A Case of Local Resection of Secondary Perianal Paget Disease Appearing during “Watch and Wait” Management of Locally Advanced Rectal Cancer after Preoperative Chemoradiotherapy

Abstract

A 78-year-old woman was diagnosed with lower rectal cancer extending to the dentate line. She underwent preoperative chemoradiotherapy, which resulted in tumor shrinkage and clinical complete response (cCR), leading to the implementation of the “Watch and Wait” strategy. At the 21-month surveillance mark, pruritus and erythematous lesions appeared around her anus, which were histologically diagnosed as secondary Paget disease with invasion based on biopsy specimens. Because the primary lesion maintained cCR, local excision of the skin lesion was performed, and negative resection margins were confirmed by pathological examination. At the 4-year postoperative follow-up, neither local recurrence nor distant metastases were observed. This case suggests that although the primary focus disappeared entirely with the use of chemoradiotherapy, microscopic perianal secondary Paget disease hidden outside the radiation field became apparent during surveillance. As total neoadjuvant therapy (TNT) becomes more widespread, the frequency of cCR is expected to increase. During the “Watch and Wait” period, vigilant observation of the perianal skin as well as the rectal region should be performed.

Introduction

Perianal Paget disease is rare. It can be classified as primary perianal Paget disease, whereby lesions originating from the anal glands around the anus spread horizontally, or secondary perianal Paget disease, which arises as an extension of a rectal or anal canal adenocarcinoma with intraepithelial spread in the perianal skin. In cases of secondary perianal Paget disease, abdominoperineal resection is often performed to excise primary and perianal skin lesions. However, there is no consensus regarding the surgical procedure or extent of resection. Here, we present a case of local excision for secondary perianal Paget disease with invasion that appeared during the “Watch and Wait” period after preoperative chemoradiotherapy for locally advanced lower rectal cancer.

Case Report

A 78-year-old woman presented with a positive fecal occult blood test, and colonoscopy revealed advanced rectal cancer with a tumor margin extending to the dentate line (Figure 1a, 1b). The biopsy specimen revealed a well-differentiated adenocarcinoma (Figure 1c, 1d). TNM staging, based on computed tomography (CT) and magnetic resonance imaging (MRI), revealed T3N0M0. The patient underwent preoperative chemoradiotherapy (CRT) (50.4 Gy/25 Fr with oral intake of S-1). The post-treatment assessment showed a clinical complete response (cCR), leading to the decision to adopt a “Watch and Wait” approach (Figure 1e, 1f). She underwent CT, MRI, colonoscopy, and digital examination every 3 months, and after 21 months, pruritic erythematous lesions were observed on the perianal skin (Figure 2a, 2b). In a biopsy of the perianal skin lesion, adenocarcinoma cells containing intracellular mucin were observed by histology within the squamous epithelium and subepithelial stroma, with the intraepithelial component exhibiting features of Paget disease. Immunohistochemistry of the lesion revealed positivity for CDX2, CK7, and CK20, and negativity for GCDFP15, and it was determined to have originated from a rectal adenocarcinoma (Figure 2c, 2d). Based on these findings, secondary perianal Paget disease with invasion originating from the rectal adenocarcinoma was diagnosed.

Figure 1.

Colonoscopy revealed an advanced low rectal cancer with the tumor margin extending to the dentate line (a, b). Histologically, biopsy specimens revealed well-differentiated adenocarcinoma comprising tubular or papillary structures (hematoxylin-eosin staining; c, low-power magnification; d, high-power magnification). Upon colonoscopy after completion of chemoradiotherapy, the tumor had completely disappeared, leaving a smooth scar (e), and consistently distributed regenerated pits were seen with crystal violet staining (f).

Figure 2.

Upon colonoscopy performed after 20 months of “Watch and Wait”, an erythematous inflammatory lesion was detected in the perianal skin (a), whereas there was no obvious regrowth of the tumor in the rectum (b). Biopsy specimens, taken from the perianal skin, revealed carcinoma cells with a pale cytoplasm in the squamous epithelium (c) and invasive adenocarcinoma in the stroma. Since the immunohistochemistry was positive for CDX2 (d), CK20, and CK7 (focal) but negative for GCDFP-15, the diagnosis was ultimately secondary perianal Paget disease with invasion originating from rectal adenocarcinoma.

The primary lesion maintained cCR, and a wide local excision of the skin lesion was performed to preserve the anus. A 20 mm resection margin was secured from the tumor edge, and a full-thickness skin excision was performed. The mucosa and the submucosa were excised 10 mm proximal to the dentate line. After confirming negative resection margins using an intraoperative frozen section diagnosis, the defect was reconstructed using a skin flap and graft (Figure 3). Pathological examination of the resected specimens revealed invasive adenocarcinoma in the dermis and intraepidermal spread of adenocarcinoma cells with Paget disease features. Immunohistochemistry confirmed the rectal adenocarcinoma origin (Figure 4). The final diagnosis was secondary perianal Paget disease with invasion, and the resection margins were negative. No local recurrence or distant metastases were observed during the 4-year postoperative follow-up period.

Figure 3.

The resection line was designed to ensure a 20-mm margin from the skin lesion (a). The rectal mucosa and submucosa were resected 10 mm proximal to the dentate line (b). The skin was sutured as closely as possible, and the defect was covered with a skin graft (c). Twelve months after wide local resection (d).

Figure 4.

