Surgery, Gastroenterology and Oncology

ABSTRACT

Extramammary Paget’s Disease is a rare cutaneous malignancy with only a few hundred cases described in the literature. Due to its rarity, diagnosis is often difficult. Here, we present a case of an 88-year-old man with a perianal lesion that persisted for two years despite treatment with multiple topical agents. A skin biopsy established the diagnosis of Perianal Extramammary Paget’s Disease. After excluding an underlying adenocarcinoma, surgical treatment was proposed to the patient. Wide local excision of the lesion was performed, and a loop ileostomy was constructed for the purpose of faecal diversion. Since the superior and lateral surgical margins were positive for tumor cells, the patient was reoperated to enlarge the resection margins. Histopathological analysis did not show Paget cells in this resected specimen. Post-operative course was uneventful. We believe that our experience will contribute to the establishment of standards of care for this condition.
Key words: extramammary perianal Paget’s disease, rare malignancy, surgery, reconstructive procedures

INTRODUCTION

Extramammary Paget's Disease (EMPD) is a rare cutaneous malignancy. Its precise incidence is unknown, with only a few hundred cases reported in the literature (1). There is a female predominance (2,3), except in Asia, where males are more commonly affected than women (4,5). It is more frequent in Caucasians (2,3) and in individuals aged 50-80 years (2,5). Lesions usually appear in areas of the skin rich in apocrine glands, such as the axillae, external genitals and perianal region (2,5). Vulva is the most commonly affected site, representing approximately 65% of the cases (5,6). EMPD that occurs in nonapocrine- bearing regions is referred to as ectopic (1).
Although EMPD pathogenesis is still subject of debate, it is generally agreed that this is a heterogeneous condition that encompasses at least two entities with distinct pathological mechanisms: primary and secondary EMPD. Primary EMPD is not associated with an underlying adenocarcinoma and it is usually limited to the epidermis. Only in exceptional cases it may progress to an invasive tumor, infiltrating the dermis and spreading both to regional lymph nodes and distant sites (1,2,7,8,9). Although neoplastic cells are thought to originate in the epidermis, it remains to clarify exactly which cells are the precursors of Paget cells in this form of the disease. Skin adnexa (eccrine or apocrine glands), ectopic mammary glands, pluripotent keratinocyte stem cells and Toker cells have all been implicated as a possible source of neoplastic cells (1,2,10). Secondary EMPD is thought to be due to epidermotropic spread of malignant cells arising either from an underlying adenocarcinoma in a dermal adnexal gland or from a contiguous epithelium neoplasm (1,2,7). It occurs less frequently than primary EMPD and it is associated with a worse prognosis (8,11). An additional theory proposes that a unique oncogenic stimulus generates (independently or simultaneously) both the intra-epidermal adenocarcinoma (EMPD) and the underlying (adnexal or visceral) one (5).
Given its rarity, there are no established staging or treatment guidelines for EMPD. In this article, we present a case of perianal Paget’s Disease. It is our hope that our experience may contribute to a better management of this condition.

CASE PRESENTATION

An 88-year-old male was referred to our hospital due to complaints of perianal pain and pruritus for more than two years, that persisted despite multiple treatments with topical agents, including corticosteroids. He had no constitutional symptoms and denied either genitourinary or gastrointestinal complaints. His medical history included arterial hypertension, depression and transurethral resection of the prostate due to benign prostate hyperplasia. There was no previous history of malignancy. At the time of the first observation, the patient was in good general condition. Upon physical examination, an erythematous plaque with approximately 8 x 10 cm, extending from the perianal region to the left gluteal region was observed (fig. 1).

The lesion had signs of maceration, and superficial weeping ulcers could be found in its medial half. Rectal examination was unremarkable, and no regional lymphadenopathy was noted.
The patient was first evaluated by a dermatologist, who performed a skin biopsy. The histopathology analysis revealed small groups of cells within the epidermis with abundant cytoplasm, large, irregular nuclei and prominent nucleoli. Immunocytochemical analysis showed that cells were positive for the expression of CK4, CEA and GCDFP-15 and negative for CK20. These finding were compatible with Paget’s disease. The patient was, then, referred to the General Surgery Department, where further investigation took place.
An upper endoscopy, colonoscopy and thoracoabdominal CT scan were performed to exclude an underlying adenocarcinoma. A pelvic MRI was added to the study in order to evaluate local tumor extension. None of the examinations revealed any suggestive changes except for the MRI, which showed an area of cutaneous thickening in the perianal region, located between 3 to 7 o’clock positions. This area was about 6 mm thick and exhibited hyperintensity on T2-weighted images (fig. 2).

