Noninvasive Extramammary Paget's Disease Research Articles

Androgen receptor, androgen-producing enzymes and their transcription factors in extramammary Paget disease

Extramammary Paget disease (EMPD) has been known to frequently express androgen receptor (AR). Therefore, androgens could play roles in the biological behavior of Paget cells. 5α-Reductase (5α-red) types 1 and 2 and 17β-hydroxysteroid dehydrogenase type 5 (17β-HSD5) are pivotal in situ regulators of androgen production in androgen-responsive tissues including androgen-dependent neoplasms. Therefore, in this study, we immunolocalized AR, androgen-producing enzymes, and their transcription factors to assess the state of in situ androgen production and actions and its correlation of invasiveness in EMPD. We studied 51 cases of EMPD with known clinicopathological status. AR, 5α-red1, 17β-HSD5, and β-catenin immunoreactivity was evaluated by using the modified H-score method while cyclin D1, p53, forkhead box protein P1, and a proliferation marker, Ki-67, were quantified using labeling index. The mean scores of AR, 5α-red1, and 17β-HSD5 in invasive EMPD were all significantly higher than noninvasive EMPD (P < .0001). Ki-67 labeling index as well as the cyclin D1 score was also significantly higher in invasive than noninvasive lesions of EMPD. These results demonstrated that androgen receptor and androgen-producing enzymes were both associated with cell cycle regulation and subsequently the invasiveness of EMPD lesions and could also indicate those above as potential markers of invasive potentials in EMPD.

Invasive extramammary Paget's disease of the bladder diagnosed 18 years after noninvasive extramammary Paget's disease of the vulva

Paget's disease of the vulva is a rare vulvar neoplasm most commonly seen in postmenopausal women. Clinically, it presents as a pink eczematoid lesion with white islands of hyperkeratosis accompanied by pruritus. Pathologically it resembles mammary Paget's disease of the nipple and areola, first described by Sir James Paget in 1874 (Paget). The mean age at diagnosis of Paget's disease of the vulva has been reported to be between 50 and 80 years, and it is most common in Caucasian women (Preti et al., 2000). Disease is often limited to the epidermis and mucosa, without invasion. The optimal management of Paget's disease of the vulva remains unclear. Surgical excision is usually the primary therapy; however, 30% to 60% of patients develop recurrent disease. Furthermore, the lesions often extend past clinically apparent borders and surgical excision is limited by the anatomy of the vulva. In addition, the disease is often multifocal. Immunohistochemistry (IHC) can help distinguish Paget's disease from other vulvar conditions. Cytokeratin 7 (CK7), cytokeratin 20 (CK20), carcinoembryonic antigen (CEA), and gross cystic disease fluid protein-15 (GCDFP-15) are common markers for Paget's disease. Approximately 10% of patients with Paget's disease of the vulva have an underlying second malignancy. These include colorectal cancer, cervical cancer, breast cancer, as well as carcinoma of the transitional epithelium from the renal pelvis to urethra. Routine screening with colonoscopy, Pap test, and mammogram is therefore recommended. In addition, in rare instances, Paget's disease may become invasive, infiltrating the dermis and even metastasizing to lymph nodes and distant sites (Reddy et al., 2012). In this report, we describe the case of a woman with noninvasive Paget's disease of the vulva who developed invasive Paget's disease of the bladder 18 years after her original diagnosis of Paget's disease of the vulva.

Positive KI67 and Periodic Acid-Schiff Mandates Wider Range of Excision in Scrotal Extramammary Paget's Disease

Extramammary Paget's disease (EMPD) of the scrotum is a rare disease that requires surgical excision. A positive margin is related to recurrence and poorer prognosis. We aimed to investigate the expression of Ki67 and periodic acid-Schiff (PAS) in a biopsy sample and to evaluate their predictive value in true margin status. Sixty-four patients with noninvasive scrotal EMPD were included. Immunohistochemical staining of Ki67 and PAS was reviewed and compared statistically with the margin status of intraoperative frozen section examination (FSE). Seventeen of 64 patients had a positive margin discovered at the first FSE. Expression of Ki67 was not significantly different between positive and negative margin status (p=.16). Expression of PAS was higher in samples with positive margins (p=.05). The incidence of positive margins was significantly higher in the double-positive group than in the double-negative group (p=.03). Positive expression of both factors in a biopsy sample requires wider excision to ensure negative margins.

