Trends in incidence and survival of patients with vulvar cancer in an Asian country: Analysis of the Korean Central Cancer Registry 1999-2018.

OBJECTIVE: To report 20-year trends in incidence and survival of vulvar cancer in Korea. METHODS: Using data from the Korean Central Cancer Registry, age-standardized incidence rates (ASRs) and annual percentage changes (APCs) were calculated. Net survival (NS) was estimated by the Pohar-Perme method, and conditional net survival (CNS) was calculated. RESULTS: A total of 2221 patients was diagnosed with vulvar cancer during the 1999-2018 period, with an ASR of 0.32 per 100,000 person-years. Among the cases, 51.4% were squamous cell carcinoma (SqCC), 21.3% were Paget disease, and 8.6% were basal cell carcinoma (BCC). There was an increase in incidence for all vulvar cancer (APC 2.4%, 95% CI 1.8-3.0). However, although BCC (APC 7.0%, 95% CI 3.3-10.8) and Paget disease (APC 5.9%, 95% CI 4.2-7.6) increased, SqCC did not (APC 0.2%, 95% CI -0.8-1.2). There was an increase in incidence in all age groups. The 5Y NS was 74.0% overall, and it did not improve significantly during the study period. The 5Y CNS of vulvar cancer increased continuously with time survived: from 74.0% (71.4-76.4) at baseline to 98.1% (95% CI, 85.4-99.8) at 5 years after diagnosis. CONCLUSIONS: The incidence of vulvar cancer in Korea showed a different pattern from those in the US and Europe: SqCC incidence was relatively low and remained stable, but the incidence of BCC and Paget's disease increased. Survival did not improve in the past two decades. Patients can be considered cured after surviving for 5 years.

Integrative bioinformatics approaches to map key biological markers and therapeutic drugs in Extramammary Paget's disease of the scrotum.

Extramammary Paget's disease (EMPD) is an intra-epidermal adenocarcinoma. Till now, the mechanisms underlying the pathogenesis of scrotal EMPD is poorly known. This present study aims to explore the knowledge of molecular mechanism of scrotal EMPD by identifying the hub genes and candidate drugs using integrated bioinformatics approaches. Firstly, the microarray datasets (GSE117285) were downloaded from the GEO database and then analyzed using GEO2R in order to obtain differentially expressed genes (DEGs). Moreover, hub genes were identified on the basis of their degree of connectivity using Cytohubba plugin of cytoscape tool. Finally, GEPIA and DGIdb were used for the survival analysis and selection of therapeutic candidates, respectively. A total of 786 DEGs were identified, of which 10 genes were considered as hub genes on the basis of the highest degree of connectivity. After the survival analysis of ten hub genes, a total of 5 genes were found to be altered in EMPD patients. Furthermore, 14 drugs of CHEK1, CCNA2, and CDK1 were found to have therapeutic potential against EMPD. This study updates the information and yields a new perspective in the context of understanding the pathogenesis of EMPD. In future, hub genes and candidate drugs might be capable of improving the personalized detection and therapies for EMPD.

Nomograms for predicting cancer-specific and overall survival in patients with invasive extramammary Paget's disease.

Aim: To develop nomograms for predicting cancer-specific survival (CSS) and overall survival (OS) in patients with invasive extramammary Paget's disease (iEMPD). Patients & methods: Retrospective data of 1955 patients with iEMPD were collected from the Surveillance, Epidemiology, and End Results database. Nomograms for predicting CSS and OS were established using competing risk regression and Cox regression, respectively, and were internally validated. Results: Five (age, surgery, tumor location, stage and concurrent malignancy) and eight (gender, age, race, marital status, surgery, tumor location, stage and lymph node metastasis) clinicopathological factors were utilized to construct nomograms for predicting CSS and OS, respectively. The concordance indices of the nomograms for predicting CSS and OS were 0.78 and 0.73, respectively. The validation of the nomograms showed good calibration and discrimination. The decision curve analyses confirmed the clinical utility of these nomograms. Conclusion: The nomograms can be a reliable tool for treatment design and prognostic evaluation of iEMPD.

