Trastuzumab monotherapy as maintenance treatment for metastatic HER2+ vulvar Paget disease: systematic review and case report

Highlights

• •Trastuzumab monotherapy was used as maintenance treatment for metastatic HER2+ vulvar Paget disease.
• •Sustained disease control and significant regression of metastatic lesions were observed.
• •A systematic review identified 7 cases of HER2+ extramammary Paget disease treated with trastuzumab.
• •Trastuzumab monotherapy may be a feasible option for patients unable to tolerate combination chemotherapy.
• •These findings support further investigation of trastuzumab monotherapy in HER2-positive EMPD.

Abstract

Vulvar Paget’s disease (VPD) is a rare intraepithelial malignancy frequently associated with HER2 overexpression. This study offers insights into managing HER2-positive extramammary Paget’s disease cases in which trastuzumab monotherapy was administered as manteinance therapy. We report the case of a 52-year-old woman with VDP and lymph node involvement, who was initially treated with paclitaxel and trastuzumab, for which chemotherapy was discontinued due to significant side effects, and trastuzumab as maintenance therapy was continued, resulting in significant regression of metastatic lesions. Additionally, a systematic review was conducted. The review included 6 studies from 2008 to 2020. Complete response was achieved in 2 out of 7 (28.6%) cases, partial response in 4 (42.9%) cases, and stable disease in 1 (14.3%) case. Mild moderate headache and flushing during trastuzumab manteinance therapy were reported in only one patient. In conclusion, trastuzumab monotherapy may be a valid alternative option, particularly in patients unable to tolerate combination chemotherapy. These findings emphasize the importance of personalized treatment approaches.

1. Introduction

Extramammary Paget’s disease (EMPD) is a rare cutaneous malignancy that primarily arises in apocrine gland-rich regions, including the anogenital area and axillae, which are distinct from mammary glands (Kimura et al., 2020). VPD is the most frequent manifestation of EMPD, accounting for less than 1 % of vulvar neoplasms (Kimura et al., 2020, Sekiguchi et al., 2020, Takahagi et al., 2009). It predominantly affects postmenopausal Caucasian women (Sekiguchi et al., 2020, Richter et al., 2010, Fukuda and Funakoshi, 2018, Watanabe et al., 2016) and most commonly presents with symptoms such as itching and eczematous patchy lesions (Fukuda and Funakoshi, 2018, Zattarin et al., 2022). VPD lesions are typically intraepithelial malignancies characterized by large, round Paget cells with abundant pale cytoplasm and occasional vacuoles (Ishizuki and Nakamura, 2021, Kibbi et al., 2022). These cells may originate from apocrine ducts or result from malignant transformation of pluripotent cells in the basal layer of the epidermis (Takahagi et al., 2009). The prognosis is generally favorable if the primary lesion is thoroughly excised and there is no metastatic involvement (Kimura et al., 2020, Sekiguchi et al., 2020). However, when the disease progresses to the metastatic stage, the prognosis markedly worsens (Takahagi et al., 2009). For intraepidermal EMPD, both surgical and non-surgical treatments can be employed depending on the patient and tumor characteristics, although cure rates tend to be higher with surgical approaches (Fukuda and Funakoshi, 2018). Radical surgical resection is the preferred treatment (Richter et al., 2010, Fukuda and Funakoshi, 2018). Patients with unresectable intraepidermal EMPD or those who are not clinically fit for surgery may undergo nonsurgical treatments, including radiotherapy, topical application of imiquimod, photodynamic therapy, or carbon dioxide laser therapy (Ishizuki and Nakamura, 2021). In cases of distant metastasis, management may involve chemotherapy or other individualized treatment approaches (Zattarin et al., 2022). When EMPD becomes invasive, it frequently metastasizes to regional lymph nodes, potentially progressing to distant sites (Watanabe et al., 2016, Zattarin et al., 2022, Ishizuki and Nakamura, 2021). Various chemotherapy regimens have been evaluated for metastatic EMPD, although their efficacy remains under continuous investigation (Richter et al., 2010). Advanced EMPD often involves the abdominal organs, and recurrence can occur years after initial radical surgery, typically indicating poor prognosis (Zattarin et al., 2022).

