Bizarre Parosteal Osteochondromatous Proliferation: <Emphasis Type="Italic">A Locally Aggressive Benign Tumor</Emphasis>

Background  

Bizarre parosteal osteochondromatous proliferation (BPOP) is a benign lesion of bone, and numerous questions remain unresolved regarding its etiology, diagnosis, and treatment.     

RAGE Gene Deletion Inhibits the Development and Progression of Ductal Neoplasia and Prolongs Survival in a Murine Model of Pancreatic Cancer

Background

The receptor for advanced glycation end-products (RAGE) is implicated in pancreatic tumorigenesis. Activating Kras mutations and p16 inactivation are genetic abnormalities most commonly detected as pancreatic ductal epithelium progresses from intraepithelial neoplasia (PanIN) to adenocarcinoma (PDAC).

Objective

The aim of this study was to evaluate the effect of RAGE (or AGER) deletion on the development of PanIN and PDAC in conditional Kras ^G12D mice.

Materials and Methods

Pdx1-Cre; LSL-Kras ^G12D/+ mice were crossed with RAGE ^?/? mice to generate Pdx1-Cre; LSL-Kras ^G12D/+ ; RAGE ^?/? mice. Pdx1-Cre; LSL-Kras ^G12D/+; p16 ^Ink4a?/? mice were crossed with RAGE ^?/? mice to generate Pdx1-Cre; LSL-Kras ^G12D/+; p16 ^Ink4a?/?; RAGE ^?/? mice. Pancreatic ducts were scored and compared to the relevant RAGE ^+/+ controls.

Results

At 16?weeks of age, Pdx1-Cre; LSL-Kras ^G12D/+; RAGE ^?/? mice had significantly fewer high-grade PanIN lesions than Pdx1-Cre; LSL-Kras ^G12D/+; RAGE ^+/+ controls. At 12?weeks of age, none of the Pdx1-Cre; LSL-Kras ^G12D/+; p16 ^Ink4a?/?; RAGE ^?/? mice had PDAC compared to a 45.5% incidence of PDAC in Pdx1-Cre; LSL-Kras ^G12D/+; p16 ^Ink4a?/?; RAGE ^+/+ controls. Finally, Pdx1-Cre; LSL-Kras ^G12D/+; p16 ^Ink4a?/?; RAGE ^?/? mice also displayed markedly longer median survival.

Conclusion

Loss of RAGE function inhibited the development of PanIN and progression to PDAC and significantly prolonged survival in these mouse models. Further work is needed to target the ligand?CRAGE axis for possible early intervention and prophylaxis in patients at risk for developing pancreatic cancer.     

Independent Roles of Estrogen Deficiency and Cellular Senescence in the Pathogenesis of Osteoporosis: Evidence in Young Adult Mice and Older Humans

Estrogen deficiency is a seminal mechanism in the pathogenesis of osteoporosis. Mounting evidence, however, establishes that cellular senescence, a fundamental mechanism that drives multiple age-related diseases, also causes osteoporosis. Recently, we systematically identified an accumulation of senescent cells, characterized by increased p16^Ink4a and p21^Cip1 levels and development of a senescence-associated secretory phenotype (SASP), in mouse bone/marrow and human bone with aging. We then demonstrated that elimination of senescent cells prevented age-related bone loss using multiple approaches, eg, treating old mice expressing a “suicide” transgene, INK-ATTAC, with AP20187 to induce apoptosis of p16^Ink4a-senescent cells or periodically treating old wild-type mice with “senolytics,” ie, drugs that eliminate senescent cells. Here, we investigate a possible role for estrogen in the regulation of cellular senescence using multiple approaches. First, sex steroid deficiency 2 months after ovariectomy (OVX, n = 15) or orchidectomy (ORCH, n = 15) versus sham surgery (SHAM, n = 15/sex) in young adult (4-month-old) wild-type mice did not alter senescence biomarkers or induce a SASP in bone. Next, in elderly postmenopausal women, 3 weeks of estrogen therapy (n = 10; 74 ± 5 years) compared with no treatment (n = 10; 78 ± 5 years) did not alter senescence biomarkers or the SASP in human bone biopsies. Finally, young adult (4-month-old) female INK-ATTAC mice were randomized (n = 17/group) to SHAM+Vehicle, OVX+Vehicle, or OVX+AP20187 for 2 months. As anticipated, OVX+Vehicle caused significant trabecular/cortical bone loss compared with SHAM+Vehicle. However, treatment with AP20187, which eliminates senescent cells in INK-ATTAC mice, did not rescue the OVX-induced bone loss or alter senescence biomarkers. Collectively, our data establish independent roles of estrogen deficiency and cellular senescence in the pathogenesis of osteoporosis, which has important implications for testing novel senolytics for skeletal efficacy, as these drugs will need to be evaluated in preclinical models of aging as opposed to the current FDA model of prevention of OVX-induced bone loss. © 2019 American Society for Bone and Mineral Research.     

