Concurrent chemoradiotherapy for metastatic vulvar extramammary Paget’s disease involving supraclavicular nodes: a case report

Abstract

Extramammary Paget’s disease (EMPD) is a rare adenocarcinoma with a poor prognosis when invasive. Here, we report an exceptionally rare case of invasive vulvar EMPD in a 70-year-old woman who presented with extensive lymphadenopathy involving the inguinal, pelvic, para-aortic, and left supraclavicular regions. Histopathology confirmed dermal and lymphovascular invasion. Given the systemic nodal spread, the patient underwent definitive concurrent chemoradiotherapy (CCRT) with weekly cisplatin. Radiotherapy was delivered to the inguinal-to-paraaortic nodes at 57.6 Gy in 32 fractions and to the supraclavicular nodes at 51.0 Gy in 17 fractions. Follow-up imaging 6 months after treatment demonstrated a complete response per Response Evaluation Criteria in Solid Tumors criteria. This case is notable because supraclavicular involvement in EMPD is extremely rare and usually reflects advanced systemic dissemination. Our findings suggest that intensive CCRT may achieve excellent locoregional and systemic disease control, supporting its potential role as an effective primary treatment option for patients with advanced metastatic EMPD.

Introduction

Extramammary Paget’s disease (EMPD) is a rare cutaneous malignancy that accounts for approximately 6.5% of all Paget’s disease cases and 1%–2% of vulvar neoplasms [1]. EMPD has been increasingly recognized in the literature since it was first described by Crocker in 1889 [2]. The disease typically arises in the apocrine gland-bearing skin and most commonly involves the vulva, scrotum, and penis [3].

Clinically, EMPD resembles mammary Paget’s disease and typically presents as chronic erythematous or eczema-like skin lesions associated with pruritus, tenderness, burning sensation, and occasionally pain [1]. These lesions are often multifocal and appear as well-demarcated erythematous scaly plaques with edges that may weep or crust [4]. Pigmentary changes, including hyperpigmentation and hypopigmentation, can also occur [4]. Because of these nonspecific clinical manifestations, EMPD is frequently misdiagnosed as dermatitis or eczema, which often leads to a delayed diagnosis until the disease becomes locally advanced [1].

EMPD is classified into two types: primary and secondary. Primary EMPD arises as an intraepithelial neoplasm originating from the epidermal or adnexal cells, whereas secondary EMPD results from the epidermotropic spread of malignant cells from an underlying primary tumor [5]. Secondary EMPD is associated with the prostate, bladder, urethra, rectum, cervix, stomach, and kidneys [5]. In contrast to secondary EMPD, primary EMPD is generally associated with a more favorable prognosis [5]. Because the prognosis and treatment strategies differ between these entities, an accurate diagnosis based on thorough histopathological evaluation and immunohistochemical (IHC) analysis is essential [3].

Pathologically, most cases of EMPD are diagnosed as carcinomas in situ and usually have an indolent clinical course [3]. However, once Paget cells invade the underlying dermis, the risk of regional lymph node metastasis and distant metastases increases substantially [3].

The diagnostic evaluation of EMPD typically includes a detailed physical examination and imaging studies, such as pelvic ultrasonography, magnetic resonance imaging (MRI), and/or computed tomography (CT), along with histopathological confirmation through biopsy [1]. Additional investigations, including breast examination, colonoscopy, cystoscopy, and assessment of serum tumor markers, may be useful in excluding underlying malignancies and distinguishing secondary EMPD from primary disease [1].

Owing to its low incidence, the optimal management strategy for EMPD remains controversial [6]. Surgical excision remains the mainstay of treatment and should be individualized according to tumor location, extent, and the patient’s clinical condition [1]. The primary goal of treatment is complete tumor removal with negative margins to minimize the risk of local recurrence [1]. Nonsurgical modalities, such as radiotherapy, chemotherapy, or topical therapies, may also be considered, particularly in patients with unresectable or recurrent disease [1].

Despite the established role of surgery, the management of advanced vulvar EMPD with systemic nodal involvement remains challenging. Supraclavicular lymph node metastasis is exceptionally rare in vulvar EMPD and is typically associated with a poor prognosis; however, its clinical implications and optimal management remain unclear. Herein, we report an exceptionally rare case of invasive vulvar EMPD in a 70-year-old postmenopausal woman with extensive lymph node metastases, including supraclavicular involvement, who achieved a complete response following surgical excision and adjuvant concurrent chemoradiotherapy (CCRT). This case highlights that a complete clinical response may be achievable even in the setting of such rare and extensive systemic dissemination. We also discuss the diagnostic challenges and therapeutic considerations associated with this rare disease.

