OBJECTIVE: The aims of the current study were to describe clinical and biochemical features of patients with Paget disease of bone (PDB) followed at our medical center, and to examine the long-term effectiveness of zoledronate.
METHODS: Retrospective cohort study included consecutive patients≥18 years with a diagnosis of PDB, followed in the Rabin Medical Center (RMC) Institute of Endocrinology from 1973 to 2023. The cohort comprised two groups: patients treated/not treated with zoledronic acid (ZOL/NZOL). The primary outcome was the percentage of patients who achieved a biochemical therapeutic response.
RESULTS: Overall, 101 patients with PDB were included, 68 in the ZOL group and 33 in the NZOL group. The mean age was 65.2 ± 10.0 years, and 47% were female. Notably, 77% exhibited monostotic involvement, and only 3% had experienced fractures attributed to PDB. Mean ALP level at diagnosis was 160 ± 70.6 U/L. The median follow-up duration was 17 years since PDB diagnosis, comparable between the groups. Primary outcome was more prevalent in the ZOL compared to the NZOL group [42 patients (88%) VS 11 patients (52%) respectively, P = 0.004]. At the end of follow-up, mean ALP levels in the NZOL group were significantly higher than the levels in the ZOL group irrespective of the number of infusions received.
CONCLUSIONS: The majority of patients with PDB experience a mild disease course, marked by monostotic involvement and a low prevalence of fractures. Zoledronic acid effectively manages PDB, providing sustained biochemical response. The necessity for multiple zoledronic acid injections remains questionable, often implemented due to osteoporosis.

OBJECTIVE: Extramammary Paget\'s disease (EMPD) is a rare, slow growing intra-epidermal malignant neoplasm that arises in areas rich in apocrine glands. Several common sites of occurrence have been reported, including the vulva, perianal region, perineum, and scrotum. Most relevant studies rely on small data bases. Our objective was to evaluate prognostic factors of EMPD patients at a single medical center.
METHODS: We retrospectively analyzed 19 patients (8 males, 11 females) diagnosed with genital EMPD who were treated at the Taichung Veterans General Hospital between 2006/04 and 2022/08. Collected information included tumor location, margin condition in the case of surgical resection, recurrence rate, recurrence management, accompanied gastrointestinal malignancy, treatment details and survival data.
RESULTS: Among 19 cases, 4 with initial margin being positive, and 3 received second surgery (one refused surgery and another expired within a year). Tumor recurrence was found in 7 cases, with 6 of them later receiving second surgery, and the remaining one received radiation therapy. Median DFS was 7.57 years. During the 15-year follow-up, 2 patients expired. Overall survival rate was 87.5%. Among all factors we had analyzed, only those accompanied with GI tract malignancy had significantly worse survival rate (p=0.018). Frozen sections taken at surgical margin during surgery significantly reduced cancer recurrence rate (p=0.45). Permanent pathology margins appeared to affect the recurrence rate, but that was not significant when comparing with intraoperative frozen sections.
CONCLUSIONS: Local wide excision with skin flap reconstruction remains the major treatment option for genital EMPD. Following the standard-of-care procedure, the overall patient outcome was excellent. Among factors potentially associated with recurrence rate, intraoperative frozen biopsy was the most significant one. Performing intraoperative frozen biopsy is essential for recurrence-free rate elevation.

