Metastatic Extramammary Paget's Disease Research Articles

Phase II clinical trial of docetaxel and trastuzumab for HER2-positive advanced extramammary Paget's disease (EMPD-HER2DOC).

No consensus has been reached regarding the optimal chemotherapy for metastatic extramammary Paget's disease (EMPD), a rare cutaneous adenocarcinoma, because of the lack of solid evidence from prospective trials. However, the immunohistochemical profile of EMPD reportedly resembles that of breast cancer, particularly in terms of human epidermal growth factor receptor 2 (HER2) expression, suggesting that HER2 is a promising therapeutic target for advanced HER2-positive EMPD. In this phase II single-arm trial, 13 Japanese patients received intravenous trastuzumab (loading dose of 8mg/kg and maintenance dose of 6mg/kg) and docetaxel (75mg/m2) every 3 weeks for up to 2 years. The docetaxel dose was reduced or discontinued according to its toxicity. The primary trial endpoints were objective response rate (ORR) after 3 cycles of treatment and safety throughout the study period. All 13 patients completed 3 cycles of combination therapy. The median follow-up was 27.9 months. The ORR was 76.9% (n = 10/13; 90% CI, 50.5-93.4). Frequently observed adverse events were neutropenia (100%), hypoalbuminemia (84.6%), and mucocutaneous infection (84.6%), all of which were well tolerated. The combination of docetaxel and trastuzumab demonstrated a favorable clinical effect and acceptable tolerability, which makes it a good treatment option for HER2-positive metastatic EMPD (ClinicalTrials.gov Identifier: UMIN000021311, jRCTs031180073).

Upregulated expression of glucose transporter isoform 1 in invasive and metastatic extramammary Paget's disease.

Glucose transporter isoform 1 (GLUT1), which is upregulated in a variety of malignant tumors, facilitates cellular glucose uptake to boost rapid tumor growth and progression. In several types of cancer, inhibition of GLUT1 suppresses tumor proliferation and metastasis, indicating that GLUT1 is a potential target of anticancer therapy. The present study performed immunohistochemistry to analyze GLUT1 expression levels in 51 patients with extramammary Paget's disease (EMPD), including 23 with only intraepidermal lesions and 28 with dermal-invasive lesions. Of the 28 patients with dermal invasion, nine had available samples of lymph node metastasis. GLUT1 staining scores were significantly higher in dermal-invasive (P<0.0001) and metastatic lesions (P=0.0008) compared with in intraepidermal lesions. GLUT1 is upregulated during the transition from preinvasive to invasive or metastatic tumor in EMPD. Moreover, GLUT1 staining scores were statistically higher in intraepidermal tumor cells of dermal-invasive EMPD compared with tumor cells of only in situ EMPD (P=0.0338). GLUT1 is upregulated even during the preinvasive phase in patients with invasive EMPD, suggesting that GLUT1 immunostaining can predict the risk of dermal invasion. The present study provides novel evidence to pursue in vitro and in vivo studies to confirm that upregulated expression of GLUT1 enhances tumor aggressiveness in EMPD.

NECTIN4-targeted antibody-drug conjugate is a potential therapeutic option for extramammary Paget disease.

Extramammary Paget disease (EMPD) is a rare skin cancer mainly found in areas rich in apocrine sweat glands. Since the effective treatments for advanced and/or metastasized EMPD are limited, there is an urgent need to develop novel therapeutic approaches. Nectin cell adhesion molecule 4 (NECTIN4) is highly expressed in cancers and considered to be a promising therapeutic target. NECTIN4 is also expressed in EMPD, but its role and the efficacy of NECTIN4-targeted therapy in EMPD remain unclear. This study investigated the potential of NECTIN4 as a novel therapeutic target for EMPD. NECTIN4 expression was immunohistochemically analysed in EMPD patients' primary (118 samples) and metastatic (21 samples) lesions. Using an EMPD cell line, KS-EMPD-1, the effects of NECTIN4 inhibition on cell proliferation and migration were investigated. NECTIN4 was expressed in primary and metastatic EMPD lesions, and the H-score of NECTIN4 staining was significantly higher in metastatic lesions than in primary ones. Knockdown of NECTIN4 significantly inhibited cell proliferation and affected cell migration. The cytotoxic effects of NECTIN4-targeted antibody-drug conjugate (ADC) were further evaluated, revealing a significant decrease in EMPD cell viability. In conclusion, NECTIN4 is a potential therapeutic target and NECTIN4-targeted ADC is promising as a therapeutic option for EMPD.

