Expression of RANKL in breast cancer tissue in patients with fibrous dysplasia/McCune-Albright syndrome.

BACKGROUND: In fibrous dysplasia/McCune-Albright syndrome (FD/MAS), mosaic mutations in the GNAS gene lead to locally abnormal bone turnover. Additionally, patients with FD/MAS, particularly with thoracic lesions, have an increased risk for breast cancer. Development and progression of breast cancer has been associated with expression of Receptor Activator of NF-κB ligand (RANKL) in mammary tissue, and due to the GNAS mutation, RANKL is systemically increased in patients with FD/MAS. Yet it is unknown whether breast cancer in FD/MAS is also dependent on RANKL. We hypothesized that the GNAS mutation might induce RANKL overproduction and an oncogenic niche in mammary tissue, and examined RANKL expression in breast cancer tissue of patients with FD/MAS compared to controls. METHODS: Nine patients with FD/MAS and breast cancer were included and clinical data were retrieved. Patients were matched to controls with breast cancer without FD/MAS based on age and tumor type. Three pregnant breast cancer patients were included as positive controls. Immunohistochemical detection of RANKL was performed on formalin-fixed paraffin-embedded breast cancer specimens. Staining intensity was classified as weak, moderate or intense. The area of positive RANKL staining divided by the total ductal-lobular area was assessed (positive area percentage, PAP). Number of patients with RANKL expression was compared between FD/MAS and control group by chi-square (χ2) test, the PAP by Mann-Whitney U test (MWU). RESULTS: RANKL expression was observed in 3 patients with FD/MAS (38 %), mainly in healthy tissue, and none of the control patients (χ2p = 0.055). The FD/MAS group demonstrated considerably more intense staining than the control group, comparable to positive controls. The median PAP was 0.64 % (range 0.14-2.04 %) in the 3 FD/MAS patients with RANKL expression, 0.01 % (Q1-Q3: 0.0003-0.514 %) in the entire FD/MAS group, 0.006 % (Q1-Q3: 0.001-0.012 %) in the control group (MWU = 0.574), and 0.19 % (0.08-0.32 %) in the pregnant patients. All patients with FD/MAS and RANKL expression had thoracic bone lesions, but no correlation was observed between RANKL expression and presence of the GNAS mutation or FD disease burden. CONCLUSIONS: The triad of a higher number of patients, higher positive area percentage and stronger intensity in the FD/MAS compared to the control group indicates that RANKL may be upregulated in mammary tissue in a subset of patients with FD/MAS, which may explain the increased risk for breast cancer, although the clinical significance remains unclear. Further research is needed to establish risk profiles for the development of RANKL-positive breast cancer and to improve early screening and treatment.

Extent of Extraskeletal Manifestations of Fibrous Dysplasia/McCune-Albright Syndrome in Patients with Mazabraud's Syndrome.

Mazabraud's syndrome (MZB) is a rare condition in which fibrous dysplasia of bone/the McCune-Albright syndrome (FD/MAS) co-exists with intramuscular myxomas. Both FD and the myxomas harbor the GNAS-mutation. Recent studies have shown that extraskeletal, GNAS-related features are associated with a more severe phenotype of FD/MAS. However, patients with MZB are often only seen by orthopedic surgeons. We therefore evaluated MZB patients seen in tertiary referral centers from the Netherlands (LUMC), USA (National Institutes of Health) and France (INSERM UMR 1033 (Lyos), Hôpital Edouard Herriot). All FD/MAS patients known in these centers with an additional diagnosis of a myxoma were included. Demographic information and data on disease extent and extraskeletal manifestations of FD/MAS such as precocious puberty (PP) or café-au-lait patches (CAL) were retrieved from patient's medical records. Thirty MZB patients were included: 20 women (67%) and 10 men (33%). Patients received a diagnosis of MZB (median 42 years, range 16-19) significantly later than the diagnosis of FD/MAS (median 30 years, range 0-60), p < 0.01. Twenty-six patients were diagnosed with polyostotic disease (87%). In 97% the myxoma was located near the skeletal FD lesion. The combination of MZB and MAS was made in 13 patients in whom PP (n = 7), CAL (n = 7), GH-excess (n = 3) and hyperthyroidism (n = 3) were present. Other extraskeletal features were (multinodular) goiter (n = 2) and thyroid cysts (n = 1). Furthermore, in this cohort of patients with MZB several (pre-)malignant tumors were observed; ductal carcinoma in situ of the breast in 3 patients (10%), breast cancer in 1 patient (3.3%), intra pancreatic mucinous neoplasms in 3 patients (10%) and liver adenomas in 2 patients (6.6%). A total of 47% of patients with MZB had an additional extraskeletal feature such as an endocrinopathy. In MZB, 87% of patients suffer from polyostotic FD, 43% of patients have extraskeletal GNAS-features such as an hyperfunctioning endocrinopathy and 30% (pre-)malignant tumors. We therefore advocate that MZB patients should undergo a complete screening and long-term follow-up for extent of bone disease, but also extraskeletal GNAS features of FD/MAS.

Increased Prevalence of Malignancies in Fibrous Dysplasia/McCune-Albright Syndrome (FD/MAS): Data from a National Referral Center and the Dutch National Pathology Registry (PALGA).

