Topical Combination of Fluorouracil and Calcipotriene as a Palliative Therapy for Refractory Extramammary Paget Disease

Topical Combination of Fluorouracil and Calcipotriene as a Palliative Therapy for Refractory Extramammary Paget Disease

Question Can a combination of fluorouracil and calcipotriene creams be used safely and effectively as a treatment for refractory extramammary Paget disease (EMPD)?

Findings In this case series, we report 3 cases of refractory EMPD treated with a topical combination of fluorouracil and calcipotriene. The treatment was well tolerated and was followed by clinical improvement in all cases with demonstrated histopathological response in 2 of the cases.

Meaning Topical combination of fluorouracil and calcipotriene may be a viable palliative treatment option for patients with refractory EMPD.

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Methylation and expression analysis of mismatch repair genes in extramammary Paget's disease

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Methylation and expression analysis of mismatch repair genes in extramammary Paget's disease

Extramammary Paget's disease (EMPD) is a rare skin cancer with relative high frequencies of germline and somatic mismatch repair (MMR) genes mutations. However, the methylation and expression of these genes have not been validated in EMPD.

This study aims to confirm the methylation and expression of MMR genes in EMPD.

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Serum cell‐free DNA levels are useful marker for extramammary Paget's disease

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Serum cell‐free DNA levels are useful marker for extramammary Paget's disease

Although carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA) are useful marker for extramammary Paget's disease (EMPD), the serum CEA and CYFRA levels are not elevated in most EMPD patients without metastasis. Therefore, further useful biomarkers are needed for the detection of EMPD including early lesions. Cell‐free DNA (cfDNA) has attracted attention as an indicator of clinical conditions in several cancers, and we studied the clinical implications of cfDNA for EMPD. The serum cfDNA levels were significantly elevated in EMPD patients with or without metastasis compared to those in healthy controls. And serum cfDNA was a better diagnostic marker for the presence of EMPD compared to serum CYFRA. Moreover, the post‐operative serum cfDNA levels were significantly lower than those from the pre‐operative samples, and the change in serum cfDNA levels reflected the clinical courses of EMPD patients treated with chemotherapy. Taken together, serum cfDNA levels may be useful marker for the diagnosis and disease progression in EMPD.

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

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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 exam- ined 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 dis- ease-free survival (DFS). Moreover, we found that tumor cells produced immunosuppres- sive 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.

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An advanced case of extramammary Paget disease: Safe and effective treatment in an inoperable elderly patient using extensive en face electron irradiation

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An advanced case of extramammary Paget disease: Safe and effective treatment in an inoperable elderly patient using extensive en face electron irradiation

Extramammary Paget disease (EMPD) is an intraepithelial adenocarcinoma characterized by epithelial infiltration of large atypical cells with prominent nuclei.1 The disease process is hypothesized to originate in the apocrine sweat glands in the anogenital region. It is often diagnosed in postmenopausal women and most commonly affects the vulva, perianal skin, and axilla but can sometimes be associated with invasive visceral or adnexal adenocarcinoma.2

Standard therapy for EMPD is wide local excision. However, many of the elderly patients affected by EMPD may be medically unfit for aggressive surgery. Radiotherapy is rarely used, and there is a paucity of reports detailing the efficacy of electron beam radiotherapy for exceptionally large EMPD lesions.

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An advanced case of extramammary Paget disease: Safe and effective treatment in an inoperable elderly patient using extensive en face electron irradiation

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An advanced case of extramammary Paget disease: Safe and effective treatment in an inoperable elderly patient using extensive en face electron irradiation

Extramammary Paget disease (EMPD) is an intraepithelial adenocarcinoma characterized by epithelial infiltration of large atypical cells with prominent nuclei. The disease process is hypothesized to originate in the apocrine sweat glands in the anogenital region. It is often diagnosed in postmenopausal women and most commonly affects the vulva, perianal skin, and axilla but can sometimes be associated with invasive visceral or adnexal adenocarcinoma. Standard therapy for EMPD is wide local excision. However, many of the elderly patients affected by EMPD may be medically unfit for aggressive surgery. Radiotherapy is rarely used, and there is a paucity of reports detailing the efficacy of electron beam radiotherapy for exceptionally large EMPD lesions.