FOXM1: a new therapeutic target of extramammary Paget disease.

Extramammary Paget disease (EMPD) is a rare skin cancer that primarily affects older individuals predominantly in areas with apocrine sweat glands. Although most early EMPD lesions are indolent, patients with metastatic EMPD have a poor prognosis due to the lack of effective systemic treatment. In this study, we investigated the role of forkhead box M1 (FOXM1), a potent transcription factor, in EMPD and assessed the potential of FOXM1 as a therapeutic target. Immunohistochemistry of 112 primary and 17 metastatic EMPD samples revealed that FOXM1 expression increased with tumor progression. Patients in whom FOXM1 was expressed in more than 10% of tumor cells had significantly shorter disease-specific survival than the other patients (p = 0.0397). In in vitro studies using our newly established EMPD cell line, KS-EMPD-1, we found high expression of FOXM1. Knockdown of FOXM1 impaired tumor cell viability, migration, and invasion. Inhibition of FOXM1 using thiostrepton also reduced tumor cell viability in a dose-dependent manner. These findings suggest that FOXM1 is a promising therapeutic target for patients with EMPD.

KS-EMPD-1: a novel cell line of primary extramammary Paget's disease.

Extramammary Paget's disease (EMPD) is a rare skin cancer that mainly occurs in apocrine sweat gland-rich areas in elderly people. The prognosis of metastatic EMPD is unfavorable because of the lack of fully effective systemic therapies. However, the difficulty in establishing a model of EMPD has hampered basic research for exploring its pathogenesis and optimal treatments. Here, we established for the first time an EMPD cell line (named KS-EMPD-1) from a primary tumor on the left inguinal region of an 86-year-old Japanese male. The cells were successfully maintained for more than 1year, with a doubling time of 31.2 ± 0.471h. KS-EMPD-1 exhibited constant growth, spheroid formation, and invasiveness, and was confirmed to be identical to the original tumor by short tandem repeat analyses, whole exome sequencing, and immunohistochemistry (CK7+CK20-GCDFP15+). Western blotting of the cells revealed the protein expression of HER2, NECTIN4, and TROP2, which have recently attracted attention as potential therapeutic targets for EMPD. KS-EMPD-1 was highly sensitive to docetaxel and paclitaxel on chemosensitivity test. The KS-EMPD-1 cell line is a promising resource for basic and preclinical research on EMPD to better define the tumor characteristics and treatment strategy of this rare cancer.

P47 Management of extramammary paget disease: a current unmet need

Abstract Extramammary Paget disease (EMPD) is a rare epithelial malignancy predominantly affecting the anogenital skin. Primary EMPD carries a risk of invasion and metastasis, as well as malignancy in contiguous organs. No UK guidelines for the management of EMPD exist, resulting in a lack of consensus for staging and screening for associated cancers. We collected consecutive cases of histologically diagnosed EMPD at a regional centre (2017–2022). The aim was to characterize disease presentation, staging and treatment. We identified 22 patients [12 (55%) women, 10 (45%) men; mean age 72 years]. Affected sites were the vulva (n = 10; 45%), male genitalia (n = 7; 32%), perianal area/buttocks (n = 3; 14%), suprapubic area (n = 2; 9%) and axilla (n = 1; 4%). One patient had vulval and anal EMPD. All patients were referred from primary care to multiple secondary care services, including dermatology (n = 9; 41%), gynaecology (n = 9; 41%), urology (n = 2; 9%) and colorectal surgery (n = 1; 4.5%). Nine patients (41%) were jointly managed with dermatology. Sixteen (73%) patients were discussed at a multidisciplinary team (MDT) meeting; nine (41%) at the specialist skin cancer MDT and seven (32%) at other MDTs (anal cancer, colorectal, urology, oncology, gynae-oncology). Screening for associated malignancy was performed for 14 patients (64%). Eleven patients (50%) had histological evidence of invasion of their primary EMPD, of which nine (82%) underwent advanced imaging with computed tomography, positron emission tomography or magnetic resonance imaging. Treatment was directed by the stage of the disease (Table 1). Three patients (14%) developed metastatic EMPD and died despite radiochemotherapy or chemotherapy and surgery. Our data confirm a low prevalence of EMPD, but mortality for metastatic EMPD appears high. EMPD is a complex disease involving the skin. Patients are best managed by a specialist skin cancer MDT in conjunction with other relevant cancer MDTs. A greater understanding of this disease is needed to standardize care. Table 1Treatment received by our patient cohort with corresponding staging of extramammary Paget disease (EMPD)TreatmentPatients, n (%)Tumour classificationEMPD stagingTopical agents5 (23)TisIntraepithelial (in situ) EMPDSurgery12 (54)T1Tumour thickness ≤ 4 mm and no lymphovascular invasionChemotherapy/radiotherapy ± surgery5 (23)T2Tumour thickness &amp;gt; 4 mm or lymphovascular invasion

Neutrophil-to-lymphocyte ratio is a potential prognostic biomarker for extramammary Paget disease: A retrospective study.

