Bone Quality in Paget’s Disease of Bone

Paget’s disease of bone is produced by a localized increase in osteoclastic and osteoblastic activity which can progress slowly to involve an entire bone if untreated. A common feature is enlarged bones which are deformed, particularly in weight-bearing regions of the skeleton such as the lower extremity. Pathologic fractures may be a consequence, and nonunion of femoral fractures is not uncommon. Analyses of bone biopsies from patients with Paget’s disease indicate that there is a lower, heterogeneous degree of bone mineralization and a younger tissue age than that found in control bone. Pagetic bone also has less resistance to plastic deformation and a straighter crack path than control bone.     

SQSTM1 and Paget’s Disease of Bone

Mutations in the Sequestosome 1 gene (SQSTM1; also known as p62) have recently been identified as the cause of 5q35-linked Pagets disease of bone (PDB). All of the mutations identified to date affect the ubiquitin-associated (UBA) domain of SQSTM1, a region of the protein that binds noncovalently to ubiquitin. In this review we consider the possible functional significance of the SQSTM1-ubiquitin interaction, and consequences of the SQSTM1 UBA domain mutations. Clarification of the in vivo roles of SQSTM1 in bone-cell function will be central to improving our understanding of the molecular pathogenesis of PDB and related conditions.     

Increased Arterial Calcification in Paget’s Disease of Bone

When examining radiographs of patients with Paget’s disease of bone (PD), we often observed calcification of the aorta and iliac or femoral arteries. The processes of extraosseous calcification or mineralization are very close to the mechanisms regulating mineralization of bone tissue. The aim of our study was to quantify the number, extent (length and thickness), and type (arteriosclerotic or medial arterial calcification) of vascular calcification in patients with Paget’s disease and to compare them with those of controls, in order to discover whether PD is accompanied by increased calcification. Vascular calcification was quantified on the aorta, the iliac arteries, and their branches, the femoral, gluteal, and pelvic arteries of 42 patients with Paget’s disease and 36 control subjects. Of the PD subjects, 52.4% had arteriosclerotic calcification versus 30.6% of controls (P = 0.05), and 38.6% of PD patients had medial arterial calcification versus 11.1% of controls (P = 0.05). The mean length of calcification was greater in PD patients: 1.93 ± 2.85 cm versus 0.84 ± 1.69 cm in controls (P = 0.04). The thickness of calcification was also greater in PD patients: 1.24 ± 1.30 mm versus 0.56 ± 0.94 mm (P = 0.01). Patients with Paget’s disease more frequently had medial arterial or arteriosclerotic calcification than controls. These calcifications were longer and thicker. Our clinical study therefore confirms that abnormal vessel wall calcification and bone remodeling in Paget’s disease are probably linked, although the mechanism of this relation is as yet unexplained.     

Paget’s Disease of Bone in New Zealand: Continued Decline in Disease Severity

We have reported previously that severe Pagets disease of bone had become less common at our center between 1973 and 1993. Data from several countries support the view that there are important secular trends in the prevalence and severity of Pagets disease. In this paper we describe recent trends in the demography of newly referred patients with Pagets disease to determine if the secular trend toward milder disease has continued. A database of all newly referred patients (n = 1487) with Pagets disease (1973 to 2002 inclusive, 30 years) was examined. Of these, 832 subjects (56%) had scintiscans. Plasma total alkaline phosphatase (total ALP) activity, disease extent on scintiscan, and a derived index of average ALP activity of pagetic bone were used as indices of severity. The number of new referrals with Pagets disease declined sharply from 1994 onward and is currently at half the rate seen 20 years earlier, while the mean age at presentation has progressively increased by 4 years per decade (P < 0.0001). Total ALP at diagnosis, disease extent on scintiscan, and the number of bones involved were all negatively correlated with both date of birth (P < 0.0001) and year of presentation (P < 0.0001), indicating that more recently born and presenting subjects had substantially less severe bone disease. The average activity of pagetic bone was only weakly correlated with year of presentation, but not with year of birth or age at presentation. Although there are a number of potential biases, these data are consistent with a continued secular trend to presentation in older subjects with less extensive skeletal involvement, and a declining prevalence of Pagets disease.     

Extramammary Paget’s Disease of the Perianal Region

Extramammary Paget’s disease (EMPD) is uncommon and only a few cases have been reported in the literature. They are identical to the Mammary Paget’s disease. This can occur where the apocrine glands are in abundance, more commonly in the genitalia and perianal area. We report here a case of Extramammary Paget’s disease in the perianal region. The colourful background of this ulcer is analysed and the literature reviewed.     

