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.

[A Case Report of Perianal Paget's Disease Treated with Robot-Assisted Surgery for Positive Margins after Local Excision].

The patient is a 73-year-old man who was diagnosed with perianal Paget's disease by skin biopsy. Biopsy from the dentate line did not show any tumor cells. The patient was considered to undergo sphincter-preserving local resection and subsequently underwent the procedure. Histopathological examination of the resected specimen revealed perianal Paget's disease with a positive anorectal margin. The patient was referred to our department due to postoperative anal stenosis. On the 32nd postoperative day, a double barreled sigmoid colostomy was performed. However, considering the inability to adequately check for detect due to anorectal stenosis and the expected unfavorable anorectal function caused by sphincter- preserving re-operation, a robot-assisted abdominoperineal resection(D1)was performed 7 months after the initial surgery. Histopathological examination of the resected specimen revealed no residual tumor cells in the resected specimen. After local excision for perianal Paget's disease, the skin of the buttock becomes scarred due to skin valve formation and skin grafting, making closure of the perineal wound difficult when performing abdominoperineal resection. In robot-assisted surgery, it is relatively easy to remove the anorectal muscles from the abdominal cavity and reach the sciatico-rectal fossa, thus reducing the size of the perineal wound.

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.

Existence of Staphylococcus aureus correlates with the progression of extramammary Paget's disease: potential involvement of interleukin-17 and M2-like macrophage polarization.

BACKGROUND: The microbiome plays an important role in the tumour microenvironment (TME). OBJECTIVES: In this study, we investigated the clinical significance of the microbiota in extramammary Paget's disease (EMPD). MATERIALS & METHODS: Patients with EMPD, treated between March 2007 and September 2019 at Kumamoto University Hospital, were investigated retrospectively. Inclusion criteria included: histological diagnosis of EMPD, inspection of the bacterial culture of the cancer lesion using swab sampling, and availability of sufficient tissue in paraffin blocks for immunohistochemistry. For the latter, primary antibodies against IL-17, CD163 and ionized calcium-binding adapter molecule 1 (Iba1) were used. RESULTS: Bacterial cultures of the cancer lesion revealed that Staphylococcus aureus (S. aureus) was highly prevalent in EMPD patients, with dermal invasion or lymph node metastasis, compared to patients without these findings. Furthermore, the number of IL-17-positive cells and CD163-positive M2-like macrophages (pro-tumour macrophages) were increased in EMPD tissues with S. aureus. Moreover, the number of IL-17-producing cells in EMPD tissues positively correlated with the accumulation of CD163-positive M2-like macrophages. In addition, the percentage of CD163-positive cells within Iba-1-positive macrophages (total macrophages) was also significantly elevated in EMPD tissues with S. aureus. CONCLUSION: Based on these findings, S. aureus may exacerbate the pathological condition of EMPD via the accumulation of IL-17 and M2-like macrophages.

Perianal Paget's disease as spread from non-invasive colorectal adenomas.

AIMS: Paget's disease of the perianal skin is a rare form of extramammary Paget's disease, and may be a primary intraepithelial adnexal neoplasm or secondary due to spread from an underlying colorectal lesion, nearly always colorectal adenocarcinoma. Secondary perianal Paget's disease associated with non-invasive colorectal adenomas is exceedingly uncommon, with only a few reported cases. METHODS AND RESULTS: Herein, we present the clinical and pathological features of the largest series of secondary perianal Paget's disease arising in association with colorectal adenomas. There was gender parity and the median age was 72 years (range = 68-76 years). In all cases, perianal Paget's disease was associated with colorectal adenomas, including three (75%) conventional tubular adenomas and one (25%) tubulovillous adenoma with serrated foci. All adenomas had high-grade dysplasia and one had intramucosal adenocarcinoma (lamina propria invasion; Tis), but all lacked submucosal invasion. The intraepithelial Paget's cells showed a colorectal phenotype by immunohistochemistry in all cases. At follow-up, two patients had no evidence of disease at 6 and 87 months, one had residual perianal Paget's disease at 8 months and one developed invasive adenocarcinoma of the perianal tissue at 36 months. CONCLUSIONS: Similar to its mammary analogue, secondary perianal Paget's disease may arise in association with invasive and/or in-situ colorectal lesions. Although the latter is an uncommon presentation of a recognised rare disease, knowledge of this phenomenon is important to forestall overdiagnosis of invasion and potential overtreatment. The clinical course is variable, such that close follow-up is required.