PI3K, Rac1 and pPAK1 are overexpressed in extramammary Paget's disease

Phosphatidylinositol 3-kinase (PI3K), Ras-related C3 botulinum toxin substrate 1 (Rac1) and P21-activated protein kinase 1 (PAK1) appear to play important roles in the pathogenesis of several tumors, but their expressions in extramammary Paget's disease (EMPD) have not been investigated yet. To investigate the potential contribution of the PI3K, Rac1 and PAK1 to the development of EMPD. Thirty-five paraffin-embedded EMPD specimens were subjected to immunohistochemical staining for PI3K (85α), Rac1 and pPAK1. All the 35 primary EMPD specimens, including 20 non-invasive EMPD, 13 invasive EMPD and 2 metastatic lymph nodes, showed cytoplasm overexpression of PI3K (85α), Rac1 and pPAK1. The expression (% positive cells) of PI3K(85α), Rac1 and pPAK1 (90.1 ± 8.6, 91.4 ± 9.5 and 89.6 ± 10.8% ) in EMPD were significantly higher than in apocrine glands of normal skin ( 20.1 ± 11.9, 29.8 ± 8.9, 41.1 ± 13.4%), and the expression in invasive EMPD with lymph node metastasis (98.2 ± 1.7, 98.8 ± 0.7 and 98.4 ± 0.9%) are significantly higher than in invasive EMPD without lymph node metastasis (94.1 ± 2.6, 96.5 ± 1.7 and 95.3 ± 1.1%) and non-invasive EMPD (85.2 ± 8.4, 87.1 ± 9.9 and 83.1 ± 10.6%). There were significant positive correlations of the expression levels between PI3K (85α) and Rac1, as well as between Rac1 and pPAK1 in EMPD. These results indicate that PI3K, Rac1 and PAK1 may play important roles in the pathogenesis of EMPD.

Maladie de Paget du scrotum d’évolution métastatique

Extra-mammary Paget's disease (EMPD) is currently considered a slowly progressing in situ adenocarcinoma. It is much more rarely associated with an invasive underlying adenocarcinoma than in mammary sites, where this association is almost always seen. However, an invasive course is to be feared where EMPD has been progressing for several years. A 59-year-old man consulted for treatment of scrotal Paget's disease present for over 15 years and treated with topical emollients alone. Two infiltrated areas had recently appeared and their excision led to a diagnosis of invasive Paget's disease at these two points. Metastasis occurred 10 months later and rapidly proved fatal. Until now, non-invasive EMPD has been considered a fairly non-aggressive disease due to its indolent progression. However, it is characterised by considerable risk of relapse following surgical excision, regardless of the surgical margin. Despite a good prognosis at the intraepithelial stage, the rising life expectancy of the population means a greater likelihood of an invasive course or of the appearance of an underlying adenocarcinoma, and management of this condition can thus no longer be neglected. The present clinical case underscores the need for closer surveillance of the disease as of the intraepithelial stage.

