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 10 years. 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.     

Risk stratification in extramammary Paget disease

Extramammary Paget disease (EMPD) is an uncommon intraepithelial adenocarcinoma that involves body sites with apocrine glands such as the genital, perineal and perianal regions. Risk stratification and treatment planning for EMPD can be challenging. This review presents important prognostic information in EMPD to assist physicians with risk stratification of patients with EMPD. The best‐understood prognostic factors are depth of invasion and involvement of extracutaneous sites. Tumours that invade into the reticular dermis or have a depth of > 1 mm are associated with poorer prognosis. Additionally, tumours spreading outside the skin into lymph nodes or other tissues are higher risk. There is an emerging understanding of the importance of tumour genetics in risk stratification, and we review the data on Ki‐67, cyclin D1, Mucin 5AC and E‐cadherin. There is less evidence supporting the importance of lesion site and patient age in risk stratification. This succinct review will be helpful in clinical practice and in EMPD research.     

乳房外Paget病的治疗进展

乳房外Paget病好发于老年人,多发生于肛门及外生殖器周围,由于早期皮损与湿疹、皮炎类似,容易误诊。乳房外Paget病的首选治疗方法为手术治疗,由于皮损边界不清、有多处病灶、肿瘤组织呈跳跃性生长,很难保证切除干净致术后复发率高。其他治疗方法有：放射治疗、化学治疗、光动力疗法、免疫调节剂治疗、分子靶向治疗等。乳房外Paget病预后主要与肿瘤的浸润深度、区域淋巴结转移、淋巴血管转移相关。前哨淋巴结活检对淋巴结清扫有指导意义,选择性淋巴结清扫有助于后续治疗,提高患者生存率。     

Extramammary Paget's disease: treatment, prognostic factors and outcome in 76 patients

BACKGROUND: Extramammary Paget's disease (EMPD) is a rare cutaneous carcinoma usually presenting as a genital erythematous lesion in the elderly. Although most EMPD tumours are in situ, invasive EMPD has a poor prognosis. OBJECTIVE: To evaluate the clinical and pathological features of EMPD and determine prognostic factors for survival. METHODS: The medical records of 76 patients with EMPD were retrospectively reviewed. RESULTS: Of the 66 patients who underwent curative surgical excision, five (8%) developed local recurrence, but surgical margin (2 cm) was not correlated with local recurrence. Thirteen of the 76 patients (17%) developed systemic metastases and 10 of these died of disease. On univariate analysis, the presence of nodules in the primary tumour, clinical lymph node swelling, elevated serum carcinoembryonic antigen (CEA) levels, tumour invasion level and lymph node metastasis were significant prognostic factors. On multivariate analysis, invasion level and elevated serum CEA were the only factors that were significantly associated with reduced survival. CONCLUSIONS: Invasion level and lymph node metastasis are important prognostic factors in EMPD. In patients with in situ tumour, local tumour control is the major aim of treatment; however, wide surgical margins are not associated with a lower risk of local recurrence.     

乳房外Paget病19例临床与随访分析

目的探讨乳房外Paget病的临床、病理特点及影响生存率的因素。方法回顾性分析2000-2010年间本院收治的19例乳房外Paget病患者的临床资料。结果 19例中女4例,男15例,平均年龄(70.26±8.90)岁。确诊时病程1月~6.5年,平均43月。临床表现主要为红斑、糜烂及湿疹、皮炎样皮损。手术治疗13例,其中2例复发;光动力治疗5例;未治疗1例。随访期间死亡7例,5年生存率61.20%。单因素变量分析显示淋巴结转移、肿瘤细胞侵袭至真皮、伴发其他肿瘤或远处转移、CEA水平升高与患者生存率有关。结论乳房外Paget病早期诊断困难,复发率高,淋巴结转移、伴发肿瘤或远处转移者预后差,需长期随访。迁延不愈的"湿疹"患者应尽早行皮肤活检,免疫组化检查可提高早期诊断率并指导早期治疗。     

Clinicopathological study of invasive extramammary Paget’s disease: subgroup comparison according to invasion depth

