Invasive Extramammary Paget's Disease Research Articles

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.

The role of sentinel lymph node biopsy in extramammary paget disease: a systematic review.

Sentinel lymph node biopsy is increasingly used to detect subclinical nodal metastases in extramammary Paget disease. We performed a comprehensive systematic review of the literature to further explore the role of sentinel lymph node biopsy in extramammary Paget disease. Five databases were searched for relevant terms. Articles were included if they were in English and presented primary data on at least one patient with extramammary Paget disease who underwent sentinel lymph node biopsy in the absence of lymphadenopathy or known metastatic disease. Twenty-eight articles were included, with 366 subjects. Seventy-seven sentinel node biopsies (21.2%) were positive, including 12 in which the primary tumor had microinvasion (15.6%) and 56 with deep invasion (72.7%). Of the positive cases, 11 (14.3%) had no further treatment, 54 (70.1%) underwent nodal dissection, 4 (5.2%) were treated with systemic agents, and 1 (1.3%) had radiation. After a mean follow up of 24months, 9 subjects with a positive lymph node biopsy experienced nodal recurrence (11.7%), 15 had distant metastases (19.5%), and 13 died of the disease (16.9%). In conclusion, invasive extramammary Paget disease is strongly associated with poor outcomes including nodal metastasis, distant metastasis, and disease specific death. Sentinel lymph node biopsy is a useful tool to screen for subclinical nodal metastases in invasive disease, and can be used to help guide clinical management.

Transcription factor activating enhancer-binding protein 2B expression correlates with invasiveness and prognosis of extramammary Paget's disease.

Extramammary Paget's disease (EMPD) is a slowly advancing malignancy that sometimes progresses to the invasion of the dermis, systemic metastases, and death. Although there have been reports that dermal invasion is associated with poor prognosis, no molecular markers of this invasion have been identified thus far. The aim of this study was to identify key molecules for predicting the risk of EMPD dermis invasion. We performed microarray screening for three cases of in-situ EMPDs, three cases of invasive EMPDs, and three cases of normal epidermis. We identified a molecule that exhibited a stepwise increase in expression. Further, we analyzed 47 cases of EMPD using immunohistochemical staining (IHC) and examined the correlated clinicopathological findings, including prognosis. We examined molecules that showed stepwise differences with invasion. We focused on transcription factor activating enhancer-binding protein 2 B (TFAP2B). Of the 47 EMPD patients, 38 (80.9%) and 9 (19.1%) had low and high TFAP2B expression, respectively. TFAP2B expression was significantly correlated with invasion into the dermis, mass formation, and preoperative lymph node metastasis (p=0.001, 0.042, and 0.033, respectively). The cumulative postoperative recurrence-free rate in the TFAP2B-high expression group was significantly lower than that in the TFAP2B-low expression group (P<0.001). In univariate analysis of recurrence-free survival, TFAP2B expression was found to be a significant factor (p=0.006). The expression of TFAP2B, which was comprehensively found by microarray screening, may correlate with the invasiveness of EMPD and may be an unfavorable prognostic factor.

Tips and Tricks for Early Diagnosis of Cervico-Vaginal Involvement from Extramammary Paget's Disease of the Vulva: A Referral Center Experience.

Cervico-vaginal (CV) localization of extra-mammary Paget's disease (EMPD) of the vulva is extremely rare. In order to investigate the incidence risk and the pathognomonic clinical and pathological features of this condition, a retrospective analysis was conducted including 94 women treated for vulvar EMPD at the European Institute of Oncology, Milan, Italy, from October 1997 to May 2020. Overall nine patients developed CV involvement from EMPD, with a cumulative incidence of 2.5% (95% CI: 0.5-8.0%) at 5 years, 6.5% (95% CI: 1.9-15.1%) at 10 years and 14.0% (95% CI: 4.8-27.8%) at 15 years, respectively. All cases except one were firstly detected by abnormal glandular cytology. None reported vaginal bleeding or other suspicious symptoms. The colposcopic findings were heterogeneous and could sometimes be misdiagnosed. Cervical and/or vaginal biopsies were always performed for histopathological diagnosis by identification of Paget cells in the epithelium or stroma. Most patients developed invasive EMPD (5/9) of the cervix and/or vagina and underwent hysterectomy with partial or total colpectomy. CV involvement from EMPD should not be underestimated in women with a long-standing history of vulvar Paget's disease. Liquid-based cytology with immunocytochemistry represents a valuable tool for early diagnosis and should be routinely performed during the required lifelong follow-up.