Popliteal pseudoaneurysm caused by Nora's lesion of the femur in a young child: A rare presentation and first report

Bizarre parosteal osteochondromatous proliferation (BPOP), or Nora's lesion, was first described by Nora et al. in 1983 as a rare, tumor-like lesion involving the bones of the hands and feet. Popliteal artery pseudoaneursyms in the pediatric population are also unusual. Here, we present a case of a young male with a popliteal artery pseudoaneurysm and distal femur lesion originally thought to be an osteochondroma. A 10-year old, Caucasian male was referred to our facility following an MRI concerning for a popliteal artery pseudoaneurysm. On physical exam, there was a palpable 5 × 5-cm pulsatile mass in the upper popliteal fossa with a normal pulse exam bilaterally. A computed tomographic angiogram demonstrated a 4.5-cm by 1.8-cm by 3.6-cm pseudoaneurysm adherent to a 3.5-cm thick, exostotic lesion of the posterior right femur. He was taken to the operating room for repair of the popliteal pseudoaneurysm and resection of his bone lesion. The final pathology was consistent with a popliteal pseudoaneurysm, osteochondroma, and bizarre parosteal osteochondromatous proliferation (BPOP), otherwise known as Nora's lesion. The location of the lesion and the age of our patient were both atypical for BPOP and to our knowledge, this represents the first report of a resulting popliteal artery pseudoaneurysm.     

Bizarre parosteal osteochondromatous proliferation (Nora's lesion): two cases

The lesion Nora described in 1983 as a bizarre parosteal osteochondromatous proliferation (BPOP) is a member of a group of osteocartilaginous surface lesions. BPOP is infrequent but new cases are regularly reported. We report two new cases with an unusual localization (ilion and distal humerus) and unusual size (9 cm for the iliac lesion). In light of these cases and reports in the literature, the main differential diagnoses of BPOP are exostosis and parosteal osteosarcoma.     

Progressive Cellular Senescence Mediates Renal Dysfunction in Ischemic Nephropathy

BackgroundPeripheral vascular diseases may induce chronic ischemia and cellular injury distal to the arterial obstruction. Cellular senescence involves proliferation arrest in response to stress, which can damage neighboring cells. Renal artery stenosis (RAS) induces stenotic-kidney dysfunction and injury, but whether these arise from cellular senescenceand their temporal pattern remain unknown.MethodsChronic renal ischemia was induced in transgenic INK-ATTAC and wild type C57BL/6 mice by unilateral RAS, and kidney function (in vivo micro-MRI) and tissue damage were assessed. Mouse healthy and stenotic kidneys were analyzed using unbiased single-cell RNA-sequencing. To demonstrate translational relevance, cellular senescence was studied in human stenotic kidneys.ResultsUsing intraperitoneal AP20187 injections starting 1, 2, or 4 weeks after RAS, selective clearance of cells highly expressing p16^Ink4a attenuated cellular senescence and improved stenotic-kidney function; however, starting treatment immediately after RAS induction was unsuccessful. Broader clearance of senescent cells, using the oral senolytic combination dasatinib and quercetin, in C57BL/6 RAS mice was more effective in clearing cells positive for p21 (Cdkn1a) and alleviating renal dysfunction and damage. Unbiased, single-cell RNA sequencing in freshly dissociated cells from healthy and stenotic mouse kidneys identified stenotic-kidney epithelial cells undergoing both mesenchymal transition and senescence. As in mice, injured human stenotic kidneys exhibited cellular senescence, suggesting this process is conserved.ConclusionsMaladaptive tubular cell senescence, involving upregulated p16 (Cdkn2a), p19 (Cdkn2d), and p21 (Cdkn1a) expression, is associated with renal dysfunction and injury in chronic ischemia. These findings support development of senolytic strategies to delay chronic ischemic renal injury.     

