Paget's Diseases Research Articles

TRPS1 expression in primary and secondary extramammary Paget diseases: An immunohistochemical analysis of 93 cases

Extramammary Paget disease (EMPD) predominantly manifests de novo as primary EMPD, with less than 30 % of cases associated with underlying internal malignancy (secondary EMPD). Differentiating primary from secondary EMPDs based solely on histopathology poses challenges, often necessitating supplementary screening, such as endoscopy or imaging studies, to definitively exclude underlying carcinomas like colonic adenocarcinoma. Recently, TRPS1 immunohistochemistry, initially identified as a sensitive and specific marker for carcinomas and mesenchymal tumors of mammary origin, has been proposed for EMPD. In this study, we conducted a systematic assessment of TRPS1 expression across 93 EMPD cases, comprising 82 primary EMPDs and 11 secondary EMPDs. Our aim was to assess the potential utility of TRPS1 as a marker to differentiate between primary and secondary EMPDs. Our findings revealed that 88 % (72/82) of primary EMPDs displayed TRPS1 expression, while secondary EMPDs consistently lacked TRPS1 expression (100 %; 11/11). Within the primary EMPD group, consistent TRPS1 immunoreactivity was observed in lesions originating outside the perianal region, such as the groin/inguinal area, axilla, and trunk. Interestingly, a majority (91 %; 10/11) of primary EMPDs originating in the perianal region exhibited an absence of TRPS1 expression. Upon excluding cases of perianal primary EMPDs, the sensitivity and specificity of TRPS1 for primary EMPDs reached 100 %. Our findings suggest that TRPS1 expression holds notable sensitivity and specificity for primary EMPDs, particularly when arising from non-perianal cutaneous sites. Hence, in suitable clinical contexts, TRPS1 immunohistochemistry may emerge as a promising and valuable tool for distinguishing primary and secondary EMPDs.

Autophagic factors in Paget disease

BackgroundDespite autophagy being a principal mechanism of tumor progression, its role has been never studied in Paget disease, a difficult to treat intraepithelial neoplasia affecting mainly the breast and the vulvar regions. Material and methodsTwenty seven cases (17 extramammary and 10 mammary) of Paget disease were immunohistochemically studied for the expression of the two principal autophagic factors, LC3B and p62. ResultsThe majority of Paget diseases showed strong cytoplasmic expression of p62 in contrast to nearby keratinocytes which presented nuclear-only p62 staining. LC3B was negative or only mildly positive in neoplastic cells. No difference was seen between mammary and extramammary cases. ConclusionThe immunohistochemical autophagic profile of Paget disease suggests a down-regulated autophagic process which, thus, may be implicated in the invasive potential of these cells.

An AI-based Prediction Model for Drug-drug Interactions in Osteoporosis and Paget's Diseases from SMILES.

The skeleton is one of the most important organs in the human body in assisting our motion and activities; however, bone density attenuates gradually as we age. Among common bone diseases are osteoporosis and Paget's, two of the most frequently found diseases in the elderly. Nowadays, a combination of multiple drugs is the optimal therapy to decelerate osteoporosis and Paget's pathologic process, which comes with various underlying adverse effects due to drug-drug interactions (DDIs). Artificial intelligence (AI) has the potential to evaluate the interaction, pharmacodynamics, and possible side effects between drugs. In this research, we created an AI-based machine-learning model to predict the outcomes of interactions between drugs used for osteoporosis and Paget's treatment, which helps mitigate the cost and time to implement the best combination of medications in clinical practice. In this study, a DDI dataset was collected from the DrugBank database within the osteoporosis and Paget diseases. We then extracted a variety of chemical features from the simplified molecular-input line-entry system (SMILES) of defined drug pairs that interact with each other. Finally, machine-learning algorithms were implemented to learn the extracted features. Our stack ensemble model from Random Forest and XGBoost reached an average accuracy of 74 % in predicting DDIs. It was superior to individual models as well as previous methods in terms of most measurement metrics. This study showed the potential of AI models in predicting DDIs of Osteoporosis-Paget's disease in particular, and other diseases in general.

The Msi1-mTOR pathway drives the pathogenesis of mammary and extramammary Paget's disease.

