities, although five patients developed a postoperative complication (20.8%). At the last follow-up visit, all fractures achieved union including the two cases of nonunion; moreover, none of the patients showed any signs of growth arrest or disturbances in radiological and clinical assessment. On the ESIN outcome measure scale, 12/24 patients (50%) had excellent results, 11/24 (45.8%) had good-satisfactory results and 1/24 (4.2%) had poor results. Fracture of the DFM can be challenging due to the relatively short length of the distal fragment, the proximity of the growth plate and the tendency of the distal fragment to displace. Following the surgical principles and understanding the anatomical constraints of the distal femur help to obtain satisfactory clinical and radiological results.

H3F3A G34 mutation DNA sequencing and G34W immunohistochemistry analysis in 366 cases of giant cell tumors of bone and other bone tumors.

H3F3A mutations and the expression of glycine 34 to tryptophan (G34W) mutants in giant cell tumors of bone (GCTBs) and other bone tumors were detected to compare H3F3A mutation types and the expression of G34W-mutant protein in order to provide a theoretical basis for using H3F3A mutations as a diagnostic and differential-diagnostic tool for GCTBs. A total of 366 bone tumor cases were investigated. The cases involved 215 men and 151 women, whose median age was 29 years (3-84). The cases included GCTB (n=180), recurrent GCTB (n=19), GCTB with lung metastasis (n=5), pediatric GCTB (n=15), primary malignant GCTB (n=5), chondroblastoma (CB, n=61), chondrosarcoma grade II (n=15), dedifferentiated chondrosarcoma (n=17), chondromyxoid fibroma (n=9), aneurysmal bone cyst (n=9), nonossifying fibroma (n=9), osteosarcoma (n=16), and undifferentiated sarcoma (n=6). Sanger DNA sequencing analysis was used to detect H3F3A mutations. Immunohistochemistry was used to assess the expression of the G34W-mutated protein in these bone tumors. DNA sequencing results revealed H3F3A mutations in 95.00% of GCTBs (171/180), including glycine 34 to tryptophan (G34W, 163/180, 90.56%), glycine 34 to leucine (G34L, 3/180, 1.67%), glycine 34 to valine (G34V, 3/180, 1.67%), and glycine 34 to arginine (G34R, 2/180, 1.11%). Recurrent GCTBs mostly had the H3F3A G34W mutation (18/19, 94.74%), and GCTBs with lung metastasis all had the H3F3A G34W mutation (5/5, 100%). Pediatric GCTBs had a mutation rate of 93.33% (14/15), including one case with G34L. Four cases of primary malignant GCTB showed the H3F3A G34W mutation (4/5, 80.00%), and the classical GCTB component and malignant component showed consistent mutation types. Immunohistochemistry showed that GCTBs harboring G34W also expressed the mutant protein in tumor cell nuclei. Furthermore, one case of GCTB and one case of recurrent GCTB showed positive G34W immunostaining results despite being negative for the genetic mutation. Other bone tumors all showed wild-type expression in both DNA sequencing and immunohistochemistry. Our large-sample DNA sequencing analysis detected four different forms of mutations in GCTBs, including three rare mutation forms. The most common mutation of H3F3A was G34W, which was in accordance with the expression of G34W in GCTBs detected by immunohistochemistry. Although DNA sequencing analysis detected rare mutation types of H3F3A, false-negative results were also present due to the small number of cells in the samples. Detection of the most common (G34W) mutant protein by immunohistochemistry was more convenient. Given the high prevalence of these driver mutations, the detection of H3F3A mutant proteins can assist in the diagnosis of GCTB and its differential diagnosis from other bone tumors.

Tumor-like bony lesions of the skeleton

Tumor-like bony lesions are, by definition bony lesions, which can be clinically, radiologically and histologically mistaken for real bone tumors. This article presents the aneurysmal bone cyst (ABC), solitary bone cyst (SBC), fibrous dysplasia, osteofibrous dysplasia Campanacci and non-ossifying fibroma (NOF). Many tumor-like bony lesions are often incidental findings. The combination of X‑ray imaging specifically supplemented by magnetic resonance imaging (MRI) or computed tomography (CT) enables a diagnostic classification in the majority of cases.