Age-Dependent Decline in ��-Cell Proliferation Restricts the Capacity of ��-Cell Regeneration in Mice

OBJECTIVE

The aim of this study was to elucidate whether age plays a role in the expansion or regeneration of β-cell mass.

RESEARCH DESIGN AND METHODS

We analyzed the capacity of β-cell expansion in 1.5- and 8-month-old mice in response to a high-fat diet, after short-term treatment with the glucagon-like peptide 1 (GLP-1) analog exendin-4, or after streptozotocin (STZ) administration.

RESULTS

Young mice responded to high-fat diet by increasing β-cell mass and β-cell proliferation and maintaining normoglycemia. Old mice, by contrast, did not display any increases in β-cell mass or β-cell proliferation in response to high-fat diet and became diabetic. To further assess the plasticity of β-cell mass with respect to age, young and old mice were injected with a single dose of STZ, and β-cell proliferation was analyzed to assess the regeneration of β-cells. We observed a fourfold increase in β-cell proliferation in young mice after STZ administration, whereas no changes in β-cell proliferation were observed in older mice. The capacity to expand β-cell mass in response to short-term treatment with the GLP-1 analog exendin-4 also declined with age. The ability of β-cell mass to expand was correlated with higher levels of Bmi1, a polycomb group protein that is known to regulate the Ink4a locus, and decreased levels of p16^Ink4aexpression in the β-cells. Young Bmi1^−/− mice that prematurely upregulate p16^Ink4afailed to expand β-cell mass in response to exendin-4, indicating that p16^Ink4alevels are a critical determinant of β-cell mass expansion.