Mammary and extramammary Paget’s Diseases (PD) are a malignant skin cancer characterized by the appearance of Paget cells. Although easily diagnosed, its pathogenesis remains unknown. Here, single-cell RNA-sequencing identified distinct cellular states, novel biomarkers, and signaling pathways — including mTOR, associated with extramammary PD. Interestingly, we identified MSI1 ectopic overexpression in basal epithelial cells of human PD skin, and show that Msi1 overexpression in the epidermal basal layer of mice phenocopies human PD at histopathological, single-cell and molecular levels. Using this mouse model, we identified novel biomarkers of Paget-like cells that translated to human Paget cells. Furthermore, single-cell trajectory, RNA velocity and lineage-tracing analyses revealed a putative keratinocyte-to-Paget-like cell conversion, supporting the in situ transformation theory of disease pathogenesis. Mechanistically, the Msi1-mTOR pathway drives keratinocyte-Paget-like cell conversion, and suppression of mTOR signaling with Rapamycin significantly rescued the Paget-like phenotype in Msi1-overexpressing transgenic mice. Topical Rapamycin treatment improved extramammary PD-associated symptoms in humans, suggesting mTOR inhibition as a novel therapeutic treatment in PD.

Experiences with Surgical Reconstruction of Penoscrotal Extramammary Paget's Disease: A review of 21 cases

Penoscrotal extramammary Paget's disease is a rarely found intraepithelial adenocarcinoma in older male patients. The challenge for surgeons to perform high-quality post-surgery reconstruction is mostly case-dependent. Here, we present a review of post-surgical reconstruction practice in 21 cases using various scrotal skin flaps. During the 10-year study period (from 2008 to 2018), all 21 male patients diagnosed with penoscrotal extramammary Paget's diseases at Sun Yat-sen memorial hospital were enrolled in this study. All patients underwent expanding resections guided by frozen sections and penoscrotal reconstructions using various scrotal skin flaps alone or combined with pubic skin flaps and partial thickness skin graft depending on individual defects. The patient's clinical data, specifically the diagnosis, surgical outcome, and follow-up evaluation were retrospectively analyzed. The size of skin lesions ranged from 4 × 5 cm to 16 × 18 cm approximately. Out of 21 total cases, 13 patients received combined scrotal and pubic flaps, three patients received single scrotal flaps, and five patients received scrotal flaps and partial thickness skin grafts. Limited flap tip necrosis (two cases) and wound dehiscence (one case) were observed, and secondary resections were performed in four cases with positive post-operative pathological results. All patients experienced complete wound healing and had well-maintained penile morphology and function. Various scrotal skin flaps alone or combined with pubic skin flaps designed for individual lesion conditions in patients with penoscrotal extramammary Paget's disease are efficient for scrotal reconstruction. A good match of the local skin texture helps to maintain the morphology and function of the penis and scrotum.

GATA3 is a sensitive marker for primary genital extramammary paget disease: an immunohistochemical study of 72 cases with comparison to gross cystic disease fluid protein 15

BackgroundGATA-binding protein 3 (GATA3) has been identified as a sensitive marker for breast carcinoma but its sensitivity in primary genital extramammary Paget diseases (EMPDs) has not been well studied.MethodsHere we investigated immunohistochemical expression of GATA3 in 72 primary genital EMPDs (35 from female, 37 from male; 45 with intraepithelial disease only, 26 with both intraepithelial disease and invasive adenocarcinoma including 14 also metastasis, 1 with metastatic adenocarcinoma only for study). We also compared GATA3 to gross cystic disease fluid protein 15 (GCDFP15) for their sensitivity.ResultsPositive GATA3 staining was seen in all 71 (100%) intraepithelial diseases, 25/26 (96%; female 10/10, male 15/16) invasive adenocarcinomas and 14/15 (93%; female 3/3, male 11/12) metastatic adenocarcinomas, respectively. Positive GCDFP15 staining was seen in 46/71 (65%; female 28/34 or 82%, male 18/37 or 49%) intraepithelial diseases, 20/26 (77%; female 9/10, male 11/16) invasive adenocarcinomas, and 12/15 (80%; female 2/3, male 10/12) metastatic adenocarcinomas, respectively (GATA3 versus GCDFP15: p < 0.01 for both intraepithelial disease and invasive adenocarcinoma, p = 0.28 for metastatic adenocarcinoma). In positive-stained cases, GATA3 stained more tumor cells than GCDFP15 (79% versus 25% for intraepithelial disease, 71% vs 34% for invasive adenocarcinoma, 73% vs 50% for metastatic adenocarcinoma, p < 0.01 for all 3 components).ConclusionsOur findings indicate that GATA3 is a very sensitive marker for primary genital EMPDs and is more sensitive than GCDFP15.