Despite the use of adjuvant therapies, data on the outcomes of chemotherapy in patients with advanced EMPD are limited (Sekiguchi et al., 2020). There is emerging evidence that trastuzumab combined with paclitaxel may induce partial or complete responses, particularly in metastatic cases of EMPD. (Zattarin et al., 2022). However, Paclitaxel is known to cause various adverse effects that affect patient quality of life and limit ongoing treatment (Takahagi et al., 2009). Despite these challenges, growing evidence supports the effectiveness of anti-HER2 monotherapy as maintenance therapy in HER2-positive cases (Zattarin et al., 2022, Kibbi et al., 2022).

We present the case of a 52-year-old woman with VPD and lymph node involvement, who was initially treated with intravenous paclitaxel and trastuzumab. Owing to significant side effects, particularly severe anemia and neutropenia, induced first by paclitaxel and subsequently by nab-paclitaxel, chemotherapy was discontinued, and the patient continued trastuzumab as maintenance therapy. This approach resulted in sustained disease control and significant regression of metastatic lesions. Additionally, a systematic review of the literature was conducted to evaluate the role of trastuzumab monotherapy as a maintenance treatment for HER2-positive metastatic EMPD.

2. Case presentation

A 52-year-old woman presented with a two-month history of erythematous vulvar lesions that were associated with itching and burning. Her medical history included bladder cancer previously treated with Transurethral resection(TURB) and there was no family history of cancer. One month after diagnosis, she underwent a simple bilateral vulvectomy at Sant'Anna University Hospital in Turin. Histology confirmed vulvar intraepithelial Paget’s disease with HER2 overexpression (IHC 3 + ) and positive surgical margins. HER2 status was assessed by immunoistochemistry, according to ASCO/CAP guidelines used for breast cancer, with strong circumferential membranous staining in more 10 % of tumor cells (score 3 + )., A topical treatment with imiquimod was initiated but dicontinued after 3 months, when the patient underwent laser excision of the right vaginal wall and skinning vulvectomy with bilateral V-Y flap reconstruction at the CRO Aviano. Histology confirmed peristent disease with microinvasion (0.37 mm) and HER2 positivity. No imaging was performed at that stage. The microinvasion was identified incidentally on histological examination, and there were no clinical or radiologic signs of lymph node involvement at that time. One year later, bladder cancer recurred and was treated with TURB. Eleven months after vulvar reconstruction, pelvic Magnetic Resonance Imaging (MRI) revealed a 17 mm left inguinal lymph node, confirmed as HER2 + positive Paget’s disease by fine-needle aspiration. This was considered a new progression of disease. The patient began off-label systemic treatment with paclitaxel (80 mg/m2 on days 1, 8, and 15) and trastuzumab (6 mg/kg every 21 days). After four cycles, due to fever and eyelid edema, necessitating the substitution of paclitaxel with nab-paclitaxel (175 mg/m2). After another four cycles, she developed grade 3 anemia (Hb 7.5 g/dL), requiring transfusion. Due to persistent hematologic toxicity, chemotherapy was stopped and trastuzumab monotherapy (6 mg/kg every 21 days) was continued. Follow-up imaging showed a clear reduction in the lyph node, and the disease has remained stable for over 12 months. Trastuzumab was well tolerated, and the patient is undergoing regular echocardiographic follow-up.

A timeline of the key events in patient treatment is shown in Fig. 1.

Fig. 1.

Timeline of the key events of the case report.

3. Materials and methods

A systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Page et al., 2021). The review focused on EMPD cases in which only trastuzumab was administered as manteinance therapy. A comprehensive bibliographic search was performed spanning from inception to 2024. Databases searched included Medline, Embase, Scopus, the Cochrane Database of Systematic Reviews, and ClinicalTrials.gov. Keywords used in the search were “vulva,” “vulvar,” “genital,” “genitalia,” “Paget,” “Trastuzumab,” “Herceptin,” “anti-HER2,” and “anti-erb-2.” The search was restricted to human studies published in English. Commentaries, letters to editors, editorials, reviews, and conference abstracts were excluded. Search results were imported into Rayyan Qatar Computing Research Institute (QCRI) for systematic screening (Ouzzani et al., 2016). Two authors (D.I. and A.P.) independently reviewed the titles and abstracts of each citation for relevance and selected articles for full-text review. Discrepancies were resolved by consensus or discussion with a third investigator (M.B.). A PRISMA flow diagram (Fig. 2) was created to summarize the selection process. Data were extracted using standardized forms, and additional relevant references found in selected articles were manually retrieved. A final abstraction form was compiled after resolving any remaining disagreements among reviewers.

