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HER-2/NEU overexpression in vulvar Paget disease: the Yale experience
  1. Christine E Richter1,
  2. Pei Hui2,
  3. Natalia Buza2,
  4. Dan-Arin Silasi1,
  5. Masoud Azodi1,
  6. Alessandro D Santin1,
  7. Peter E Schwartz1,
  8. Thomas J Rutherford1
  1. 1Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Gynecologic Oncology, Yale University School of Medicine, New Haven, Connecticut, USA
  2. 2Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
  1. Correspondence to Dr Christine E Richter, Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Gynecologic Oncology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA; christine.richter{at}yale.edu

Abstract

Aims To determine the level of HER-2/neu overexpression in vulvar Paget disease (PD) in order to assess the possibility of using HER-2/neu as a target for the treatment of Paget disease.

Methods A medical record search identified 39 patients with a histologically confirmed diagnosis of vulvar PD between 1986 and 2009. A tissue microarray containing all 39 tumour samples was created, and corresponding sections were stained immunohistochemically with an anti-HER-2/neu-antibody (HercepTest). Staining results were reported on a scale from 0 to 3+. 2+ and 3+ were considered as HER-2/neu overexpression. The HER-2/neu expression was correlated with clinical, pathological and outcome data.

Results Negative staining for HER-2/neu was noticed in four patients (12%), 1+ in 10 patients (30%), 2+ in 11 patients (33%) and 3+ in eight patients (25%), resulting in 19 patients with HER-2/neu overexpression (2+ and 3+, 58%) and 14 patients without HER-2/neu overexpression (0 and 1+, 42%). The proportion of HER-2/neu overexpression was higher in the patients with invasive than with non-invasive PD (71%, n=5/7 invasive PD vs 54%, n=14/26 non-invasive PD). There was no significant correlation between HER-2/neu staining results and clinical, pathological or outcome data.

Conclusions Surgical treatment of vulvar Paget disease is associated with a high recurrence rate and extensive reconstructive procedures. In this study, over 50% of the patients with vulvar Paget disease overexpress HER-2/neu. Anti-HER-2/neu-antibodies like trastuzumab may therefore be an interesting treatment option for HER-2/neu-positive vulvar Paget disease. Clinical trials are needed to evaluate the efficacy of trastuzumab in this disease.

  • Gynaecologic pathology
  • Paget's disease
  • immunohistochemistry
  • antibodies
  • oncology

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Introduction

Vulvar Paget disease (PD) is the most common manifestation of extramammary PD1 and accounts for <1% of all vulvar neoplasms.1–3 It is a disease of the postmenopausal Caucasian female2 4–6 and most commonly presents with pruritus and patchy, eczematous lesions.4–6 Most vulvar PD lesions are an intraepithelial form of malignancy1 3 7 characterised by large round Paget cells with abundant, pale cytoplasm which can be vacuolated.8 9 They either arise from an apocrine duct or result from malignant transformation of a pluripotent cell in the basal layer of the epidermis.7 10 Invasive PD occurs in 15–25% of patients.2 3 6 Vulvar PD is associated with an underlying adenocarcinoma, usually of sweat gland origin, in approximately 4%.1–3

The primary treatment of vulvar PD is surgical excision.2–4 6 Despite aggressive treatment, recurrence rates are as high as 30% within the first 8 years after treatment.2 4 6 After radical and repeated surgeries, patients may require major reconstructive procedures.10 Non-surgical treatment options for recurrent disease such as local and systemic chemotherapy, radiation or photodynamic therapy have yielded mixed results.4

Human epidermal growth factor receptor 2 (HER-2/neu) is a 185 kDa transmembrane tyrosine kinase receptor with close homology to the epidermal growth factor receptor.11 It causes activation of the phosphatidylinositol 3 kinase (PI3K) and extracellular signal-regulated kinase (ERK) signal pathways.12 A motility factor acting through the HER-2/neu receptor is believed to contribute to the spread of Paget cells through the epidermis.11 HER-2/neu helps control proliferation, migration and invasion.4 13 In breast cancer, overexpression of HER-2/neu is associated with poor prognosis.3 In mammary PD, HER-2/neu expression has been demonstrated in >90% of Paget cells.14–16 In vulvar PD, studies have shown a wide range of HER-2/neu expression, ranging from 5 to 80% of cases.3 7 8 10 12 13 16–19 HER-2/neu is the target for trastuzumab, a recombinant, humanised IgG1 monoclonal HER-2/neu-antibody with antiproliferative effects.4 13 It is used in the treatment of metastatic HER-2/neu-positive breast cancer.1 3 7 To date, two case reports describe the use of trastuzumab in HER-2/neu-positive extramammary PD: Karam et al reported a case of a patient with recurrent HER-2/neu-positive vulvar PD who reported a significant symptomatic improvement and a decrease in the lesion size after two doses of intravenous trastuzumab.4 The second case was a male patient with extramammary PD treated with a combination of paclitaxel and trastuzumab with significant improvement of his skin lesions.20 These studies suggest that vulvar PD may be a candidate for treatment with HER-2/neu antibody therapy.