Sequestosome 1 (SQSTM1) Mutations in Paget’s Disease of Bone from the United States

Paget’s disease of bone (PDB) is a localized bone disease characterized by excessive bone resorption due to overactive osteoclasts. Seven genetic loci (PDB1-PDB7) have been reported for late-onset PDB. PDB3 is the only locus where a gene, sequestosome 1 (SQSTM1), has been identified. Mutations in SQSTM1 have been associated with both sporadic and hereditary PDB in different populations. However, the SQSTM1 mutation frequency in PDB patients from a more heterogeneous population has never been reported. To investigate this, we determined the frequency of mutations in patients from the United States. Blood was collected from sporadic and hereditary PDB patients in the United States. DNA was isolated from whole blood or from serum. The SQSTM1 sequence was determined for exons and intron/exon junctions from whole blood and serum. A total of 112 (39 hereditary, 73 sporadic) samples were collected. Eight mutations were found in hereditary PDB patients, for a mutation frequency of 20.5% (95% confidence interval [CI] 10.8–35.5%) and did not differ significantly from mutation rates observed in studies in Canada, Great Britain, and The Netherlands. No mutations were found in sporadic patients, for a frequency of 0% (95% CI 0.0–5.0%), which was statistically significantly lower than the mutation rates previously observed in populations from Australia (P = 0.009), Canada (P = 0.008), Great Britain (P = 0.02), and France (P = 0.04) but not compared to rates from Belgium, The Netherlands, and Italy. Four out of five families with the P392L mutation carried it on the H2 haplotype. Mutations in SQSTM1 seem to contribute to the pathogenesis of PDB in hereditary, but not sporadic, patients in the United States.     

Genetic Epidemiology of Paget’s Disease of Bone in Italy: sequestosome1/p62 Gene Mutational Test and Haplotype Analysis at 5q35 in a Large Representative Series of Sporadic and Familial Italian Cases of Paget’s Disease of Bone

Families affected by Paget’s disease of bone frequently harbor mutations in the SQSTM1/p62 gene. In this multicentric study we collected 345 sporadic and 12 familial PDB cases throughout Italy, identifying 12 different mutations, 5 of which are newly reported and 3, D335E, A381V, and Y383X, external to the UBA domain. Subjects with truncating mutations, E396X, showed a significantly younger age at clinical diagnosis, while the Y383X subjects had a higher average number of affected skeletal sites. All the mutants exhibited the CGTG-H2 haplotype. In two pairs and one triad of unrelated Italian PDB families from different Italian regions, we detected a common SQSTM1/p62 mutation for each P392L, M404V, and G425R group. Since the CGTG-H2 haplotype frequency was also high in normal subjects, and genetic influence due to migratory fluxes of different ethnic groups exists in the Italian population, to refine the search for a more geographically specific founder effect, we extended the haplotype analysis in these families using polymorphic microsatellite repeat markers, within and flanking the SQSTM1/p62 locus, from chromosome 5q35, other than the exon 6 and 3′UTR polymorphisms. All mutant carriers from two of the three M404V families and from the G425R families exhibited common extended chromosome 5q35 haplotypes, IT01 and IT02, respectively, which may be reflecting influences of past migrations. This may be helpful in estimating the true rate of de novo mutations. We confirm the data on the existence of both a mutational hotspot at the UBA domain of SQSTM1/p62 and a founder effect in the PDB population.     

Loss of Ubiquitin Binding Is a Unifying Mechanism by Which Mutations of SQSTM1 Cause Paget’s Disease of Bone

Ubiquitin-associated (UBA) domain mutations of SQSTM1 are an important cause of Paget’s disease of bone (PDB), which is a human skeletal disorder characterized by abnormal bone turnover. We previously showed that, when introduced into the full-length SQSTM1 protein, the disease-causing P392L, M404V, G411S, and G425R missense mutations and the E396X truncating mutation (representative of all of the SQSTM1 truncating mutations) cause a generalized loss of monoubiquitin binding and impaired K48-linked polyubiquitin binding at physiological temperature. Here, we show that the remaining three known PDB missense mutations, P387L, S399P, and M404T, have similar deleterious effects on monoubiquitin binding and K48-linked polyubiquitin binding by SQSTM1. The P387L mutation affects an apparently unstructured region at the N terminus of the UBA domain, some five residues from the start of the first helix, which is dispensable for polyubiquitin binding by the isolated UBA domain. Our findings support the proposal that the disease mechanism in PDB with SQSTM1 mutations involves a common loss of ubiquitin binding function of SQSTM1 and implicate a sequence extrinsic to the compact globular region of the UBA domain as a critical determinant of ubiquitin recognition by the full-length SQSTM1 protein.     