Lay abstract Invasive extramammary Paget's disease (iEMPD) is a rare type of cutaneous malignancy with a heterogeneous prognosis. The prognostic factors remain poorly described, resulting in unclear risk stratification of the patients with iEMPD. The purpose of this study is to identify the prognostic factors associated with cancer-specific and overall survival rates in iEMPD and to develop accurate risk stratification models to guide the design of individualized treatment regimens. Clinicopathological data of 1955 patients pathologically diagnosed with iEMPD were retrospectively collected from the Surveillance, Epidemiology, and End Results database, and were utilized for analysis and construction of models for predicting the long-term survival in patients with iEMPD. Eventually, five (age, surgery, tumor location, stage and concurrent malignancy) and eight (gender, age, race, marital status, surgery, tumor location, stage and lymph node metastasis) factors were chosen to develop models for predicting cancer-specific and overall survival, respectively. The prediction accuracy and clinical utility of the established models were confirmed in subsequent evaluation. Because iEMPD is an extremely rare disease that a lot of clinical practitioners might not be familiar with, the availability of these quantifiable predictive models will provide convenience in daily practice.

Overexpression of Janus kinase 2 protein in extramammary Paget's disease.

Extramammary Paget's disease is a rare malignant tumor of the skin that occurs primarily in the genitocrural region. Although the prognosis of extramammary Paget's disease with distant metastasis is poor, an effective therapy has not been established. Because Janus kinase 2 has attracted attention as a therapeutic target in several cancers, we investigated the expression of the Janus kinase 2 protein and the relationship between its level of expression and clinical significance in 53 patients with extramammary Paget's disease in our hospital. Immunohistochemistry showed that most extramammary Paget's disease tissues were positive for Janus kinase 2 (50/53, 94.3%), and the immunostaining intensity of Janus kinase 2 was correlated with the degree of invasiveness, lymph node metastasis and distant metastasis. Based on these findings, Janus kinase 2 may be a promising therapeutic target in extramammary Paget's disease.

Vulvar Paget's disease and stromal invasion: Clinico-pathological features and survival outcomes.

PURPOSE: To evaluate clinico-pathological features, treatments and survival outcomes of vulvar Paget's disease (VPD). METHODS: We retrospectively reviewed VPD diagnosed between 1983 and 2018 at the Department of Surgical Sciences, Sant'Anna Hospital, Turin. Clinico-pathological characteristics and surgical treatment outcomes were investigated according to the depth of invasion. RESULTS: A total of 122 patients were identified. Eighty-seven patients were diagnosed with intraepithelial VPD, 22 with microinvasive (<=1 mm) VPD and 16 with invasive VPD. The median follow-up was 94.6 months (interquartile range 25th-75th, 26-120). Most of patients 95/122 (77%) were treated by surgery. Local recurrence was observed in 69/95 (73%) patients without significant difference between the 3 groups (p = 0.33), however, total vulvectomy showed better local control in microinvasive and invasive VPD than in intraepithelial tumors. At 120 months the cancer-specific survival was 100% for intraepithelial and microinvasive VPD versus 31% for invasive VPD (log-rank p = <0.0001) Age ≥65 years (OR: 4.17 CI 1.12-15.5, p = 0.03) and VPD's area ≥15 cm2 (OR: 5.83 CI 1.75-19.3, p = 0.004) were associated with risk of invasiveness. CONCLUSION: Microinvasive VPD has an identical prognosis to intraepithelial VPD, suggesting the omission of lymphadenectomy or adjuvant treatments are safe in this subset of patients. We recommend caution to propose medical treatment in patients who are ≥65 years old and with wide tumor area, as they are at the greatest risk of invasiveness.

Programmed Death-Ligand 1 and Programmed Death-Ligand 2 Expression Can Affect Prognosis in Extramammary Paget's Disease.