Case Report

A 70-year-old postmenopausal woman was referred to the Department of Obstetrics and Gynecology at Dong-A University Hospital after malignancy was identified on a vulvar excisional biopsy performed at a local hospital. The patient had initially presented with vulvar pruritus and was treated with topical medications, but her symptoms persisted. The patient later noticed a palpable mass in the right vulva, prompting an excisional biopsy at the local hospital, which confirmed the malignancy. The patient was subsequently referred to our institution for further evaluation and management. The patient had no significant medical, surgical, or family history, and no known genetic predispositions.

Upon presentation, a solid mass measuring approximately 2 cm in diameter was observed in the right vulva. For initial staging, CT, MRI, and positron emission tomography (PET) were performed. CT and MRI revealed multiple enlarged lymph nodes suspicious of metastasis in the retroperitoneal space along the common iliac arteries, right internal and external iliac arteries, and both inguinal regions (Fig. 1A–1D). In addition, a single enlarged lymph node in the left supraclavicular region was identified and considered suspicious for distant metastasis (Fig. 1E). PET revealed hypermetabolic lymph nodes in the aforementioned regions, including the left supraclavicular lymph node, consistent with metastatic disease (Fig. 1F). However, owing to its anatomical depth and the risk of potential complications, a histopathological biopsy of the left supraclavicular lymph node was not performed. Instead, the diagnosis of metastasis was clinically established based on the high metabolic activity on PET and the systematic exclusion of other primary malignancies. Additionally, although a hypermetabolic nodule was incidentally identified in the right thyroid lobe on PET, fine-needle aspiration was performed to exclude synchronous thyroid malignancy or metastasis, which confirmed a benign follicular nodule. Laboratory findings were within normal limits and no other synchronous malignancies were identified. Consequently, the extensive nodal involvement was clearly established through multimodal imaging (CT, MRI, and PET-CT) without major diagnostic challenges.

Fig. 1.

Pre-treatment imaging findings. (A–F) Initial imaging workup. (A, B) Pelvic magnetic resonance imaging (MRI); T2-weighted coronal (A) and sagittal (B) views, showing multiple enlarged lymph nodes (LNs) suspicious for metastasis in the retroperitoneal space, bilateral common iliac, right internal/external iliac, and bilateral inguinal regions. (C, D) Abdominopelvic computed tomography (CT) scans displaying multiple metastatic lymphadenopathies, consistent with the MRI findings. (E) Chest CT scan showing a single enlarged metastatic LN in the left supraclavicular region (yellow arrow). (F) Positron emission tomography scan demonstrating hypermetabolic activity in the right vulvar region and extensive metastatic LNs across the supraclavicular, abdominal, pelvic, and inguinal regions.

After pathological slides from the previous biopsy were reviewed at our institution, the residual vulvar lesions were excised. Histopathological examination confirmed invasive EMPD with dermal and lymphovascular invasion. IHC analysis revealed that the tumor cells were positive for PMS2, MLH1, MSH2, MSH6, cytokeratin 7 (CK7), androgen receptor (AR), gross cystic disease fluid protein-15 (GCDFP-15), and p16, and negative for cytokeratin 20 (CK20), p63, p40, and human melanoma black-45 (HMB-45).

Given extensive lymph node metastases extending from the inguinal to the supraclavicular regions, adjuvant CCRT was planned. Radiotherapy was administered to the inguinal-to-paraaortic lymph nodes with a total dose of 57.6 Gy in 32 fractions and to the left supraclavicular lymph node with a total dose of 51.0 Gy in 17 fractions. Concurrent chemotherapy consisting of weekly cisplatin (40 mg/m²) was administered for six cycles. Treatment was completed as planned without dose reduction or modification, as no significant treatment-related complications occurred.

Follow-up CT and PET scans performed 6 months after CCRT completion demonstrated a complete response per Response Evaluation Criteria in Solid Tumors (RECIST) criteria, with resolution of the previously identified metastatic lymph nodes (Fig. 2A–2D). At the 6-month follow-up, the patient remained alive with no evidence of disease recurrence.

Fig. 2.