Fig. 2.

PRISMA flow diagram.

4. Results

Fig. 2 summarizes the process of literature identification and selection of the studies. A systematic bibliographic search identified 54 records through database searching. After the removal of 13 duplicate records, 41 records were screened. During the screening process, 18 records were excluded. Subsequently, 23 full-text articles were assessed for eligibility, and 17 of these articles were excluded based on predefined criteria. Ultimately, 6 studies met the inclusion criteria and were included in the systematic review (Hanawa et al., 2011, Barth et al., 2015, Bartoletti et al., 2020, Bruce and Tran, 2020, Karam et al., 2008, Wakabayashi et al., 2012) (Table 1).

Table 1.

Author, year	Country	Age (years)	Comorbidities	Primary tumor site	Immunochemical staining	Previous therapies	Initial surgery	Relapse sites	Surgery / radiotherapy for relapse	Initial anti-HER2 therapy	Subsequent anti-HER2 therapy	Response to maintenance trastuzumab therapy	Adverse drug reactions	Duration of response with maintenance trastuzumab therapy
Bartoletti et al., 2020 (Bartoletti et al., 2020)	Italy	45	NA	Vulva and anal/perianal region (with adenocarcinoma)	HER2+	Laser therapy, radiotherapy, topical imiquimod, and photodynamic therapy	1. Wide vulvo-perianal resection with packaging of a left colostomy 2.Ileo-inguinal lymphadenectomy and enlargement of previous perianal resection	1. Invasive locoregional recurrence, polmon, one para-aortic lymph node and two iliac lymph nodes (after 8 months) 2. Re-appearance of the perirectal lesion and new pleural lesions (after 15 months)	NA	1. paclitaxel 80 mg/m2 i.v. weekly and trastuzumab 2 mg/kg i.v. weekly (loading dose 4 mg/kg) for 9 months. 2. Re-challenge with paclitaxel 80 mg/m2 i.v. weekly and trastuzumab 2 mg/m2 i.v. weekly for 7 months 3. Maintenance with trastuzumab 6 mg/kg i.v. 3-weekly for 7 months	3.Trastuzumab emtansine 3.6 mg/kg i.v. 3-weekly for 3 months	1. CR 2. PR: perirectal lesion no longer measurable and the sub-pleural lesion nearly disappeared	1. Paclitaxel and trastuzumab: grade 3 neutropenia	Not specified
	Italy	58	None	Posterior hemi-vulva to anus	HER2+	Steroids, hyaluronic acid, tocopherol, antifungal, for vulvar lichen (misdiagnosed), topical imiquimod (VPD)	1 Laser vaporization of anal/perianal mucosa and simple vulvectomy with skin grafts, with two large triangular flaps bilaterally (V-Y plastic) 2. Skinning vulvectomy of the anterior hemi-vulva with plastic reconstruction and perianal/anal excision	1. Two locoregional recurrences (after 12 and 20 months, respectively) 2. persistence of intraepitelial Paget’s disease with microfoci of stromal infiltration	NA	1. trastuzumab i.v. 3-weekly 2. paclitaxel and trastuzumab i.v.	Trastuzumab i.v. 3-weekly	PR: reduction of the lesions	NA	Not specified
Barth et al., 2015 (Barth et al., 2015)	USA	71	Hypertension, end-stage renal disease on hemodialysis	Scrotum and perianal skin	HER2+, CAM5.2+, CK7+, BRST2+, CK20-, MART1-, S100-	NA	Surgical resection and reconstruction with a local flap + adjuvant radiation	Cervical and left axillary lymph nodes, 7th left rib and T10 vertebra (after 2 years)	NA	After relapse: Trastuzumab 8 mg/kg i.v. 3-weekly	Trastuzumab 6 mg/kg i.v. 3-weekly	CR	Trastuzumab: mild fatigue	12 months