BACKGROUND: Extramammary Paget's disease (EMPD) is a type of carcinoma that usually progresses slowly but may cause metastasis and subsequent death of patients. We investigated the relationship between the expression of programmed death-ligand 1 (PD-L1)/programmed death-ligand 2 (PD-L2) and stromal CD8+ tumor-infiltrating lymphocytes (TILs) in EMPD and clinicopathological findings, including prognosis. MATERIALS AND METHODS: We examined 47 cases of EMPD and performed immunohistochemical staining of formalin-fixed paraffin-embedded full-face sections. RESULTS: PD-L1 expression in tumor cells was observed in 13 cases (27.7%) while PD-L2 expression was observed in 21 cases (44.7%). The cumulative postoperative recurrence-free rate in the group with positivity for PD-L1 and/or PD-L2 with a low CD8+ TIL count was significantly lower than that of the corresponding group with a high CD8+ TIL count and of the PD-L1- and PD-L2-negative group (p=0.026). CONCLUSION: The expression of PD-L1/PD-L2 in tumor cells was shown to be a factor for poor prognosis.

Invasive vulvar extramammary Paget's disease in the United States.

OBJECTIVE: To assess the incidence, treatment, and outcomes in patients with invasive vulvar extramammary Paget's disease (EMPD) in a national cohort of patients. METHODS: Patients from the Surveillance, Epidemiology and End Results (SEER) database with diagnoses of vulvar EMPD from 1992 to 2016 were included. Demographic, treatment, and outcome data were analyzed. RESULTS: A total of 1268 cases of invasive EMPD were identified. Of those, 69.6% had localized disease, 12.0% regional disease, 1.3% distant disease, and 17.1% were unstaged. The annual incidence of invasive vulvar EMPD was 0.36 per 100,000 person years: rates have increased >2-fold since 1992 (1992: 0.19 per 100,000 person years to 0.50 per 100,000 person years in 2016). Most patients underwent primary surgery (n = 1034; 81.5%). Five-year cancer specific survival (CSS) was 95.5% and was associated with stage. Compared to patients with localized disease, patients with distant metastases had dramatically worse CSS (HR: 85.8 (31.8-248) p < 0.0001). Synchronous cancers (diagnosed within one calendar year of EMPD diagnosis year) were observed in 35 cases (2.8%), and 195 patients (15.4%) developed a secondary malignancy (diagnosed >one year from year of EMPD diagnosis year). The most common synchronous breast, gastrointestinal tract, melanoma and the most common secondary cancers were breast, gastrointestinal tract and genitourinary tract. CONCLUSIONS: The incidence of invasive vulvar EMPD has increased over time. CSS is excellent for localized disease, but those with metastatic disease are in need of novel therapies. Approximately 15% will develop a secondary malignancy, indicating that patients with invasive vulvar EMPD should undergo site specific preventative health screens during recurrence surveillance.

Outcomes of lymph node dissection in the treatment of extramammary Paget's disease: A single-institution study.

Extramammary Paget's disease (EMPD) often invades the dermis and metastasizes to the lymph nodes. Patients with EMPD associated with lymph node metastases have poor prognosis; to date, effective treatment has not yet been established. Lymph node dissection, aiming to control the local disease, is a standard form of management for EMPD patients with lymph node metastases (LNM). We investigated the clinical and pathological features, treatment strategies and prognostic factors of patients with metastatic EMPD who underwent lymph node dissection. We retrospectively evaluated 38 cases of extramammary Paget's disease with lymph node metastasis over 10 years. All patients underwent wide resection of the primary lesion and lymph node dissection. Univariate analysis revealed the number of metastatic nodes and lymphadenopathy as prognostic factors. In multivariate analysis, the number of metastatic lymph nodes retained statistical significance (hazard ratio, 35.3; 95% confidence interval, 3.23-387.0; P = 0.003). The 5-year survival rate was 100% and 19.1% in patients with two or less LNM and with three or more LNM, respectively. In patients with three or more LNM, the 5-year survival rate after adjuvant radiation therapy was better than that after surgery alone (75% vs 0%). In conclusion, patients with two or less LNM can be expected to have long-term survival with lymph node dissection only, while patients with three or more LNM may require adjuvant radiation therapy to improve prognosis. These results suggest that lymph node dissection may be a strategy to treat EMPD with regional LNM.