Comparison of characteristic features and local recurrence in syndromic versus non-syndromic multifocal non-ossifying fibroma

BackgroundMultiple non-ossifying fibromas (MNOF) could be presented with other extraskeletal anomalies (syndromic) or not (non-syndromic). In this study, we aimed to compare characteristic features and local recurrence between symptomatic syndromic and non-syndromic MNOFs. MethodsThirty-five patients with symptomatic MNOF were included in this study, comprised of 30 patients without the café-au-lait spot (non-syndromic) and five with café-au-lait spots plus other signs of neurofibromatosis type 1 (syndromic). Characteristic features of the patients and lesions were compared between syndromic and non-syndromic MNOFs. The lesions were treated with curettage and bone graft. The rate of local recurrences was also compared between the two groups of syndromic and non-syndromic MNOF. ResultsStudy population included 19 (54.3%) males and 16 (45.7%) females with the mean age of 7.63 ± 3.1 years (range 4–11). The mean follow-up of the patients was 65.6 ± 38.2 months (range 24–96). The lesion was bilateral in 13.3% of non-syndromic MNOFs and 80% of syndromic MNOFs. This difference was statistically significant (p = 0.01). After curettage and bone grafting, the lesion recurred in 6.7%of non-syndromic MNOFs and 60% of the syndromic MNOF. This difference was statistically significant, as well (p = 0.01). No other significant difference was found between syndromic and non-syndromic MNOFs. ConclusionsThe syndromic form of MNOF is much less prevalent and is associated with a higher rate of recurrence after surgical removal. Therefore, a more rigorous removal of the MNOF lesions might be necessary when presented in a syndromic context.

Tumorähnliche Knochenläsionen des Skeletts

Tumor-like bony lesions are, by definition bony lesions, which can be clinically, radiologically and histologically mistaken for real bone tumors. This article presents the aneurysmal bone cyst (ABC), solitary bone cyst (SBC), fibrous dysplasia, osteofibrous dysplasia Campanacci and non-ossifying fibroma (NOF). Many tumor-like bony lesions are often incidental findings. The combination of X‑ray imaging specifically supplemented by magnetic resonance imaging (MRI) or computed tomography (CT) enables a diagnostic classification in the majority of cases.

KRAS mutations in brown tumor of the jaws in hyperparathyroidism.

Brown tumors are giant cell-rich lesions that result from abnormal bone metabolism in hyperparathyroidism, one of the most common endocrine disorders worldwide. Brown tumors occasionally affect the jaws and, despite well-known clinical and microscopic features, their molecular pathogenesis remains unclear. We investigated the presence of pathogenic activating mutations in TRPV4, FGFR1, and KRAS in a cohort of brown tumors since these have recently been reported in giant-cell lesions of the jaws and non-ossifying fibromas of the bones (FGFR1 and KRAS), which are histologic mimics of brown tumors. We target sequenced 13 brown tumors of the jaws associated with primary or secondary hyperparathyroidism. As mutations in these genes are known to activate the MAPK/ERK signaling pathway, we also assessed the immunostaining of the phosphorylated form of ERK1/2 (pERK1/2) in these lesions. KRAS pathogenic mutations were detected in seven cases (p.G12V n=4, p.G12D n=1, p.G13D n=1, p.A146T n=1). KRAS variants of unknown significance (VUS), p.A134T and p.E37K, were also detected. All samples showed wild-type sequences for FGFR1 and TRPV4 genes. The activation of the MAPK/ERK signaling pathway was demonstrated by pERK1/2 immunohistochemical positivity of the brown tumors´ mononuclear cells. Mutations in KRAS and activation of the MAPK/ERK signaling pathway were detected in brown tumors of hyperparathyroidism of the jaws, expanding the spectrum of giant cell lesions whose molecular pathogenesis involve RAS signaling.