The neutrophil-to-lymphocyte ratio (NLR) is a useful prognostic biomarker for many cancer types. However, the prognostic value of NLR in patients with extramammary Paget disease (EMPD) remains unclear. This study aimed to determine whether NLR is associated with overall survival (OS) in patients with EMPD. In this single-center retrospective case series, we analyzed data of 109 patients with previously untreated EMPD who presented to our hospital. Data on age, sex, primary tumor site, invasion level, presence of lymph node and distant metastases, baseline NLR, and OS were analyzed. The enrolled patients were classified into the metastatic or non-metastatic EMPD groups. The metastatic EMPD group had higher invasion level and NLR value (p< 0.001 and p= 0.005, respectively) compared with the non-metastatic EMPD group. Cox proportional hazards model analysis showed invasion level (p= 0.0093) and NLR value (p= 0.019) to be independent prognostic factors for OS. Notably, multivariate analysis revealed that invasion level (p= 0.045) and NLR value (p= 0.036) were independent prognostic factors for OS in the metastatic EMPD group. The limitations of this study include the small number of participants and its retrospective nature. In conclusion, since NLR can be routinely assessed with high feasibility, it might be a useful biomarker for predicting prognosis in patients with EMPD.

Management and outcomes of hydronephrosis in patients with metastatic extramammary Paget's disease: A retrospective analysis.

Hydronephrosis in extramammary Paget's disease (EMPD) with distant metastasis (metastatic EMPD) has been observed in medical practice; however, its prognosis remains unclear. Retrospective analyses were performed to assess the management and outcomes of hydronephrosis in metastatic EMPD. During a follow-up of 44 patients with metastatic EMPD, 13 (30%) developed hydronephrosis. Ten (77%) of the 13 patients with hydronephrosis had impaired renal function (estimated glomerular filtration rate: <60 ml/min/1.73m2 ), and ureteral stents were placed in every patient with impaired renal function. The stent was placed successfully in all 10 patients, and their renal function recovered within a median period of 7 days. Importantly, each of these patients continued chemotherapy, and none of them experienced stent failure. The median overall survival time (OS) in patients with metastatic EMPD and hydronephrosis (n=13) was 7.8 months. Treatment for hydronephrosis was not a significant factor for OS, and median OS in patients who underwent ureteral stent replacement (n=10) was 14.7 months. Collectively, our results indicate that hydronephrosis is relatively common, and ureteral stent placement should be considered in cases of metastatic EMPD with hydronephrosis to maintain renal function and continue chemotherapy toward a better prognosis.

Current Management and Treatment of Extramammary Paget's Disease.

Extramammary Paget's disease (EMPD) is a rare neoplastic disease affecting areas rich in apocrine glands in the elderly. EMPD clinically resembles a benign inflammatory skin disease, and ill-defined tumor borders can lead to misdiagnosis and incomplete excision. Several prognostic factors have been reported, including nodule formation, tumor thickness, tumor invasion, lymphovascular invasion, and a perianal location, which are characteristic of primary tumors. EMPD typically presents as an in situ tumor spreading horizontally within the epidermis and then invading into the dermis as it transitions to a vertical growth phase. For this reason, tumor thickness, rather than tumor size, is correlated with patient prognosis. The best treatment for resectable EMPD is complete surgical removal of the tumor. EMPD sometimes has unclear tumor borders, and it can unexpectedly spread beyond its clinical boundaries. Surgical resection in such cases is often associated with tumor-positive margins, which can result in recurrence. However, surgical excision with wide margins may deteriorate patients' organ functions and quality of life. Mohs micrographic surgery may be ideal for controlling the surgical margins and minimizing the sacrifice of normal tissue, but this technique is not always feasible because of constraints associated with the medical environment. No standard treatment for unresectable or metastatic EMPD has been established. Although conventional chemotherapy has been used as the first-line treatment, it frequently causes adverse events, and consequently, targeted therapy will become more valuable in the near future.