CONCLUSIONS

β-Cell proliferation and the capacity of β-cells to regenerate declines with age and is regulated by the Bmi1/p16^Ink4apathway.Hyperglycemia in type 1 and 2 diabetes is, by definition, caused by insufficient insulin secretion to meet insulin demand. Defective insulin secretion in both forms of diabetes is caused in part by loss of β-cell mass (1–4). Diabetes can be reversed in type 1 and 2 diabetes by replacement of β-cell mass, as demonstrated by pancreas and islet transplantation (5,6). However, given the shortage of organ donors and the need for chronic immunosuppression, pancreas transplantation has limited applicability in the treatment of diabetes.Regeneration of β-cell mass is one promising approach to replace the deficit in β-cell mass in diabetic patients. Regeneration occurs in rodents after injury or genetic ablation of β-cells (7). Lineage tracing experiments show that new β-cells can arise from proliferation of preexisting β-cells (8). However, both the capacity of regeneration and the mechanism involved can differ significantly depending on the experimental model. An alternative source of β-cells has recently been proposed showing that facultative progenitors can be found in regenerating pancreatic ducts (9). Several studies have shown that the endocrine pancreas has endogenous renewal capacity in response to metabolic demands such as pregnancy and insulin resistance (10). Changes in insulin demand caused by physiological states such as insulin resistance have been shown to lead to adaptive changes in β-cell mass. The cell source and mechanism leading to the endogenous renewal is not clear, although proliferation of β-cells appears to play an important role (11). Elucidating mechanisms of regeneration and endogenous renewal in response to metabolic demands may provide novel insights into approaches to restore functional β-cell mass in diabetes.Most of the studies exploring the capacity of endogenous renewal have been carried out on rodents at relatively young ages, and several studies suggest that the capacity to expand or regenerate β-cell mass may decline with age. For example, a threefold increase of insulin content was measured in the residual pancreas after 90% pancreatectomy in 1-month-old rats; however, a comparable increase was not observed in rats that were 5 or 15 months old (12). Moreover, consistent with the adaptive increase in pancreatic insulin content in the 1-month-old but not older animals after a 90% pancreatectomy, blood glucose values in the 1-month-old rats declined 2 weeks after surgery, whereas no such decline was observed in 5- and 15-month-old rats (12). The rate of β-cell proliferation gradually declines with aging in rats to a steady state by 7 months of age (13). Furthermore, long-term bromodeoxyuridine labeling in 1-year-old mice also suggests that β-cell replication rates decline with age (14). The decline in β-cell proliferation with age correlates with increased expression of the cell cycle regulator p16^Ink4a in islet cells (15). p16^Ink4a inhibits the cyclin-dependent kinase 4 (CDK4)-cyclin D2 complex and can inhibit cell cycle progression and regeneration of islet cells. Transgenic mice that overexpressed p16^Ink4a showed reduced islet cell proliferation and a reduction in the regenerative capacity of islets after toxin-mediated destruction. However, the mechanisms that regulate the increase in p16^Ink4a with aging are not known.Establishing the basis of aging in affecting the capacity of adaptive changes in β-cell mass in adult humans versus young rodents has important clinical implications. If it is a species difference, then caution will need to be exercised extrapolating findings in rodents to the potential for β-cell regeneration in humans. For example, partial pancreatectomy in young mice is followed by extensive regeneration of β-cells through β-cell replication. In contrast, partial pancreatecomy in adult humans does not lead to β-cell regeneration (16). To date, it is not clear whether this different outcome is a species difference or a consequence of partial pancreatectomy at different ages. Also of interest, genetically obese mice have a several-fold increase in β-cell mass, whereas obese adult humans have only a much more modest 0.5-fold increase in β-cell mass (1). Again, it is not known whether this is a species difference or the consequence of a different response to obesity-induced insulin resistance during aging.Studies to date that have reported an increase in β-cell mass with glucagon-like peptide 1 (GLP-1)-1 based therapies were undertaken in young rodents (17–21). On the strength of those observations, it has been proposed that these therapies might serve to foster β-cell regeneration in humans with either type 1 or type 2 diabetes (22–25). However, it is plausible that GLP-1–induced expansion of β-cell mass may only be achievable in young subjects. Similarly, the rapid regeneration of β-cell mass in young mice after a single dose of the β-cell toxin streptozotocin (STZ) has been widely used as a model for β-cell regeneration in type 1 diabetes, but it is not yet known whether there is comparable recovery of β-cell mass in mice during the adult phase of β-cell turnover, a circumstance more clinically relevant to most humans.In the current studies, the capacity of endogenous renewal of β-cells in response to either a high-fat diet or the GLP-1 analog exendin-4 as well as the capacity to regenerate after toxin administration was examined in young and old mice. β-Cell mass and metabolic measurements were measured after high-fat diet or exendin-4 treatment. β-Cell proliferation was measured to probe the mechanism by which age could affect the capacity for β-cell renewal. Furthermore, the levels of p16^ink4a were linked to the capacity of β-cell proliferation. Because several studies have established a role for the polycomb group protein Bmi1 in the regulation of p16^Ink4a (26–28), we analyzed the levels of Bmi1. We further showed that loss of Bmi1 results in premature increase in the expression of p16^ink4a. Because aging can lead to many changes in the β-cell other than p16^Ink4a upregulation, we used Bmi1 knockout mice as a model to explore the endogenous capacity to renew in young mice in which p16^ink4a is prematurely upregulated. This result indicates that levels of p16^ink4a are the primary determinant of the capacity to expand β-cell mass. Our data suggest that the older mice, unlike younger mice, have a limited capacity to expand β-cell mass because of age-related accumulation of p16^Ink4a.     

Distinct chromosomal rearrangements in subungual (Dupuytren) exostosis and bizarre parosteal osteochondromatous proliferation (Nora lesion)

BACKGROUND: Proliferative lesions of the bone surface, such as subungual (Dupuytren) exostosis and bizarre parosteal osteochondromatous proliferation (BPOP, Nora lesion) are currently classified as reactive, proliferative processes that mimic primary neoplasms of bone. METHODS: Cytogenetic analysis was performed on 3 subungual exostoses of the great toe and 2 BPOP lesions of the radius and ulna. RESULTS: A balanced translocation t(X;6) was identified in all cases of subungual exostoses. The chromosomal rearrangements observed in 1 case of BPOP differed from those seen in subungual exostosis. CONCLUSIONS: The presence of chromosomal abnormalities in subungual exostosis and BPOP suggests that these lesions are neoplastic, with a different molecular pathogenesis, and that each is a distinct clinicopathologic entity.     

