Vulvar Cancer, Version 3.2024, NCCN Clinical Practice Guidelines in Oncology.

Vulvar cancer is annually diagnosed in an estimated 6,470 individuals and the vast majority are histologically squamous cell carcinomas. Vulvar cancer accounts for 5% to 8% of gynecologic malignancies. Known risk factors for vulvar cancer include increasing age, infection with human papillomavirus, cigarette smoking, inflammatory conditions affecting the vulva, and immunodeficiency. Most vulvar neoplasias are diagnosed at early stages. Rarer histologies exist and include melanoma, extramammary Paget's disease, Bartholin gland adenocarcinoma, verrucous carcinoma, basal cell carcinoma, and sarcoma. This manuscript discusses recommendations outlined in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for treatments, surveillance, systemic therapy options, and gynecologic survivorship.

EXTRA, EXTRA, Treatment Approaches for EXTRAmammary Paget Disease.

Desai S, McCormick E, Nelson K, et al. EXTRA, EXTRA, treatment approaches for EXTRAmammary Paget disease. J Drugs Dermatol. 2023;22(8):844-845. doi:10.36849/jdd.NVRN0823.

Perianal Paget's-an aggressive disease.

AIM: Perianal Paget's disease (PAPD) is a rare disorder with a predisposition to anal and colorectal malignancies and an unclear prognosis. Our previous 25-year series demonstrated a non-aggressive nature. This study aims to describe our updated institutional experience. METHODS: This is a retrospective review of all patients diagnosed with primary PAPD from 1991 to 2021. A prospectively maintained institutional database was searched which included demographics, clinical and pathological manifestations, treatment methods, recurrence, oncological outcome and mortality. RESULTS: Thirty patients were diagnosed with PAPD. Fifteen were women (50%); the average age at diagnosis was 71 ± 10.7 years, and the average lesion size was 3.7 ± 2.6 cm. At diagnosis, 12 (40%) were harbouring invasive anal adenocarcinoma. Eight (27%) developed adenocarcinomas concurrent with PAPD recurrence at a mean interval of 9 ± 4.4 years (range 1.9-14.8). The Kaplan-Meier curve estimated overall survival of 93%, 86%, 82%, 65% and 56% at 1, 3, 5, 10 and 15 years, respectively. Median survival was 16 years. Six (20%) had disease-related mortality. Initially, nine (30%) were treated with abdominoperineal resection (APR), 15 (50%) underwent local resection, three (10%) were treated with radiotherapy, two (7%) received only topical therapy and one (3%) chose observation. Fifteen (50%) experienced recurrence of PAPD, two after undergoing APR. Five (17%) had persistent disease until death. Only 10 (33%) did not experience PAPD recurrence, seven of whom underwent APR. The mean follow-up time was 9.2 ± 6.2 years. CONCLUSIONS: Perianal Paget's disease is an aggressive entity with high rates of synchronous anal adenocarcinoma at diagnosis and development of metachronous adenocarcinoma later in life.

Extramammary Paget's Disease of the Vulva and Concomitant Premalignant/Malignant Vulvar Lesions: A Potential Challenge in Diagnosis and Treatment.

The aim of the present study was to evaluate the incidence of concomitant vulvar cancers or premalignant lesions in women surgically treated for extramammary Paget's disease of the vulva (EMPDV) through a multicenter case series. The medical records of all women diagnosed with and treated for EMPDV from January 2010 to December 2020 were retrospectively analyzed. Women with EMPDV and synchronous vulvar cancer, vulvar intraepithelial neoplasia (VIN) and/or lichen sclerosus (LS) at the histology report were included in the study. A total of 69 women eligible for the present study were considered. Concomitant vulvar lesions occurred in 22 cases (31.9%). A total of 11 cases of synchronous VIN (50%) and 14 cases (63.6%) of concomitant LS were observed. One patient (4.5%) had synchronous vulvar SCC (FIGO stage 1B). Women with EMPDV and concomitant premalignant/malignant vulvar lesions had a significantly higher rate of invasive EMPDV and wider lesions with an extravulvar involvement. The specific meaning of the association between EMPDV, VIN, SCC and LS remains unclear. The potential overlapping features between different vulvar lesions highlight the importance of dedicated gynecologists and pathologists in referral centers.