Sentinel lymph node biopsy in extramammary Paget disease: A 13-year institutional experience.

Whether sentinel lymph node biopsy status is a prognostic factor or effective in determining treatment strategies in extramammary Paget disease remains unclear. This study aimed to investigate the significance of sentinel lymph node biopsy in extramammary Paget disease. We retrospectively reviewed the clinical information of previously untreated patients with invasive extramammary Paget disease who underwent wide local excision of the primary tumor and sentinel lymph node biopsy at our hospital between April 2008 and March 2021. Clinical data including the baseline neutrophil-to-lymphocyte ratio and recurrence-free survival were analyzed. Sentinel lymph node metastases were classified as macrometastases and micrometastases, with a cut-off value for sentinel lymph node tumor burden of 2 mm. Univariate and multivariate analyses of factors affecting sentinel lymph node biopsy positivity and recurrence-free survival rates were performed. Overall, 85 patients were included in the analysis. Patients in the sentinel lymph node biopsy-positive group (n=26) had a significantly higher invasion level and neutrophil-to-lymphocyte ratio. According to multivariate analyses, invasion level and a high neutrophil-to-lymphocyte ratio were independent predictive factors for sentinel lymph node biopsy positivity, and the sentinel lymph node biopsy status was an independent prognostic factor for recurrence-free survival. In conclusion, sentinel lymph node biopsy provides an accurate risk classification and clinical indication for postoperative follow-up in patients with invasive extramammary Paget disease.

Cell origin and genome profile difference of penoscrotum invasive extramammary Paget disease compared with its in situ counterpart

Penoscrotum extramammary Paget disease (pEMPD) is a rare cutaneous carcinoma with an unknown cell origin. pEMPD always presents as a tumor in situ with an indolent process, whereas some progress into invasive forms with more aggressive behavior. The in situ and invasive cases display different morphologies and biological behavior, and thus far, a relationship between these two components has not been demonstrated. Immunohistochemistry was used to disclose the immunotype of pEMPD, and the results revealed that invasive/in situ pEMPD possessed with some identical immunophenotypes such as CK7, P63, and CK10, which inferred the clonal relatedness. The variable expressions of GCDFP-15 and carcino embryonic antigen hinted that tumor cell origin might be an epidermal sweat gland in epiderma. In our cohort, invasive pEMPD presented increased expression of androgen receptor and decreased MUC5CA expression, and these two changes might bring to the shift of invasive phenotype. To better understanding the relationship between these distinct tumor forms, we performed whole exome sequencing testing to evaluate overlapping genomic alterations of six paired invasive/in situ pEMPDs. The results showed that missense mutation was the predominant mutation type, and C>T transition accounted for 65.1% in all SNP mutation. Among the top 20 differential genes obtained from the six paired invasive/in situ pEMPD analysis, MUC4 (one missense, one in frame del, and one multi-hit), AHNAK2 (two missense and one multi-hit), DOT1L (two missense and one multi-hit), and FRG1 (two missense and one-multi hit) mutations were most enriched in invasive pEMPDs, which postulated that these genes may play roles in the disease progression.

Postoperative radiation therapy improves prognoses in extramammary Paget's disease presenting with multiple lymph node metastases.