Genomic landscape of circulating tumour DNA in metastatic extramammary Paget's disease.

Although cancer personalized profiling by deep sequencing (CAPP-Seq) of cell-free DNA (cfDNA) has gained attention, the clinical utility of circulating tumour DNA (ctDNA) in extramammary Paget's disease (EMPD) has not been investigated. In this study, genomic alterations in the cfDNA and tumour tissue DNA were investigated in seven patients with metastatic EMPD. CAPP-Seq revealed mutations in 18genes, 11 of which have not yet been reported in EMPD. The variant allele frequency of some of the mutated genes reflected the disease course in patients with EMPD. In one patient, the mutation was detected even though imaging findings revealed no metastasis. In another patient with triple EMPD (genital area and both axilla), cfDNA sequencing detected the mutation in a rib metastatic lesion, which was also detected in both axilla lesions but not the genital region. Investigations of the ctDNA may be useful towards the elucidation of clonal evolution in EMPD.

Metastatic extramammary paget disease, a remarkable clinical case and a brief review of a rare disease.

Extramammary Paget Disease (EMPD) is an often-misdiagnosed rare disorder, whose cause remains unknown. Diagnosis is confirmed by skin biopsy. Primary treatment for EMPD is surgery. Recurrence is common in the first two years and prognosis is good if the disease is localized and there is no underlying associated cancer. Patients with invasive and metastatic EMPD are uncommon and exhibit a poor prognosis, even when there is good response to a first chemotherapy line. Multiple chemotherapeutic regimens, with varying levels of success, have been attempted, but standard of care is not established. The central nervous system seems to be a common metastatic site with better survival than visceral metastasis.We report a case of metastatic EMPD that addresses the difficulties associated with the treatment of this rare disease, that has no current guidelines.

S1803 Extramammary Paget’s Disease of the Anal Canal: A Rare Diagnosis

INTRODUCTION: Extramammary Paget's disease (EMPD) is an uncommon intraepithelial malignancy that often involves areas of skin with high apocrine gland density. Cases of EMPD involving the anal canal are extremely rare. We present a case of anal EMPD where subsequent work up was unsuccessful in locating the primary site of the associated gastrointestinal (GI) cancer. CASE DESCRIPTION/METHODS: 76 year old male with history of diabetes, hypertension, immune thrombocytopenic purpura treated with rituximab, and chronic lymphocytic leukemia in remission after treatment with chemotherapy, presented with chronic constipation. He denied hematochezia, weight loss, or family history of GI malignancy. He underwent colonoscopy where one polyp was removed from the cecum with pathology revealing a tubular adenoma as well as a one centimeter whitish area of abnormal-appearing mucosa in the anal canal extending proximally into the anal transition zone and initial biopsy demonstrated invasive EMPD (BerEP4, CK7, CK20 & mucicarmine positive) (Image 1). A second biopsy of the lesion showed anal intraepithelial neoplasia (AIN 2–3) with EMPD (CK7, CK20, CDX2 & mucicarmine positive) (Image 2). Later, PET/CT scan showed linear FDG uptake in the anorectal region and several FDG-avid lymph nodes in the right external iliac chain and inguinal region. Subsequent excisional biopsy of the right inguinal lymph nodes showed metastatic tumor, with an immunohistochemistry profile similar to prior EMPD biopsies (Image 3). Patient underwent a repeat colonoscopy which did not reveal any new findings. An EGD and capsule endoscopy were also done which did not show any suspicious masses or lesions. Wide local excision with lymph node dissection was recommended, but the patient declined further management. Two months later, the patient got a CT abdomen and pelvis due to increasing abdominal pain which showed worsening metastatic disease in the liver and abdominal lymph nodes. Patient opted for hospice care and died a few weeks afterwards. DISCUSSION: To our knowledge, EMPD involving the anal canal is a rare finding with only a handful of cases reported in the literature. It was an incidental diagnosis and most likely associated with an unidentified colorectal adenocarcinoma. Surgery is the treatment of choice for localized disease, provided there is no evidence of dermal invasion or distant metastasis. Radiation and chemotherapy may be trialed in advanced cases, but efficacy remains poor.Figure 1.: Colonoscopy (A &B) showing mucosal lesion in anal canal (arrows), extending proximally into the anal transition zone. Anus biopsy on H & E stain (C ) showing invasive extramammary Paget’s disease with nests of malignant epithelial cells showing a high nuclear-to-cytoplasmic ratio with arrows indicating invasive carcinoma which is confirmed with BerEP4 immunohistochemistry stain (D) confirming in situ (red arrows) and invasive extramammary Paget's disease (blue arrows).Figure 2.: Anus biopsy (20X) with H & E stain (B) showing foci of extramammary Paget’s disease (black arrows) in tissue composed of high grade anal intraepithelial neoplasia (AIN 2-3). CDX2 immunohistochemistry stain (C) and Mucicarmine stain (D) highlighting extramammary Paget's disease.Figure 3.: PET/CT (A) shows FDG-avid lymph nodes in the right external iliac chain and inguinal region (white arrow). Right inguinal lymph node biopsy shows metastatic extramammary Paget's disease (40X) with H & E stain (B), confirmed with CK 7 immunohistochemistry stain expression (10X) in (C) and CDX2 immunohistochemistry expression (40X) in (D).