Bizarre Parosteal Osteochondromatous Proliferation (Nora’s Lesion) of the Mandible. A Rare Bony Lesion

Bizarre parosteal osteochondromatous proliferation (BPOP) also eponymically called “Nora’s lesion”, is a rare benign reactive bone lesion first reported in 1983. BPOP occurs classically on the bones of the hands and feet and long bones. This lesion can easily be confused, both clinically and microscopically, with other benign and malignant lesions of bone, including osteochondroma, parosteal osteosarcoma, myositis ossificans and reactive periostitis. BPOP has been reported to have a high rate of recurrence. Only 3 cases of BPOP of the head and neck have been reported in the literature, of which one involved the maxilla. We present a rare case of BPOP involving the mandible in a 10 year old African American male. Microscopically, a fibro-cartilaginous cap giving rise to a proliferation of variably mineralized osteophytic finger-like projections of bone was seen. Multiple trabeculae of “blue bone” were noted as well as numerous atypical appearing chondrocytes. The lesion recurred within 4 months following the initial excision but has not recurred to date after the second local excision. To the best of our knowledge, this is the first report of BPOP arising in the mandible. In addition, we discuss the clinical and microscopic features, differential diagnosis, and prognosis of this rare entity. We present a case of BPOP of the mandible and believe this is the first report of such a case in the mandible.     

Identification of Senescent Cells in the Bone Microenvironment

Cellular senescence is a fundamental mechanism by which cells remain metabolically active yet cease dividing and undergo distinct phenotypic alterations, including upregulation of p16^Ink4a, profound secretome changes, telomere shortening, and decondensation of pericentromeric satellite DNA. Because senescent cells accumulate in multiple tissues with aging, these cells and the dysfunctional factors they secrete, termed the senescence‐associated secretory phenotype (SASP), are increasingly recognized as promising therapeutic targets to prevent age‐related degenerative pathologies, including osteoporosis. However, the cell type(s) within the bone microenvironment that undergoes senescence with aging in vivo has remained poorly understood, largely because previous studies have focused on senescence in cultured cells. Thus in young (age 6 months) and old (age 24 months) mice, we measured senescence and SASP markers in vivo in highly enriched cell populations, all rapidly isolated from bone/marrow without in vitro culture. In both females and males, p16^Ink4a expression by real‐time quantitative polymerase chain reaction (rt‐qPCR) was significantly higher with aging in B cells, T cells, myeloid cells, osteoblast progenitors, osteoblasts, and osteocytes. Further, in vivo quantification of senescence‐associated distension of satellites (SADS), ie, large‐scale unraveling of pericentromeric satellite DNA, revealed significantly more senescent osteocytes in old compared with young bone cortices (11% versus 2%, p < 0.001). In addition, primary osteocytes from old mice had sixfold more (p < 0.001) telomere dysfunction‐induced foci (TIFs) than osteocytes from young mice. Corresponding with the age‐associated accumulation of senescent osteocytes was significantly higher expression of multiple SASP markers in osteocytes from old versus young mice, several of which also showed dramatic age‐associated upregulation in myeloid cells. These data show that with aging, a subset of cells of various lineages within the bone microenvironment become senescent, although senescent myeloid cells and senescent osteocytes predominantly develop the SASP. Given the critical roles of osteocytes in orchestrating bone remodeling, our findings suggest that senescent osteocytes and their SASP may contribute to age‐related bone loss. © 2016 American Society for Bone and Mineral Research     

Assessing the Use of p16 Promoter Gene Methylation in Serum for Detection of Bladder Cancer

Objective: This study was undertaken to investigate whether hypermethylation in p16^INK4a gene promoter could serve as plasma biomarker of bladder cancer.Methods and Patients: We examined the p16^INK4a status using methylation-specific PCR in 86 cancer patients and 49 controls (31 healthy people and 18 patients with benign urological diseases).Results: The p16^INK4a methylation was found in 22% of the serum samples and in 26% of the bladder cancer biopsies; one of them with carcinoma in situ. The presence of hypermethylated p16^INK4a in serum seems to be a product from tumour cells because a strong statistical association was found between both matched DNA signals (p<0.0001). Using the control group, the presence of methylated p16^INK4a in the serum of individuals with suspicion of bladder cancer was found to be associated with the tumour presence (p=0.0009). Aberrant p16^INK4a methylation was also observed in one non-cancer patient, which is undergoing further assessment.Conclusions: According with our results, methylation of p16^INK4a promoter may be involved in the bladder cancer genesis and the presence of p16^INK4a methylated in serum of these patients could be useful in the cancer diagnosis with values of sensitivity, specificity and positive predictive value of 0.226, 0.950 and 0.98, respectively. These figures support the use of methylated p16^INK4a as a new class of tumour marker in bladder cancer.     