The Role of Sentinel Lymph Node Biopsy in Paget’s Disease of the Breast

Background Sentinel lymph node (SLN) biopsy has become a standard of care for axillary lymph node staging in breast cancer and appears suitable for virtually all patients with clinically node-negative (cN0) invasive disease. However, its role in Paget’s disease of the breast, a condition in which invasion may or may not be present, remains undefined. Methods Among 7,083 consecutive SLN biopsy procedures, we retrospectively identified 39 patients with Paget’s disease of the breast. Nineteen patients had no associated clinical/radiographic features (“Paget’s only”), and 20 patients had associated clinical/radiographic findings (“Paget’s with findings”). Results The mean ages for the Paget’s alone and with findings groups were 63.6 and 49.6 years, respectively. The use of breast conservation therapy was 32% in the Paget’s alone group and 10% in the Paget’s with findings group. Invasive carcinoma was found in 27% of patients in the Paget’s alone group and 55% of patients in the Paget’s with findings group. The success rate of SLN biopsy was 98%, and the mean number of SLNs removed was 3 in both groups. In the entire cohort of Paget’s disease, 28% (11/39) of the patients had positive SLNs (11%, Paget’s alone; 45%, Paget’s with findings). Conclusion In our “Paget’s only” cohort, invasive cancer was found in 27% of cases and positive SLNs in 11%. SLN biopsy should be considered in all patients with Paget’s disease of the breast, whether associated clinical/radiographic findings are present. Previous presentations: Sukumvanich P, Bentrem DJ, Cody HS, Brogi E, Fey JV, Borgen P, Gemignani ML. The Role of Sentinel Lymph Node Biopsy in Paget Disease of the Breast. Society of Clinical Oncology, Orlando, FL. May 16, 2005. (Accepted for poster presentation).     

Risedronate and Pamidronate Treatment in the Clinical Management of Patients with Severe Paget’s Disease of Bone and Acquired Resistance to Bisphosphonates

The aim of this study was to evaluate the efficacy and safety of risedronate and pamidronate in 30 patients (mean age = 57.86 ± 8.90 years) with severe Pagets disease of bone (PDB), showing acquired resistance to intravenous (IV) clodronate treatment. Fifteen patients were treated with oral risedronate (30 mg/day for 8 weeks). Treatment was repeated in patients without evidence of PDB remission [total alkaline phosphatase (tALP) serum levels in the normal range] at day 120. Fifteen patients were treated with IV pamidronate (30 mg/day for 3 days). Pamidronate treatment (60 mg/day for 3 days) was repeated in patients without evidence of PDB remission at day 120. At day 60, a significant decrease in tALP serum levels was obtained in all pagetic patients. At day 360, 13 (86.6%) patients treated with risedronate achieved PDB remission, 9 patients during the initial treatment and 4 after retreatment. Two patients showed a significant decrease in tALP serum levels without clinical remission after two risedronate treatments. At the same time, 12 (80%) patients treated with pamidronate achieved PDB remission, 6 patients during the first treatment and 6 after retreatment. Three patients showed a significant decrease in tALP serum levels but no clinical remission after two pamidronate courses. Two of these patients showed a relapse during the study. The incidence of minor side effects and transient hyperparathyroidism related to bisphosphonate treatment was significantly lower after risedronate therapy. In patients with resistant PDB, oral risedronate therapy has comparable efficacy to IV pamidronate with a lower incidence of treatment-related side effects.     

Extra-mammary Paget’s Disease of the Scrotum and Penis: a Case Report

Extra-mammary Paget’s disease is a rare disease mainly observed in elderly patients. It is an intra-epithelial adenocarcinoma that involves the area rich in apocrine glands. The most common affected lesions are the vulva and perianal region, followed by the axillae and inguinoscrotal area. Mostly, extra-mammary Paget’s disease is restricted to the epidermis, but advanced invasion to the dermis is possible with a poor prognosis of disease. The associated occult malignancy is reported and often exists for more than 10 years without clinical manifestation. We report a case of a 66-year-old male with extra-mammary Paget’s disease of the scrotum and penis. The diagnosis and treatment are discussed.     