There was no involvement of the anal sphincter by the above-described lesion and no suspicious lymph nodes were found. Serum levels of both carcinoembryonic antigen (CEA) and carbohydrate antigen 19.9 (CA 19.9) were within the normal range. Following a multidisciplinary discussion involving General Surgery, Oncology, Radiology and Plastic Surgery, surgical treatment was proposed to the patient. After obtaining patient’s consent, a wide local excision of the lesion was performed. A loop ileostomy was constructed for the purpose of fecal diversion. Surgical wound was left open to heal by secondary intention. The histopathological analysis of the surgical specimen confirmed Paget’s disease; there was no dermal invasion. The superior and lateral surgical margins were positive for tumor cells. Given this finding, the patient was reoperated to enlarge the resection margins. Histopathological analysis did not show Paget cells in this resected specimen.
Postoperative course was uneventful. Currently, the surgical wound is healing by secondary intention, and there are no signs of complications. The patient is being followed by a plastic surgeon. The necessity and timing for a reconstructive procedure are being evaluated. Closure of the ileostomy should be considered once perianal region is completely healed.

DISCUSSION

Since EMPD is a rare condition, a delay in the diagnosis is common. A median delay of two years has been reported (12). Patients are frequently though to have anal eczema and treated with topical agents, namely corticosteroids (13). Definitive diagnosis can only be achieved by cutaneous biopsy.
Once the diagnosis has been made, management of these patients is not standardized, as was previously stated. Nevertheless, it is of paramount importance to exclude the existence of an underlying adenocarcinoma (8,9). Most authors suggest a complete medical history and physical examination, including a complete cutaneous examination and evaluation of lymph nodes, liver and spleen. Breast and gynaecological examination are also recommended for female patients (1). Given the fact that perianal EMPD tends to be associated with gastrointestinal neoplasms (6), an upper endoscopy and colonoscopy are usually required in these cases. Additionally, a cystoscopy may be valuable in order to exclude an urothelial carcinoma of the bladder (1). Measurement of CEA levels has also been previously endorsed by some authors (1).
The presented case reflects the delay frequently present in the diagnosis of EMPD. Since the clinical investigations described above did not encounter an underlying adenocarcinoma, we may assume that this is a case of primary EMPD. Although primary EMPD has the potential to become disseminated, patients with this form of the disease usually have a better prognosis than the ones with secondary EMPD. Several factors may portend a greater risk of death, namely: i) presence of dermal invasion; ii) elevated CEA levels; iii) presence of regional lymphadenopathy and iv) bilateral lymph node metastases. Presence of dermal invasion is probably the most significant factor affecting survival (12). As none of the factors known to negatively affect survival are present in this case, the clinical course is expected to be positive.
Although there are no established guidelines for treatment of EMPD, surgery is considered the mainstay of treatment (1,5). In an effort to reduce the morbidity frequently associated with the surgical treatments performed, many other therapeutic approaches have been attempted on patients with EMPD. Therapeutic regimens other than surgery include radiotherapy (15-21), topical chemotherapy with 5-fluorouracil (22,23) and imiquimod (24-30), CO2 laser therapy (31) and photodynamic therapy (32-37). Since EMPD is a rare and heterogeneous condition, studies reviewing or proposing different treatment strategies are often retrospective and include a small number of patients. Therefore, regimens like radiotherapy and topical chemotherapy, despite being associated with promising results in some studies, are usually reserved for patients unfit for surgery (1,5).
In the reported case, the patient was considered fit for surgery. Although a wide local resection was performed, surgical margins were positive, which led to a reoperation. No Paget cells were found in the resected specimen after the second procedure. Several methods for intraoperative assessment of margin involvement were previously described in literature, including the use of frozen sections and fluorescein (38-41), but are still of unproven value.
Complete post-operative recovery will require several months and at least one more surgical procedure. Meanwhile, patient is back to his usual activities.

CONCLUSIONS

EMPD is a rare cutaneous neoplasm that can affect the perianal region and that may be misdiagnosed as chronic intertrigo, eczematous dermatitis or tinea cruris. Therefore, considering this pathological entity in the differential diagnosis of perianal skin lesions is of paramount importance to avoid a delay in the diagnosis and to achieve an optimal management. Definitive diagnosis can only be made by cutaneous biopsy. EMPD may be primary or secondary in its etiology. Primary EMPD is thought to arise as a primary intraepithelial adenocarcinoma in most cases, while secondary EMPD represents extension of an underlying adnexal adenocarcinoma or visceral malignancy. Investigations should be made in order to exclude an underlying malignancy.
This reported case of EMPD was successfully treated with surgery, the mainstay of treatment.

Conflicts of interest

All authors declare that they have no conflicts of interest.

Funding

This case report received no specific grant from any funding agency in the public, commercial, or notfor- profit sectors.

Ethical statement

Informed consent was obtained from the patient for the publication of this case report and any accompanying figures.

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