Invasive extramammary Paget's disease may cause lymph node and distant metastases. Complete lymph node dissection is generally performed for extramammary Paget's disease presenting with lymph node metastases. Patients with extramammary Paget's disease and multiple lymph node metastases typically have poor prognoses, and there is no effective postoperative treatment to prevent recurrence or further metastases in such patients to date. This study aimed to evaluate the efficacy of postoperative radiotherapy in patients with extramammary Paget's disease and multiple lymph node metastases. We enrolled 26 patients with extramammary Paget's disease with ≥3 lymph node metastases who were treated at the National Cancer Center Hospital in Japan between January 2000 and June 2021. The patients were divided into those who underwent complete lymph node dissection only or with postoperative radiotherapy. We evaluated recurrence-free survival, distant metastasis-free survival, and overall survival outcomes with Kaplan-Meier curves. Among the 26 enrolled patients, 16 underwent complete lymph node dissection only and 10 underwent complete lymph node dissection with postoperative radiotherapy. The median follow-up period was 16 months. The 5-year recurrence-free, distant metastasis-free, and overall survival values were 47.3%, 63.0%, and 90% in those with complete lymph node dissection and postoperative radiotherapy, while these outcomes were all 0% (p=0.001, 0.004, and 0.009, respectively) in those with only complete lymph node dissection. Thus, survival was significantly prolonged with postoperative radiotherapy. Additional postoperative radiotherapy may substantially improve the prognoses of patients with extramammary Paget's disease and ≥3 lymph node metastases, and undergoing curative surgery.

Value of pseudopod sign on high‐frequency ultrasound in predicting the pathological invasion of extramammary Paget's disease lesions

Vertical invasion of extramammary Paget's disease (EMPD) is associated with poor prognosis. The usual vertical invasion route is directly downward or along the skin appendages. High-frequency ultrasound (HFUS) can be used to measure the EMPD lesion thickness, and visualize the pseudopod extensions due to skin appendage involvement. It is a non-invasive method for evaluating the extent of vertical invasion in EMPD. To investigate the value of HFUS in predicting the extent of vertical invasion in EMPD. In this retrospective study, 85 patients with EMPD were divided into two groups based on the pathology: invasive EMPD (iEMPD) group (n = 13) and in situ EMPD group (n = 72). The clinical and HFUS features of both the groups were analysed. The different types of pseudopodia morphology on HFUS were as follows: no pseudopodia, irregular bottom, small sphere, short strip, long strip, vase shape and nodular convex. These were further stratified into low-risk and high-risk levels. The clinical features were comparable between the two groups (P > 0.05). There were significant differences between the two groups in the HFUS features (lesion thickness, lesion shape, bottom shape, layer involvement, pseudopodia morphology and colour Doppler blood flow signal; all P < 0.05). The distribution of the pseudopodia morphology types in the in situ EMPD and iEMPD groups was as follows: no pseudopodia, 30/72 and 0/13; irregular bottom, 5/72 and 0/13; small sphere, 5/72 and 0/13; short strip, 21/72 and 0/13; long strip, 8/72 and 3/13; vase shape, 3/72 and 3/13; and nodular convex, 0/72 and 7/13 (P < 0.05 for all). The sensitivity and specificity of high-risk pseudopodia in identifying iEMPD were 100% and 84.7%, respectively. High-frequency ultrasound provides morphological information regarding EMPD lesions. Risk stratification for pseudopodia can help to distinguish between iEMPD and in situ EMPD lesions.

Stage 3 perianal extra mammary Paget's disease: A case report of a non-operative approach.