Founder Effect in Different European Countries for the Recurrent P392L SQSTM1 Mutation in Paget’s Disease of Bone

Paget's Disease of Bone (PDB) is one of the most frequent metabolic bone diseases, affecting 1-5% of Western populations older than 55 years. Mutations in the sequestosome1 (SQSTM1) gene cause PDB in about one-third of familial PDB cases and in 2.4-9.3% of nonfamilial PDB cases, with the 1215C-->T (P392L) mutation being the most frequent one. We investigated whether a founder effect of the P392L SQSTM1 mutation was present in Belgian (n = 233), Dutch (n = 82), and Spanish (n = 64) patients without a PDB family history. First, direct sequencing analysis of exon 8 in these three populations showed that the P392L mutation occurred in 17 Belgian patients (7.3%), three Dutch patients without a family history (3.7%), and two Dutch patients with a family history. In the Spanish population, 15.6% of patients (n = 10) had the P392L mutation, including one homozygous mutant. This is by far the highest mutation frequency of all populations investigated so far. Next, we examined the genetic background of 33 mutated chromosomes by analyzing haplotypes. We genotyped four single-nucleotide polymorphisms (SNPs) in exon 6 and the 3'-untranslated region of SQSTM1 (rs4935C/T, rs4797G/A, rs10277T/C, and rs1065154G/T) and used software programs WHAP and PHASE to reconstruct haplotypes. Finally, allele-specific primers allowed us to assign the mutation to one of the two haplotypes from each individual. Sequencing results revealed that all 33 P392L mutations were on the CGTG (H2) haplotype. The chance to obtain this result due to 33 independent mutation events is 3.97 x 10(-14), providing strong evidence for a founder effect of the P392L SQSTM1 mutation in Belgian, Dutch, and Spanish patients with PDB.     

Bone Mineral Density in Patients with Treated Addison’s Disease

Some studies have reported low bone mineral density (BMD) in patients with Addison’s disease, whereas others have found BMD to be normal. It is possible that over-replacement of corticosteroids and adrenal androgen deficiency may contribute to a reduction in BMD in these patients. The aims of this study were to examine BMD using dual-energy X-ray absorptiometry in patients with treated Addison’s disease at multiple skeletal sites and to investigate the relationships between these measurements and corticosteroid dose. Nineteen men, 3 premenopausal and 7 postmenopausal women with Addison’s disease were studied and data from these patients were analyzed separately and as a group. The mean SEM age and duration of Addison’s disease of the men were 44 ± 3.8 years and 15 ± 2.2 years, in the premenopausal women 40 ± 2 years and 5 ± 2.4 years, and in the postmenopausal women 68 ± 4 years and 20 ± 5 years, respectively. Eight men were unexpectedly hypogonadal (serum testosterone <13 nmol/l). BMD was expressed as a percent of values in normal controls (n= 418) adjusted for age, sex, ethnic origin, menopausal status and body weight. In the whole group (n= 29), mean BMD of the patients with Addison’s disease was not different from normal at any site [mean (± SEM) lumbar spine 99.5%± 2.9%; femoral neck 99.3%± 2.5%; Ward’s triangle 96.2%± 3.5%; trochanter 99.2%± 2.9%; radius 99.8%± 2.1%; total body 98.5%± 1.4%]. However, there was a wide range of bone densities, with some patients having a low BMD at multiple sites. Bone density was negatively correlated with current and cumulative corticosteroid dose per kilogram body weight and duration of Addison’s disease. In conclusion, BMD in patients with Addison’s disease is little different from normal, but may be lower in patients with disease of long duration and a high cumulative corticosteroid dose. Unexpected hypogonadism in men with Addison’s disease is common. Received: 18 November 1998 / Accepted: 22 April 1999     

Paget’s Disease of the Breast: There Is a Role for Breast-Conserving Therapy

Background The optimal surgical management of Pagets disease of the breast remains to be defined. Mastectomy has been the standard of care, but several institutions have recently advocated breast-conserving surgery, particularly for patients with minimal disease. In an effort to develop rational treatment guidelines, we examined our institutional experience with Pagets disease of the breast.Methods Patients with Pagets disease of the breast who had surgical therapy at our institution between 1949 and 1993 were reviewed. In addition to patient and tumor characteristics, charts were reviewed for treatment modalities, locoregional recurrence patterns, and survival. Subgroups were compared for differences in survival in both univariate and multivariate analyses.Results A total of 104 patients met the study criteria. The most common presenting symptoms were nipple discharge and eczematous changes of the nipple/areola complex. Ninety-seven patients (93.2%) had an underlying invasive or noninvasive cancer associated with Pagets disease. Ninety-two patients (88.5%) underwent mastectomy, and 12 (11.5%) had a breast-conserving procedure. On univariate analysis, patients with age <60 years at diagnosis, stage II disease, positive lymph nodes, invasive disease, or a palpable mass had significantly lower 10-year disease-specific and recurrence-free survival. There were four locoregional recurrences (three after mastectomy and one after breast conservation). There were no significant differences in overall, disease-specific, or recurrence-free survival according to the type of surgery.Conclusions Pagets disease of the breast is almost always associated with an underlying breast cancer. Breast-conserving approaches result in local control and survival rates similar to those achieved with mastectomy.Presented in part at the 26th Annual San Antonio Breast Cancer Symposium, San Antonio, Texas, December 2-6, 2003.Published by Springer Science+Business Media, Inc. © 2005 The Society of Surgical Oncology, Inc.     