Jaffe-Campanacci syndrome or neurofibromatosis type 1: a case report of phenotypic overlap with detection of NF1 gene mutation in non-ossifying fibroma

BackgroundJaffe-Campanacci syndrome is characterized by multiple non-ossifying fibromas, café-au-lait macules and giant cell granulomas of the jaw. Even if the association between all these peculiar features and neurofibromatosis type 1 have been described, it has not yet been clarified whether Jaffe-Campanacci syndrome represents a distinct entity or it can be regarded as a neurofibromatosis type 1 subtype.Case presentationThe patient here described is a young boy, who fulfilled the clinical diagnostic criteria for both syndromes. He had a complex clinical history with café-au-lait macules, axillary and inguinal freckling, multiple non-ossifying fibromas, giant-cell granuloma of the jaw, neurofibromas, plexiform fibroma, ocular Lisch nodules, optic chiasmatic- hypothalamic glioma, pseudarthrosis, scoliosis, short stature, vascular anomalies, seizures. Molecular analysis of the NF1 gene both on blood cells and non-ossifying fibroma’s biopsy tissue allowed the detection of a novel variant within the coding region, NM_000267.3:c.2789_2791delATC(p.Tyr930_Pro931delinsSer), with loss of heterozygosity (second hit mutation) in the non-ossifying fibroma.ConclusionThis result indicates that every patient with clinical features of Jaffe-Campanacci syndrome should be further evaluated to detect features related to neurofibromatosis type 1 and genetically investigated for mutations in the NF1 gene, since this could lead to a definite diagnosis, but also could clarify and quantify the real genotype-phenotype overlap between neurofibromatosis type 1 and Jaffe-Campanacci syndrome.

SAT-LB68 A Rare De Novo Mutation in LRP5 Gene in an Adolescent Female With Juvenile Onset Primary Osteoporosis

Background: Juvenile onset of primary osteoporosis is a rare skeletal disorder with a highly heterogenous clinical presentation and complex poorly understood genetic etiology. Low-density lipoprotein receptor-related protein 5 (LRP5), a Wnt-β-catenin pathway receptor involved in bone mineral density (BMD) regulation, has been reported in children with primary osteoporosis mainly due to missense and frame-shift mutations. To our knowledge, there is only one report of in-frame deletions in exon 21 possibly being implicated in pregnancy related osteoporosis (1). We report the first case of a rare heterozygous de novo in-frame deletion in exon 21 of LRP5 gene in a girl with juvenile onset primary osteoporosis. Clinical Case: A 7.5 yo previously healthy European-African-American female born to non-consanguineous family, was noted to have left ankle and bilateral wrists fractures during sport activities occurring over the span of 1 y. On exam, she was of normal stature, had normal sclerae and vision, but was found to have hypermobile joints. Initial blood work revealed an elevated iPTH 72 pg/mL (9-59), normal Ca 9.6 mg/dL (8.9-10.4), and low 25OH-Vitamin D 17 ng/mL (30-100), which normalized with supplementation to 30.4 ng/mL. By 10.5 yo, she had sustained multiple sports related and pathologic fractures of long bones with progressive bone pain and functional ambulatory impairment. Radiographic evaluation showed osteopenia, multiple healed long bone fractures with presumed non-ossifying fibroma in the distal right femoral metaphysis, and subtle height loss of T4-5 vertebrae. CT bone densitometry at 12 yo showed low mean cancellous lumbar vertebral BMD of 190 mg/cm3 (ref. 285 ± 45) and normal cortical BMD of the femoral midshaft of 1977 mg/cm3 (ref. 2000 ± 60). Genetic testing for Osteogenesis Imperfecta returned negative for COL1A1 and COL1A2 mutations. Whole exome sequencing (WES) revealed a rare, de novo heterozygous mutation in exon 21 that involved deletion of nucleotides 4454 to 4465 resulting in an in-frame deletion of amino acid 1485 to 1488. This mutation is predicted to be deleterious by in silico analysis. Conclusion: We present the first case of a young female with progressive pathologic fractures, functional ambulatory impairment, and low BMD in childhood, consistent with juvenile onset primary osteoporosis. WES revealed a rare de novo heterozygous in-frame deletion mutation in LRP5, providing a plausible biological mechanism for her clinical presentation, and further contributing to the increasing genetic heterogeneity of juvenile onset primary osteoporosis and LRP5-related bone disorders. Reference: (1) Cook, F., Mumm, S., Whyte, M., Wenkert, D. Pregnancy-associated osteoporosis with a heterozygous deactivating LDL receptor-related protein 5 (LRP5) mutation and a homozygous methylenetetrahydrofolate reductase (MTHRF) polymorphism. JBMR. 2014;29 (4): 922-8.