Characteristics and prognosis of Japanese female breast cancer patients: The BioBank Japan project.

BackgroundBreast cancer is currently the most common type of cancer in Japanese females. Unlike most other types of cancer, breast cancer develops more frequently in middle-aged females than in elderly females.MethodsOf all Japanese female breast cancer patients aged ≥20 years whom the BioBank Japan Project originally enrolled between 2003 and 2008, 2034 were registered within 90 days after their diagnosis. We described the lifestyle and clinical characteristics of these patients at study entry. Furthermore, we examined the effect of these characteristics on all-cause mortality.ResultsIn the female patients registered within 90 days after diagnosis, the frequency of stage 0 or unclassified, stage I, II, III and IV were 11.4%, 47.9%, 37.0%, 2.9% and 0.8%, respectively. The proportion of histological types was 12.9% for non-invasive carcinoma (ductal carcinoma and lobular carcinoma), 81.0% for invasive carcinoma (papillotubular carcinoma, solid tubular carcinoma, scirrhous carcinoma and special types), 0.2% for Paget's diseases and 5.8% for others. Those positive for the estrogen and progesterone receptors accounted for 75.8% and 62.1% of all patients, respectively. Among 1860 female participants registered within 90 days, 218 participants died during 144,54 person-years of follow-up. More advanced stage, elevation of serum carcinoembryonic antigen and carbohydrate antigen 15-3 levels and absence of the estrogen receptor at study entry were crudely associated with an increased risk of all-cause mortality after adjustment for age.ConclusionsThis study showed the association of several clinical characteristics with all-cause mortality in female breast cancer patients.

Immunohistochemistry for CD117 (KIT) is effective in distinguishing cutaneous adnexal tumors with apocrine/eccrine or sebaceous differentiation from other epithelial tumors of the skin.

The aim of this study was to evaluate the effectiveness of CD117 immunostaining for diagnosing cutaneous adnexal tumors, which has not been previously established. CD117 immunostaining was performed on representative sections of 87 clinicopathologically confirmed cutaneous apocrine/eccrine tumors, 13 sebaceous tumors, 52 follicular tumors, 55 keratinocytic tumors, 24 metastatic tumors of the skin of known origin and 1 mammary Paget disease. Staining of 5-50% of cells was considered focally positive, and staining of 51-100% of cells was considered diffusely positive. Staining intensity was semi-quantitatively graded as weak, moderate or strong. A total of 82 (94.3%) tumors with apocrine/eccrine differentiation were CD117-positive, whereas one mucinous carcinoma, one apocrine carcinoma, and three primary cutaneous extramammary Paget diseases were CD117-negative. For most positive cases, staining was diffuse (64/82 cases) and moderate to strong in intensity (74/82). Twelve (92.3%) sebaceous tumors were CD117-positive, showing mainly focal (9/12) and weak (7/12) positivity. Of the 52 follicular tumors, all 4 cases of pilomatricoma and other 5 tumors were positive for CD117. Of the 55 keratinocytic tumors, only 2 cases were CD117-positive. The 24 metastatic tumors and mammary Paget disease were CD117-negative. CD117 may be useful for the differential diagnosis of cutaneous adnexal tumors.