Surgical Management of Peyronie’s Disease

The development of a lymphocele after pelvic surgery is a well-documented complication, especially where pelvic lymph node dissection (PLND) is part of the operation. However, not all lymphoceles are symptomatic and require treatment. Most lymphoceles spontaneously resolve, and even lymphoceles that become symptomatic may resolve without any intervention. Robotic assisted radical prostatectomy (RARP) is a common operation in urology where PLND is likely to be performed in intermediate and high-risk prostate cancer patients. The rationale for performing a PLND in prostate cancer is for accurate staging and potential therapeutic benefits. However, due to potential intraoperative and postoperative complications there is still a debate regarding the value of PLND in prostate cancer. In this review, we will discuss the potential risk factors to be aware of in pelvic surgery in order to minimize the formation of a lymphocele, along with the management for clinically significant lymphoceles.     

Perianal Paget’s disease

Perianal Paget’s disease is a rare intraepithelial adenocarcinoma of the anal margin. Because of its rarity, delay in diagnosis is common and requires a high index of suspicion. Although its etiology has never been definitively determined, it now appears that 2 types of perianal Paget’s disease exist. Primary perianal Paget’s disease likely represents intra-epithelial neoplasm from an apocrine source, whereas secondary disease may represent “pagetoid” spread from an anorectal malignancy. Diagnosis of the 2 types of disease can be established from distinct immunohistochemical stain patterns. Wide local excision remains the treatment of choice for primary disease, with or without local invasion. Although local recurrence is high, re-excision can still be curative. Treatment of secondary disease is less clear, though aggressive therapy appears indicated for curative intent. Although adjuvant therapy is desirable, experience is still very limited.     

Quantitative Ultrasound of Bone and Markers of Bone Turnover in Cushing’s Syndrome

Quantitative ultrasound (QUS) of bone is a valuable tool in the assessment of postmenopausal osteoporosis. QUS and new markers of bone turnover have been poorly assessed in Cushing’s syndrome, however. Twenty-five patients with Cushing’s syndrome (20 women, 3 men; mean age ± SEM: 38 ± 2 years) were studied and compared with 35 age- and sex-matched control patients (mean age ± SEM: 38 ± 2 years). The following variables were measured in both groups: QUS parameters at the heel (BUA; SOS; Stiffness Index, SI); bone mineral density (BMD) at both the lumbar spine (LS) and femoral neck (FN) by dual-energy X-ray absorptiometry; and serum markers of bone turnover (osteocalcin, procollagen type I N- and C-terminal propeptides (PINP and PICP), bone alkaline phosphatase (BAP), procollagen type I C-terminal telopeptide (ICTP) and urinary type I collagen C-telopepetide breakdown products (CTX)). Both BUA and SI were decreased in patients with Cushing’s syndrome (p<0.01) but not SOS (p=0.08). BMD was also strongly decreased in Cushing’s syndrome, at both the LS and FN (p<0.005). The two markers of bone turnover statistically significantly different between the two groups were osteocalcin (mean ± SEM: 3.5 ± 0.7 ng/ml (Cushing’s syndrome) vs 6.4 ± 0.5 ng/ml (controls, p<0.01)) and CTX (mean ± SEM: 148.7 ± 17.1 μg/mmol Cr (Cushing’s syndrome) vs 220.8 ± 22.9 μg/mmol Cr (controls), p<0.05). The areas under the receiver operating characteristic curve (AUC) were 0.72 (BUA), 0.73 (SI), 0.90 (BMD_LS), 0.81 (BMD_FN), 0.83 (osteocalcin) and 0.64 (CTX) respectively. AUC was significantly higher for BMD_LS than for both BUA and SI (p<0.05). Conversely AUC was not statistically significantly different for BMD_FN as compared with either BUA or SI. AUC was also higher for osteocalcin than for other markers of bone turnover. In conclusion, QUS of bone seems to be a relevant tool for assessing bone involvement in Cushing’s syndrome. QUS does have a lower sensitivity compared with DXA, however, and the relevance of QUS cannot be ascertained until some longitudinal data are forthcoming. Except for CTX, the other new markers of bone turnover assessed in this study (PINP, PICP, BAP and ICTP) do not seem of interest in Cushing’s syndrome. Received: February 2000 / Accepted: 24 August 2000