Extramammary Paget Disease: A Review of the Literature-Part I: History, Epidemiology, Pathogenesis, Presentation, Histopathology, and Diagnostic Work-up.

BACKGROUND: Extramammary Paget disease (EMPD) is a rare malignancy with unclear pathophysiology that occurs predominantly on apocrine rich skin. Surgery is the treatment of choice; however, procedures tend to be extensive and associated with a high rate of recurrence. OBJECTIVE: To review the current literature on EMPD regarding epidemiology, pathogenesis, clinical presentation, histology, diagnostic work-up, treatment, and prognosis. MATERIALS AND METHODS: Literature review using PubMed search for articles related to EMPD. RESULTS: Extramammary Paget disease classically presents as a slowly growing red plaque, which often mimics an inflammatory condition leading to significant delay in diagnosis. Diagnosis requires histopathologic examination and is often supported by immunohistochemical analysis. Once a diagnosis of EMPD is made, the patient must be risk-stratified and evaluated for an underlying malignancy. CONCLUSION: Standard of treatment is surgery, with data suggesting that Mohs micrographic surgery may have superior clinical outcomes and lower recurrence rates. Alternatives such as photodynamic therapy and topicals have been explored and may be appropriate in certain situations. Patients with EMPD generally have a good prognosis with a 5-year overall survival rate of 75% to 95%.

Extramammary Paget's disease: what do we know and how do we treat?

INTRODUCTION: Extramammary Paget's disease (EMPD) is a rare and complex condition, for which no established guidelines exist regarding diagnosis and management. There have been recent improvements in the diagnosis and management in EMPD, largely due to an enhanced understanding of its underlying pathogenesis. MATERIALS AND METHODS: A literature search on PubMed including articles that describe pathogenesis, clinical diagnosis, treatment modalities, and future treatment were selected and included to build this review. RESULTS: Recent studies would suggest the expression of HER2 and androgen receptors which could be useful targets for future treatment strategies. Carcinoembryonic antigen as a biomarker for EMPD has shown the potential to aid in the detection of metastatic EMPD and assessment of treatment response. Studies have also demonstrated the initial site of EMPD can be predictive of secondary malignancies, which helps guide initial work up and evaluation. CONCLUSIONS: Significant developments in understanding the pathogenesis of EMPD have been made, especially of the genomic aberrations associated with EMPD. This has allowed for the development and use of therapeutic options which may improve outcomes for patients with 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.

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

BACKGROUND: 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. CASE PRESENTATION: Here, we report a 76-year-old man presented with pruritus in the perianal area. Investigation revealed a fist-sized perianal erythema, diffuse liver tumors, and right inguinal lymph node swelling. Pathological examination of biopsies from the erythema suggested secondary extramammary Paget disease with positive cytokeratin-7 and -20 expressions and negative GCDFP-15 expression. The anal canal tumor was confirmed by digital examination and endoscopy. Biopsies from the anal canal tumor, swollen lymph node, and Paget lesion all showed poorly differentiated adenocarcinoma with neuroendocrine features expressing synaptophysin and chromogranin A. Serum CEA and NSE levels were high, 809.4 ng/ml and 85.8 ng/ml, respectively. After chemotherapy with modified FOLFOX6 for 2 months, the Paget lesion disappeared, and the primary anal canal tumor and liver metastases shrunk remarkably. Serum CEA and NSE levels decreased promptly to within normal ranges. CONCLUSIONS: 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.

Surgical Treatment for Extramammary Paget's Disease.

OPINION STATEMENT: Extramammary Paget's disease (EMPD) is a rare, slow growing non-melanoma skin cancer.Diagnosis is often significantly delayed, since clinical presentation may resemble common benign dermatoses. Treatment is characterized by high recurrence rates. This is in part due to ill-defined margins and by frequent development of satellites. Improvement of outcome needs a better preoperative planning with fluorescence diagnostics or scouting biopsies. Mohs micrographic surgery has some advantages for patients, such as reduced relapse rates and prolonged relapse-free survival. Improved identification of Paget cells in cryosections by immunostainings or alternatively the use of delayed Mohs with formalin-fixed material reduces the rate of false-negative results. Surgery remains the cornerstone of treatment.