A macroscopic presentation of the resected specimen (a) and micrographs (b-f). The representative area contains an invasive adenocarcinoma component within the dermis (hematoxylin and eosin staining; b, low-power magnification; c, high-power magnification). Meanwhile, the peripheral region of the lesion exhibited intraepidermal spread of Paget cells (d, high-power magnification of hematoxylin and eosin staining). Immunohistochemistry positive for CDX2 (e) and CK20 (f) confirming the diagnosis of secondary perianal Paget disease originating from rectal adenocarcinoma.

Discussion

Extramammary Paget disease is rare, with an incidence of 0.7 individuals per 100,000 persons per year[1], and the perianal region is a common site, following the vulva. Secondary perianal Paget disease is estimated to constitute 30-60% of all perianal Paget cases[2]; however, there is currently a lack of consolidated reports on treatment strategies and long-term outcomes. The treatment approaches differ significantly between primary and secondary perianal Paget disease. Shutze and Gleysteen proposed a treatment strategy for perianal Paget disease based on the distinction between primary and secondary cases as well as the localization and extent of the primary carcinoma (Table 1)[3]. According to these recommendations, wide local excision (WLE) is recommended for primary or secondary perianal Paget disease with associated adnexal carcinoma, whereas abdominoperineal resection (APR) is recommended for secondary perianal Paget disease with associated anorectal carcinoma. With this treatment strategy, it is crucial to accurately diagnose whether the disease is primary or secondary. Differentiation between the two is achieved through pathological evaluation, with immunohistochemistry being particularly valuable. Primary perianal Paget disease is typically positive for GCDFP15 and CK7 (+), and negative for CK20, whereas secondary perianal Paget disease originating from rectal adenocarcinoma is often characterized as positive for CK20 and CDX2 and negative for GCDFP15[4]. However, approximately 50% of patients diagnosed with secondary perianal Paget disease do not have visible mucosal lesions upon colonoscopy[5]. In such cases, local excision is sometimes performed out of necessity, and pathological examination may occasionally identify cancer cells within the anal glands[6].

Table 1.

Staging and Management of Perianal Paget Disease Summarized by Shutze WP.

Stage	Description	Management
I	Paget’s cells in the perianal epidermis and adnexa without primary carcinoma	WLE
IIA	Cutaneous Paget’s disease with associated adnexal carcinoma	WLE
IIB	Cutaneous Paget’s disease with associated anorectal carcinoma	APR
III	Paget’s disease in which associated carcinoma has spread to regional nodes	Inguinal lymph node dissection and APR/WLE
IV	Paget’s disease with distant metastases of associated carcinoma	Chemotherapy, radiotherapy, local palliative management

WLE: wide local resection, APR: abdominoperineal resection

The case presented here involved a patient with lower rectal cancer, with the tumor border extending to the dentate line; therefore, anal preservation was deemed impossible at the initial consultation. Then, preoperative chemoradiotherapy achieved a cCR, and a “Watch and Wait” approach was adopted to preserve the anus. However, microscopic secondary perianal Paget disease, potentially present at the time of the initial consultation and located outside the radiation field, might have become apparent during follow-up observation. An APR was considered as a salvage; however, since the primary tumor remained in clinical cCR, we opted for WLE, successfully preserving the anus. While mapping biopsy is sometimes used to determine resection margins, in this case, we set the incision line 10 mm proximal to the dentate line and confirmed negative margins through intraoperative frozen section examination.

In Western countries, the standard treatment strategy for locally advanced low rectal cancer is preoperative CRT followed by total mesorectal excision (TME). Total neoadjuvant therapy (TNT), which integrates preoperative (chemo)radiotherapy with systemic chemotherapy, has been increasingly adopted for the treatment of locally advanced low rectal cancer. According to previous randomized controlled trials, preoperative CRT achieves pathological complete response (pCR) rates of approximately 12%, whereas TNT is associated with anticipated rates of 15-30%[7-11]. Furthermore, the OPRA trial reported a TME-free survival of 40-50% with TNT[12]. Secondary perianal Paget disease complicates approximately 1.1% of low rectal cancers where the lower border of the tumor reaches the dentate line[13]. However, the actual prevalence of microscopic secondary perianal Paget disease in the perianal skin may be higher, as detailed pathological examination is not always deemed necessary in routine practice. With the increasing adoption of TNT, cases of secondary perianal Paget disease may become more common during the “Watch and Wait” period, as observed in the present case. It suggests that careful examination not only of the rectal mucosa but also of the perianal skin is necessary during the “Watch and Wait” period.

Conclusion

We report a case of locally excised secondary perianal Paget disease that became apparent during follow-up after preoperative CRT, enabling anal preservation. During the “Watch and Wait” period, vigilant observation is crucial, focusing not only on the rectal mucosa but also on the perianal skin.

Conflicts of Interest

There are no conflicts of interest.

Author Contributions

All authors contributed to the conception and design of this study. TA and TM prepared the materials and collected the data. HK and MA pathologically evaluated all resected specimens. TA and TM wrote the first draft of the manuscript, and all authors commented on previous versions of the manuscript. All the authors have read and approved the final version of this manuscript.

Approval by Institutional Review Board (IRB)

The Ethics Committee of the Cancer Institute Hospital approved this retrospective study (IRB number 2018-GA-1109).

Informed Consent

Witten's informed consent was obtained from the patient and her family.