Experiences of trastuzumab plus paclitaxel combination therapy in metastatic human epidermal growth factor receptor 2-positive extramammary Paget's disease: Four cases and a review.

Tumor cells in extramammary Paget's disease sometimes overexpress human epidermal growth factor receptor 2 (HER2). Several case reports indicated successful response to HER2 inhibitor in patients with HER2-positive metastatic extramammary Paget's disease. However, these were single-case reports, and most cases were evaluated only by immunohistochemistry and treated with HER2 inhibitor monotherapy. Here, we report cases of HER2-positive metastatic extramammary Paget's disease identified by both immunohistochemistry and in situ hybridization, and the patients were treated with HER2 inhibitor (trastuzumab) and paclitaxel combination chemotherapy. Partial response was observed in one case. The case was positive on both immunohistochemistry (3+) and in situ hybridization (HER2/chromosome 17 centromere, ≥2.0). Our observations suggest that HER2 should be checked in patients with advanced and/or metastatic extramammary Paget's disease, and that therapy with HER2 blockers should be considered as an option for treatment of HER2-positive extramammary Paget's disease, especially in cases positive for both HER2 gene amplification and overexpression.

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 10years. 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 (25mg/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 26.4months (95% CI, 16.7-36.1), respectively. Furthermore, the median PFS was 7.3months (95% CI, 4.5-10.0) in patients aged 65years and younger and 7.1months (95% CI, 4.4-9.9) in patients older than 65years. 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.

Ado-trastuzumab emtansine (T-DM1) for a case of HER2-amplified metastatic extramammary Paget's disease of scrotum: Clinical next-generation sequencing for precision medicine

Ado-trastuzumab emtansine (T-DM1) for a case of HER2-amplified metastatic extramammary Paget's disease of scrotum: Clinical next-generation sequencing for precision medicine

Sequential somatic mutations upon secondary anti-HER2 treatment resistance in metastatic ERBB2S310F mutated extramammary Paget's disease.

Metastatic extramammary Paget’s disease is a rare adenocarcinoma with poor prognosis. Several reports of human epidermal growth factor receptor 2 alterations point to its pathogenic role in the disease. However, the occurrence of treatment resistance to anti-HER2 therapy demand the need for further knowledge. We report of a patient with metastatic penoscrotal extramammary Paget’s disease, with an ERBB2S310F mutation, in which near complete response was achieved upon treatment with trastuzumab and carboplatin. However, after 10 cycles of trastuzumab and carboplatin, widespread metastasis re-occurred. Analysis of a newly developing metastasis revealed additional genomic alterations including ERBB3A232V and PIK3CAG106V point mutations as well as MET and CDK6 amplification, providing a potential mechanism of acquired treatment resistance. Therefore, ERBB family inhibitor afatinib was initiated. Unfortunately, the patient succumbed to disease-related complications shortly after treatment initiation. This is the first report of ERBB2S310F mutated, metastatic extramammary Paget’s disease with secondary resistance to trastuzumab / carboplatin, potentially due to additional acquired genomic alterations. This case contributes to the growing evidence of HER2 in the pathogenesis of metastatic extramammary Paget’s disease and emphasizes the importance of repetitive, genomic analysis in rare diseases.

Serum cytokeratin 19 fragment 21-1 and carcinoembryonic antigen combination assay as a biomarker of tumour progression and treatment response in extramammary Paget disease.