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/1.73 m2 ), 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.

Management of secondary Paget's disease of the vulva associated with transitional cell carcinoma.

PURPOSE: Secondary extramammary Paget's disease (EMPD) related to urothelial carcinoma is rare, with some cases presenting synchronously with either a primary neoplasm or recurrence of a neoplasm and other cases presenting up to 13 years prior to the detection of urothelial carcinoma. In this report, we will review the presentation, diagnosis, pathophysiology, management, and literature review of cases of secondary EPMD associated with urothelial carcinoma. METHODS: We reviewed the English literature for all cases of secondary EMPD presenting synchronously with or in patients with a history of urothelial carcinoma, as well as treatment data for secondary vulvar Paget's. RESULTS: We identified 16 case reports and case series with a total of 20 cases of vulvar EMPD associated with urothelial carcinoma. Twelve cases presented asynchronously and 8 had EMPD preceding the diagnosis of the underlying neoplasm. There is a paucity in the literature regarding management and surgical resection is a common treatment strategy; however, nonsurgical interventions may also be effective. CONCLUSION: There is a paucity in the literature regarding management of secondary EPMD of urothelial origin, but consideration of radiation and systemic chemotherapy may be a reasonable treatment approach.

Evidence-Based Clinical Practice Guidelines for Extramammary Paget Disease.

IMPORTANCE: Extramammary Paget disease (EMPD) is a frequently recurring malignant neoplasm with metastatic potential that presents in older adults on the genital, perianal, and axillary skin. Extramammary Paget disease can precede or occur along with internal malignant neoplasms. OBJECTIVE: To develop recommendations for the care of adults with EMPD. EVIDENCE REVIEW: A systematic review of the literature on EMPD from January 1990 to September 18, 2019, was conducted using MEDLINE, Embase, Web of Science Core Collection, and Cochrane Libraries. Analysis included 483 studies. A multidisciplinary expert panel evaluation of the findings led to the development of clinical care recommendations for EMPD. FINDINGS: The key findings were as follows: (1) Multiple skin biopsies, including those of any nodular areas, are critical for diagnosis. (2) Malignant neoplasm screening appropriate for age and anatomical site should be performed at baseline to distinguish between primary and secondary EMPD. (3) Routine use of sentinel lymph node biopsy or lymph node dissection is not recommended. (4) For intraepidermal EMPD, surgical and nonsurgical treatments may be used depending on patient and tumor characteristics, although cure rates may be superior with surgical approaches. For invasive EMPD, surgical resection with curative intent is preferred. (5) Patients with unresectable intraepidermal EMPD or patients who are medically unable to undergo surgery may receive nonsurgical treatments, including radiotherapy, imiquimod, photodynamic therapy, carbon dioxide laser therapy, or other modalities. (6) Distant metastatic disease may be treated with chemotherapy or individualized targeted approaches. (7) Close follow-up to monitor for recurrence is recommended for at least the first 5 years. CONCLUSIONS AND RELEVANCE: Clinical practice guidelines for EMPD provide guidance regarding recommended diagnostic approaches, differentiation between invasive and noninvasive disease, and use of surgical vs nonsurgical treatments. Prospective registries may further improve our understanding of the natural history of the disease in primary vs secondary EMPD, clarify features of high-risk tumors, and identify superior management approaches.

Extramammary Paget's Disease: Diagnosis, Pathogenesis, and Treatment with Focus on Recent Developments.