Background Extramammary Paget’s disease (EMPD) is a distinct form of malignant skin neoplasm. Invasive EMPD is relatively rare and its detailed histopathological features have not been investigated to date. Methods Surgical specimens were obtained from 51 patients with primary invasive EMPD. Clinical data including lymph node status were retrieved from the patients’ medical records. Cases were divided into subgroups according to invasion depth: dermal invasion ≤1 mm (minimal invasion) and dermal invasion >1 mm in depth. Histological patterns (nodular/glandular pattern or micronodular pattern), lymphatic/venous invasion, mitosis and lymph node status were compared between the two groups. Results The invasive EMPDs included 26 cases (51.0%) with dermal invasion ≤1 mm (minimal invasion) and 25 cases (49.0%) with dermal invasion >1 mm in depth. Lymph node metastasis was detected in 2/26 (7.7%) patients with minimally invasive EMPD. Nodular/glandular pattern (72.0%), lymphatic/venous invasion (52.0%), mitosis (88.0%) and nodal metastasis (88.0%) were all significantly more frequent in cases with dermal invasion >1 mm, compared to EMPDs with dermal invasion ≤1 mm (minimal invasion) (P < 0.001). Conclusion These results suggest that invasive EMPD can be divided according to invasion depth, with a cut‐off depth of 1 mm. This might represent the basis for a useful, EMPD‐specific staging system.     

Extramammary Paget's disease: a review of the literature

Extramammary Paget's disease (EMPD) is a rare cutaneous malignancy. The disease typically affects older individuals aged 60–80 years and is seen most frequently in postmenopausal Caucasian women and Asian men. EMPD exhibits a predilection for the genital and perianal regions and may be associated with an underlying carcinoma in adjacent organs. EMPD presents a challenge in both diagnosis and management. Often treated empirically as various dermatitides, the correct diagnosis is frequently delayed by many years. Following diagnosis, an extensive search for an associated malignancy should be initiated. If invasive disease is present on biopsy, a sentinel lymph node biopsy may guide further treatment. Mohs micrographic surgery appears to be superior to wide local excision when considering tissue sparing ability and disease recurrence. Nonsurgical interventions have also been investigated with varied results. Regardless of treatment method, long-term follow-up is recommended to monitor for local disease recurrence, development of internal malignancy, regional lymphadenopathy, or distant metastasis.     

Primary extramammary Paget's disease with extensive skeletal metastases

Extramammary Paget's disease (EMPD) is an uncommon malignancy that is most commonly seen in the vulval area in postmenopausal women. Pruritus is the predominant symptom. The clinical presentation can be so nonspecific that it can be misdiagnosed as an inflammatory or infective condition. We report an elderly male patient with EMPD over the pubic area, which remained asymptomatic for 5 years; he presented with severe low backache of 5 months' duration. Skin biopsy and immunohistochemistry showed the typical epidermal changes and deep dermal invasion. Positron emission tomography scan revealed involvement of regional lymph nodes as well as extensive skeletal metastases.     

骨桥蛋白和CD44v6在乳房外Paget病中的表达及其生物学意义

目的探讨骨桥蛋白(OPN)和CD44v6在乳房外Paget病中的表达特点及其生物学意义。方法应用免疫组化二步法分别检测34例乳房外Paget病患者皮损及20例正常对照皮肤中OPN和CD44v6的表达情况。结果 OPN和CD44v6在乳房外Paget病中阳性表达分别为70.59%和82.35%,显著高于正常皮肤组织的40%和0,差异有统计学意义(P0.05)。乳房外Paget病中OPN和CD44v6阳性表达与淋巴结转移有关(P0.05),OPN和CD44v6的表达呈正相关(P0.05)。结论 OPN和CD44v6高表达在乳房外Paget病的发生发展中起着重要的协同作用,两者的高表达与乳房外Paget病的淋巴结转移有关。     

反射式共聚焦显微镜在乳房外Paget病的应用进展

乳房外Paget病是一种起源于顶泌汗腺的皮肤恶性肿瘤,老年男性多见,好发于外阴等部位,皮损类似湿疹样表现。该病进展缓慢,临床表现无明显特异性,患者由于症状轻对疾病的重视程度不够,早期易误诊。多数患者愈后较好,病程越长、真皮浸润深度越深、局部淋巴结转移提示预后越差。乳房外Paget病治疗首选外科扩大切除,然而由于术前肉眼判断肿瘤边界不准确导致切缘肿瘤细胞阳性率较高。反射式共聚焦显微镜作为一种良好的实时、在体成像技术,可用于乳房外Paget病的诊断、术前定位,降低手术切缘肿瘤细胞阳性率,减少肿瘤复发,改善预后。     

乳房外Paget病的组织发生学研究

对14例乳房外Paget病(EMPD)进行了组化、免疫组化及病理、超微结构的研究,以探讨它的组织发生.结果表明,EMPD的Paget细胞可能源于表皮内多潜能的胚芽细胞,并具有向汗腺分化的能力.     

Enfermedad de Paget extramamaria

Background and objectiveExtramammary 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 methodsRetrospective 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.ResultsTwenty 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.ConclusionsThe 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.     