Weekly docetaxel monotherapy for metastatic extramammary Paget's disease: Retrospective single-institute analysis.

Monthly docetaxel (DTX) monotherapy is the first-line regimen that is preferably used for metastatic extramammary Paget's disease (EMPD). However, the high-dose DTX regimen frequently causes severe hematological adverse events (AE). To overcome such safety concerns, a weekly low-dose DTX monotherapy has been proposed for use in the treatment of various cancer types. In this study, we aimed to evaluate the feasibility and efficacy of weekly DTX (25 mg/m2 ) monotherapy for metastatic EMPD by retrospectively analyzing the clinical courses of 14 patients treated with this regimen. Weekly DTX monotherapy was well tolerated and all patients completed the treatment schedule without treatment withdrawal, dose reduction or treatment-related death. While five cases (35.7%) experienced hematological AE, their severity was mild. The response rate was 35.7% (5/14 cases), which included five partial responses. The mean progression-free survival (PFS) and overall survival were 7.1 (95% confidence interval [CI], 5.1-9.1) and 26.4 months (95% CI, 16.7-36.1), respectively. Furthermore, the median PFS was 7.3 months (95% CI, 4.5-10.0) in patients aged 65 years and younger and 7.1 months (95% CI, 4.4-9.9) in patients older than 65 years. These results suggest that weekly DTX monotherapy may be a useful regimen that has a high treatment continuation rate with low levels of hematological toxicity, regardless of the patient's age for metastatic EMPD.

Extramammary Paget Disease of the Scrotum: A Contemporary Clinicopathologic Analysis of 20 Cases in the United States.

Extramammary Paget disease (EMPD) often involves apocrine gland-bearing locations including vulva and perianal area. EMPD of the scrotum is rare. Twenty patients were identified from the pathology files of 4 institutions between 2000 and 2018. Patients were 63- to 87-year-old (mean: 73 y) with a history of symptoms of between 4 months and 10 years. Two patients had a history of prostate cancer. Follow-up was available in 11 patients for a median of 71 months (range: 8 to 126 mo). Nine of 11 patients (82%) had positive margins, and 73% required reexcisions. Three patients had a focal dermal invasion, 1 of whom reportedly died of another etiology 25 months post diagnosis and 2 were disease-free at 24 and 68 months. No patient had inguinal lymphadenopathy. Two patients were alive with disease. Immunohistochemically, GATA3 and GCDFP15 were expressed in 6/6 cases, CK7 in 8/8 cases, and androgen receptor in 13/13 cases. HER2 was positive in 5/12 cases. PSA was positive in 1 patient who had a history of prostate cancer, whereas other prostate markers (NKX3.1 and prostein) were negative, and CK7 and GCDFP15 were positive, rendering primary EMPD diagnosis. Twelve other cases were negative for PSA and NKX3.1. In conclusion, EMPD of the scrotum has an insidious onset and its nonspecific symptoms can be misdiagnosed as dermatitis or fungal infection. Although localized EMPD has a favorable prognosis, the invasive disease is rare and did not predict metastasis or progression. Margins are frequently positive requiring reexcision. Occasionally, cases can be positive for PSA leading to diagnostic pitfalls.

Extramammary Paget disease of the vulva: Management and prognosis.