Malignant transformation of fibrous dysplasia lesions has been reported in patients with fibrous dysplasia/McCune-Albright syndrome (FD/MAS). Recently, we have observed an increased risk for breast cancer. In this study, the prevalence of skeletal and extraskeletal malignancies in patients with FD/MAS in the Netherlands was assessed by analyzing data from our cohort of FD/MAS patients, the Dutch Pathology Registry (PALGA), and the Netherlands Cancer Registry (NCR). We extracted data on sex, age at diagnosis of FD/MAS, type of FD/MAS, type of malignancy, and age at diagnosis of malignancy and histology of bone and malignant tissue when available, including GNAS-mutation analysis from patients' medical records. Standardized Morbidity Ratios (SMRs) with 95% confidence intervals were calculated. Twelve malignancies were identified in the LUMC FD/MAS cohort and 100 in the PALGA cohort. In this cohort, SMR was increased for osteosarcoma (19.7, 95% CI 3.5-48.9), cervical cancer (4.93, 95%CI 1.7-8.2), thyroid cancer (3.71, 95% CI 1.1-7.8), prostate cancer (3.08, 95% CI 1.8-4.6), and melanoma (2.01, 95%CI 1.2-3.1). SMRs for pancreatic cancer or hepatocellular carcinoma could not be calculated due to low numbers. The small number of malignancies identified in our FD/MAS cohort precluded the calculation of SMRs for our cohort specifically. Our findings show that patients with FD/MAS appear to have an increased risk for osteosarcoma, cervical, thyroid, and prostate cancer and melanoma. However, these data should be interpreted with caution, as true incidence rates of the identified malignancies may be influenced by the inclusion of only patients with histologically confirmed FD/MAS. The etiology of this increased risk for malignancies still needs to be elucidated.

Passive Coping Strategies Are Associated With More Impairment In Quality Of Life In Patients With Fibrous Dysplasia.

Impairments in quality of life (QoL) have been reported in patients with fibrous dysplasia (FD). Here, we examine coping strategies in FD and assess whether these coping strategies are associated with QoL and disease severity. Ninety-two patients (66% females) filled out the Utrecht Coping List (UCL), Short Form-36, and the Brief Pain Inventory (BPI). Coping strategies of patients with FD were compared with reference data from a random sample of Dutch women and patients with chronic pain. Compared to healthy adults, patients expressed more emotions (p < 0.01). Compared to patients with chronic pain, patients with FD used more active coping strategies (p < 0.001), and sought more distraction (p = 0.01) and more social support (p < 0.001). Using more passive coping strategies was associated with more impairment in social function, physical role, mental health, vitality (all p < 0.001), and general health (p < 0.01). Using more avoidant coping strategies was associated with worse mental health and less vitality (both p < 0.01). More expression of emotions was associated with worse mental health (p < 0.01). Type and clinical severity of FD were not associated with coping behavior. Patients with FD have different coping strategies compared to random Dutch reference populations with or without pain. In FD, using more passive coping strategies was associated with more impairment in several aspects of QoL. There was no relationship between coping behavior and clinical characteristics, pointing to biomedical variables not determining the way patients cope with their illness. Recognition of less effective coping strategies can be helpful in the understanding and adaptation of these coping strategies, improving personalized clinical care, with the ultimate goal to improve QoL in patients with FD.

Illness Perceptions are Associated with Quality of Life in Patients with Fibrous Dysplasia.

Fibrous dysplasia (FD) is a rare bone disorder in which normal bone is replaced by fibrous tissue resulting in pain, deformities, pathological fractures or asymptomatic disease. Illness perceptions are patients' cognitions and emotions about their illness and its treatment, which may impact on Quality of Life (QoL). Here, we explore illness perceptions in patients with FD compared to other disorders, identify factors associated with illness perceptions and evaluate their relationship with QoL. Ninety-seven out of 138 eligible patients from the LUMC FD cohort completed the Illness Perception Questionnaire-Revised (IPQ-R) and the Short Form-36 (SF-36). Age, Gender, Skeletal Burden Score (SBS), FGF-23 levels, type of FD and SF-36 scores were analysed for an association with illness perceptions. We observed significant (p < 0.01) differences in patients' illness perceptions between FD subtypes in the domains: identity, timeline acute/chronic and consequences. Patients with craniofacial FD reported to perceive more consequences (p = 0.022). High SBS was associated with perceiving more negative consequences and attributing the cause of FD to psychological factors (p < 0.01), and high FGF-23 levels with attributing more symptoms to the disease and perceiving more consequences (p < 0.01). The IPQ-R domain identity, timeline acute/chronic, timeline cyclical, consequences, emotional representations and treatment control were significantly associated with impairments in QoL. Illness perceptions in patients with FD relate to QoL, differ from those in patients with other disorders, and are associated with disease severity. Identifying and addressing maladaptive illness perceptions may improve quality of life in patients with FD.

[Fibrous dysplasia: a heterogeneous disease]. / Fibreuze dysplasie: een heterogeen ziektebeeld.

Fibrous dysplasia is a rare genetic bone disorder with a wide variation in clinical expression, ranging from asymptomatic patients to severely affected patients with extensive bone disease, pain, repetitive fractures and deformities and serious endocrinological symptoms (McCune-Albright syndrome). Here, we report on three different cases of fibrous dysplasia. First, a 46-year-old woman with a small solitary lesion in the proximal femur. Second, a 25-year-old man with polyostotic disease of the left leg who received both surgical and medical treatment. Third, a 7-year-old girl with McCune-Albright syndrome who was diagnosed with precocious puberty as a baby and who had extensive disease throughout the skeleton, including multiple lesions in the craniofacial region. The aetiology, clinical expression, diagnostic work-up and therapeutic options for fibrous dysplasia are discussed in a short résumé of the disease.