Bruce et al., 2020 (Bruce and Tran, 2020)	USA	37	SCAD, ongoing pregnancy	Vulva (with adenocarcinoma), left inguinal lymph node	HER2+, ER+, PR+	NA	Left radical vulvectomy and left inguinal lymphadenectomy (margins: positive for EMPD and negative for adenocarcinoma)	NA	NA	Before delivery: carboplatin + paclitaxel i.v. for two cycles After breastfeeding: weekly cisplatin and 33 fractions of 180 cGy of pelvic radiation, followed by trastuzumab 8 mg/kg i.v. 3-weekly	Trastuzumab 6 mg/kg i.v. 3-weekly (planned for 1 year)	CR	NA	Planned duration: 12 months
Hanawa et al., 2011 (Hanawa et al., 2011)	Japan	70	NA	Vulva, pararenal artery lymph node, left inguinal lymph node and subclavian axillary lymph node	HER2+, AKT+, ERK+	NA	NA	Left inguinal lymph node	Local radiotherapy of primary lesion and inguinal lymph nodes	Trastuzumab 4 mg/kg i.v. weekly	Trastuzumab 2 mg/kg i.v. weekly for 5 weeks	SD paclitaxel 80 mg/m2 and trastuzumab 2 mg/kg i.v. combination therapy was required for 4 cycles (6 weeks followed by a 2-weeks rest)	Paclitaxel and trastuzumab: grade 3 neutrophilic leukopenia	NA (SD)
Karam et al, 2008 (Karam et al., 2008)	USA	52	NA	Vulva and perianal region	HER2+	Topical imiquimod	8 surgical excisions	NA	NA	Trastuzumab 300 mg i.v. monthly for 12 cycles and 260 mg i.v. for 2 additional cycles		PR: reduction of the lesions	NA	14 months
Wakabayashi et al., 2012 (Wakabayashi et al., 2012)	Japan	68	NA	Right labia major, urethra, vaginal wall, and uterine cervix	HER2+, GCDFP15+	NA	Wide local excision and radical hysterectomy (margins: positive)	Right pelvic floor (after 3 years) Multiple pelvic, para-aortic, and mesenteric lymph nodes, lingular superior of the left lung and segment VIII in the liver (after 8 years)	1st relapse: resection of the tumor in the right pelvic floor	After surgery for 2nd relapse: trastuzumab 8 mg/kg i.v. 3-weekly	Trastuzumab 6 mg/kg i.v. 3-weekly	PR: residual disease of 3 mm in the left lung	Trastuzumab: moderate headache and flushing during the first infusion	12 months
Present case	Italy	52	Bladder cancer and relapse treated with TURB	Vulva	HER2+	NA	Simple bilateral vulvectomy (margins: positive) and topical imiquimod for 3 months	Left inguinal lymph nodes (after 23 months)	Laser excision of the right vaginal wall and skinning vulvectomy with bilateral V-Y flap reconstruction	After surgery for relapse: paclitaxel 80 mg/m2 i.v. weekly and trastuzumab 6 mg/kg (loading dose 4 mg/kg) i.v. 3-weekly, followed by nab-paclitaxel 175 mg/m2 i.v. weekly and trastuzumab 6 mg/kg i.v. 3-weekly	Trastuzumab 6 mg/kg i.v. 3-weekly	PR: reduction of left inguinal lymphadenopathy	− Paclitaxel and trastuzumab: fever, eyelid edema − nab-paclitaxel and trastuzumab: anemia (Hb 7.5 g/dl), grade 2 neutrophilic leukopenia	>12 months

Abbreviations: pAKT, phosphorylation of AKT; CK7, cytokeratin 7; CR, complete response; ER, estrogen receptor; ERK, extracellular signal-regulated kinase; GCDFP-15, gross cystic disease fluid protein 15; HER2, human epidermal growth factor receptor; i. v., intravenous injection; NA, not available; PD, progressive disease; PFS, progression-free survival; PgR, progesterone receptor; PR, partial response; SCAD, spontaneous coronary artery dissection; SD, stable disease; VPD, vulvar Paget’s disease; TURB, transurethral resection of bladder.