Comparison of Foxp3+ Regulatory T cells and CD163+ Macrophages in Invasive and Non-invasive Extramammary Paget’s Disease

Regulatory T cells (Tregs), identified by the expression of CD4, CD25 and Foxp3, together with immunosuppressive macrophages, such as CD163+ M2 macrophages, are involved in maintaining peripheral tolerance. The aim of this study was to elucidate the involvement of Tregs and CD163+ macrophages in invasive and non-invasive extramammary Paget's disease. The presence of CD4+CD25+Foxp3+ Tregs, CD163+ M2 macrophages and matrix metalloproteinase-9+ cells was examined immunohistologically in fixed sections of lesional skin from 10 patients with non-invasive extramammary Paget's disease and 7 patients with invasive extramammary Paget's disease. Fewer CD4+CD25+Foxp3+ Tregs were observed in non-invasive extramammary Paget's disease than in invasive extramammary Paget's disease. In contrast, higher numbers of CD163+ macrophages and metalloproteinase-9+ cells were detected only in invasive extramammary Paget's disease. These findings suggest that the induction of immunosuppressive cells in extramammary Paget's disease differs according to the tumour stage.

Hematopoietic Progenitor Kinase 1, Mitogen-Activated Protein/Extracellular Signal-Related Protein Kinase Kinase Kinase 1, and phosphoMitogen-Activated Protein Kinase Kinase 4 are Overexpressed in Extramammary Paget Disease

The c-Jun amino-terminal kinase (JNK) pathway seems to play important roles in the pathogenesis of several tumors, but its significance in extramammary Paget disease (EMPD) has not been investigated yet. The purpose of the study was to investigate the potential contribution of the JNK-associated molecules, such as hematopoietic progenitor kinase 1 (HPK1), mitogen-activated protein/extracellular signal-related protein kinase kinase kinase1 (MEKK1), transforming growth factor-β activated kinase 1 (TAK1), and phosphomitogen-activated protein kinase kinase 4 (p-MKK4) to the development of EMPD. Thirty-five paraffin-embedded EMPD specimens were subjected to immunohistochemical staining for HPK1, MEKK1, TAK1, and p-MKK4. All the 35 EMPD, including 13 dermal invasive EMPD and 2 lymph node metastasis, showed cytoplasmic overexpression of HPK1, MEKK1, and p-MKK4. The expression (%positive cells) of HPK1, MEKK1, and p-MKK4 in EMPD (92.3% ± 8.6%, 92.9% ± 8.6%, and 92.7% ± 7.4%, respectively) were significantly higher than in normal eccrine sweat gland cells (51.6% ± 10.4%, 44.7% ± 11.7%, 0% ± 0%). In addition, the expression of HPK1-, MEKK1-, and p-MKK4 in invasive EMPD was significantly higher than in noninvasive EMPD. Meanwhile, the expression of TAK1 was basically low and no significantly different between EMPD and normal controls. In conclusion, these results indicate that JNK pathway may play a role in the pathogenesis of EMPD.

Noninvasive Extramammary Paget's Disease Treated with Photodynamic Therapy

Extramammary Paget's disease (EMPD) is a rare low-grade cutaneous malignancy that affects apocrine gland-bearing areas and most commonly occurs on the perineal skin. Photodynamic therapy (PDT) may represent a useful treatment option for extensive, noninvasive EMPD, alone or as part of multimodal therapy. To analyze the clinical outcomes of PDT for noninvasive EMPD with topical aminolevulinic acid (ALA) or intravenous porfimer sodium as photosensitizing agents and argon laser as the photoactivator. Retrospective case series of patients with noninvasive EMPD treated at Roswell Park Cancer Institute with PDT from April 20, 1995, to December 4, 2008. Identified patients included five men and three women aged 50 to 80 (mean age 67) with a total of 24 distinct lesions of noninvasive EMPD without distant metastases. Four patients received topical ALA only as a photosensitizer, three received intravenous porfimer sodium only, and one received both. All patients were treated using a 632.8-nm argon-pumped dye laser, and some were also treated using a red lamp (590-729 nm). Seven of nine lesions (78%) treated with PDT using intravenous porfimer sodium showed a complete response (CR) and were disease free at 12 to 96 months. Eight of 16 lesions (50%) treated with PDT using topical ALA showed a CR, and 38% were disease free at 9 to 88 months. None of the treated patients developed any serious cosmetic or functional impairments, such as loss of sphincter control or dysesthesias. PDT with intravenous porfimer sodium or topical ALA and argon laser may represent a useful, surgery-sparing therapeutic option for management of noninvasive EMPD in selected patients. Prospective, randomized clinical trials are necessary to compare the effectiveness of PDT with that of surgery for noninvasive EMPD.