XRCC1 Arg194Trp polymorphism, risk of nonmelanoma skin cancer and extramammary Paget’s disease in a Japanese population

The X-ray repair cross-complementing groups 1 gene plays an important role in base excision repair. At least three common single nucleotide polymorphisms frequently occur in this gene (Arg399Gln, Arg194Trp and Arg280His). Recent studies reported that these polymorphisms were associated with not only risk of visceral malignancy but also that of skin cancer such as basal cell carcinoma and squamous cell carcinoma, whereas the results of previous study vary among races. In this case–control study, we investigated whether these single nucleotide polymorphisms were associated with the risk of skin cancer in a Japanese population. The study population was composed of 197 patients with skin cancer (27 actinic keratoses, 47 basal cell carcinomas, 27 squamous cell carcinomas, 29 Bowen’s diseases, 46 malignant melanomas and 21 extramammary Paget’s diseases) and 93 control subjects. We genotyped two single nucleotide polymorphisms (Arg194Trp and Arg399Gln) using polymerase chain reaction-restriction fragments length polymorphism analysis. We found a significantly increased risk for basal cell carcinoma, squamous cell carcinoma and extramammary Paget’s disease associated with Arg194Trp [adjusted odds ratio (AOR) = 2.347, 3.587, 3.741, 95 % confidence interval (CI) 1.02–5.39, 1.19–10.8, 1.15–12.2, respectively]. We also found a significantly decreased risk for basal cell carcinoma associated with Gln399Gln (AOR = 0.259, 95 % CI 0.07–0.96). Our data suggest that the Arg194Trp polymorphism could be associated with nonmelanoma skin cancer and extramammary Paget’s disease risk in a Japanese population.

Results of carbon ion radiotherapy for skin carcinomas in 45 patients

BACKGROUND; Heavy ions represent the best tool for external radiotherapy (RT) of inoperable tumours. Heavy ion RT has been used in the treatment of various tumours, especially for radioresistant tumours mediated by hypoxia, localized near organs at risk. Most of these treatments are concentrated in deep-seated tumours such as those of the brain, head, lung, liver, rectum and urogenital organs, and treatment of skin carcinomas is limited. To evaluate the outcome and toxicity after carbon ion RT for skin carcinomas at the Heavy Ion Research Facility in Lanzhou, China. Between November 2006 and March 2009, 45 patients with skin carcinoma [squamous cell carcinoma (SCC) (n = 16), basal cell carcinoma (BCC) (n = 12), malignant melanoma (MM) (n = 7), Bowen disease (n = 8) and Paget disease (n = 2)] were treated with carbon ion RT within a clinical Phase I trial. Patients received total doses of 60-70 GyE for SCC and BCC, 61-75 GyE for MM, 60 GyE for Bowen disease and 42·5 GyE for Paget disease, administered in 6-11 fractions over 6-11 days, with a fraction dose of 7-10 GyE. The mean follow-up was 24 months, range 12-36 months. The actuarial local control rates at 1 and 3 years were 90·9% and 65·5% for SCC, 91·7% and 80·2% for BCC, 85·7% and 42·9% for MM, 90% and 90% for Bowen and Paget diseases, respectively. The actuarial 1- and 3-year overall survival rates for 45 patients were 88·9% and 86%, respectively. No severe side-effects greater than Common Toxicity Criteria grade 3 have been observed. The results demonstrated that heavy ion RT offers high local tumour control and progression-free survival rates without significant radiation-induced toxicity for patients with skin carcinomas.

Metastasis: Genetics, Mechanism, and Diagnostic and Therapeutic Strategies

Metastasis: Genetics, Mechanism, and Diagnostic and Therapeutic Strategies

Bone mass, vitamin D levels and immunosuppressive treatment in patients with liver transplant and risedronate treatment