The systematic review included 6 studies from 2008 to 2020, comprising 7 cases of HER2-positive metastatic EMPD. The ages of the cases ranged from 37 years (Bruce and Tran, 2020) to 71 years (Barth et al., 2015), with a mean age of 57.2 years. Among the 7 cases analyzed, 2 cases (28.6 %) presented with the primary tumor located in both the vulva and anal/perianal region (Bartoletti et al., 2020), while 3 cases (42.9 %) had the tumor confined to the vulva. One case (14.3 %) involved the scrotum and perianal skin (Barth et al., 2015), and another case (14.3 %) exhibited tumor involvement in the right labia major, urethra, vaginal wall, and uterine cervix (Wakabayashi et al., 2012). In 1 case, the primary tumor in the vulva extended to the pararenal artery lymph nodes, left inguinal lymph nodes, and subclavian axillary lymph nodes (Hanawa et al., 2011).Recurrence was observed in 5 out of 7 cases (71.4 %) (Hanawa et al., 2011, Barth et al., 2015, Bartoletti et al., 2020, Wakabayashi et al., 2012), highlighting the aggressive nature of metastatic EMPD despite initial treatments. Complete response (CR) to trastuzumab monotherapy was achieved in 2 cases (28.6 %) (Barth et al., 2015, Bruce and Tran, 2020), while partial response (PR) was observed in 4 cases (57.1 %) (Bartoletti et al., 2020, Karam et al., 2008, Wakabayashi et al., 2012). Stable disease (SD) was reported in 1 case (14.3 %) (Hanawa et al., 2011) during combination therapy with trastuzumab and paclitaxel, and no cases of progressive disease (PD) were noted. Adverse effects varied depending on the treatment. Among cases treated with paclitaxel and trastuzumab, grade 3 neutropenia was the most common side effect, occurring in 2 cases (28.6 %) (Hanawa et al., 2011, Bartoletti et al., 2020). For trastuzumab monotherapy, adverse effects were generally milder, with 1 case (14.3 %) reporting moderate headache and flushing during the first infusion (Wakabayashi et al., 2012).

5. Discussion

5.1. Epidemiology

Our case describes a 52-year-old postmenopausal woman with vulvar EMPD and HER2 overexpression. This aligns with the typical demographic profile, as EMPD predominantly affects postmenopausal women, usually in their 60 s and 70 s (Hanawa et al., 2011, Barth et al., 2015, Bartoletti et al., 2020, Wakabayashi et al., 2012). However, younger patients have also been reported, including rare cases during pregnancy (Bruce and Tran, 2020, Karam et al., 2008). These findings suggest that while EMPD primarily occurs in older individuals, age alone should not guide therapeutic decisions, especially in HER2-positive cases that may benefit from targeted treatments.

5.2. Localization and clinical-pathological presentation

Paget’s disease is classified into two distinct forms, mammary (MPD) and extramammary (EMPD). MPD typically involves the nipple-areola complex and is strongly associated with underlying ductal carcinoma in situ or invasive breast cancer, presenting clinically with characteristic eczematous changes (Watanabe et al., 2016). In contrast, EMPD predominantly arises in apocrine gland-rich regions such as the vulva and perianal areas. Although often diagnosed in situ, the progression to dermal invasion significantly increases the risk of a more aggressive disease course. In our case, the patient presented with vulvar EMPD characterized by HER2 overexpression and localized microinvasion, offering a distinct perspective when compared to other reports in the literature. Wakabayashi et al. described HER2-positive EMPD involving the labia majora, which demonstrated more advanced disease features at diagnosis, underscoring the variable presentations of EMPD (Wakabayashi et al., 2012). Similarly, a case from Bartoletti et al.’s series and the case reported by Karam et al. involved a multifocal vulvar and perianal EMPD, demonstrating more complex disease patterns than the localized nature of our patient's condition (Bartoletti et al., 2020, Karam et al., 2008). The importance of early and accurate diagnosis is further emphasized by another case in Bartoletti et al.’s series, in which a patient was initially misdiagnosed with vulvar lichen sclerosus, leading to delayed treatment (Bartoletti et al., 2020). This highlights the pivotal role of prompt recognition, which is crucial for effective management of our patients. Moreover, Bruce et al. reported a unique instance of EMPD under challenging clinical conditions, whereas Barth et al. broadened the spectrum of EMPD by describing its occurrence in the scrotum, further illustrating the diversity of anatomical sites affected by this disease (Barth et al., 2015, Bruce and Tran, 2020). In summary, the comparison between our case and those documented in the literature underscores the heterogeneity of EMPD, not only in its anatomical distribution but also in its clinical and pathological presentations.

