Extramammary Paget disease (EMPD) is a rare malignancy of the skin. Because of the scarcity of the cases, genomic alterations in EMPD are poorly characterized. To address this issue, we have interrogated 39 EMPD samples and patients blood with exome sequencing. The mutational load of EMPD was moderately high; the median prevalence of somatic mutations was above 3 mutations per megabase, a number comparable to the one of kidney renal cell carcinoma. Our study identified several putative driver events. ERBB2 mutation, as well as amplification, is frequent in our samples and likely the key driver of EMPD. The mutations are enriched in the tyrosine kinase domain of ERBB2, and are likely to cause functional alteration of the gene product. This observation is in line with previous papers reporting the efficacy of trastuzumab for EMPD. Other cancer genes including ERBB3, KMT2C, MLL4, and COL1A1 are also frequently mutated in EMPD. Driver mutation analysis by OncodriveFM identified potential novel cancer genes that are previously unreported in other cancer types. Copy number analysis identified recurrent somatic copy number aberrations. Frequent deletion peaks included CDKN2A and TSC2, both of which were important tumor suppressor genes. Mutational signature analysis showed that APOBEC3B activation, coupled with aging, was driving the somatic mutations in EMPD. We also identified evidence of APOBEC3B activation including kataegis and strand bias in the EMPD genome. In conclusion, our study provides the comprehensive landscape of somatic mutations in EMPD as well as insights into the mechanisms behind the carcinogenesis of EMPD. We have identified putative driver mutations including ERBB2 and ERBB3, which are readily targeted. We also suggest that EMPD may be treated with cancer immunotherapy, for the moderately high mutational load observed in EMPD is associated with the response to cancer immunotherapy in other cancer types. These insights provide rationale for use of systemic treatments in patients with EMPD.
Extramammary Paget disease (EMPD) is a rare dermatologic condition that frequently presents in areas where apocrine sweat glands are abundant, most commonly the vulva, although perineal, scrotal, perianal, and penile skin may also be affected. Lesions clinically present as erythematous, well-demarcated plaques that may become erosive, ulcerated, scaly, or eczematous. Extramammary Paget disease has a female predominance and usually occurs in the sixth to eighth decades of life. Professionals disagree about many aspects of EMPD, for example, the prevalence of concurrent vulvar adenocarcinoma or invasive EMPD, association with regional and distant cancers, and recurrence rates following surgical excision. Early recognition is imperative because the diagnosis is frequently delayed and there is a high incidence of associated invasive disease.
Metastatic EMPD is an aggressive skin adenocarcinoma with poor prognosis. Since current chemotherapeutic regimens are only moderately effective, improving clinical outcomes is imperative. The basic and translational research to date has provided an insight into the mechanisms promoting metastasis of EMPD that provide potential therapeutic targets for new drug development. Seemingly, Paget cells augment the ability of proliferation and survival by activating the RAS–RAF–MEK–ERK signaling, PI3K–AKT–mTOR signaling, or androgen–AR signaling. In addition, the interaction of Paget cells with other cells, such as LECs and CD163+Arg1+ macrophages in a tumor through the CXCR4–SDF-1 signaling and RANKL–RANK signaling, respectively, could establish a favorable tumor microenvironment to promote metastasis of Paget cells. Furthermore, recent genomic analysis of MMR has revealed that a decent percentage of EMPD comprises MMR-deficient EMPD cases that might achieve durable clinical response by an anti-PD-1 antibody. Hence, we are now beginning to understand multiple aspects involved in the pathogenesis of metastatic EMPD, and these findings will be sure to lead to better treatments for patients with metastatic EMPD in the future.
Extramammary Paget's disease (EMPD) is one of the cutaneous adenocarcinomas. The effective chemotherapy for advanced EMPD has not been established. This study was designed to evaluate the efficacy of combination 5‐fluorouracil (500 mg/body, 7 days/week) and cisplatin (5 mg/body 5 days/week) for invasive EMPD. Seventeen EMPD patients with multiple metastases who visited our dermatology clinic between October 2004 and May 2016 (mean age, 76.9 years; 10 men, seven women) were retrospectively analyzed. Eight EMPD patients underwent low‐dose 5‐fluorouracil/cisplatin therapy and nine patients chose best supportive care. The average number of treatment cycles was 12.3. All patients had a confirmed response, four (50%) showed a partial response, two (25%) stable disease and two progressive disease. The median times to progression‐free and overall survival were 25.0 and 77.4 weeks, respectively. There was no severe (grade 3 and 4) adverse event. Although not significant, the survival of the patients treated with low‐dose 5‐fluorouracil/cisplatin therapy showed a trend toward improved survival as compared with best supportive care (P = 0.08, log–rank test). This regimen had low risk and relatively high disease control rate, suggesting that this regimen be recommended as one of the treatment options for advanced EMPD.
