Extramammary Paget's Disease in Two Brothers.

Extramammary Paget's disease (EMPD), which is considered to be an adenocarcinoma of the apocrine glands, is a rare, slow-growing neoplasm. The standard treatment for local EMPD is surgical resection, however, so far, no effective treatment is found for advanced EMPD. Trastuzumab, which is a recombinant monoclonal antibody against the human epidermal growth factor receptor 2 HER2 has been proved to be effective in the treatment of advanced EMPD in some cases where HER2 protein is overexpressed. Herein, we report two cases of EMPD in two brothers. The younger brother who presented as local EMPD on the scrotum received surgical resection and had no recurrence in 15 months following. The older brother suffered from invasive EMPD also on the scrotum with inguinal region multiple metastatic lymph nodes and was treated with combination chemotherapy and Trastuzumab to target HER2 consecutively after a wide surgical excision.

What was known?

The HER2 protein is sometimes overexpressed in EMPD and the HER2 signal pathway leads to vigorous tumor cell proliferation. Clinical trials of HER2-targeted therapy are awaited for improvement of the prognosis of patients with aggressive EMPD.

Introduction

Extramammary Paget's disease (EMPD) is most often observed in areas that are rich in apocrine glands. Patients usually present with eczematous crusted or excoriated gray white plaques.[1] EMPD can present as carcinoma in situ or as invasive disease that can subsequently metastasize to lymph nodes and distant sites.[2] There is also a familial EMPD, although, the genetic bases are still unknown.[3] Effective chemotherapy for advanced EMPD has not yet been established.[4] Trastuzumab is a humanized monoclonal antibody which selectively targets human HER2. The HER2 protein is sometimes overexpressed in EMPD and the HER2 signal pathway leads to vigorous tumor cell proliferation. In such cases, therapy employing Trastuzumab combined with paclitaxel or using Trastuzumab alone has already been proved to be effective in some cases.[567] Here we report two case of scrotal EMPD in two brothers.

Case 1

A 67-year-old Chinese man presented with a 2-year history of left scrotal itchy eczematous skin lesion which had gradually increased in size and a 1-year history of left inguinal lymphadenopathy. He was referred to Urology Department of our hospital in January 2013. On physical examination, an erosive erythematous plaque measuring 50 × 60 mm was noted on the left side of the scrotum. Enlarged lymph nodes were palpated in his left (2 cm and 1cm in size) and right (1 cm in size) inguinal area. His past history included subtotal gastrectomy and colorectal polyposis excision, which was performed 10 years ago. Histological examination of both specimens showed no malignancy. Therefore, the patient has had an extensive cancer work-up. The tumor markers were within normal range: Carcinoembryonic antigen 3.03 ng/mL (normal range, 0-5 ng/mL), alpha-fetoprotein 2.84 ng/mL (normal range, 0-13.4 ng/mL), prostate-specific antigen 0.471 ng/mL (normal range, 0-4 ng/mL), Carbohydrate antigen 12-5 8.30 U/mL (normal range, 0-35 U/mL), Carbohydrate antigen 19-9 19.00 U/mL (normal range, 0-37.00 U/mL), and Carbohydrate antigen 15-3 19.10 U/mL (normal range, 0-31.30 U/mL). While admitted to the hospital, the patient underwent excision of primary site with a sentinel node biopsy (SLNB) of the left inguinal lymphadenopathy. A biopsy of the skin lesion showed that Paget's cells were single dispersed or arranged in rows or small nests concentrated above the basal layer of the epidermis, however, a little of them invaded to dermis [Figure 1a]. Metastatic tumor cells were found in the SLNB. Immunohistochemistry of the skin showed cytokeratin 7(CK7)+, CK20 –, gross cystic disease fluid protein 15(GCDFP15)–, S100 protein –, melanoma associated antigen (HMB45)−, epithelial membrane antigen (EMA)+, carcinoembryonic antigen (CEA)+, Ki67+ (30%), and anti-cytokeratin (CAM 5.2) +. The diagnosis of invasive EMPD was confirmed histochemically and immunohistochemically. Magnetic resonance imaging (MRI) after 1 week of surgery indicated lymphadenopathy in bilateral inguinal area. So the patient underwent a wide local excision and bilateral groin lymph node dissection. Intraoperative frozen section examination (FSE) showed clear surgical margins. However, review of the MRI revealed multiple lymph node metastases, not only along the iliac artery but also in the retroperitoneum after 2 months of surgery [Figure 2a]. The patient was given four courses of combination chemotherapy every-3-week: Cisplatin 20 mg/m2 (d1-d3), 5-fluorouracil 350 mg/m2 (d1-d5) and docetaxel 60 mg/m2 (d1). There was no recurrence in the scrotum and other skin, but the lymph node metastases did not respond. An additional immunohistochemical staining revealed human HER2 overexpression in the metastatic lymph nodes [Figure 3a and b]. We then treated the patient with Trastuzumab 600 mg at 3-week intervals to residual or recurrent lymph node metastasis. After four courses of the regimen, the metastatic lymph nodes of retroperitoneal and iliac artery partly regressed [Figure 2b]. Review of the tumor markers showed a little decline: Carcinoembryonic antigen 2.60 ng/mL (normal range, 0-5 ng/mL), alpha-fetoprotein 2.61 ng/mL (normal range, 0-13.4 ng/mL), and carbohydrate antigen 19-9 17.58 U/mL (normal range, 0-37.00 U/mL). Fifteen months after surgery, the patient is alive.