Introduction and importanceExtra mammary Paget's disease (EMPD) is a rare disease characterised by intraepithelial involvement of the skin by non-squamous carcinoma cells in the vulva, perineum, and scrotum. Secondary EMPD is even rarer and accounts for roughly 25% of cases (Delport, 2012) [1]. Surgery (Mohs/wide local excision) is the standard treatment for primary non-invasive disease, but management of secondary invasive EMPD is less defined as there are no current treatment guidelines.Case presentationA 76-year-old lady had a 1-year history of a pruritic perianal rash that was refractory to multiple topical agents. A biopsy confirmed a diagnosis of EMPD in June 2020 and on staging imaging was found to have metastatic disease in her right inguinal lymph node. Upon discussion at a multi-disciplinary team (MDT) meeting, she proceeded chemo radiation therapy followed by systemic chemotherapy as she had such extensive perianal disease that would make surgery quite morbid. She had interval imaging 3 monthly to assess response to treatment. In June 2021, the patient had a complete clinical response and has ongoing 6 monthly surveillance.Clinical discussionEMPD is extremely rare and currently treatment options for secondary EMPD are still being navigated. Specifically, there are no current randomised control trials (RCTs) that compare outcomes in secondary EMPD between radiation therapy and surgery and in the context of stage III disease. This case report documents the treatment approach governed by MDT consensus and has a 1 year follow up. The case report has been reported in line with the SCARE 2020 criteria (Agha et al., 2020) [2].ConclusionThe patient has had a good outcome with treatment, however ongoing surveillance is required.

Invasive extramammary Paget's disease of the vulva: incidence, trends and outcomes

<h3>Objectives:</h3> To explore the incidence, trends and survival outcomes of invasive extramammary vulvar Paget's disease compared to squamous and basal cell vulvar cancers. <h3>Methods:</h3> Incidence data were extrapolated from the United States Cancer Statistics (USCS) from 2001 to 2017 by SEER*Stat. Trends analysis was performed by Joinpoint regression program and presented by average annual percent change (AAPC). Clinical data on demographics, disease and treatment were recorded from the National Cancer Database from the same period. Chi-squared test, Kaplan-Meier survival estimates, and Cox proportional hazards model adjusted for covariates were used. <h3>Results:</h3> From 2001-2017, there were 3,715 cases of malignant extramammary Paget's disease of the vulva. Whites comprised 3,172 cases (85.4%), followed by Asian/Pacific Islanders with 227 cases (6.1%), Hispanics with 198 cases (5.3%), and Blacks with 44 cases (1.2%). Most cases had localized disease (73.1%), 10.4% had regional spread and 1.2% had distant disease. The overall incidence was 0.12/100,000 women per year in 2017. The incidence increased with an average percent increase of 0.4% per year from 2001 to 2017 (p<0.01). Of 1,388 patients with invasive vulvar Paget's disease from the NCDB, the median age was 72 (range: 63-80) years. Local excision was performed in 77.4% of cases, and 10.7% underwent radical surgery. The overall five-year survival was 85.9%. Older age (HR=7.95, p<0.001), advanced disease (HR=6.0, P<0.001), positive LVSI (HR=2.81, p<0.001), and Charlson comorbidity index ≥ 1 (HR 2.17, p<0.001) had worse survival. Using the NCDB, we compared the 5 year survival rates of vulvar squamous cell carcinoma (SCC) (n=28,587) and basal cell carcinoma (BCC) (n=1,720) to invasive Paget's disease. The survival of SCC and BCC were 63.5% and 77.9% compared to 85.9% for invasive Paget's disease. More specifically, the survival of early stage I and II were SCC: 73.7% and 59.3%, BCC: 79.5% and 60.5% and Paget's: 83.6% and 81.3%. Survival of advanced stage III and IV were SCC: 45.3% and 24.8%, BCC: 71.4% and 50.0% and Paget's: 52.5% and 41.7%. <h3>Conclusions:</h3> Invasive extramammary Paget's disease of the vulva is uncommon though the incidence is increasing. Older age and advanced stage are associated with poorer survival. Patients with metastatic vulvar Paget's disease and squamous cell carcinoma have a poorer survival compared to metastatic vulvar basal cell carcinoma.