As bone matures type I collagen undegoes β isomerisation at the DG motif of the CTX epitope. Measurements of αCTX and βCTX allow us to distinguish between bone turnover in newly formed and mature bone, respectively. In states of pathologically high bone turnover such as Paget's and malignant bone diseases, there is a relatively greater increase in the resorption of newly formed bone. Treatment of these with bisphosphonates results in a relatively greater decrease in the resorption of newly formed bone. The aims were to investigate 1) the relative increase in αCTX in postmenopausal osteoporosis and 2) the relative decrease in αCTX with bisphosphonate treatment. We recruited 60 postmenopausal women (mean age 68: range 55-85) with a BMD T-score of <2.5 or <1 and a fracture. They were randomised into 3 treatment groups: ibandronate (n=19), alendronate (n=23) and risedronate (n=18). 75 healthy premenopausal women (mean age 38: range 30-45) were recruited. We measured α and βCTX (Nordic Biosciences Diagnostics, Copenhagen, Denmark) in second morning void urine samples and serum βCTX (Roche Diagnostics, Pensberg, Germany). The median urinary α and βCTX and serum βCTX were significantly lower in healthy premenopausal compared to postmenopausal osteoporotic women at baseline 62%, 110% and 65% respectively (P<0.0001). The median urinary α and βCTX and serum βCTX showed a significant decrease by 68%, 88%, and 79% from baseline respectively (P<0.0001) after 13 weeks of treatment. The α/β CTX ratio increased by 62% (P<0.05). We conclude that resorption of type I collagen in postmenopausal osteoporosis is greater compared to healthy premenopausal women. There is no relative greater increase in the resorption of newly formed bone. With bisphosphonate treatment, the resorption of type I collagen is decreased after 13 weeks of treatment, but there is no greater decrease in the relative resorption of newly formed bone. In fact, there is a preferential decrease in the resorption of mature bone.

Penile and Scrotal Paget’s disease: 130 Chinese patients with long‐term follow‐up

To report a retrospective series of 130 Chinese patients with penoscrotal extramammary Paget's diseases (EMPD), with a long-term follow-up, and thus improve the diagnosis and therapy of this disease. The history, clinical presentation, pathology, treatment, and prognosis of 130 patients were analysed. All cases were confirmed by skin biopsy, and then the patients had local wide resection to remove the involved skin and subcutaneous tissue. The large defective wound was reconstructed using a split-thickness skin graft or local flap. Forty-five patients were evaluated by frozen-section biopsy of the margins during surgery, five of whom had positive margins and then had an extended resection immediately. Most of these patients had local skin or adjacent scrotal flaps to cover their skin defects. Of the 130 patients, 81 had a mean (range) follow-up of 3.2 (0.5-10) years after surgery. Five of nine patients with positive margins and three (4%) of 72 with negative margins had tumour recurrence. Five patients died from metastatic disease. Penoscrotal EMPD needs be differentiated from other chronic dermatitis. A 3 cm surgical margin should be sufficient and frozen-section pathological examinations are necessary for some complicated conditions. Skin grafts or local flaps are good for large skin defects.

Diagnostik und Therapie des Analkarzinoms

Of all carcinomas in the anal canal, 75-80% are squamous cell carcinomas-the remaining 25% being adenocarcinomas. Carcinomas of the anal margin are to be differentiated from basal cell carcinomas and Paget's and Bowen's diseases. More than 80% of anal carcinomas show high-risk HP viruses. Every suspicious lesion in the anal canal and margins must be examined histologically. Primary radiochemotherapy is the first treatment option for epidermoid carcinomas of the anal canal and anal margin. Overall 5-year survival is reported at up to 90%. Surgery is reserved for the primary biopsy or excision of small tumors and for salvage abdominoperineal resection in patients with tumor persistence or local recurrence after radiochemotherapy. Systematic inguinal lymphadenectomy is not indicated. The first follow-up examination should be done 6 weeks after the end of radiochemotherapy. A biopsy is necessary after 3 months.

Concordant overexpression of p-FAK and p-ERK1/2 in extramammary Paget’s disease

Focal adhesion kinase (FAK) is a tyrosine kinase which is at the crossroad of extracellular signal-regulated kinase-1/2 (ERK1/2), PI3K/Akt, MAPK and JAK/STAT signaling pathways. We have previously reported that p-ERK1/2, p-Akt, p38MAPK and p-STAT3 are overexpressed in extramammary Paget's diseases (EMPD), this study aimed to examine the expression of phosphorylated (p)-FAK and p-ERK1/2 proteins in EMPD and to evaluate the relationships among them. Paraffin-embedded EMPD specimens (35 tissue samples from 33 patients with primary EMPD, including two samples of metastatic lymph nodes from two of the 33 patients) were subjected to immunohistochemical staining for p-FAK and p-ERK1/2. All of the 35 EMPD specimens, including all of six invasive EMPD and two metastatic lymph node specimens, showed cytoplasmic overexpression of p-FAK and nuclear overexpression of p-ERK1/2. The expression levels (% positive cells) of p-FAK and p-ERK1/2 (88.34 +/- 14.66 and 91.26 +/- 11.21%) in EMPD were significantly higher than those in normal skin (22.38 +/- 2.13 and 29.00 +/- 4.44%), respectively. The expression levels of p-FAK (95.38 +/- 4.57%) and p-ERK1/2 (96.25 +/- 5.01%) in the advanced EMPD showed slightly higher than that in the non-invasive EMPD (86.26 +/- 15.99 and 89.78 +/- 12.15%), respectively. There exhibited a significantly high positive correlation between expression levels of p-ERK1/2 and p-FAK in EMPD. The present study shows that the concordant overexpression of p-FAK and p-ERK1/2 in EMPD which is associated with the grade of malignancy of EMPD, indicating that p-FAK and p-ERK1/2 may play pivotal roles in the tumorigenesis and further malignant transduction of EMPD.