Spectrum of Changes in Anogenital Mammary-like Glands in Primary Extramammary (Anogenital) Paget Disease and Their Possible Role in the Pathogenesis of the Disease.

To determine whether a subset of primary extramammary Paget disease (EMPD) may originate in anogenital mammary-like glands (AGMLG), the authors studied 181 specimens of EMPD, detailing alterations in AGMLG. The latter were identified in 33 specimens from 31 patients. All patients were women, ranging in age from 38 to 93 years (median, 65 y). In all cases, lesions involved the vulva and in 1 patient the perianal skin was affected. Histopathologically, AGMLG manifested changes identical to columnar cell change (CCC) (87.1%), usual ductal hyperplasia (22.6%), columnar cell hyperplasia (CCH) (9.7%), oxyphilic (apocrine) metaplasia (6.5%), and atypical duct hyperplasia (3.2%). Four cases (12.9%), in addition to intraepidermal carcinoma, harbored invasive carcinoma. In all 4 of these, AGMLG displayed a range of alterations including ductal carcinoma in situ, CCC, and CCH. Three further cases (9.7%) showed ductal carcinoma in situ without any definite invasive carcinoma. Colonization of AGMLG by neoplastic Paget cells was noted in 6 cases. As CCC and CCH may be encountered in normal AGMLG, these alterations are unlikely to play a significant role in the pathogenesis of the disease. However, by analogy with mammary Paget disease, rare cases of primary EMPD may originate in AGMLG with a subsequent upward migration of the neoplastic cells into the epidermis and possible later breach through the basal membrane. Usual ductal hyperplasia and atypical duct hyperplasia can then be regarded as earlier precursor lesions, linking both ends of the spectrum.

[A Case Report of Adenocarcinoma with Pagetoid Growth(Secondary Paget's Disease)of the Anal Canal].

Differentiating primary Paget's disease from secondary Paget's disease, which is also known as Pagetoid growth of other cancers, in the perianal region is difficult. Given that the treatment strategies of both disease are significantly different, diagnosis of such conditions should be performed with caution. We report a case of secondary Paget's disease. A 76-year-old man previously visited a hospital because of erythematous plaque around the anus. It was diagnosed as extramammary Paget's disease based on skin biopsy results; consequently, perianal skin resection was performed. Pathological examination of the resected specimen indicated Pagetoid growth of mucinous carcinoma, and it was positive for stump. Consequently, laparoscopic abdominoperineal resection was performed. Finally, the plaque was diagnosed as anal canal adenocarcinoma with Pagetoid growth, and all the previous results were deemed as initial diagnosis. CONCLUSION: Discriminating between primary and secondary Paget's disease, even with immunohistological techniques, is difficult. Novel methodology that might facilitatemoreaccuratediagnosis preoperatively for erythematous plaquearound theanus and morecurativethe rapeutic strategy are needed.

Skin cancer incidence among atomic bomb survivors from 1958 to 1996.

The radiation risk of skin cancer by histological types has been evaluated in the atomic bomb survivors. We examined 80,158 of the 120,321 cohort members who had their radiation dose estimated by the latest dosimetry system (DS02). Potential skin tumors diagnosed from 1958 to 1996 were reviewed by a panel of pathologists, and radiation risk of the first primary skin cancer was analyzed by histological types using a Poisson regression model. A significant excess relative risk (ERR) of basal cell carcinoma (BCC) (n = 123) was estimated at 1 Gy (0.74, 95% confidence interval (CI): 0.26, 1.6) for those age 30 at exposure and age 70 at observation based on a linear-threshold model with a threshold dose of 0.63 Gy (95% CI: 0.32, 0.89) and a slope of 2.0 (95% CI: 0.69, 4.3). The estimated risks were 15, 5.7, 1.3 and 0.9 for age at exposure of 0-9, 10-19, 20-39, over 40 years, respectively, and the risk increased 11% with each one-year decrease in age at exposure. The ERR for squamous cell carcinoma (SCC) in situ (n = 64) using a linear model was estimated as 0.71 (95% CI: 0.063, 1.9). However, there were no significant dose responses for malignant melanoma (n = 10), SCC (n = 114), Paget disease (n = 10) or other skin cancers (n = 15). The significant linear radiation risk for BCC with a threshold at 0.63 Gy suggested that the basal cells of the epidermis had a threshold sensitivity to ionizing radiation, especially for young persons at the time of exposure.