Patients with EMPD in this series have a high rate of recurrence. Many undergo multi-modal therapy often with multiple providers. However, patients experience relatively long disease-free intervals with a low rate of associated malignancy. We propose an algorithm for management that focuses on symptom control and minimizing morbidity of treatment intervention once invasive disease has been excluded.
Caucasian postmenopausal women are found to be more prone to Paget’s disease of the vulva. Symptoms include long-standing tenderness and itching, irritation, and burning sensation. Usually, symptoms are present for 2 years or even more before a diagnosis made. The lesions may be painful at times; however, some individuals are asymptomatic during diagnosis.
Though the appearance of the rash can create confusion with other similar vulvar rashes, biopsy typically provides a confirmation of the diagnosis. When Paget’s disease of the vulva is suspected, colonoscopy or cystoscopy is done as an additional diagnostic measure to look for cancers in the colon or bladder, respectively, if urinary or bowel symptoms are present.
Forty-two patients completed the survey. At a mean age of 64 years, patients most commonly developed rash, pruritus, or erythema in the genital and perianal regions. Patients presented to their primary care physician, gynecologist, or dermatologist and were initially treated with topical agents for benign diagnoses. After failing conservative treatments, patients underwent biopsy by a dermatologist or gynecologist and were diagnosed with EMPD on average 21 months after the onset of symptoms. Wide local and Mohs excisions were the most frequently administered treatments with positive margins reported in 43% of patients. Fewer patients underwent non-invasive treatment with Imiquimod cream and radiation. In total, 29% of patients developed regional recurrence and distant disease. There was wide variation regarding medical specialties involved, diagnostic evaluation, treatment, and clinical follow up.
This study provides a novel view of the varied clinical and pathological details from patients treated across varying institutions and medical specialties. This study will hopefully educate providers of the overall disease process of EMPD and encourage the development of standardized treatment recommendations.
We describe a computer vision-based mosaicking method for in vivovideos of reflectance confocal microscopy (RCM). RCM is a microscopic imaging technique, which enables the users to rapidly examine tissue in vivo. Providing resolution at cellular-level morphology, RCM imaging combined with mosaicking has shown to be highly sensitive and specific for non-invasively guiding skin cancer diagnosis. However, current RCM mosaicking techniques with existing microscopes have been limited to two-dimensional sequences of individual still images, acquired in a highly controlled manner, and along a specific predefined raster path, covering a limited area. The recent advent of smaller handheld microscopes is enabling acquisition of videos, acquired in a relatively uncontrolled manner and along an ad-hoc arbitrarily free-form, non-rastered path. Mosaicking of video-images (video-mosaicking) is necessary to display large areas of tissue. Our video-mosaicking methods addresses this need. The method can handle unique challenges encountered during video capture such as motion blur artifacts due to rapid motion of the microscope over the imaged area, warping in frames due to changes in contact angle and varying resolution with depth. We present test examples of video-mosaics of melanoma and non-melanoma skin cancers, to demonstrate potential clinical utility.
Chemokines are involved in many aspects of oncogenesis, including regulation of cancer cell growth, dissemination and host-tumor response. However, the potential of the chemokine receptors, CXCR4 and CXCR7, in serving as biomarkers in extramammary Paget's disease (EMPD) has been rarely examined. Expressions of CXCR4 and CXCR7 were evaluated in 92 EMPD specimens by immunohistochemistry. High expression of CXCR4 and CXCR7 were both correlated with regional lymph node metastasis and presence of lymphovascular invasion. High expression of CXCR7 also correlated with the depth of invasion. The prognostic value of these two chemokines were also investigated in progression-free survival (PFS) and cancer-specific survival (CSS). Both high expression of CXCR4 and CXCR7 were indicative of shorter PFS and CSS. In the combined prognostic model, concomitant high expression of CXCR4 and CXCR7 were suggestive of poor prognosis compared with the other two groups. In the multivariate analysis, depth of invasion, combined prognostic model and regional lymph node metastasis at diagnosis were the independent prognostic factors for EMPD patients for PFS, and the former two factors independently impacted CSS. Our results demonstrated that CXCR4 and CXCR7 can be used as prognostic biomarkers and prediction of aggressiveness of EMPD. Therapy targeting CXCR4 and CXCR7 may helpful to prevent EMPD progression and improve the prognosis of EMPD.