Usefulness of sentinel lymph node biopsy for the detection of metastasis in the early stage of extramammary Paget’s disease

Background

Invasive cases of extramammary Paget’s disease have a poor prognosis, owing to its rapid progression and resistance to irradiation and chemotherapy. Morton et al. introduced a technique to identify sentinel lymph nodes by local injection of vital dyes and reported its benefit for managing the progress of malignant melanoma.

Objectives

Since the rate of lymph node metastasis of extramammary Paget’s disease is not uncommon (reported from 8.5% to 26%), this study tested the hypothesis that sentinel lymph node biopsy would be useful to detect lymph node metastasis in the clinically early stage of extramammary Paget’s disease.

Materials & Methods

Eighteen patients with primary extramammary Paget’s disease were enrolled in the study. The precise location of sentinel lymph nodes was visualized using either intraoperative patent blue dye injection or indocyanine green dye injection in combination with a hand-held gamma-detecting probe after a ^99mTc phytate injection.

Results

Of the 18 patients, sentinel lymph node metastasis was identified in 2 (Cases 2 and 15) of the 2 patients with deep invasion and in 1 (Case 12) of the 7 patients with minimal dermal invasion, however, it was absent in 9 patients who had been categorized into the intraepidermal group.

Conclusion

This study demonstrates that extramammary Paget’s disease possibly causes metastasis via regional lymphatic systems to which the lesion belongs, even in the early stages of no nodule or tumor formation, and that sentinel lymph node biopsy is useful to detect lymph node metastasis.

     

Usefulness of sentinel lymph node biopsy for prognostic prediction in extramammary Paget’s disease

Background

Complete excision of the primary lesion has long been considered the standard treatment for extramammary Paget’s disease (EMPD). However, the presence of lymph node metastases has been reported as an important prognostic factor.

Objectives

We evaluated the association between lymph node metastasis and prognosis for EMPD using sentinel lymph node (SLN) biopsy.

Materials and methods

This retrospective study included 59 patients with histopathologicallyconfirmed primary EMPD. A total of 45 patients with microinvasion to the papillary dermis and deep invasion into the reticular dermis or subcutaneous tissue were included in the analysis. The survival curves of the SLN-negative group and the SLN-positive group were compared and we examined the risk factors for SLN positivity.

Results

A total of 139 SLNs were excised from one (28 patients) or both inguinal regions (31 patients). The average number of detected SLNs was 2.4. The incidence of SLN metastases was 16.9%. SLN positivity rates according to level of invasion were 0% for intraepithelial lesions, 4.1% for microinvasion, and 42.8% for dermal invasion. The five-year survival rates were 100% in the SLN-negative and 24% in the SLN-positive groups (p = 0.0001).

Conclusion

Reticular dermis or subcutaneous tissue invasion was a significant independent risk factor for SLN positivity according to multivariate analysis. The result of SLN biopsy affected prognosis. It is extremely important to accurately ascertain the presence, i.e. the number, or absence of regional lymph node metastases in patients with EMPD. We conclude that SLN biopsy may be appropriate for cases where invasion is suspected.

     

Double cancer of plantar malignant melanoma and vulvar extramammary Paget’s disease

A 75‐year‐old woman presented with a 2‐year history of a pigmented nodular lesion on her left sole and a 9‐year history of a red infiltrative plaque on the vulva. The plantar lesion was a 15‐mm ulcerated nodule located at the center of a 25‐mm atypical pigmentation region; the nodule was clinically suspected to be a malignant melanoma. Histopathological analysis of the vulvar lesion biopsy sample indicated extramammary Paget’s disease (EMPD). There was no evidence of metastasis in the computed tomography (CT) and ¹⁸F‐fluorodeoxyglucose positron emission tomography scans. We simultaneously performed a wide excision of both lesions and a left inguinal sentinel lymph node biopsy. Melanoma cells were identified in the sentinel lymph nodes, and left radical lymph node dissection was performed after a course of neoadjuvant chemotherapy. All the lymph nodes that were resected during the second operation tested negative for melanomas, and the plantar lesion was diagnosed as a stage IIIB malignant melanoma (pT4b, Na2, M0). Thereafter, we administrated four courses of chemotherapy, and 8 months after the operation, there was no evidence of recurrence or metastatic lesions. We present a case report of double cancer: a plantar malignant melanoma and vulvar EMPD, and also discuss the possible genetic mutations responsible for these two tumors.     