Nerve growth factor, brain‐derived neurotrophic factor and their high‐affinity receptors are overexpressed in extramammary Paget's disease

Neurotrophin (NT) systems appear to play important roles in the pathogenesis of several tumors, but their expression in extramammary Paget's disease (EPD) has not been investigated. Thirty-four paraffin-embedded EPD specimens (32 primary EPD and 2 metastatic to lymph nodes) were subject to immunohistochemical staining for nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), NT3, NT4, their high-affinity receptors (TrkA, TrkB and TrkC) and the common low-affinity receptor, p75 NT receptor (p75). All 34 EPD specimens, including 2 metastatic to lymph nodes, showed cytoplasmic overexpression of NGF, BDNF, TrkA and TrkB. The expression (% positive cells) of NGF, BDNF, NT3, NT4, TrkA and TrkB (81.6 ± 14.9, 86.0 ± 10.4, 89.6 ± 14.9, 87.8 ± 17.9, 83 ± 14.4 and 86.2 ± 11.7%) in EPD was significantly higher than in normal skin (21.6 ± 6.5, 27.6 ± 4.5, 19.7 ± 10.1, 8.2 ± 10.0, 25.0 ± 5.3 and 25.4 ± 6.4%), and the expression of these factors in invasive EPD was significantly higher than in noninvasive EPD. Interestingly, Paget cells were negative for p75 and TrkC in all the 34 EPD specimens. These results suggest that overexpression of NGF, BDNF and their high-affinity receptors (TrkA and TrkB) might play a role in the pathogenesis of EPD.

HER‐2/neu expression in extramammary Paget disease: a clinicopathologic and immunohistochemistry study of 47 cases with and without underlying malignancy

Extramammary Paget disease (EMPD) is an infrequent skin cancer sometimes representing a secondary event caused by extension of an underlying carcinoma. Her-2/neu overexpression in breast cancer is correlated with a more aggressive behavior, but anti-Her-2/neu therapy improves survival in these patients. We investigated Her-2/neu expression by immunohistochemistry in cases of EMPD with and without underlying malignancy to try to correlate with tumor recurrence, progression and possible targeted therapy. Forty-seven cases were analyzed (6 from the scrotum, 7 perianal region, 1 axilla and 33 vulva). Two cases had invasive EMPD (one from vulva and one from scrotum). The overall Her-2/neu expression was 31.9%. Of the noninvasive EMPD of the vulva (32 cases), Her-2/neu was shown in 38%. The case of invasive vulvar EMPD was negative. All six scrotal EMPD lacked Her2/neu expression. Her-2/neu was expressed in two of seven perianal cases (33.3%). The EMPD on the axilla (one case) was negative. Eighteen cases had recurrence, and of these, 44.4% expressed Her-2/neu in the initial lesion. A high proportion of EMPD showed Her-2/neu expression (31.9%), indicating that these patients may benefit from targeted therapy. The proportion of positive cases was higher in lesions that had recurred at last follow up (44.4%), suggesting a more aggressive behavior.

Immunohistochemical Study of c-&lt;i&gt;erb&lt;/i&gt;B-2 Oncoprotein Expression in Extramammary Paget’s Disease

Sections of formalin-fixed, paraffin-embedded tumor tissue from 20 patients with noninvasive extramammary Paget's disease and 2 patients with invasive extramammary Paget's disease were stained immunohistochemically by means of anti-c-erbB-2 product monoclonal antibody. Membrane staining of intraepidermal tumor cells was found in only 3 of 20 cases of noninvasive extramammary Paget's disease. In the 2 invasive cases, tumor cells of invasive lesions and metastases were positive while intraepidermal tumor cells were negative.