To determine whether a subset of primary extramammary Paget disease (EMPD) may originate in anogenital mammary-like glands (AGMLG), the authors studied 181 specimens of EMPD, detailing alterations in AGMLG. The latter were identified in 33 specimens from 31 patients. All patients were women, ranging in age from 38 to 93 years (median, 65 y). However, by analogy with mammary Paget disease, rare cases of primary EMPD may originate in AGMLG with a subsequent upward migration of the neoplastic cells into the epidermis and possible later breach through the basal membrane. Usual ductal hyperplasia and atypical duct hyperplasia can then be regarded as earlier precursor lesions, linking both ends of the spectrum.
GATA-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.
Positive 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).
Our findings indicate that GATA3 is a very sensitive marker for primary genital EMPDs and is more sensitive than GCDFP15.
Park et al. report their experience in the management of extramammary Paget’s Disease (EMPD) of the penoscrotal region and specifically compare outcomes among cohorts of men with the disease who either did or did not undergo mapping biopsies prior to their definitive surgical procedure. The rationale for the study and this comparison is that Paget’s disease initially spreads insidiously through the epidermis, sometimes in a single-cell fashion, and establishing the diagnosis can be very difficult subsequent to intraoperative frozen sections. Thus, several studies have described the use of outpatient mapping biopsies under more permanent section pathology techniques to facilitate the diagnosis and to ‘clear’ the surgical margins (references 19–21 in the article). This should theoretically lead to a lower incidence of positive frozen section margins intraoperatively, a lower incidence of positive permanent section margins, and lower recurrence rates for patients.
Oriol Yélamos, MD 1, 2
1. Dermatology Service, Memorial Sloan Kettering Cancer Center, New York, NY
2. Dermatology Department, Hospital Clínic, Universitat de Barcelona, Barcelona
Extramammary Paget disease or EMPD is a rare skin cancer that presents with a red patch in the vulva or anus in women, and in the scrotum, penis and anus in men. Diagnosing EMPD is challenging because the entire area affected by the disease is not visible with the naked eye, or can be misdiagnosed with other skin conditions such as infection or inflammation. This is particularly important when monitoring treatment response, as treatments can irritate the skin and look identical (red patch) to residual EMPD.
Reflectance confocal microscopy or RCM is an imaging system which uses a light source that does not damage the skin and that allows to see cells on the superficial layers on the skin. RCM has been used to diagnose EMPD as one can see the cancer cells in the skin in real time. However, RCM has not been evaluated to identify if EMPD remains active after therapy. Recently we have published in JAMA Dermatology the first study using RCM in patients with previously treated EMPD. We studied 5 patients with previously treated EMPD (4 men and 1 woman). We evaluated 22 sites in the skin suspicious for EMPD using RCM and later obtaining a skin biopsy of these sites. We have found that if we saw EMPD using RCM, in all the cases (9 out 9) the biopsy revealed active EMPD. On the other hand, in the cases where we did not see cancer using RCM, there was a small chance of missing active EMPD (3 out of 13 sites). We believe this may happen because EMPD cells may form small groups of cells that can be difficult to see with RCM, especially in cases which had received therapy, or may be located too deep to be seen with RCM.
Our study has shown that RCM can be very useful to identify EMPD after treatment, and eventually if one sees EMPD on RCM, biopsies may not be necessary and can be spared in such a sensitive location. However, because there is a small chance of missing disease recurrence if RCM does not see cancer, biopsies may be needed in this setting. To sum up, we believe that by assessing previously treated EMPD with RCM, our patients will need less biopsies to know if their disease is still active or not, and whether further treatment is required.
Yélamos O, Hibler BP, Cordova M, Hollmann TJ, Kose K, Marchetti MA, Myskowski PL, Pulitzer MP, Rajadhyaksha M, Rossi AM, Jain M. Handheld Reflectance Confocal Microscopy for the Detection of Recurrent Extramammary Paget Disease. JAMA Dermatol. 2017 May 10. doi: 10.1001/jamadermatol.2017.0619
Extramammary Paget’s Disease (EMPD) is a rare intraepithelial adenocarcinoma. It mostly affects women in their seventies. EMPD develops principally in the apocrine genital, anal, and axillary zones . We conducted a retrospective study at the University Hospital of Reims over a period of 20 years (1994- 2014). 9 patients were included of which 7 were female. The median age of onset was 78 years (60-91). The diagnosis time ranged from a few months to 5 years prior to diagnosis. Vulvar localization remains by far the most common localization. 6 patients, all females, had pruritus (vulvar); 2 (22%) felt pain from the lesions.