Magnetic resonance imaging characteristics of bizarre parosteal osteochondromatous proliferation of the hand: a case report

Bizarre parosteal osteochondromatous proliferation (BPOP) is a reactive lesion of cortical bone. A case of fifth metacarpal BPOP with intramedullary inflammatory extension is shown by magnetic resonance imaging. Histologically the intramedullary extension showed fibrosis with inflammatory cell infiltration. The surrounding adipose tissue showed fibrosis, focal inflammatory cell infiltration, and vascular proliferation. It is important to recognize that BPOP can bear radiologic resemblance to malignant lesions or osteomyelitis when there is an intramedullary inflammatory extension. Preservation of cortical bone under the osteocartilaginous mass on T1-weighted magnetic resonance imaging, and homogenous intramedullary enhancement with gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA), can be helpful for distinguishing BPOP from malignant lesions.     

Microcirculation surrounding end-stage human chronic skin wounds is associated with endoglin/CD146/ALK-1 expression,endothelial cell proliferation and an absence of p16Ink4a

Angiogenesis is an essential part of normal skin healing, re-establishing blood flow in developing granulation tissue. Non-healing skin wounds are associated with impaired angiogenesis and although the role of re-establishing macroscopic blood flow to limbs to prevent wound chronicity is well investigated, less is known about vascular alterations at the microcirculatory level. We hypothesised that significant phenotypic changes would be evident in blood vessels surrounding chronic skin wounds. Wound edge tissue, proximal to wound (2 cm from wound edge) and non-involved skin (>10 cm from wound edge) was harvested under informed consent from 20 patients undergoing elective amputation due to critical limb ischemia. To assess blood vessel structure and viability, tissue was prepared for histological analysis and labelled with antibodies specific for PECAM-1 (CD31), CD146, endoglin, ALK-1, ALK-5, and p16^Ink4a as a marker of cellular senescence. Density of microvasculature was significantly increased in wound edge dermis, which was concomitant with increased labelling for endoglin and CD146. The number of CD31 positive vessel density was unchanged in wound edge tissue relative to non-involved tissue. Co-labelling of endoglin with the transforming growth factor receptor ALK-1, and to a lesser extent ALK-5, demonstrated activation of endothelial cells which correlated with PCNA labelling indicative of proliferation. Analysis of p16^Ink4a staining showed a complete lack of immunoreactivity in the vasculature and dermis, although staining was evident in sub-populations of keratinocytes. We conclude that the endoglin-ALK-1-endothelial proliferation axis is active in the vasculature at the edge of chronic skin wounds and is not associated with p16^Ink4a mediated senescence. This information could be further used to guide treatment of chronic skin wounds and optimise debridement protocols.     

Bizarre parosteal osteochondromatous proliferation of bone (BPOP): an unusual foot mass in a child

This report describes an unusual case of bizarre parosteal osteochondromatous proliferation of bone (BPOP) which developed in the foot of an eight year-old child. Also described as Nora's lesion, BPOP is a rare benign bone tumor found most commonly in the hands and feet with a radiographic appearance occasionally confused with malignancy. Resembling osteochondromas at first glance, these lesions have a distinct radiographic and histologic appearance that permits differentiation from other benign lesions or low-grade malignant tumors. Treatment of BPOP consists of simple excision, although there is high rate of recurrence. Despite this high recurrence rate, there have been no reported metastases and local excision is still recommended.     

Bizarre parosteal osteochondromatous proliferation (Nora's lesion). Description of six cases and a review of the literature

The authors report their experience with 6 cases of bizarre parosteal osteochondromatous proliferation (BPOP) observed in 4 patients in its typical site (distal ends of the limbs), and in 2 patients where it was instead atypically localized in the humerus and femur. The histories of the patients revealed that 50% reported previous trauma in the site of lesion. Five patients were submitted to surgical exeresis, while the remaining patient refused to undergo any type of treatment because he was asymptomatic. At a mean follow-up of 36 months 1 patient presented with recurrence (20%). BPOP is a rare pseudotumorous lesion with typical radiographic and histopathologic findings similar to to those of other benign and malignant tumor forms. A review of the small amount of literature in existence is used to analyze the elements that may lead to accurate differential diagnosis.     