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

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

Aberrant Melan-A Expression in Extramammary Paget Disease

To the Editor: A 50-year-old White man was diagnosed with invasive extramammary Paget disease (EMPD) on the left inguinal fold. Excisional biopsy revealed an intraepithelial (in situ) and subjacent intradermal/subcutaneous neoplasm composed of single, nests and cords of cells containing pale staining/vacuolated/foamy cytoplasm and large vesicular nuclei (Figs. 1A–C). Focal glandular/pseudoglandular differentiation was noted. There was intracellular cytoplasmic/interstitial positivity for PAS and Alcian blue (Fig. 1D). By immunohistochemistry, tumor cells were strongly reactive for AE1/AE3, Cam 5.2, CK7, CEA, and GATA-3, with focal nuclear reactivity for estrogen receptor and strong (3+) membranous expression for Her-2/neu. Tumor cells were negative for p63, D2-40, CK20, villin, CDX2, TTF-1, prostate-specific antigen, and progesterone receptor, in addition to S-100, HMB-45, SOX10, and MITF. The tumor showed diffuse intracytoplasmic grainy positivity for melan-A (A103 clone) (Figs. 2A–F).FIGURE 1.: In situ and invasive components of EMPD (A–C). Tumor cells show cytoplasmic positivity for Alcian blue (A, B, original magnification ×40; (C) original magnification ×100; and (D) original magnification ×200).FIGURE 2.: By immunohistochemistry, tumor cells are positive for CK7 (A) and negative for p63 (B) and S-100 (C). There is diffuse intracytoplasmic grainy immunoreactivity for melan-A (A103 clone) (D–F) (A–D, original magnification ×40; (E) original magnification ×100; and (F) original magnification ×200).Melan-A (A103 clone) and MART-1 (melanoma antigen recognized by T cells) (M2-7C10 clone) antibodies recognize the same gene product, a melanosome-associated protein that is involved in melanosome biogenesis by ensuring the stability of GPR143.1 This protein plays a vital role in the expression, stability, trafficking, and processing of melanocyte protein PMEL, which is critical to the formation of stage II melanosomes.1 Both antibodies are widely used in dermatopathology and expressed by normal melanocytes, nevi, and melanoma.2 Melan-A and MART-1 staining are also well-known observations in clear cell sarcoma and other nonmelanocytic tumors that contain premelanosomes, including perivascular epithelioid cell tumor (PEComa), angiomyolipoma, lymphangioleiomyomatosis, and sugar tumor of the lung.1,2 Furthermore, melan-A but not MART-1 expression has been documented in steroid-synthesizing normal cells and their respective benign and malignant tumors of the adrenal cortex and gonads (which lack premelanosomes).1 These findings suggest a lower specificity for premelanosomes of the melan-A antibody as compared to MART-1. Melan-A positivity [in addition to expression of other melanogenic markers (ie, HMB45)] has been reported in melanotic Xp11-associated tumor of the gastrointestinal and genitourinary tracts.3 With reference to cutaneous pathology, reactivity for both melan-A and MART-1 antibodies has been reported in pigmented (melanotic) and nonpigmented variants of diffuse neurofibroma, in addition to melanotic schwannomas.4,5 Melan-A and MART-1 expression was identified in 2 cases of atypical fibroxanthoma and one case of undifferentiated pleomorphic sarcoma of the skin.1 Staining was reported as multifocal rather than diffuse and almost exclusively within large multinucleated tumor cells, although one case showed immunoreactivity within mononucleated epithelioid cells.1 Smith-Zagone et al6 also identified melan-A expression (in addition to HMB-45) limited to large, multinucleated cells with vacuolated cytoplasm in atypical fibroxanthoma. More recently, immunohistochemical expression of melanocytic markers (melan-A, HMB45, and S-100) has been reported in cases of mammary Paget disease and EMPD.7,8 Eftimie et al7 highlighted aberrant melan-A expression in the pagetoid (in situ) cells in EMPD. Our case of EMPD demonstrated diffuse reactivity for melan-A in both intraepithelial and invasive tumor cells. Cross-reactivity of melan-A antibody with an unrecognized epitope within tumor cells has been proposed as the underlying pathogenetic mechanism in nonmelanocytic skin neoplasms in previous reports.1,4–8 Of note, melan-A antibody cross-reactivity has also been identified in molluscum contagiosum bodies.9 This phenomenon likely accounts for the finding of melan-A reactivity in our case of EMPD. Another possibility is that immunoreactive melanosomes/melanin granules produced by stimulated melanocytes in the epidermis might be transported into the cytoplasm of adjacent in situ EMPD cells, although this is unlikely to explain the diffuse melan-A positivity noted throughout the invasive component of our tumor. “False-positive” melan-A expression in EMPD demonstrates the need for caution in microscopic interpretation and for using multiple immunohistochemical stains (including other markers of melanocytic differentiation) to corroborate clinical and histopathological features and ensure accurate diagnosis. This report adds to the growing literature of aberrant melan-A expression in cutaneous nonmelanocytic tumors.