RATIONALE: Biological therapies, such as imiquimod, may stimulate the immune system in different ways and stop tumor cells from growing. Applying topical imiquimod to the vulva may be an effective treatment for recurrent Paget's disease.
PURPOSE: This clinical trial is studying how well topical imiquimod works in treating patients with recurrent Paget's disease of the vulva.
OBJECTIVES: To assess the clinical and histologic effects of topical imiquimod therapy on recurrent extramammary Paget's disease.
Extramammary Paget’s disease (EMPD) is a rare malignancy, and little was known about its prognostic factors and optimal treatment. In the current study, we aimed to discuss clinical and pathological features of scrotal EMPD and determine the prognostic factors for cancer-specific survival and local recurrence. A total of 206 patients with scrotal EMPD lesions surgically treated at our institute were studied. All clinical and pathological data were reviewed. Immunohistochemical staining of TP53 and Ki67 was examined as well. At the last follow-up, 175 patients (84.95%) were alive. Twelve patients (5.83%) had died of the disease due to distant metastases. Fifteen patients (7.28%) developed local recurrences of scrotal EMPD. Ki67 expression was significantly elevated in patients with wide horizontal invasion (P = 0.003). In univariate analysis, high invasion level, presence of nodule, presence of lymphovascular invasion, adnexa invasion, lymph node metastasis and high p53 expression were significant factors for poor cancer-specific survival. In multivariate analysis, high p53 expression was significantly correlated with poor cancer-specific survival. Wide horizontal invasion was independently correlated with local recurrence-free survival of scrotal EMPD. In conclusion, wide horizontal invasion is an independent risk factor for local recurrence-free survival in the patients with scrotal EMPD.
In this study, we examined whether the presence of podoplanin expression in tumor cells or peritumoral basal keratinocytes correlated with aggressive behavior in patients with EMPD and investigated the mechanisms of podoplanin-mediated tumor invasion in this disorder.
The presence of podoplanin expression in peritumoral keratinocytes correlates with aggressive behavior in EMPD and might therefore serve as a useful prognostic marker for patients with EMPD.
mmune evasion by cancer is a well-recognized mechanism that promotes tumour growth and metastases which in recent years has been shown to be amenable to therapeutic exploitation. Extramammary Paget disease (EMPD) is a rare form of skin cancer affecting apocrine glands in anogenital regions. The prognosis of the disease is good if treated early by surgical removal of the tissue, with a 5-year survival rate close to 95%. The prognosis is worse for invasive disease, partly due to the lack of definitive treatment options in this setting. Understanding the mechanisms of EMPD evolution has the potential to identify new treatment targets for this entity. In this edition of the BJD, Fujimura et al. have looked into a suspected link between Langerhans cells (LCs) and regulatory T-cell (Treg) activity in EMPD that could contribute to the immunosuppressive environment that supports tumour growth and invasion by immune evasion.
Cytokeratin 19 fragment 21-1 (CYFRA 21-1) has been used as a tumor marker for several malignancies. However, to date, no studies have assessed whether CYFRA 21-1 could be a useful marker for extramammary Paget's disease (EMPD). The present study aimed to evaluate the significance of CYFRA 21-1 as a serum tumor marker for EMPD progression. Concentrations of serum CYFRA 21-1 and carcinoembryonic antigen (CEA) in 13 cases of EMPD were measured prior to undergoing treatment at Sapporo Medical University Hospital from January 2014 to May 2016. Four of the 13 patients had lymph node metastases at diagnosis, but none had distant metastases. Immunohistochemistry indicated that all 13 primary tumors and four metastatic tumors in lymph nodes were positive for cytokeratin 19. Although none of the 13 patients showed high serum CEA levels, six patients (46.2%) had elevated serum CYFRA 21-1. Furthermore, CYFRA 21-1 was reduced in association with post-treatment tumor reduction in all six patients. Among these six patients, four developed recurrence and metastasis during the follow-up period. CYFRA 21-1 was re-elevated in all four of these patients; however, serum CEA was elevated only in the patient with distant metastasis. These results suggest that CYFRA 21-1 is more sensitive compared with CEA, and can be useful as a tumor marker for evaluating tumor progression and treatment efficacy in patients with EMPD.