5.2.1. Metastasis and recurrence

Recurrence and metastasis are defining features of EMPD, especially when dermal invasion is present, as this substantially impacts prognosis and clinical evolution. Regional lymph node involvement frequently represents the first manifestation of metastatic disease, marking a crucial step in disease progression and functioning as a significant negative prognostic factor (Ouzzani et al., 2016). EMPD may further disseminate to distant sites via lymphatic pathways (Fukuda and Funakoshi, 2018). In the present case, the patient developed vulvar EMPD with confirmed metastasis to the left inguinal lymph nodes, consistent with the typical pattern of lymphatic spread. Among the cases reviewed, complete response was observed in 28.6 % of patients (Barth et al., 2015, Bruce and Tran, 2020), partial response in 57.1 % (Bartoletti et al., 2020, Karam et al., 2008, Wakabayashi et al., 2012), and stable disease in 14.3 % (Hanawa et al., 2011).

5.2.2. Secondary tumors

The recurrence of bladder cancer in this patient adds further complexity to the clinical course and raises the possibility of an underlying association between EMPD and secondary malignancies. While EMPD involving the perianal or penoscrotal areas has been more frequently linked to synchronous or metachronous tumors particularly colorectal or urothelial cancers (Fukuda and Funakoshi, 2018, Ishizuki and Nakamura, 2021). The relationship between vulvar EMPD and other neoplasms remains insufficiently defined. Although this co-occurrence may be incidental, the hypothesis of a shared pathogenic mechanism cannot be excluded. This possibility emphasizes the need for comprehensive diagnostic evaluation, especially in EMPD of the lower genital tract (Barth et al., 2015, Bartoletti et al., 2020).

5.2.3. Clinical heterogeneity

Literature data illustrate the marked heterogeneity in EMPD clinical behavior. Wakabayashi et al. reported a highly advanced case with aggressive metastatic evolution (Wakabayashi et al., 2012). Bruce et al. described a case involving lymph node metastasis and lymphovascular invasion without distant spread, made more complex by concurrent pregnancy (Bruce and Tran, 2020). Barth et al. documented EMPD of the scrotum with lymph node and bone metastases (Barth et al., 2015). Bartoletti et al. further highlighted the variability of clinical course, with cases of multifocal recurrences, deep local invasion requiring extended surgical procedures, and even an initial misdiagnosis of vulvar lichen sclerosus (Bartoletti et al., 2020). In contrast, the current case was characterized by lymphatic dissemination without distant involvement. Similarly, Karam et al. reported persistent local recurrence over 15 years without lymph node metastasis (Karam et al., 2008), again underscoring the unpredictable nature of EMPD. HER2 overexpression, as observed in our case, has been documented in association with more advanced disease. Nevertheless, due to the limited number of cases and the absence of standardized HER2 testing in EMPD, its prognostic relevance remains unclear and warrants further investigation (Fukuda and Funakoshi, 2018).

5.3. Treatment

Management of EMPD requires a multidisciplinary approach that integrates surgical and pharmacological strategies tailored to the extent of the disease and HER2 status. Wide local excision remains the standard first-line treatment for localized EMPD (Isnard et al., 2021). However, the multifocal nature of the disease often complicates achieving clear surgical margins, necessitating additional interventions such as laser ablation or skin grafting in cases of positive or inadequately clear margins (Kibbi et al., 2022).

Systemic therapy plays a crucial role in advanced or metastatic EMPD, particularly in cases with HER2 overexpression (Chilelli et al., 2024). Paclitaxel is commonly used as an initial treatment due to its microtubule-stabilizing properties and ability to inhibit cell division (Wakabayashi et al., 2012). Standard regimens include weekly (80 mg/m²) i.v. weekly or 3-weekly dosing, although adverse effects such as peripheral neuropathy and bone marrow suppression often necessitate dose adjustments (Kibbi et al., 2022). Trastuzumab, a monoclonal antibody targeting HER2, has demonstrated significant efficacy in HER2-positive EMPD by interrupting HER2-mediated signaling and promoting immune-mediated tumor cell destruction (Isnard et al., 2021, Chilelli et al., 2024). While HER2 testing is routinely performed in breast and gastric cancers, there is currently no validated scoring system specific to EMPD. In clinical practice, most reports—including ours—apply breast cancer scoring criteria, although this approach may not fully capture the heterogeneity of HER2 expression in extramammary sites. Treatment protocols often combine trastuzumab with paclitaxel or docetaxel, as evidenced in multiple cases (Sekiguchi et al., 2020, Takahagi et al., 2009, Wakabayashi et al., 2012).