Nora’s lesion. Clinical and therapeutic considerations

In this article we report a case of bizarre paraosteal osteochondromatous proliferation (BPOP), also known as Nora’s lesion, arising on the distal phalanx of the fifth finger of the hand in a young-adult subject. In this paper, we discuss the possible therapeutic programme related to the grade of severity of the clinical features and underline the rarity of this lesion and the difficulty of diagnosis, which is exclusively histological.     

Nora's lesion. Clinical and therapeutic considerations

In this article we report a case of bizarre paraosteal osteochondromatous proliferation (BPOP), also known as Nora's lesion, arising on the distal phalanx of the fifth finger of the hand in a young-adult subject. In this paper, we discuss the possible therapeutic programme related to the grade of severity of the clinical features and underline the rarity of this lesion and the difficulty of diagnosis, which is exclusively histological.     

Genetic abnormalities involved in the pathogenesis of gallbladder carcinoma

While considerable progress has been made in the understanding of the genetic changes involved in the pathogenesis of several human neoplasms, there is limited information about the genetic changes involved in the development of gallbladder carcinoma. Several studies indicate that TP53 (17p13) and p16 ^Ink4 /CDKN2 (9p21-22) gene loci abnormalities are frequent and early events in the pathogenesis of this neoplasm, in some cases preceding the onset of histological changes of invasion. Preliminary data also suggest that deletions at other chromosomal regions (8p21 and DCC at 18q21 loci) may play an important role in the development of gallbladder carcinoma; however, they need to be further analyzed. K-ras gene mutations appear to be an infrequent event in this neoplasm, except in gallbladder carcinomas associated with congenital abnormalities of the biliary tract. Genetic studies confirm that the sequence dysplasia-carcinoma in situ (CIS) is the usual route for the development of gallbladder carcinoma, and our recent data strongly suggest that adenomas are not precursors of this neoplasm. Received for publication on Jan. 17, 1999; accepted on March 29, 1999     

Nora's lesion at the second metacarpal bone of a twelve-year-old female

The extremely rare condition of bizarre parosteal osteochondromatous proliferation (BPOP) was first described in 1983 by the pathologist Nora, and a few more than 100 cases have since been reported. The lesion is defined as a reactive heterotopic ossification and is mostly found in the hands or feet of adults in the third decade of life, although it has also been described in long bones and in other age groups. A high rate of local recurrence of up to 50 % has been noted, but the lesion is benign and does not metastasise. An association with chromosomal rearrangements has recently been described. We here report the case of a 12-year-old girl with a BPOP at the second metacarpal bone, thus at an unusual age. The lesion was marginally resected after biopsy, but recurred locally within 2 years, resulting in subtotal resection of the second metacarpal bone, autologous fibula grafting and temporary external fixation. The clinical, plain radiographic and MRI appearance of the lesion and the prominent histological findings are described, and the difficulties in establishing the correct diagnosis in cases of BPOP are discussed.     

Bizarre parosteal osteochondromatous proliferation (Nora's lesion) in the hand

PURPOSE: The purpose of this study was to review our experience with a benign surface bone lesion referred to as bizarre parosteal osteochondromatous proliferation (BPOP) or Nora's lesion, named for the pathologist who described it in 1983. The lesion may be confused with a variety of tumors, particularly solitary osteochondromas, which are rare. METHODS: The files in the Department of Pathology at the Hospital for Joint Diseases were reviewed over a 21-year period for all surface bone lesions involving the tubular bones in the hand. There were a total of 10 cases of BPOP compared with only a single case of an osteochondroma. RESULTS: Radiographs generally showed a well-marginated uniformly dense mass arising from the surface of the affected bone without any disruption in its bony architecture. Surgical excision is the definitive treatment and included the fibrous pseudocapsule over the lesion, any periosteal tissue beneath the lesion, and any area of the cortex of the host bone that appeared abnormal. Although in the medical literature the recurrence rate for BPOP is high, we had only one recurrence in our series. CONCLUSIONS: BPOP is a benign surface bone lesion that may be confused with benign and malignant tumors. Although there is a cleavage plane between the lesion and host bone, we recommend excising the pseudocapsule over the lesion, any periosteal tissue beneath the lesion, and decorticating any abnormal-appearing areas in the underlying host bone. This may explain the low recurrence rate in our series.