Our study is one of the largest evaluations of HER-2/neu expression in vulvar PD to date. The goal was to confirm the level of HER-2/neu positivity in vulvar PD in our study population, and to correlate HER-2/neu expression with outcome, clinical and histological factors. Our findings may allow for the use of HER-2/neu as a target for therapy in this potentially debilitating disease.

Material and methods

A total of 39 patients who presented to the Yale-New Haven Hospital Gynecologic Oncology Division between 1986 and 2009 with a histologically confirmed diagnosis of vulvar PD were identified using a medical record search. The medical records including epidemiological (age, ethnicity), clinical (chief complaint, duration of symptoms, prior medical and surgical treatment, diagnosis of other malignancies), histopathological data (location and extent of lesion, multifocality, margin status, underlying adenocarcinoma, invasion, intraoperative frozen section result) as well as outcome (survival, recurrence) were extracted.

All tissues were formalin-fixed and embedded in paraffin. After confirmation of the diagnosis of vulvar PD on a haematoxylin & eosin-stained slide, selected tissue paraffin blocks of each tumour were obtained, and a standard tissue microarray block was constructed. The tissue sections of the array block were cut and used for immunohistochemical staining with an HER-2/neu antibody (Hercept test antibody, Dako, Carpinteria, California). The intensity of staining was evaluated on a semiquantitative scale (0, 1+, 2+ and 3+) by two pathologists who were blinded to the clinical, epidemiological and outcome-related information. Appropriate positive and negative controls were used during the staining. Staining was considered to be 0 for no staining, 1+ with less than 10% positively stained cells or cells that showed only faint staining, although more than 10% of cells were positive, 2+ when they showed more than 10% weak or moderate and complete membrane staining, and 3+ when more than 10% of tumour cells showed strong complete membrane staining.21 According to the standard guideline used for breast cancer, 2+ and 3+ tumours were recorded as ‘overexpressed’, 0 and 1+ tumours as ‘non-overexpressed’.21

Fluorescence in situ hybridisation (FISH) was attempted on all samples. However, the majority of samples were too old for adequate results.

The χ2 test was used for the comparison of categorical variables, and the Mann–Whitney and Kruskall–Wallis tests were used for the statistical analysis of continuous variables. SPSS 17.0 was used for the statistical analysis (SPSS, Chicago, Illinois). p Values of <0.05 were considered statistically significant. This study was approved by the necessary ethics committee (Human Investigation Committee at Yale University School of Medicine, HIC # 0909005672).

Results

A total of 39 patients were diagnosed as having vulvar PD at Yale-New Haven Hospital between 1986 and 2009. Table 1 presents a summary of the patients' demographic data. The median age at diagnosis was 68.5 years (range 42–86). Caucasians represented 97% of the patients (n=38), while one (3%) was Hispanic. Thirty-two patients (82%) were parous, and 27 patients (69%) were non-smokers. The majority of patients presented with vulvar pruritus as the most bothersome symptom (61%, n=24). Seven (18%) complained of a lesion, three (8%) complained of vulvar pain, and the disease was diagnosed incidentally during a routine gynaecological exam in two of the patients (5%). No information on the presenting symptom was available on three patients (8%). The median duration of symptoms by the time of the patients' presentation to a gynaecological oncologist was 12 months (range 1–190 months). Twelve patients (31%) had used topical ointments, and one patient had been treated with radiation to the vulva (56.8 Gy total dose; table 1). The surgical treatment consisted of a radical vulvectomy in 26 patients (67%), simple vulvectomy in nine patients (22%) and superficial vulvectomy in one patient (3%; table 1). Two patients (n=5%) did not undergo any surgical treatment. Data were missing on one patient (3%). Twenty-five patients (64%) have been recurrence-free, while 14 (36%) developed recurrent disease. The median time from primary diagnosis to recurrence was 60 months (range 3–144 months).

Table 1

Patient demographics and clinical information

The pathological data are summarised in table 2. No invasion was identified in 30 patients (77%). On final pathological evaluation, 18 patients (46%) had positive margins, and 18 (46%) had negative margins. Information regarding the margin status was missing on three patients (8%). Twenty-six patients (67%) had no other malignancies (n=26). Among the patients who were diagnosed as having another malignancy, five (13%) had a history of invasive ductal breast cancer, three (8%) a history of skin cancer (melanoma, basal cell carcinoma), two (5%) a history of transitional cell bladder carcinoma and one (3%) a history of leukaemia, colon cancer or endometrial adenocarcinomas.