OBJECTIVE: Extramammary Paget\'s disease (EMPD) of the esophagus is very rare and the clinicopathologic features are not well characterized.
METHODS: We analyzed 10 cases with reported presence of Paget or Pagetoid tumor cells in the esophageal specimens collected between 2005 and 2018 at our institution.
RESULTS: The cohort included 7 males and 3 females with a median age of 67 years. Histologically, 7 cases were secondary Pagetoid spread of tumor cells directly from an underlying invasive adenocarcinoma (pADC) located at the distal esophagus, all CK7 + with variable intracytoplasmic mucin. The clinical course of those secondary cases was dependent on the underlying malignancies. Only 3 cases were primary, including 2 Pagetoid squamous cell carcinoma in-situ (pSqCCis) and 1 Pagetoid adenocarcinoma in-situ (pADCis) with focalstromal invasion. The primary cases showed similar clinical and endoscopic presentations. Immunohistochemically, the singly dispersed Paget or Pagetoid tumor cells frequently showed loss of E-cadherin and gain of vimentin expression. Seven cases, including 5 pADC, 1 pSqCCis and the pADCis showed aberrant p53 expression. Four patients, all pADC, died of disease at a median follow-up of 10 months, while the others were alive.
CONCLUSIONS: Paget or Pagetoid tumor cells in the esophagus can be primary or secondary to an invasive carcinoma. The clinical outcomes depend on the underlying malignancy and extensiveness of disease. Frequent p53 aberrancies and epithelium-mesenchymal transition likely play a role in the pathogenesis.

The applications of 3D bioprinting are becoming more commonplace. Since the advent of tissue engineering, bone has received much attention for the ability to engineer normal bone for tissue engraftment or replacement. While there are still debates on what materials comprise the most durable and natural replacement of normal tissue, little attention is given to recreating diseased states within the bone. With a better understanding of the cellular pathophysiology associated with the more common bone diseases, these diseases can be scaled down to a more throughput way to test therapies that can reverse the cellular pathophysiology. In this review, we will discuss the potential of 3D bioprinting of bone tissue in the following disease states: osteoporosis, Paget\'s disease, heterotopic ossification, osteosarcoma, osteogenesis imperfecta, and rickets disease. The development of these 3D bioprinted models will allow for the advancement of novel therapy testing resulting in possible relief to these chronic diseases.

BACKGROUND: Total hip arthroplasty (THA) in patients with Paget\'s disease can be associated with technical difficulties related to deformities and altered mechanical bone properties, and hypervascularity leads to significative intra-operative bleeding. The purpose of this registry and single-institution study was to investigate overall survival and causes of failure of THA in pagetic patients, together with an analysis of the clinical and radiological complications.
METHODS: Registry-based survival and complication analysis, type of fixation, intra- and post-operative complications, clinical (pharmacological history, blood transfusions, Harris hip score [HHS]) and radiographic (cup orientation, stem axial alignment, osteolysis around the cup and the stem and heterotopic ossification [HO]) data were reviewed.
RESULTS: In total, 66 patients (27 males and 39 females, mean age at surgery 71.1 years for males and 74.8 years for female) from the registry study presented a 10-year survival of 89.5%. In the institutional study, involving 26 patients (14 males and 12 females, 69 years average) and 29 THAs, hip function improved significantly. Average cup orientation was 40.5°, while varus stem alignment was 13.8%. In total, 52% of hips had heterotopic ossifications. Peri-acetabular osteolysis was in 13.8% of implants and in 45% of hips was found around the stem. Allogenic and autologous blood transfusion rate were 68.2% and 31.8%, respectively, with an average transfusion of 2 units of blood (range 1-6 units). HHS improved by an average of 34 points, with excellent result in 64.3% of patients. Two implants failed, one due to traumatic ceramic head fracture 64 months after surgery, and one due to mobilization of the cup on the second post-operative day.
CONCLUSIONS: THA surgery in Paget\'s patients is a safe procedure, and implant survival is only partly affected by bone remodelling and choice of fixation. The post-operative functional outcome is largely similar to that of other patients. Bleeding-related complications are the main complications; a careful pharmacological strategy should be recommended to decrease the risk of transfusions and of HO development.
METHODS: Level III.