Human epidermal growth factor receptor 2 protein overexpression and gene amplification in extramammary Paget disease

Background Several recent studies have reported on the overexpression of human epidermal growth factor receptor (HER)2 in extramammary Paget disease (EMPD). However, there are only a few cases in which both overexpression and gene amplification of HER2 have been examined. Objectives To evaluate the overexpression and gene amplification of HER2 using a standardized method with a large number of cases of EMPD. Methods Immunohistochemically, the overexpression of the HER2 protein was examined in 104 cases of EMPD, including 31 intraepithelial cases and 73 invasive cases (35 superficially invasive and 38 deeply invasive). When the HER2 protein was overexpressed or potentially overexpressed, further analysis of amplification of the gene encoding HER2, ERBB2, was undertaken using fluorescence in situ hybridization. Results The HER2 protein was overexpressed in 16 cases (15%) in total, and in 13 of 73 cases (18%) of invasive EMPD. The ERBB2 gene was amplified in all cases with a HER2 score of 3+. A HER2 score of 3+ or 2+, and ERBB2 amplification were significantly more frequent in the cases of deeply invasive EMPD than in intraepithelial/superficially invasive EMPD (24% vs. 6%/3%, P = 0·012) and were correlated with a larger number of lymph‐node metastases (P = 0·047). Log‐rank tests for survival curves showed that lymph‐node metastasis and ERBB2 amplification were significant prognostic factors (P = 0·0001 and P = 0·043, respectively). However, by a multivariate analysis, only lymph‐node status was a significant indicator of Paget‐disease‐specific survival (P = 0·0001). Conclusions A subset of EMPD, both intraepithelial and invasive, showed HER2 overexpression and gene amplification. These HER2 alterations were correlated with biologically aggressive EMPDs, i.e. those with deep invasion and lymph‐node metastasis. Clinical trials of HER2‐targeted therapy are awaited for improvement of the prognosis of patients with aggressive EMPD.     

Hematopoietic progenitor kinase 1, mitogen-activated protein/extracellular signal-related protein kinase kinase kinase 1, and phosphomitogen-activated protein kinase kinase 4 are overexpressed in extramammary Paget disease

The c-Jun amino-terminal kinase (JNK) pathway seems to play important roles in the pathogenesis of several tumors, but its significance in extramammary Paget disease (EMPD) has not been investigated yet. The purpose of the study was to investigate the potential contribution of the JNK-associated molecules, such as hematopoietic progenitor kinase 1 (HPK1), mitogen-activated protein/extracellular signal-related protein kinase kinase kinase1 (MEKK1), transforming growth factor-β activated kinase 1 (TAK1), and phosphomitogen-activated protein kinase kinase 4 (p-MKK4) to the development of EMPD. Thirty-five paraffin-embedded EMPD specimens were subjected to immunohistochemical staining for HPK1, MEKK1, TAK1, and p-MKK4. All the 35 EMPD, including 13 dermal invasive EMPD and 2 lymph node metastasis, showed cytoplasmic overexpression of HPK1, MEKK1, and p-MKK4. The expression (%positive cells) of HPK1, MEKK1, and p-MKK4 in EMPD (92.3% ± 8.6%, 92.9% ± 8.6%, and 92.7% ± 7.4%, respectively) were significantly higher than in normal eccrine sweat gland cells (51.6% ± 10.4%, 44.7% ± 11.7%, 0% ± 0%). In addition, the expression of HPK1-, MEKK1-, and p-MKK4 in invasive EMPD was significantly higher than in noninvasive EMPD. Meanwhile, the expression of TAK1 was basically low and no significantly different between EMPD and normal controls. In conclusion, these results indicate that JNK pathway may play a role in the pathogenesis of EMPD.     

Squamous metaplasia of Paget's disease

A patient had triple extramammary Paget's disease of both axillary and genital regions. Right inguinal lymphadenopathy was found 1 year after excision of all the skin lesions. Excisional biopsy of the lymph node demonstrated a mixture of Paget cells and atypical squamoid cells with horn pearls suggestive of keratinization. The squamoid cells were positive for cytokeratin 10, a marker of suprabasal epidermis, and also positive for laminin gamma2 which is often expressed in invasive squamous cell carcinoma. The coexistence of these different cells within the same tumour island suggested that the squamoid cells derived from metaplasia of Paget cells.     

降低乳房外Paget病手术复发率的研究进展

【摘要】 乳房外Paget病是一种较为少见的皮肤恶性肿瘤,手术是治疗该病的重要方法,但由于本病的临床、病理特点和手术方式等因素影响,术后复发率仍较高。本文综述近年来有关降低EMPD手术复发率的研究进展。