Clinicopathologic evaluation of mammary Paget′s disease

Mammary and extramammary Paget's diseases are rare neoplasms of epidermis and mucosal epithelium. Due to their nonspecific and variable clinical view, they have differential diagnosis with eczema, melanoma, Bowen's disease, etc. To the best of our knowledge, no such study has been performed in Iran regarding the prevalence, clinical aspects, underlying disease and pathological characteristics of these two diseases. In this study, we have evaluated the clinical and histopathological aspects of this disorder.Materials and Methods:In this retrospective study, all Paget's biopsied samples referred to the Pathology Department of Imam-Reza hospital, Mashhad, since 1984 till 2004 were evaluated. Collected data were analyzed by descriptive statistical methods.Results:Among 98925 specimens, there were 29 cases of Paget's disease. All cases were married women suffering from mammary Paget. The mean age was 53 ± 11 years. Left and right breast involvement was observed in 17 and 12 cases, all unilateral. The most common clinical view was ulcerated (27%) and then erythematosus exudative plaques. More than 50% of patients were symptomatic. Most common symptoms were itching, pain and burning. The exclusive underlying pathological diagnosis was ductal carcinoma (55%).Discussion:In most cases, the clinical view of mammary Paget's disease was helpful. Unilateral ulcerated plaque was the most common clinical sign. Majority of the accompanying pathology was ductal carcinoma. We had no cases of extramammary Paget's disease in our study.

Pharmacological therapy of Paget's and other metabolic bone diseases

Paget's disease is a relatively common high-turnover metabolic bone disease that can serve as a model for osteoporosis and other metabolic bone diseases in investigation of therapeutic strategies to normalize bone turnover. Aims of treatment include rapid normalization of bone formation and resorption to prevent loss of mechanical integrity. Treatment will also reduce pain, while long-term maintenance of normal turnover may prevent long-term complications. Newer bisphosphonates have high antiresorptive potency and increased retention in bone, permitting a strategy of intermittent intravenous (IV) administration in achieving and maintaining normal bone turnover. In pivotal zoledronic acid Paget's disease trials, patients received a single 15-min IV infusion of zoledronic acid 5 mg (ZOL 5 mg) or risedronate 30 mg/day orally for 2 months. Treatment with ZOL 5 mg was associated with significant improvement in serum alkaline phosphatase, normalization in both the short and long term, and significant prolongation of biochemical therapeutic response in long-term follow-up. No changes in serum creatinine levels were observed with either treatment, and no clinically significant renal abnormalities were reported. Intermittent IV administration of potent bisphosphonates constitutes an intriguing strategy for treatment of Paget's disease and other metabolic bone diseases.