OBJECTIVE: To evaluate the clinicopathological characteristics, management and prognosis of patients with vulvar extramammary Paget disease of the vulva (EMPD). MATERIALS AND METHODS: The U.S National Cancer Database was accessed and patients diagnosed between 2004 and 2015 with microscopically confirmed vulvar EMPD were selected. Overall survival (OS) was calculated for patients diagnosed between 2004 and 2014, who had at least one month of follow-up. Five year OS rates were calculated following generation of Kaplan-Meier curves while comparisons were made with the log-rank test. RESULTS: A total of 2602 patients were identified. Median age at diagnosis was 72 years (range 31-90 years) and the majority were of White race (92%), without any co-morbidities (80.9%). Personal history of another tumor was present in 36.9% of patients. In situ EMPD was diagnosed in 994 cases (38.2%) and the majority (95.1%) were managed with local excision or vulvectomy. Five-year OS was 85.8%, while presence of positive margins was not associated with worse OS (p = 0.38). Invasive EMPD was diagnosed in 1608 (61.8%) patients. Staging information was available for 1172 patients, 75.3% had early stage disease. Most patients underwent surgical treatment (91.6%); 53.6% had positive margins. Performance of lymphadenectomy was infrequent (6.8%). Moreover, immunotherapy (4.5%), chemotherapy (1.5%) and radiation therapy (2.2%) were rarely employed in the management of invasive EMPD. Patients with early stage disease (n = 766) had better OS compared to those with advanced stage (n = 278) (5-yr OS rates were 84.3% and 73.6% respectively, p = 0.015) while presence of positive margins was not associated with worse OS (p = 0.35). CONCLUSIONS: Extramammary Paget disease is a rare vulvar tumor. Surgical excision is the main treatment option while other modalities are rarely employed. Overall survival rates are encouraging.

Combination Cisplatin-Epirubicin-Paclitaxel Therapy for Metastatic Extramammary Paget's Disease.

Extramammary Paget's disease (EMPD) is a rare cutaneous adenocarcinoma that clinicopathologically resembles breast cancer. The prognosis of metastatic EMPD is poor. Although several chemotherapies have been tried, the effects are temporary; better drugs and combinations are required.In the present study, we retrospectively analyze the efficacy and safety of combination of cisplatin, epirubicin, and paclitaxel in five metastatic EMPD cases. The efficacy was better than that for previously reported regimens: 80% partial responses, including two patients who were refractory to taxane- and/or platinum-based regimens. In terms of safety, four patients who were able to continue treatment exhibited acceptable tolerability.This is the first regimen to combine taxane and anthracycline. When treating breast cancer, anthracycline is regarded as the key cytotoxic agent, and anthracycline in combination with taxane constitutes a key chemotherapeutic regimen. Given our results, we speculate both drugs are critical chemotherapeutic agents for the treatment of metastatic EMPD.

Accumulation of exhausted CD8+ T cells in extramammary Paget's disease.

Cancer immunotherapy has highlighted the clinical relevance of enhancing anti-tumor response of CD8+ T cells in several cancer types. Little is known, however, about the involvement of the immune system in extramammary Paget's disease (EMPD). We examined the cytotoxicity and the effector functions of CD8+ T cells using paired samples of peripheral blood and tumors by flow cytometry. Expression levels of perforin, granzyme B, IFN-g, TNF-a, and IL-2 in CD8+ tumor-infiltrating lymphocytes (TILs) were significantly lower than those in CD8+ T cells of peripheral blood. Significantly higher expression of PD-1 was found in CD8+TILs than in CD8+ T cells of peripheral blood. A high number of CD8+ cells was significantly associated with poor overall survival (OS) adjusted with age, sex, and clinical stage (hazard ratio [HR] = 5.03, P = 0.045, 95% confidence interval [CI] 1.03-24.4). On the other hand, the number of PD-1+ cells was not associated with OS or disease-free survival (DFS). Moreover, we found that tumor cells produced immunosuppressive molecule indoleamine 2,3-dyoxygenae (IDO). In conclusion, CD8+ TILs displayed an exhausted phenotype in EMPD. IDO expression seemed more relevant in inducing CD8 exhaustion than PD-1 upregulation or PD-L1 expression by immune cells. Restoring the effector functions of CD8+ TILs could be an effective treatment strategy for advanced EMPD.