Figure 1

Microscopic examination revealed Paget's cells appeared as large, pale, vacuolated cells with vesicular nuclei and prominent nucleoli. Some of Paget's cells invade to dermis in Case 1 (HE × 200) (a); however, Paget's cells only in the epidermal basal layer in Case 2(HE × 100) (b)

Figure 2

Magnetic resonance imaging scans: Enlargement of the para-iliac artery lymph node before using trastuzumab (a); substantial reduction in size of lymph node after four courses of trastuzumab (b)

Figure 3

IHC for HER2 protein in the metastatic lymph nodes. Paget's cells were uniformly stained positive (IHC × 100) (a). High magnification (IHC × 400) (b)

Case 2

A 56-year-old Chinese man presented with an 8-year history of itchy erythema on the right scrotum that had gradually increased in size. His brother (case 1) had been diagnosed as invasive EMPD a few days ago. A biopsy specimen indicated EMPD from the other hospital. Therefore, he was referred to Urology Department of our hospital in January 2013. Physical examination revealed an erythematous plaque on the right scrotum to the basal portion of the penis, measuring 60 × 35 mm. He underwent a wide local excision with SLNB. FSE showed clear surgical margins. The pathology report of the skin lesion postoperative [Figure 1b] was in accordance to preoperative. The SLNB showed no tumor invasion. The immunohistochemistry of the skin was CK7+, CK20 –, GCDFP15+, EMA+. Fifteen months after surgery, the patient is alive and without recurrence.

Discussion

In 1973, Kuehn et al.[8] described the first case of familial EMPD. They indicated that one might hypothesize a linkage between genetic factors and predisposition to cancer. Since then, only another seven cases familial EMPD have been reported, which are all from Japan.[910] Ours is the first case of Chinese familial EMPD in two brothers.

Surgical resection for local EMPD is represented as a preferred treatment; case 2 is alive and without recurrence 15 months after surgery. However, once the tumor has invaded into dermis with metastases to lymph nodes and other organs, it imposes a surgical challenge, resulting in poor prognosis. Systemic therapy is needed; however, no prospective study is available and no standard has been established. We treated case 1 with combination chemotherapy according to previous reports when MRI after 2 months of surgery revealed multiple lymph node metastases.[11] After three courses we found that the lymph node metastases did not respond, which impelled us to try other treatments. An additional immunohistochemical staining revealed HER2 protein overexpression in the metastatic lymph nodes. The previous literature shows that the overexpression of HER2 protein is detected in 20–60% of EMPD.[1213] A patient with metastatic scrotal EMPD and HER2 overexpression treated with paclitaxel and Trastuzumab with partial response in the skin lesions has been reported.[5] Since then, responses with this combination or with Trastuzumab alone in patients with vulvar EMPD have also been described.[67] We treated the patient with Trastuzumab 600 mg at 3-week intervals. After four courses of the regimen, the metastatic lymph nodes of retroperitoneal and iliac artery partly regressed and review of the tumor markers showed a little decline. Fifteen months after surgery, the patient is alive. A study in 2013 using a standardized method with a large number of cases of EMPD demonstrated that in a subset of EMPD, both intraepithelial and invasive showed HER2 overexpression and gene amplification. These HER2 alterations were correlated with biologically aggressive EMPD, 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.[14] Our findings imply that Trastuzumab is useful for the treatment of the patients with advanced EMPD where HER2 protein is overexpressed. We suggest that immunohistochemical staining of HER2 should be done immediately after surgery.

Conclusion

The familial occurrence of Paget's disease is extremely rare, ours is the first case of Chinese familial EMPD in two brothers. Trastuzumab may be effective in the treatment of advanced EMPD in the cases where HER2 protein is overexpressed and immunohistochemical staining of HER2 should be done immediately after surgery.

What is new?

Ours is the first case of Chinese familial EMPD in two brothers. Trastuzumab may be effective in the treatment of advanced EMPD in the cases where HER2 protein is overexpressed.