Post-treatment imaging findings. (A–D) Follow-up imaging 6 months after concurrent chemoradiotherapy. (A) Follow-up chest computed tomography (CT) scan showing complete resolution of the previously noted left supraclavicular lymph node (LN). (B, C) Follow-up abdominopelvic CT scans demonstrating near-complete resolution of the metastatic LNs in the retroperitoneal, iliac, and inguinal regions. (D) Follow-up positron emission tomography scan showing marked interval improvement, with no significant hypermetabolic lesions remaining in the vulva or previously involved LN stations.

Discussion

EMPD is generally characterized by a slow-growing and indolent clinical course when confined to the epidermis [6,7]. Although it is a rare malignancy with an estimated incidence of 0.12 per 100,000 individuals, its potential for aggressive behavior should not be underestimated [8]. Once tumor cells invade the underlying dermis, the disease acquires substantial metastatic potential, and the prognosis declines sharply. Reports indicate that more than one-third of patients with lymph node metastases eventually develop distant metastases, resulting in a 5-year survival rate of less than 10% [7,9].

The clinical diagnosis of EMPD is often challenging because of its subtle, nonspecific manifestations—such as erythematous or brownish plaques—frequently misdiagnosed as benign conditions such as dermatitis, eczema, or fungal infections [5,10]. This results in substantial diagnostic delay, with patients presenting an average of two years after symptom onset [10]. Here, the initial symptoms were also treated with topical medications at a local clinic, which may have contributed to the disease progressing to an invasive state with extensive lymphatic spread.

The metastatic pattern in this case was particularly remarkable. Although invasive EMPD typically spreads to regional inguinal and pelvic lymph nodes, supraclavicular lymph node involvement is exceptionally rare. This manifestation represents systemic lymphatic spread extending beyond the conventional sentinel drainage of the vulva, emphasizing the necessity for thorough systemic evaluation in patients with invasive disease.

Histopathological examination is essential for diagnosing EMPD and distinguishing it from other conditions, such as inflammatory dermatoses, Bowen disease, and pagetoid malignant melanoma [11,12]. Paget’s cells typically demonstrate abundant pale cytoplasm and large nuclei with prominent nucleoli, and are usually positive for diastase-periodic acid–Schiff staining [3,11]. Comprehensive screening for associated malignancies is also critical, as EMPD is associated with adnexal carcinoma in 24–33% and visceral malignancies in 12%–15% of cases [10]. IHC studies remain the gold standard for distinguishing primary from secondary EMPD [3]. Primary EMPD usually exhibits a CK7+/CK20– pattern, whereas secondary EMPD of colorectal or urothelial origins often shows different profiles [3,5]. Here, the tumor cells demonstrated positivity for CK7, AR, and GCDFP-15, but were negative for CK20 and HMB-45, confirming primary invasive vulvar EMPD and excluding secondary spread and melanoma [3,10].

Regarding the diagnostic evaluation, the absence of a confirmative biopsy for the left supraclavicular lymph node could be a limitation. However, owing to its anatomical depth and the risk of potential complications, a histopathological biopsy was not performed. Instead, the diagnosis of metastasis was established clinically, based on the high metabolic activity on PET and the systematic exclusion of other primary malignancies. Although a hypermetabolic nodule was incidentally identified in the right thyroid lobe, fine-needle aspiration confirmed it as a benign follicular nodule, further supporting metastatic EMPD diagnosis.

As prognosis differs substantially between localized and metastatic disease, treatment strategies should be individualized according to disease stage [13]. However, TNM staging is widely used for many malignancies; no universally accepted staging system specific to EMPD exists [13]. In 2016, Ohara et al. [14] proposed a staging system based on tumor thickness, lymphovascular invasion, and lymph node metastasis. The stage distribution was as follows: stage 0, in situ disease; stage I, tumor thickness <4 mm and no lymphovascular invasion; stage II, tumor thickness >4 mm or lymphovascular invasion; stage IIIA, single lymph node metastasis; stage IIIB, two or more lymph node metastases; and stage IV, distant metastasis [14]. According to this system, stage IV disease is defined as the presence of distant metastases. Here, extensive lymph node involvement, including inguinal, pelvic, para-aortic, and supraclavicular lymph nodes, was classified as stage IV disease according to the staging system proposed by Ohara et al. [14]