Extramammary Paget's disease (EMPD) is a rare neoplasm that usually develops in apocrine gland-bearing areas, such as the vulva, scrotum, and penis. EMPD may present with a focal, multifocal, or an ectopic lesion. Clinically, EMPD lesions often exhibit infiltrative erythema, which is sometimes similar to other skin disorders such as eczema. While primary EMPD arises as intraepithelial neoplasm of the epidermis, EMPD-like lesions may occur from epidermotropic spread of malignant cells or direct extension from an underlying internal neoplasm, known as secondary EMPD. Because treatment strategies differ for primary EMPD and secondary EMPD, accurate diagnosis based on detailed histopathological evaluation is required. In the early stages, EMPD usually shows indolent growth, and most cases are diagnosed as carcinoma in situ. However, invasive lesions may result in metastases, and deep invasion is associated with high incidence of metastases. Conventional chemotherapies have been used for EMPD treatment in patients with distant metastases, but the efficacy is not satisfactory, and the prognosis for such patients remains poor. Recent studies have provided various insights into the molecular pathogenesis of the development and advancement of EMPD, which may lead to novel treatment approaches for metastatic EMPD. This review addresses the diagnosis, pathogenesis, and treatment of EMPD with focus on recent progress in understanding this disease.

Multidisciplinary Approach for the Management of Penoscrotal Extramammary Paget's disease -An eUROGEN study.

INTRODUCTION: We reviewed the medical and surgical management and long-term outcomes for patients diagnosed with penoscrotal extramammary Pagets disease (EMPD) within an eUROGEN centre. PATIENTS AND METHODS: Retrospective review of cases from an institutional database with biopsy proven penoscrotal EMPD. RESULTS: A total of 10 patients were identified with penoscrotal EMPD over a 10-year period. Two patients had a previous history of gastrointestinal and urogenital cancers (20%) and no synchronous or metachronous cancers were identified. Eight patients with non-invasive EMPD (80%) underwent wide local excision of the affected skin, with at least a 5mm macroscopic resection margin and in selected cases simultaneous multiple mapping biopsies around the lesion were performed. Residual disease was present at the margins in seven patients (87.5%), of which three required further surgical excision or adjuvant topical immunotherapy (42.8%). Recurrence after complete excision was 12.5% and was successfully treated with topical imiquimod immunotherapy and CO2 laser therapy. Two patients (20%) had invasive carcinoma and metastatic disease at diagnosis. CONCLUSION: Reported recurrence rates of non-invasive penoscrotal EMPD are high and residual disease is present in most cases requiring either close clinical surveillance or adjuvant treatment. We propose an algorithm in the management of this rare disease.

Perianal Paget's disease: one century later and still a challenge.

Perianal Paget disease (PPD) is a rare neoplastic condition defined by the presence of atypical Paget cells in the perianal skin, the aetiology of which remains largely unknown. It can be divided in primary forms, arising as an intraepithelial disease or manifestation of an underlying skin adenocarcinoma or secondary forms resulting from epidermotropic spread or metastasis of a concealed carcinoma. Indeed, because of its rarity, clear options regarding the treatment of these patients are yet to be clarified. A high level of suspicion is needed whenever dealing with any unhealed perianal skin lesions and, therefore, the need for close long-term follow-up must be highlighted. Herein, two cases of PPD, one primary and another secondary, treated at the same institution, are presented in an attempt to document the involved complexity and to bring further insight into the understanding of this entity.

Penoscrotal Paget's disease.

Paget's disease (PD) denotes an initially intra-epidermal adenocarcinoma that can later invade the dermis and metastasise. Among the extramammary forms of PD (EMPD), penoscrotal presentations are rarer than the vulvar and perianal forms. Once diagnosis has been confirmed by histopathological examination, a search for associated neoplasia must be conducted, although penoscrotal EMPD is less frequently associated with underlying neoplasia than mammary PD (MPD). The associated cancer most often involves a neighbouring organ, with prostate cancer being the most common, or in some cases consists of underlying cutaneous adnexal tumours. First-line therapy consists of surgical excision. Alternatives to surgery (imiquimod, CO2 laser vaporisation, dynamic phototherapy) may be considered in certain cases.

Paget's disease of the vulva: A challenge for the gynaecologist.