Extramammary Paget's Disease.

Extramammary Paget disease (EMPD) is a rare cutaneous malignancy most commonly affecting the genitals, perineum, and perianal area of the elderly. Despite its rarity, to those impacted, the disease and its treatment can have a tremendous impact on quality of life. Commonly confined to the epidermis, EMPD can be invasive, associated with contiguous extension or upward pagetoid spread of underlying malignancy or with distant synchronous malignancy. Because of its association with other cancers, formal evaluation is warranted. Treatment varies widely and evidence-based approaches are lacking. The authors review the workup and management options for the patient with EMPD.

Prognostic Factors of Extramammary Paget's Disease.

OPINION STATEMENT: Most patients with extramammary Paget's disease (EMPD) show a good prognosis; however, some patients develop fatal metastases. Early detection is important for improving prognosis, due to the difficulties associated with the treatment of distant EMPD metastases. Several studies have emphasized the importance of the invasion level of the primary lesion for predicting the presence of metastasis, and deeper invasion or increased thickness is correlated with poorer prognosis. Vascular tumor invasion of the primary lesion can also predict the risk of metastasis. Lymph node metastasis is a strong indicator for poor prognosis, and the number of lymph node metastases affects patient outcome, in that there is a significant difference in survival between patients with zero or one lymph node metastasis and those with more than two lymph node metastases. Serum markers may be able to predict the presence of systemic metastases, and carcinoembryonic antigen and cytokeratin 19 fragment 21-1 reflect disease progression and may be clinically valuable. Although several genetic alterations have been determined for EMPD, factors determining prognosis should be further explored.

Survival analysis of patients with invasive extramammary Paget disease: implications of anatomic sites.

BACKGROUND: Extramammary Paget disease (EMPD) is a rare malignant dermatosis with poorly defined outcomes. We investigated clinical characteristics of invasive EMPD at different anatomic sites and by subject demographics to determine prognostic factors for overall survival (OS). METHODS: All patient data were collected from the Surveillance, Epidemiology, and End Results (SEER) program, 1973-2013, of the U.S. National Cancer Institute. Patients with invasive EMPD of skin, vulva/labia, vagina, scrotum/penis, or other sites were included. After excluding patients with unknown radiation status, data of 2001 patients were analyzed. Primary endpoint was EMPD mortality by anatomic sites. Independent variables included patients' demographic data, concurrent malignancy (ie, non-EMPD related cancers), tumor size, distant metastasis, and surgery and/or radiation or not. RESULTS: Multivariate regression analysis showed that mortality was significantly higher in patients with vaginal EMPD than in patients with vulvar/labial EMPD (adjusted hazard ratio [aHR] = 3.26, p < 0.001). Patients with distant metastasis had higher mortality than those without (aHR = 3.36, p < 0.001). Patients who received surgery had significantly lower mortality than those who did not receive surgery (aHR = 0.77, p = 0.030), and those treated with radiation had significantly higher mortality than those who did not receive radiation (aHR = 1.60, p = 0.002). Older age was associated with significantly increased mortality (aHR = 1.09, p < 0.001), and mortality was significantly higher in males than in females (aHR = 1.42, p = 0.008). CONCLUSIONS: In conclusion, among EMPD patients, mortality is higher in patients with vaginal EMPD than in those with vulvar/labial EMPD and higher in those who are older, those with concurrent malignancy or distant metastasis. Mortality is also higher in males than in females. Surgery is a protective factor and radiation is a risk factor for OS. Greater understanding of EMPD clinical characteristics, and considering EMPD in differential diagnosis of chronic genital and perianal dermatoses may provide support for early EMPD diagnosis and definitive surgical treatment.

Efficacy of low-dose 5-fluorouracil/cisplatin therapy for invasive extramammary Paget's disease.

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.