Hanawa et al. described a case of a 70-year-old Japanese woman with HER2-positive vulvar EMPD and multiple metastatic lymph nodes. Following the failure of initial trastuzumab monotherapy, the patient was treated with weekly trastuzumab (2 mg/kg) combined with paclitaxel (80 mg/m²). After four courses, the patient exhibited significant regression of the primary vulvar lesion and metastatic lymph nodes. However, treatment was discontinued after six courses due to grade 3 neutropenia, emphasizing the need for close monitoring of hematologic toxicity during combination therapy (Hanawa et al., 2011).

Wakabayashi et al. similarly reported the case of a 68-year-old woman with HER2-positive EMPD involving the labia majora, urethra, vaginal wall, and uterine cervix. After experiencing multiple relapses, trastuzumab monotherapy (6 mg/kg every 3 weeks) achieved a partial response with significant reduction in residual lesions (Wakabayashi et al., 2012). Bartoletti et al. documented a 45-year-old woman with multifocal vulvar and perianal EMPD. Initial combination therapy with paclitaxel and trastuzumab achieved a partial response, with subsequent maintenance trastuzumab used to manage progression (Bartoletti et al., 2020).

Hematological toxicity, including grade 3 neutropenia, was observed in 30 % of cases treated with paclitaxel and trastuzumab combinations (Hanawa et al., 2011, Bartoletti et al., 2020). Bruce et al. reported a complete response in a 37-year-old pregnant woman with HER2-positive EMPD treated with chemotherapy and radiotherapy, followed by trastuzumab maintenance (Bruce and Tran, 2020). The case reported by Karam et al. further supports the efficacy of trastuzumab as a long-term therapy, demonstrating significant symptomatic improvement and lesion reduction in a patient with recurrent EMPD treated for over 15 years with multiple excisions (Karam et al., 2008). These findings emphasize the efficacy of trastuzumab in managing HER2-positive metastatic EMPD, with an overall response rate (CR and PR) of 85.7 %. Nonetheless, the high recurrence rates and the potential for treatment-related toxicities underscore the necessity for individualized follow-up strategies and meticulous management to optimize patient outcomes.

In the present case, the patient transitioned to trastuzumab monotherapy following severe hematological toxicities, including grade 3 neutropenia and anemia, observed during combination therapy with paclitaxel and nab-paclitaxel. Despite these adverse events, sustained disease control and significant regression of metastatic lesions were achieved. These observations highlight trastuzumab's potential both as monotherapy and in combination regimens for HER2-positive EMPD. However, the management of adverse effects and the adoption of flexible, patient-centered treatment plans remain crucial for improving therapeutic outcomes.