Paget's disease of the vulva is a rare form of extramammary Paget's disease mainly affecting postmenopausal women. Its pathophysiology remains largely unknown. Up to fairly recently, the only treatment for this disease was surgery, often mutilating the vulva, with significant psychosexual repercussions without the assurance of complete therapeutic efficacy. New therapeutic approaches -topical treatments, radiotherapy or chemotherapy- have emerged in recent years but lack consensual guidelines. We present a literature review of the recent results published in this field.

Brain metastasis from extramammary Paget's disease.

Herein, we present a case of extramammary Paget's disease with brain metastasis that was diagnosed pathologically for the first time in Japan. Moreover, invasive extramammary Paget's disease (with distant metastasis) highly resistant to treatment. Only for brain metastasis, we may control the tumor by surgical resection and stereotactic radiosurgery (SRT) for the treatment of intracranial metastases was assessed. An 76-year-old man was diagnosed with extramammary Paget's disease of the vulva at nearby hospital. Surgical resection and sentinel lymph node dissection were then performed, and the patient received chemotherapy because multiple lymph node metastases were suspected. The patient's response to chemotherapy was poor, and he was in the state of Progressive Disease. He complained of dyslexia and was referred to another hospital when he was 81 years old. Plain magnetic resonance imaging (MRI) was conducted, and two brain tumors in the vicinity of the left cerebellar tent were suspected. In our hospital, gadolinium contrast-enhanced MRI was performed and showed a tumor in the cerebellum (left posterior temporal lobe) and another tumor under the tent (left cerebellar hemisphere). Significant edema was also noted. Based on these findings, the intracranial lesion was diagnosed as metastatic brain tumor. The pathological diagnosis was brain metastasis from extramammary Paget's disease. Postoperative intracranial residual disease was treated with stereotactic radiosurgery. MRI showed that the size of the cerebellar lesions decreased, and no recurrence of cerebral lesions was observed. SRT for extracranial lymph node metastases was performed. Mass reduction and SRT may be the best way to treat brain metastasis from extramammary Paget's disease.

PD-1 signaling in extramammary paget disease.

Primary extramammary Paget disease (EMPD) is an intraepidermal adnexal carcinoma of the apocrine gland ducts with the potential to become invasive or metastatic. The pathogenesis of primary EMPD remains unclear; however, there have been recent studies investigating the genetic characteristics of EMPD lesions. The interaction between the programmed cell death receptor 1 (PD-1) and its ligand is one of the pathways recently reported to be a potential target in EMPD. Given the advances of immunotherapy in the field of oncology and the paucity of effective agents to treat EMPD, this article serves to shed light on recent data studying PD-1 signaling in EMPD and highlights the potential clinical use of immunotherapy for EMPD.

Enfermedad de Paget perianal: un trastorno raro que enmascara un carcinoma anorrectal subyacente / Perianal Paget's disease: A rare disorder masking an underlying anorectal carcinoma

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Enfermedad de Paget extramamaria / Extramammary Paget Disease

ANTECEDENTES Y OBJETIVOS: Existen pocos estudios sobre la enfermedad de Paget extramamaria (EPEM) en la población mediterránea. Nuestro objetivo fue revisar las características de nuestros pacientes con EPEM, su asociación con neoplasia en continuidad y su evolución a largo plazo. PACIENTES Y MÉTODOS: Realizamos un estudio observacional retrospectivo sobre 27 pacientes diagnosticados de EPEM entre 1990-2015. Las historias clínicas fueron revisadas retrospectivamente para obtener los datos clínico-patológicos y de seguimiento. RESULTADOS: Se trata de 20 mujeres y 7 varones de entre 42 y 88 años de edad (mediana de 76 años). Las lesiones se localizaron en la vulva (16 casos), en el pubis-región inguinal (5), en la región perianal (4) y en la axila (2). El tiempo de evolución al diagnóstico osciló entre 1 y 60 meses (mediana de 12 meses) y el diámetro máximo entre 20 y 140 mm (mediana de 55 mm). En 3 casos (11,1%) la EPEM fue secundaria. Ningún caso se desarrolló sobre adenocarcinoma anexial cutáneo previo. Diez de 24 EPEM primarias (41,7%) presentaban invasión de la dermis. Ocho de los 27 pacientes (29,6%) presentaron recidiva local tras el tratamiento quirúrgico inicial. Tres pacientes (11,1%) fallecieron a consecuencia de metástasis de la EPEM. CONCLUSIONES: La presencia de un adenocarcinoma anexial cutáneo subyacente es poco frecuente pero no es rara la existencia de un adenocarcinoma extracutáneo en continuidad. A pesar de que la EPEM suele evolucionar lentamente, es frecuente la invasión de la dermis y no son excepcionales las metástasis. Las recidivas locales son frecuentes a pesar de la extirpación con márgenes amplios y pueden ser tardías, por lo que es preciso un seguimiento a largo plazo