Extramammary Paget disease (EMPD) is a rare intraepithelial adenocarcinoma affecting the genitals and axillary regions. As metastasis of these tumours is itself rare, solid disease management strategies have not been established. Serum carcinoembryonic antigen (CEA) and cytokeratin 19 fragment 21-1 (CYFRA 21-1) levels have been identified as candidate biomarkers for tumour progression in EMPD. To determine the accuracy of and the correlation between these markers in patients with EMPD. Serum CEA and CYFRA 21-1 levels were examined in 30 patients with EMPD treated at Keio University Hospital, and compared against clinical information. Both assays were performed at the time of diagnosis, during the postoperative observation period, and following systemic treatment in those with confirmed metastasis. Serum levels were then correlated with tumour progression status and treatment responses. Normal levels for both assays were observed in all 11 patients with primary localized disease (100%). In patients with metastatic disease the CEA positivity rate was 79% (15 of 19 patients), with a rate of 63% (12 of 19 patients) for CYFRA 21-1. Changes in CEA and CYFRA 21-1 levels were statistically independent; however, using a combined view, elevated levels of either marker improved the positivity rate to 95% (18 of 19 patients). Use of both markers also correlated well with treatment responses. The combination of CEA and CYFRA 21-1 is useful for predicting metastasis and treatment response in patients with EMPD, especially in those who only have elevation of a single marker. What's already known about this topic? Serum levels of carcinoembryonic antigen (CEA) and cytokine 19 fragment 21-1 (CYFRA 21-1) have been shown to be elevated in patients with extramammary Paget disease (EMPD). Elevation of serum CEA levels is associated with tumour progression of EMPD. A single small study reported that serum CYFRA 21-1 levels are elevated in patients with EMPD with lymph node metastasis. What does this study add? Serum CEA and CYFRA 21-1 were present in 79% and 63% of 19 cases of metastatic EMPD, respectively. Elevations of CEA and CYFRA 21-1 were statistically independent. CEA and CYFRA 21-1 combination assays were positive in 95% of cases of metastatic EMPD. What is the translational message? Combination assays with CEA and CYFRA 21-1 are useful for monitoring treatment response in patients with metastatic EMPD, particularly in those with elevation of either marker.

Human epidermal growth factor receptor 2 amplification as a biomarker for treatment in patients with lymph node-metastatic penoscrotal extramammary Paget's disease.

The role of human epidermal growth factor receptor 2 (HER2) amplification as a biomarker for treatment in patients with lymph node (LN)-metastatic penoscrotal extramammary Paget's disease (EMPD) was investigated in the present study. A total of 11 male patients with LN-metastatic penoscrotal EMPD were retrospectively reviewed. Positron emission tomography/computed tomography (PET/CT) was conducted prior to surgery. Immunohistochemistry and fluorescence in situ hybridization were used to evaluate HER2 gene amplification in LN samples. Sanger sequencing was used to investigate HER2 mutations. A literature review of the prevalence of HER2 amplification in EMPD and the efficacy of HER2-targeted therapy was also undertaken. PET/CT is effective in detecting metastatic sites. The sensitivity and specificity of PET/CT was 90.9 and 100.0% for inguinal LNs, and 85.7 and 80.0% for pelvic LNs, respectively. The median time from LN dissection to disease progression was 15.9±1.5 months. Of the 11 patients, 3 (27.3%) indicated HER2 amplification. Patients with HER2 amplification showed shorter median times from disease discovery to LN metastasis (HER2 amplification vs HER2 non-amplification; 15.6 vs. 10.0 months; P=0.50) and from LN dissection to disease progression (HER2 amplification vs. HER2 non-amplification, 16.2 vs. 13.6 months; P=0.11). However, the aforementioned observations were not indicated to be statistically significant. No HER2 mutations were identified. Trastuzumab, a HER2-targeted monoclonal antibody, was administered to 2 of the patients with HER2 amplification. A literature review of the prevalence of HER2 amplification in EMPD and the efficacy of HER2-targeted therapy showed similar results. Altogether, 485 cases of EMPD were reported, 35 of which had metastases. The results in the present study suggest that PET/CT should be used on all metastatic EMPD patients. EMPD may be effectively treated with trastuzumab. The present study and case reports from the literature provide evidence for the benefit of testing for HER2 amplification in this rare disease and highlight the requirement for a multicenter clinical trial to assess the impact of trastuzumab therapy in treating this disease.

A case of metastatic extramammary Paget's disease successfully treated using combination therapy with trastuzumab and paclitaxel

A case of metastatic extramammary Paget's disease successfully treated using combination therapy with trastuzumab and paclitaxel