5.4. Follow-up

Effective follow-up is essential for patients with EMPD to monitor recurrence and metastasis, and to manage treatment-related toxicities. International guidelines recommend personalized follow-up strategies that incorporate regular physical examinations, targeted imaging, and laboratory evaluations (Chilelli et al., 2024). Surveillance is typically more intensive during the initial years post-treatment, given the heightened risk of early recurrence (Fukuda and Funakoshi, 2018). Advanced imaging modalities, such as MRI and Computed Tomography (CT), are integral for detecting disease progression (Fukuda and Funakoshi, 2018), whereas long-term effects, including cardiotoxicity from trastuzumab, necessitate ongoing evaluation (Karam et al., 2008). In our case, follow-up included frequent MRI to track the disease response after paclitaxel and trastuzumab therapy. With the transition to trastuzumab monotherapy, the focus shifted to cardiotoxicity monitoring and management of hematological side effects, such as anemia (Kibbi et al., 2022). A comparative analysis of other cases highlights the diversity of follow-up strategies based on the clinical context. Wakabayashi et al.’s case involved a detailed follow-up with regular clinical evaluations and imaging, which revealed no significant long-term side effects, resulting in a less complex regimen than our patient’s more intensive protocol (Wakabayashi et al., 2012). Bruce’s case, which involved a pregnant patient managed surgically, prioritized local recurrence detection owing to positive margins, reflecting a narrower follow-up focus (Bruce and Tran, 2020). Similarly, Hanawa et al.’s case required intensive imaging to monitor the response and manage severe treatment-related leukopenia, underlining the need for flexibility in follow-up planning (Hanawa et al., 2011). Barth et al.’s report of a patient on hemodialysis highlighted a more focused follow-up approach centered on trastuzumab efficacy and cardiotoxicity monitoring while maintaining stable renal function (Barth et al., 2015). In contrast, our patient’s broader follow-up addressed additional challenges, including hematological toxicity due to paclitaxel. Karam et al. further emphasized the role of follow-up in recurrent vulvar EMPD, with clinical symptom checks and echocardiograms, to manage cardiotoxicity from trastuzumab (Karam et al., 2008). In contrast to our approach, mild recurrence was managed conservatively, which prioritized advanced imaging for early detection and treatment adjustments (Karam et al., 2008). The study series by Bartoletti et al. provides further insights into follow-up strategies tailored to specific disease scenarios. One patient required intensive monitoring to manage pulmonary and abdominal metastases, and another had involved recurrent lymphatic metastases with subsequent brain metastases, necessitating neurological monitoring.. Additionally, a patient with persistent local recurrences required repeated biopsies and ongoing evaluations, mirroring the reliance on trastuzumab maintenance therapy observed in our approach (Bartoletti et al., 2020). In summary, follow-up strategies for EMPD must be highly individualized to address the risks of recurrence, metastasis, and treatment-related toxicity. Regular imaging and flexible protocols are critical for ensuring effective long-term management and maintaining patient quality of life.

6. Strengths and limitation

The study presents several strengths and limitations. Among its strengths, it addresses a rare case of HER2-positive metastatic VPD treated utilizing trastuzumab monotherapy as manteinance treatment due to the patient's intolerance to combination chemotherapy, highlights the importance of individualized care. The systematic review included in the study provides a comprehensive overview of existing data on HER2-positive EMPD, allowing meaningful comparisons with the presented case. However, the study also has limitations. It is based on a single case report and a systematic review comprising only seven cases of HER2-positive EMPD, limiting the generalizability of its findings. The relatively short follow-up duration may not capture late events such as recurrence or long-term adverse effects. Additionally, the lack of randomized controlled trials or large-scale studies prevents a robust comparison of trastuzumab monotherapy with other therapeutic approaches. Lastly, the management of adverse effects might not represent the broader patient population, particularly those with varying comorbidities or disease severity.

7. Conclusion

Trastuzumab monotherapy as a maintenance treatment for HER2-positive metastatic EMPD may represent a valid option, particularly in patients who are not able to tolerate combination chemotherapy. In selected cases, initial combination with a taxane can be considered, while trastuzumab alone may be appropriate in the maintenance setting or in the presence of treatment-related toxicity. Although standardized treatment protocols are lacking, a sequential approach based on HER2 expression, patient condition, and response to therapy could help guide clinical decisions. The absence of severe cardiotoxicity further supports its role as a safe therapeutic option. Given the rarity of this malignancy, further studies are needed to confirm these findings, define treatment duration, and establish shared therapeutic strategies. Clinicians should maintain heightened awareness for early diagnosis and individualized management to improve patient outcomes.

Ethical Approval

Not required.

Informed Consent

Informed consent was obtained from the patient for publication of this case report.

Funding Statement

This research received no external funding.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

CRediT authorship contribution statement

Dalila Incognito: Writing – original draft, Resources, Investigation, Data curation, Conceptualization. Massimiliano Berretta: Writing – original draft, Supervision, Resources, Project administration, Investigation, Data curation, Conceptualization. Giosuè Giordano Incognito: Writing – review & editing. Ferdinando Antonio Gulino: Writing – review & editing. Roberta Foti: Visualization, Validation. Vincenzo Canzonieri: Methodology, Formal analysis. Claudia Gelsomino: Resources, Investigation. Marco Palumbo: Software. Antonio Picone: Writing – original draft, Resources, Data curation, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.