HER-2/neu expression in Paget disease of the vulva and the female breast

Objectives. Paget disease of the vulva is a rare lesion that accounts for <1% of vulva neoplasms. A 12% prevalence of invasive Paget carcinoma and a 4% prevalence of associated adenocarcinomas are described. Furthermore, a high recurrence rate of 30% after surgical therapy is observed. This study aims to search for therapeutic strategies for recurrent Paget disease, which are less mutilating and less aggressive than reexcision, x-ray therapy, or chemotherapy. Trastuzumab (Herceptin™) is a recombinant monoclonal antibody against HER-2/neu, approved by the U.S. FDA for the treatment of patients with HER-2/neu-positive metastatic breast carcinomas. The results of recent studies indicate that HER-2/neu oncoprotein may play a role in the pathogenesis of extramammary Paget disease. Methods. Using HercepTest™, we analyzed HER-2/neu overexpression in seven noninvasive Paget lesions, two invasive lesions, and one Paget disease of the vulva with underlying adenocarcinoma. In addition, we investigated five mammary Paget diseases. Results. Overexpression of HER-2/neu oncoprotein labeling exclusively the membranes of Paget cells was demonstrated in 8 out of 10 cases. One noninvasive and one with underlying adenocarcinoma stained negatively. Overexpression of HER-2/neu was demonstrated in all five cases of mammary Paget disease. Conclusion. Using HercepTest™ as a standardized detection system, overexpression of HER-2/neu can be demonstrated in a majority of both noninvasive and invasive Paget disease of the vulva. The use of Trastuzumab should be considered for the treatment of patients with recurrent Paget disease of the vulva with overexpression of HER-2/neu.

Skeletal affinity of Tc(V)-DMS is bone cell mediated and pH dependent.

In spite of recent advances in bone cellular and molecular biology, there is still a poor correlation between these parameters and data obtained from bone scintigraphy. Diphosphonate derivatives radiolabelled with technetium-99m (Tc-BPs) have long been recognised as bone-seeking agents with an affinity for areas of active mineralisation. However, during clinical trials with a pH-sensitive tumour agent, the pentavalent technetium complex of dimercaptosuccinic acid [Tc(V)-DMS] showed a noticeable osteotropic character only in bone pathologies (bone metastases, Paget's diseases) and lacked accumulation in normal mature bone. To decipher the osteotropic character of Tc(V)-DMS, a study at the cellular level was considered necessary. Moreover, to learn more about the role of Tc bone agents, acid-base regulation by bone tissue or cells was studied. First, biological parameters in body fluid were measured under systemic acidosis, induced by glucose administration, in normal and Ehrlich ascites tumour (EAT)-bearing mice. Then, in vivo biodistribution studies using Tc(V)-DMS or a conventional Tc-BP agent were carried out. The effect of glucose-mediated acidification on the skeletal distribution of the Tc agents in the mice provided valuable hints regarding the differential mediation of bone cells in skeletal tissue affinity for the agents. Thereafter, in vitro studies on osteoblast and osteoclast cells were performed and the comparative affinity of Tc(V)-DMS and Tc-BP was screened under diverse acidification conditions. Moreover, studies were also carried out on acid-base parameters related to the cellular uptake mechanism. Very specific pH-sensitive Tc(V)-DMS accumulation only in the osteoclastic system was detected, and use of Tc(V)-DMS in the differential detection of osteoblastic and osteoclastic metastases is discussed.

Indications for Lymph Node Dissection in the Treatment of Extramammary Pagetʼs Disease

BACKGROUND In extramammary Paget's disease, compared with patients with carcinoma in situ (CIS), patients with malignancies underlying dermis and subcutaneous tissues or lymph node metastasis appear to have a much worse prognosis. OBJECTIVE The purpose was to examine our extramammary Paget's diseases patients in terms of pathological tumor invasion, lymph node metastasis, and prognosis and to refer to indications of lymph node dissection. METHODS The 34 patients were divided into four groups by pathological tumor invasion: CIS, microinvasion to the papillary dermis (MIPD), invasion to the reticular dermis (IRD), and invasion to subcutaneous tissues (IST). Their age, sex ratio, follow-up periods, history of other cancers, lymph node metastasis, and prognosis were compared among the four groups and referred to indications of lymph node dissection. RESULTS In the groups of CIS and MIPD, all patients appeared to have no lymph node metastasis and death caused by this disease. In the groups of IRD and IST, 8 of 12 patients showed pathological lymph node metastasis, and all of them died due to metastasis of the tumor. In the cumulative survival rate of the patients according to the level of invasion, 5-year survival rate was 100% in CIS and MIPD groups, 33.3% in the IRD group, and 0% in the IST group. CONCLUSION In the treatment of extramammary Paget's disease, indications of lymph node dissection are an important issue as well as wide local excision. From this prospective study, we have developed an algorithm for indications of lymph node dissection.