SATB2 is frequently expressed in ossifying and non-ossifying peripheral oral fibroma of the gingival region but not in reactive fibromatous lesions from other intraoral sites

Ossifying and non-ossifying peripheral oral fibromas (POF) of the gingival and alveolar mucosa are localized, cellular, small fibrous nodular lesions likely resulting from diverse external/ internal physical and chemical irritation or injuries. A central nidus of metaplastic woven bone characterizes and defines the ossifying variant. The inherent tendency of these lesions to ossify remains elusive. We herein analyze SATB2 expression as osteoblastic transcription and differentiation factor in 28 gingival POFs (10 of them ossifying) and compare them to 28 fibrous lesions from different non-gingival intraoral sites. Strong to moderate diffuse nuclear SATB2 immunoreactivity was detected in all ossifying (10/10; 100%) and in 8/18 (44%) non-ossifying gingival POFs, but in only 1/28 (3%) non-gingival oral reactive nodular fibrous lesions. This study illustrates for the first-time consistent expression of the osteoblastic marker SATB2 in ossifying and most of non-ossifying POFs of the gingival area but lack of this marker in reactive fibrous lesions from other oral cavity sites. This finding is in line with the proposed origin of gingival POFs from periodontal ligaments and may explain the frequent ossification observed in them. It is mandatory to consider this finding when assessing biopsies from SATB2-positive oral cavity neoplasms to avoid misinterpretation.

Spectrum of histological features of Denosumab treated Giant Cell Tumor of Bone; potential pitfalls and diagnostic challenges for pathologists

ObjectivesDenosumab is Receptor Activator of Nuclear factor Kappa-B Ligand (RANKL) inhibitor which is being used in the treatment of locally advanced, recurrent and metastatic Giant Cell Tumor of Bone (GCTB). It causes reduction in monocyte recruitment and Osteoclast-Like Giant Cell (OLGC) formation which limits bone destruction. After Denosumab treatment, GCTB exhibit diverse morphological features which can pose diagnostic challenge.Our aim was to study the spectrum of histologic features seen in Denosumab treated GCTB which could be helpful in establishing correct diagnosis. MethodsWe retrieved and reviewed H&E stained microscopic glass slides of 38 GCTB cases who received Denosumab as neoadjuvant treatment. These cases were treated at different institutes and diagnosed at our institute between January 2017 and October 2019. Morphologic features such as presence of residual OLGC, appearances of mononuclear stromal and bony components were assessed along with other non-specific features. ResultsPatients' median age was 29 years. Male to female ratio was 1.53:1. Femur was the most commonly involved bone. Microscopically, peripheral shell of reactive bone was observed in all cases. In 20 (52.6%) cases, there was complete elimination of OLGC. Mononuclear stromal cells were predominantly bland spindle shaped and arranged in fascicular and storiform patterns. Focal atypia was noted in 3 cases. Bony component manifested as trabeculae of woven bone with osteoblastic rimming and immature trabeculae of unmineralized osteoid with haphazardly present osteoblasts.Spectrum of stromal changes included cystic spaces, foamy macrophages, inflammatory infiltrate, hemangiopericytoma-like (HPC-like) vessels, hyalinization, edematous areas and hemosiderin pigment.The tumors showed areas which resembled other bony and soft tissue lesions such non-ossifying fibroma, fibrous dysplasia, osteoblastoma, sclerosing epithelioid fibrosarcoma and osteosarcoma. ConclusionDenosumab treatment induces a variety of changes in GCTB. Clinical history and knowledge of these features are necessary for excluding differential diagnoses and avoiding misdiagnosis.

Nonossifying Fibroma

Nonossifying Fibroma