BACKGROUND: Perianal Paget\'s disease (PPD) is rare and mostly described in clinical literature as case reports or small series.
METHODS: We investigated the clinicopathologic and immunohistochemical features of PPD in a total of 13 cases retrieved from multiple academic institutions.
RESULTS: The median age at diagnosis was 75 (range 50-86) years. Males were predominant with a male to female ratio of 2.25:1. Four (30.8%) cases were classified as primary PPD due to lack of synchronous or metachronous underlying malignancies, while nine (69.2%) were classified as secondary PPD with concurrent invasive adenocarcinoma (n = 8) or tubular adenoma with high-grade dysplasia (n = 1). Immunohistochemically, there is no differential expression of CK7 or CK20 in Paget\'s cells between primary and secondary PPD; however, GCDFP-15 was only positive in primary PPD (3/3 vs. 0/6, P = 0.012), while CDX2 was only positive in secondary PPD (0/3 vs. 7/7, P = 0.008), suggesting different cell origin. All patients received local surgical resection with or without adjuvant therapy. After a median follow-up of 47 months, one patient with secondary PPD (7.7%) died of disease progression from underlying adenocarcinoma.
CONCLUSIONS: PPD occurs in elderly patients with male predominance and is frequently associated with underlying malignancies. Differential expression of CDX2 and GCDFP-15 may help distinguishing primary vs. secondary PPD, which is important for management as the presence of an underlying malignancy impacts clinical course and prognosis. Surgical excision remains the major treatment strategy for PPD. Long-term follow-up is required to monitor the disease recurrence and metastasis.

OBJECTIVE: To explore the prognostic significance of mammary Paget\'s disease (PD) in breast cancer (BC) patients and to investigate the association between clinical manifestation and outcome in invasive ductal carcinoma patients with PD (PD-IDC).
METHODS: Eighty-five patients diagnosed with mammary PD with underlying BC from 2006 to 2012 at Zhejiang Cancer Hospital were recruited. A matched group comprised 85 patients diagnosed with BC without PD. Patients were matched according to four variables: stage (0-IV), age at diagnosis (within 5 years), histologic subtype, and the year of surgery. The 74 patients diagnosed with PD-IDC were divided into three groups based on their clinical presentation.
RESULTS: Compared with the matched group, the PD group had more HER2 positivity (P<0.01) and hormone receptor negativity (P<0.01), and a worse outcome (Kaplan-Meier analysis, P<0.001 for disease-free survival and P=0.002 for overall survival). Multivariate Cox regression analyses showed that PD was an independent prognostic predictor for BC patients with PD. In addition, the 22 PD-IDC patients who presented with skin lesions in the nipple/areola and a mass in the breast or axilla had a higher risk of disease relapse than patients who presented with a mass in the breast without skin lesions or patients who presented with skin changes without a palpable mass (adjusted hazards ratio, 0.24; 95% CI, 0.08-0.73; P=0.012 and adjusted hazard ratio, 0.30; 95% CI, 0.06-1.40; P=0.124, respectively).
CONCLUSIONS: PD is an independent prognostic indicator of outcome in BC patients with PD. Furthermore, the primary symptoms at presentation may be an available indicator of prognosis in PD-IDC.

Paget\'s disease of the breast is uncommon and patients may present with nipple discharge, eczema, plaque or nipple destruction with or without a lump. The aim of the present study was to evaluate the presentation, clinicopathological features and treatment given for patients presenting with Paget\'s disease of the breast. We performed a retrospective analysis of medical records of patients who were treated at our centre for Paget\'s disease of the breast from 2006-2011. Twenty patients were treated in this period. Twelve patients had associated lump and eight patients did not have a lump in the breast. Two patients did not have a lump or any detected abnormality in mammography. Multicentricity was present in five patients. Diagnosis of malignancy was made by fine-needle aspiration cytology for patients with palpable lump and nipple wedge biopsy for patients with no lump. Modified radical mastectomy was done in 10 patients: 2 patients underwent total mastectomy and sentinel lymph node biopsy and 8 patients underwent central quadrantectomy and sentinel lymph node biopsy. Eleven patients had invasive ductal carcinoma, one patient had ductal carcinoma in situ with foci of invasion and eight patients had ductal carcinoma in situ. Seven patients had lymph node metastases. Three patients had recurrence, one had local recurrence and two had distant recurrences. The mean follow up period was 28 months (range 15-64 months). Paget\'s disease of the breast is a rare entity and one needs imaging and biopsy to diagnose these patients as they have associated cancer. They can be considered for breast conservation surgery with good cosmetic and oncological results.