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Anal canal adenocarcinoma with neuroendocrine features accompanying secondary extramammary Paget disease, successfully treated with modified FOLFOX6: a case report

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Anal canal adenocarcinoma with neuroendocrine features accompanying secondary extramammary Paget disease, successfully treated with modified FOLFOX6: a case report

Anal canal cancer occasionally accompanies extramammary Paget disease. Although most of them are squamous cell carcinoma, anal canal adenocarcinoma with neuroendocrine features accompanying secondary extramammary Paget disease has never been reported.

This is a clinically significant case, as it reveals novel pathological features about anal canal cancer with secondary Paget disease and successfully treated with modified FOLFOX6. Careful pathological investigation and appropriate treatment choice are needed for this rare cancer.

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Paget Disease, Extramammary

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Paget Disease, Extramammary

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.

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Rare perianal extramammary Paget disease successfully treated using topical Imiquimod therapy

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Rare perianal extramammary Paget disease successfully treated using topical Imiquimod therapy

Background: Perianal Paget’s disease (PPD) is a rare intraepithelial adenocarcinoma of the anal margin. Primary PPD likely represents intra-epithelial neoplasm from an apocrine source, whereas secondary disease may represent“pagetoid” spread from an anorectal malignancy.

Case presentation: Histologic CDX-2 and CK20 are hallmark markers for colorectal-derived Paget’s cells. Interestingly, our primary PPD patient presented both positive and no internal malignancy was identified. In addition, a negative CK7 marker was observed in our case in contrast with previously reported. Surgical excision is the standard treatment; however, previous studies have demonstrated good response with Imiquimod 5% cream in patients with vulval extramammary Paget disease (EMPD). The efficiency of Imiquimod treatment for PPD has not been well described. Our PPD patient was successfully treated using Imiquimod 5% cream.

Conclusions: This study describes a primary cutaneous PPD patient CDX-2+/CK20+/CK7- without invasion of the dermis and no associated colorectal carcinoma effectively treated using topical Imiquimod therapy, suggesting that Imiquimod might potentially be considered as a first-line treatment for PPD.

Prognostic Factors of Extramammary Paget’s Disease

Prognostic Factors of Extramammary Paget’s Disease

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.

Mayo Clinic: Prospective Registry of Gynecologic Patients With Extramammary Paget's Disease Study

Mayo Clinic: Prospective Registry of Gynecologic Patients With Extramammary Paget's Disease Study

The Mayo Clinic (Rochester, MN, USA) is currently recruiting women with vulvar Extramammary Paget's Disease for an EMPD study. This includes EMPD of the vulva, vagina or perianal EMPD. The 25-year study will allow physicians to better understand EMPD. The researchers also want to learn more about the microorganisms (microbiome) that live on or near the areas of skin affected by EMPD, in order to better understand this condition. Tumor tissues will be obtained in order to perform tumor molecular profiling to identify targetable somatic mutations in EMPD. This EMPD study is for women only. More information on the Prospective Registry of Gynecologic Patients With Extramammary Paget's Disease study can be found here. 

Evidence-Based Screening Recommendations for Occult Cancers in the Setting of Newly Diagnosed Extramammary Paget Disease

Evidence-Based Screening Recommendations for Occult Cancers in the Setting of Newly Diagnosed Extramammary Paget Disease

To identify the rates of associated and occult cancers in patients with extramammary Paget disease (EMPD) discovered using cancer screening methods at a tertiary medical center; to propose evidence-based cancer screening guidelines at the time of diagnosis of EMPD; and to clarify terminology associating EMPD with underlying malignancies.

A total of 161 patients met the inclusion criteria. Most (59.6%) were female patients, and the mean age at the time of EMPD diagnosis was 70.8±10.1 years. Most (82%) of the 161 patients had at least 1 cancer screening test performed, though screening practices varied widely. Of those screened for an underlying malignancy, 17 distant, noncontiguous malignancies were identified in 15 patients (11.4%), with prostate (n=5), urinary tract (n=5), and breast (n=2) malignancies found most frequently. Most malignancies were identified by urine cytology, mammography, and prostate-specific antigen blood test. Of all patients, 37 (23.0%) had an underlying contiguous malignancy identified by pathology.