Treatment of Extramammary Paget Disease and the Role of Reflectance Confocal Microscopy: A Prospective Study.

Extramammary Paget disease (EMPD) poses treatment challenges. Invasive and noninvasive treatment modalities exist with variable success reported. Reflectance confocal microscopy (RCM) is emerging as an adjuvant diagnostic tool. To evaluate the treatment of EMPD patients and the role of RCM. Prospective study. Demographic and tumor characteristics were recorded. Handheld-RCM was performed and correlated with histology. Treatment, clearance, pathology, and follow-up were all recorded. Thirty-six EMPD lesions in 33 patients were included. Mean age was 71.7 years, and 23 were men. Mean number of surgical stages needed to clear margins was 1.9 (SD, 0.9; 1.0-3.0 stages), and mean margin needed to clear was 1.8 cm. Reflectance confocal microscopy correlated well with scouting punch biopsies (kappa, 0.93; p < .001). Disruption of the dermoepidermal junction was associated with invasive EMPD versus in situ (83.3% vs 25.9%) on histology (p = .01). Relatively small sample size. Extramammary Paget disease is challenging, and lesion demarcation is of the utmost importance. Using a staged surgical excision approach, the mean margins needed were 1.8 cm, less than previously reported. Nonsurgical modalities, including radiation therapy, imiquimod, or photodynamic therapy can be considered if surgery is not pursued. Reflectance confocal microscopy is a valuable noninvasive imaging modality for the management of 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).

Intradermal Band-like Lipomatous Metaplasia Can Be Associated With the Regression of Overlying Skin Neoplasms: A Clinicopathologic Study of 20 Cases.

Lipomatous metaplasia has been rarely reported in both neoplastic and inflammatory dermatological disorders. Most neoplastic cases show the lipomatous change within the tumor silhouette, but band-like lipomatous metaplasia in the dermis under tumors has not been well-described. The aim of this study was to reveal the characteristics and relationship of intradermal band-like lipomatous metaplasia and coexisting skin tumors. A total of 20 cases with intradermal band-like lipomatous metaplasia were retrieved from 10,992 archive cases between April 1997 and March 2020 at Hyogo Cancer Center, and subjected to a detailed clinicopathologic analysis. Nine (45%) patients had superficial variant basal cell carcinoma as a coexisting neoplasm. Eight (40%) patients had squamous cell carcinoma, 5 of which were in situ. The remaining 3 (15%) cases were invasive extramammary Paget disease. All 20 cases showed at least one of 3 signs of tumor regression, namely, partial loss of overlying neoplasia, significant inflammatory infiltrate under the tumor, and fibrosis around the tumor. We concluded that intradermal band-like lipomatous metaplasia could be seen in association with the regressing process of cutaneous superficially-spreading neoplasms.