Extramammary Paget disease in peristomal skin: report of a unique case.

PURPOSE: Extramammary Paget disease is a rare neoplasm most often found in the perianal area which can be primary in origin or secondary from underlying colorectal adenocarcinoma with epidermotropic spreading. However, the occurrence of extramammary Paget disease has not been described in peristomal skin. METHODS: We describe a single case of Paget disease in the peristomal skin of a 61-year-old woman with ulcerative colitis who underwent a proctocolectomy 33 years prior to now with chronic intestinal obstruction and an area of "ectopic mucosa" adjacent to her ileostomy. The patient was taken to surgery for exploratory laparotomy and revision of her stoma. RESULTS: Macroscopic and microscopic examinations of the peristomal lesion demonstrated Paget disease with intraepidermal spreading of dysplastic intestinal/glandular cells but no invasive adenocarcinoma in the peristomal skin after extensive sampling. CONCLUSIONS: To our knowledge, this is the first reported case of extramammary Paget disease occurring in peristomal skin. The current case emphasizes the importance of recognizing such disease and the potential for associated neoplasia in patients with intestinal stomas.

Extramammary Paget's disease of the scrotum associated with hepatocellular carcinoma.

Extramammary Paget's disease (EMPD) is a rare cutaneous carcinoma of epidermal origin. The diagnosis is frequently delayed, and the disease tends to be associated with an underlying adnexal or internal malignancy. There have been several reports of EMPD associated with carcinoma of the bladder, prostate, kidney, and colon. The association of hepatocellular carcinoma (HCC) with EMPD appears to be exceedingly rare; to our knowledge, it has been reported only once in the English literature. Herein, we report an unusual case of EMPD of the scrotum associated with HCC. EMPD was diagnosed 1 year after the appearance of an erythematous plaque, and HCC was noted 19 months after the diagnosis of EMPD. From our experience and literature review, in patients with nonspecific skin lesions that are unresponsive to conventional treatment, EMPD should be considered and skin biopsy performed. Long-term follow-up is needed to watch for the appearance of adnexal carcinoma or internal malignancy.

Immunohistochemical analysis of the mammalian target of rapamycin signalling pathway in extramammary Paget's disease.

BACKGROUND: We have previously observed that persistent activation of the serine/threonine kinase, protein kinase B (AKT) is a frequent event in extramammary Paget's disease (EMPD). AKT promotes cell proliferation by its ability to coordinate mitogenic signalling with energy- and nutrient-sensing pathways that control protein synthesis through the atypical serine/threonine kinase, mammalian target of rapamycin (mTOR). CDK2, a member of the serine/threonine kinase family of cyclin-dependent kinases, is a key regulator of G(1)-S cell cycle progression, and has recently been shown to be one of the targets of AKT. The AKT-mTOR-p70 ribosomal protein S6 kinase (p70S6K) pathway has been described in some human malignancies, but not in EMPD. OBJECTIVE: To investigate the immunohistochemical staining of the AKT-mTOR-p70S6K pathway in EMPD and to evaluate the relationships among the components. METHODS: Samples of primary EMPD tissue were subjected to immunohistological staining with phosphorylated (p)-AKT, p-mTOR, p-4E-binding protein 1 (p-4EBP1), p-p70S6K/S6K1, p-ribosomal protein S6 (p-S6) and CDK2. Ten normal skin samples served as a control. RESULTS: Of the 32 EMPD tissue samples, 29, 27, 26, 29, 26 and 32 samples were positive for p-AKT, p-mTOR, p-4EBP1, p-p70S6K/S6K1, p-S6 and CDK2 staining, respectively. All these cell signalling molecules showed higher positivity in invasive EMPD than in EMPD in situ. There were significant correlations between p-AKT, p-mTOR, p-4EBP1, p-p70S6K/S6K1 and p-S6 and CDK2. CONCLUSIONS: The activation of the AKT-mTOR-p70S6K pathway may play an important role in the pathogenesis of EMPD. The high expression of the components of the pathway was highly correlated with CDK2 expression, suggesting that the AKT/mTOR pathway may induce the malignant transition through CDK2 in EMPD. The AKT-mTOR-p70S6K pathway might be a potential therapeutic target in EMPD.