IP with new bone formation is extremely rare: only five cases have been reported to date.3–5
In the present study, we document three additional cases of sinonasal IP with new bone formation, its clinical management, and a possible role for BMP in osteogenesis. Calcifications may be classified as entrapped bone structures or as primary tumoral calcifications. Essentially, entrapped bone is a bone fragment enclosed within the tumor that erodes because of pressure atrophy, whereas primary tumorous calcification is calcification created by the tumor itself. Both may appear as calcifications on CT.1,2,4
The histopathological examination revealed no entrapped bone or primary tumor calcification in the current bone structure. The examination showed new bone formation consisting of randomly organized trabeculae lined by osteoblasts. These randomly organized trabeculae were divided with prominent capillaries and mesenchymal cells. In general, however, the entrapped bone should be in a lamellar structure; however, in our case, the bone trabeculae were woven and represented active osteoblast production of newly formed bone. In addition, intraoperative findings showed that the newly generated bone in the tumor was independent of anatomically normal anatomic bone structure. Thus, the current cases were diagnosed as IP with new bone formation. Differential diagnosis for IP with new bone formation might be osteoma or fungal ball. A pathological examination by preoperative biopsy is important for the treatment.
Because IP is rare with accompanying new bone formation, the clinical difference between this disease and common IP is unclear. Aggressiveness has not been shown in the reported cases and in our cases. Generally, the treatment of choice for sinonasal IPs is surgery. To date, many series of sinonasal IPs have been reported,8–11
and different approaches, including lateral rhinotomy with external ethmoidectomy, the Caldwell-Luc approach, midfacial degloving, or ESS, have been used depending on tumor extension.9,10
ESS is now widely accepted and commonly performed in cases requiring nose or paranasal sinus surgery. It provides excellent magnification, illumination, and angled visualization, thereby allowing the surgeon to isolate the base of the tumor and accurately define the extent of disease. Among the five reported cases of IP with new bone formation, two were treated by ESS and three by external approaches. No recurrences have been observed in these cases.3–5
In our cases, two were successfully treated by ESS and one is being followed with watchful waiting. Long-term follow-up of our patients will help in the optimal clinical management of IP with new bone formation.
Another important finding in this report is the appearance of BMP expression in the tumor. This is the first report showing BMP expression in sinonasal IPs. BMPs belong to the transforming growth factor β superfamily that mediates a multitude of developmental processes in various tissues.6
This class of >20 proteins has been shown to have roles in cellular lineage commitment, differentiation, proliferation, patterning/morphogenesis, cellular maintenance/survival, and apoptosis.7,12
BMPs facilitate intramembranous and endochondral bone formation as well as formation of cartilage.13
Although numerous growth factors such as platelet-derived growth factor and vascular endothelial growth factor may be involved in new bone formation, available studies suggest only BMPs are capable of initiating the process.14
By induction differentiation of pluripotent progenitor cells along an osteogenic line, BMPs are able to stimulate osteogenesis at tissues distant from bone, a process termed “osteoinduction.”15
Extensive studies have indicatted that the BMPs with greatest osteogenic capacity are BMP-2, -4, -5, -6, -7, and -9.7,12
BMP-2 plays a key role in osteoblast differentiation, osteogenesis, and chondrogenesis. It is potentially a retinoid mediator and plays a possible role in apoptosis. BMP-2 is also involved in dorsoventral patterning, craniofacial development, and heart development.7
BMP-4 regulates the formation of teeth, limbs, lung, eye, and bone from mesoderm and also plays a role in fracture repair and is involved in dorsoventral patterning and craniofacial development.7
BMP-7 plays a crucial role in osteoblast differentiation, eye development, renal development/repair, and craniofacial development and may play a role in cerebral protection from ischemic stroke.7
In addition to their multifunctional roles in the regulation of cell proliferation, survival, differentiation, and apoptosis, BMPs have shown to be involved in tumorigenesis of various types of tumors by in vivo
and in vitro
Expression of BMPs in tumor tissues has been reported.12,16
BMP-2/-4 was localized predominantly to the cytoplasm of malignant cells with primitive mesenchymal features; no or little BMP is detected in the more differentiated elements of bone and soft tissue sarcomas.16
Different levels of BMP-2/-4 expressions in bone and soft tissue sarcomas have been considered to be associated with the stage of mesenchymal differentiation. The ectopic formation of cartilage and bone mediated by BMP recapitulates the developmental processes that occur in the limb bud.17
BMP is synthesized as precursor molecule consisting of a signal peptide. Mature BMP is then secreted in an active form, with dimerization taking place either intracellulary or extracellulary on secretion. These active molecules bind to BMP type I and type II extracellular surface protein receptors, which have serine–threonine kinase activity. Mesenchymal stem cells have a number of BMP receptors, and through their action, BMPs become potent inducers of osteoblast differentiation from these cells, as shown in vitro
The process of endochondral bone formation is responsible for the majority of the limb skeleton. During this process, mesenchymal stem cells migrate via
chemotaxis, condense, and then differentiate into chondrocytes, which, in turn, lay the extracellular matrix elements of cartilage. Invasion by osteoblasts, osteoclasts, blood vessels, and hematopoietic cells follows. The resulting cartilaginous matrix is then degraded and replaced by bone, completing the endochondral bone formation process.19
BMPs have been shown to facilitate this process, particularly at the mesenchymal stem cell chemotaxis and differentiation stage.19
In addition, BMPs induce proliferation and secretion of extracellular matrix elements in these cells. In this manner, BMPs may self-regulate via
extracellular matrix–ligand binding in addition to their growth functions. The antagonism of BMP activity has particular importance during the osteogenic and chondrogenic embryonic developmental processes.20
Intramembranous bone formation, in which mesenchymal stem cells condense and differentiate into osteoblasts without the formation of a cartilaginous scaffold, is also facilitated by BMPs.20,21
In this manner, BMPs have extensive roles not only in mediating the development of the bone skeleton and its supporting structures, but also in craniofacial development.21
In the present study, IPs with new bone formation expressed BMP-4 but not BMP-2 or BMP-7. These findings suggest that BMP-4 might be involved in the osteogenesis in IPs. IP cells might induce new bone in the stroma via
BMP-4/BMP receptor signaling.
In conclusion, we have described an additional three cases of sinonasal IP with new bone formation. ESS was successful in achieving complete removal of the tumor. BMP-4 might be associated with new bone formation in the tumor.