BACKGROUND AND OBJECTIVE: Extramammary Paget disease (EMPD) has seldom been studied in Mediterranean populations. We aimed to review the characteristics of our patients with EMPD, the presence of a neoplasm in continuity, and the long-term course of the disease. PATIENTS AND METHODS: Retrospective observational study of 27 patients diagnosed with EMPD between 1990 and 2015. All clinical and pathology findings related to clinical course and outcomes were retrieved for analysis. RESULTS: Twenty patients were women and 7 were men. Ages ranged from 42 to 88 years (median, 76 years). Lesions were in the following locations: vulva (16 cases), pubis-groin (5), perianal region (4), and axilla (2). Time from onset to diagnosis ranged from 1 to 60 months (median, 12 months) and maximum lesion diameter from 20 to 140 mm (median, 55 mm). In 3 cases (11.1%) EMPD was a secondary condition. None of the lesions developed on a previous cutaneous adnexal adenocarcinoma. Ten of the 24 primary EMPDs (41.7%) invaded the dermis. Eight of the 27 patients (29.6%) experienced local recurrence after the initial surgical treatment.Three patients (11.1%) died as a consequence of metastasis from the EMPD. CONCLUSIONS: The presence of an underlying cutaneous adnexal adenocarcinoma is uncommon, but it is not unusual to find an extracutaneous adenocarcinoma in continuity. Although EMPD is a slow-growing tumor, dermal invasion is frequent and metastasis is not uncommon. Local recurrence is common even after excision with wide margins and may be delated, so long term follow-up is essential

Nonsurgical Treatments for Extramammary Paget Disease: A Systematic Review and Meta-Analysis.

INTRODUCTION: Surgery is commonly regarded as the mainstay of treatment of extramammary Paget disease (EMPD); however, nonsurgical approaches have gained popularity in recent years. OBJECTIVES: To review the published evidence for the efficacy and safety of nonsurgical modes of therapy for EMPD. METHODS: A systematic review and meta-analysis of nonsurgical EMPD treatments was performed. The primary outcome was complete response (CR); secondary outcomes were clinical regression by ≥50%, adverse events, and recurrence rate. RESULTS: The systematic review included 43 observational studies (341 patients; 7 prospective cohort studies, 19 retrospective cohort studies, and 17 cases series) evaluating 5 treatment modalities. Imiquimod (13 studies, 110 patients) administered at variable doses ranging from daily to twice weekly for 2-56 weeks demonstrated CR of 54% (95% CI, 40-67%; I2 = 37%) and had a satisfactory safety profile. In 14 heterogeneous studies (122 patients) evaluating photodynamic therapy (PDT), only 36% (95% CI, 22-53%; I2 = 52%) of patients achieved CR. Radiotherapy (12 studies, 67 patients) showed CR of 97%, but was associated with local and systemic side effects. Ablative lasers and topical fluorouracil and calcipotriene lacked adequate evidence of efficacy. CONCLUSIONS: Imiquimod and radiotherapy are the most appropriate nonsurgical modalities for EMPD treatment given their good efficacy and safety profile. PDT has limited efficacy but may be appropriate in selected clinical settings.