Wide local excision is the most widely accepted primary treatment for EMPD [5]. However, achieving clear surgical margins is often challenging because of the irregular and multifocal nature of the disease. Attempts to delineate tumor margins using frozen section analysis have proven challenging, with false-negative rates of up to 13% reported in the literature [5]. Mohs micrographic surgery has gained popularity because it facilitates intraoperative microscopic evaluation of the entire tumor margin and may reduce recurrence rates [3]. As EMPD may demonstrate ill-defined margins or extend beyond clinically apparent borders, mapping biopsies have frequently been employed to reduce the risk of positive surgical margins [3]. Lymph node dissection is generally recommended in patients with clinically positive lymph nodes [5]. For patients who are not candidates for surgery or have unresectable disease, alternative treatments, including topical therapies, photodynamic therapy, radiotherapy, and systemic chemotherapy, may be considered.

Radiotherapy may be used as a primary, adjuvant, or palliative treatment in selected patients with EMPD [5]. Radiation doses of approximately 50–60 Gy are generally recommended depending on the treatment intent [15,16]. A dose of ≥50 Gy using an appositional field may be considered for patients who are medically unfit for surgery, those with recurrent disease after surgery, or those who wish to avoid mutilating surgical procedures [15]. In cases of residual gross disease or unresectable tumors, dose escalation up to approximately 65 Gy using the shrinking-field technique may be applied [15]. Although microscopic diseases may be controlled with doses of approximately 50 Gy, higher doses of at least 60 Gy are generally required to eradicate gross tumors [16]. Prophylactic irradiation of the regional lymph nodes may also be considered in patients with dermal invasion or lymph node metastasis because these factors are associated with poor prognosis [16].

The prognosis of metastatic EMPD remains poor, with a 5-year survival rate of less than 10%, and no standard systemic therapy has been established to date [5]. However, several chemotherapeutic regimens have been reported, such as 5-fluorouracil and cisplatin (FP therapy); 5-fluorouracil, epirubicin, carboplatin, vincristine, and mitomycin C; cisplatin, epirubicin, and paclitaxel; and regimens based on S-1 or docetaxel, including S-1 plus docetaxel, S-1 monotherapy, and docetaxel monotherapy [5]. Among these, docetaxel monotherapy and FP therapy are the most frequently used, with comparable reported efficacy [3]. Recent studies have also explored targeted therapies, such as trastuzumab for human epidermal growth factor receptor 2 overexpression reported in 15%–58% of cases, and androgen blockade therapy for AR expression found in 54%–90% of cases [5,8]. Immune checkpoint inhibitors have also been investigated; however, their efficacy in EMPD remains unclear [3]. Considering the presence of extensive nodal metastases involving multiple lymphatic stations in the present case, CCRT was selected to achieve locoregional disease control and potential systemic therapeutic effects.

Although intraepithelial EMPD is typically managed surgically and carries a favorable prognosis, invasive cases often exhibit more aggressive behavior. Consequently, these cases may be managed similarly to vulvar squamous cell carcinoma, with chemotherapy or CCRT frequently being considered [17]. In this report, the patient underwent adjuvant CCRT and achieved a complete response per RECIST. This favorable response suggests that CCRT may represent a highly effective and viable treatment modality for patients with advanced metastatic EMPD for whom standard systemic treatment guidelines are not currently established.

This study has some limitations, including the relatively short follow-up period and inherent lack of generalizability of a single-center case report. Additionally, the absence of long-term survival data and lack of a standardized treatment protocol for metastatic EMPD make it difficult to draw definitive conclusions regarding sustained treatment efficacy. From the patient’s perspective, treatment was well tolerated without remarkable complications, and the patient expressed high satisfaction with the complete clinical response achieved through this non-invasive therapeutic approach following the initial excision.

EMPD is a rare cutaneous adenocarcinoma that often presents with nonspecific clinical features, leading to delayed diagnosis. Although most cases remain confined to the epidermis and have a favorable prognosis, invasive EMPD may behave aggressively, with regional and distant metastases. We report an exceptionally rare case of invasive vulvar EMPD with extensive lymph node metastases, including supraclavicular involvement that achieved a complete clinical response after definitive CCRT. This case illustrates an unusual metastatic pattern and underscores the importance of comprehensive staging and multidisciplinary management in advanced disease. Despite these limitations, our findings suggest that CCRT may be a promising therapeutic option for carefully selected patients with advanced metastatic disease.