Table 2

Histopathological data and immunohistochemistry results

Thirty-three of the 39 tissue specimens were available for Her-2/neu testing. The tissue was negative for HER-2/neu in four patients (12%), 1+ in 10 patients (30%), 2+ in 11 patients (33%) and 3+ in eight patients (25%), resulting in 19 patients with HER-2/neu overexpression (2+ and 3+, 58%) and 14 patients without HER-2/neu overexpression (0 and 1+, 42%). The proportion of HER-2/neu overexpression was higher in the patients with invasive than with non-invasive PD (71%, n=5/7 invasive PD vs 54%, n=14/26 non-invasive PD). Among the five patients with ductal breast cancer, two patients showed no HER-2/neu overexpression (1+), two were HER-2/neu-positive (2+), and tissue was unavailable for staining on one patient. There was no significant relationship between HER-2/neu staining results and clinical data (age, presenting symptom, duration of symptoms, smoking status, parity or ethnicity), pathological factors (location and extent of lesion, multifocality, margin status, underlying adenocarcinoma, invasion, frozen section result) or the rate of recurrences (p>0.05).

Discussion

Although the prognosis of PD is overall favourable with surgical treatment, there is a high recurrence rate of up to 30%,1 and conservative, effective treatments for advanced disease are not available.12 HER-2/neu may be an interesting target for medical therapy of HER-2/neu-positive vulvar PD.

The status of HER-2/neu expression in vulvar PD has been evaluated in several studies, yielding very different results, with reports of HER-2/neu overexpression in 5–80% of the cases.3 7 10 12 18 19 22 Our current study, one of the largest reports to date, revealed HER-2/neu overexpression in 58% of the patients with vulvar PD (table 2). Consistent with our results, the majority of studies have documented HER-2/neu overexpression in 33–100% of the vulvar PD.1 3 7 9 10 12 18 19 22 Few studies, however, have shown low levels of HER-2/neu expression in vulvar PD, ranging from 0 to 14%.8 11 17 This variability of the HER-2/neu overexpression may arise in part from the small and very heterogeneous study populations as well as differences in staining and scoring techniques used.10 Importantly, the two largest recent studies (our study along with that of Plaza et al9) are consistent, detecting HER-2/neu overexpression in >35% of the cases. It is noteworthy that most of the studies reporting HER-2/neu overexpression in vulvar PD are more recent than the studies showing no HER-2/neu overexpression. This may be attributable in part to more refined antibodies. The HercepTest system was used in three of the eight studies showing HER-2/neu overexpression in vulvar PD.3 12 19 Additional FISH studies on vulvar Paget disease specimen are needed in the future.

There is no consensus on the possible influence of the HER-2/neu status and clinical or histopathological factors, particularly of the level of HER-2/neu expression in invasive vulvar PD, and further studies are needed to evaluate this variable.9 18 Consistent with reports from the literature, 33% of the patients included in this study were diagnosed as having other malignancies, mainly in the breast and genitourinary tract8 (table 2).

The treatment of vulvar PD is challenging. Recurrence rates after primary surgery are approximately 30%,2 5 6 and the surgical margin status does not predict recurrence.1 In addition, surgical treatment in this anatomical area can be difficult, particularly with multifocal disease.1 Case reports suggest that trastuzumab may be an effective therapeutic option for patients with extramammary PD.4 20 Trastuzumab administration may be associated with cardiotoxicity,19 but it is important to keep in mind that this toxicity has mainly been documented in patients with breast cancer after prior treatment with cardiotoxic anthracyclines.23

Given the high expression of HER-2/neu in vulvar PD and the need for alternative treatment methods, trastuzumab may be an interesting new agent in the treatment of vulvar PD. A non-surgical treatment targeting a molecular pathway might provide an alternative to debilitating surgery, provide treatment options in recurrent or extensive disease and for patients who are poor surgical candidates. Clinical trials are necessary to evaluate the efficacy of trastuzumab in this disease.

Take-home message

  • Vulvar Paget disease (PD) is the most common manifestation of extramammary PD. The primary treatment of vulvar PD is surgical excision. Despite aggressive treatment, recurrence rates are as high as 30% within the first 8 years after treatment. In this study, over 50% of the patients with vulvar Paget disease overexpress HER-2/neu. Anti-HER-2/neu-antibodies like trastuzumab may therefore be an interesting treatment option for HER-2/neu-positive vulvar Paget disease.

References

Footnotes

  • Competing interests None.

  • Ethics approval Ethics approval was provided by the Yale University School of Medicine, Human Investigation Committee, New Haven, CT, USA (HIC# 0909005672).

  • Provenance and peer review Not commissioned; externally peer reviewed.