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131 Mutational landscape of extramammary Paget disease

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131 Mutational landscape of extramammary Paget disease

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.

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Survival analysis of patients with invasive extramammary Paget disease -- Implications of anatomic sites

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Survival analysis of patients with invasive extramammary Paget disease -- Implications of anatomic sites

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). 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. 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). 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.

Vulvar Paget’s disease presenting on the background of clinically diagnosed lichen sclerosus

Vulvar Paget’s disease presenting on the background of clinically diagnosed lichen sclerosus

61-year-old woman was referred to the outpatient’s department due to persistent vulvar itchiness and soreness. She had been clinically diagnosed with lichen sclerosus (LS) in primary healthcare two years before referral and was being treated with topical steroids. year before her presentation, she was diagnosed with breast cancer and had a lumpectomy, axillary lymph node dissection, and adjuvant radiotherapy. She had a history of hysterectomy for benign reasons, suffered from pernicious anemia and was a non-smoker. panel board in our case, due to overlapping symptoms with LS there can be a time delay before the diagnosis of VPD is established through vulvar biopsies.

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R Inguinal/R Scrotum Extramammary Paget’s Disease with Diffuse Spine Metastasis Complicated by Microangiopathic Hemolytic Anemia

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R Inguinal/R Scrotum Extramammary Paget’s Disease with Diffuse Spine Metastasis Complicated by Microangiopathic Hemolytic Anemia

A 47-year-old male presented with a groin lesion in 2011. Initial treatment with antifungals and vinegar was unsuccessful. In 2016, biopsy of this lesion was pursued with diagnosis of extramammary Paget’s disease (EMPD). Prior to the scheduled excision, he developed constant lower back pain with radiation to his lower extremities. MRI confirmed vertebral metastasis. Despite surgical and radiation therapy, his back pain progressed, and repeat imaging showed epidural spread of tumor in the thoracic spine. Later, the patient was admitted to the hospital due to severe anemia and thrombocytopenia. Further work-up confirmed the diagnosis of microangiopathic hemolytic anemia (MAHA). As we know, there are only few reports of spinal metastases in patients with EMPD. To the best of our knowledge, this is the first case report of EMPD complicated by MAHA.

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Extramammary Paget Disease

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Extramammary Paget Disease

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.

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Successful treatment of metastatic extramammary Paget's disease with pemetrexed monotherapy systemically and 5-fluorouracil topically

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Successful treatment of metastatic extramammary Paget's disease with pemetrexed monotherapy systemically and 5-fluorouracil topically

Abstract 
Advanced extramammary Paget's disease does not have a standardized treatment guideline as its incidence is low and has been rarely reported in literature. Here we describe a case of metastatic extramammary Paget's disease successfully treated with topical 5-fluorouracil (5-FU) and systemic pemetrexed. The therapy was safe without any appreciable adverse effects like diarrhea, rash, neutropenia or fatigue; maintaining remission for more than 6 months. Thus, we propose 5-FU and pemetrexed as the first-line therapy for advanced extramammary Paget's disease, especially for aged patients with unresectable skin lesions.

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Evidence-Based Screening Recommendations for Occult Cancers in the Setting of Newly Diagnosed Extramammary Paget Disease

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Evidence-Based Screening Recommendations for Occult Cancers in the Setting of Newly Diagnosed Extramammary Paget Disease

To identify the rates of associated and occult cancers in patients with extramammary Paget disease (EMPD) discovered using cancer screening methods at a tertiary medical center; to propose evidence-based cancer screening guidelines at the time of diagnosis of EMPD; and to clarify terminology associating EMPD with underlying malignancies.

All patients diagnosed with EMPD should undergo cancer screening. At minimum, evaluation should include age-appropriate screening and the addition of urine cytology, mammography, and prostate-specific antigen blood test—if not already performed—may be of particular use. An algorithm for evaluation of patients with newly diagnosed EMPD is proposed.

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Metastatic Extramammary Paget’s Disease: Pathogenesis and Novel Therapeutic Approach

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Metastatic Extramammary Paget’s Disease: Pathogenesis and Novel Therapeutic Approach

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.

 

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