Invasive vulvar extramammary Paget's disease in the United States

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

P16 Expression in Primary Vulvar Extramammary Paget Disease.

P16 immunohistochemistry has been widely used in facilitating the diagnosis of human papillomavirus (HPV)-related usual type vulvar intraepithelial neoplasm. However, studies of p16 expression in primary vulvar extramammary Paget disease (EMPD) are limited. We assessed the p16 expression by immunohistochemistry in 40 cases of primary vulvar EMPD, including 34 cases of intraepithelial vulvar EMPD and 6 cases of invasive vulvar EMPD and correlated p16 expression patterns with disease progression. Overall, p16 expression was present in 36 cases (90%), including 20 cases (50%) with focal staining pattern and 16 cases (40%) with diffuse staining pattern. All 20 cases with focal p16 staining pattern were intraepithelial vulvar EMPD. Diffuse p16 staining pattern was present in 10/30 cases (33.3%) of intraepithelial EMPD and in 6/6 cases (100%) with invasive vulvar EMPD. Negative p16 staining was present in four intraepithelial EMPD cases. Using a highly sensitive RNA in situ hybridization method, we did not detect high-risk HPV in the selected 10 cases with diffuse p16 staining pattern, including 6 cases of intraepithelial EMPD and 4 cases of invasive EMPD. We also observed that intraepithelial EMPD had predominantly cytoplasmic p16 immunoreactivity, whereas nuclear p16 immunoreactivity was mainly seen in invasive EMPD components. Our study demonstrated that the p16 positive immunostaining was seen in the majority of primary vulvar EMPD which is not related to HPV infection. Therefore, knowing the overlapping p16 immunostaining patterns in vulvar EMPD and usual type vulvar intraepithelial neoplasm is important to render the correct diagnosis.

Radiotherapy for invasive extramammary Paget's disease: A case report

Radiotherapy for invasive extramammary Paget's disease: A case report

Heterogeneity of PD-L1 expression and CD8 tumor-infiltrating lymphocytes among subtypes of cutaneous adnexal carcinomas.

Adnexal carcinomas are rare and heterogeneous skin tumors, for which no standard treatments exist for locally advanced or metastatic tumors. To evaluate the expression of PD-L1 and CD8 in adnexal carcinomas, and to study the association between PD-L1 expression, intra-tumoral T cell CD8+ infiltrate, and metastatic evolution. Eighty-three adnexal carcinomas were included. Immunohistochemistry using anti-PD-L1 monoclonal antibodies (E1L3N and 22C3) and CD8 was performed. PD-L1 expression in tumor and immune cells, and CD8+ tumor-infiltrating lymphocyte (TIL) density were analyzed semi-quantitatively. Among the 60 sweat gland, 18 sebaceous and 5 trichoblastic carcinomas, 11% expressed PD-L1 in ≥ 1% tumor cells, more frequently sweat gland carcinomas (13%, 8/60) including apocrine carcinoma (40%, 2/5) and invasive extramammary Paget disease (57%, 4/7). Immune cells expressed significantly more PD-L1 than tumor cells (p < 0.01). Dense CD8+ TILs were present in 60% trichoblastic, 43% sweat gland, and 39% sebaceous carcinomas. CD8+ TILs were associated with PD-L1 expression by tumor cells (p < 0.01). Thirteen patients out of 47 developed metastases (27%) with a median follow-up of 30.5months (range 7-36). Expression of PD-L1 by tumor cells was associated with the development of metastasis in univariate analysis (HR 4.0, 95% CI 1.1-15, p = 0.0377) but not in multivariate analysis (HR 4.1, 95% CI 0.6-29, p = 0.15). PD-L1 expression is highly heterogeneous among adnexal carcinoma subtypes, higher in apocrine carcinoma and invasive extramammary Paget disease, and associated with CD8+ TILs. Our data suggest the interest of evaluating anti-PD1 immunotherapy in advanced or metastatic cutaneous adnexal carcinoma.