Abstract
Extramammary Paget’s disease (EMPD) is a rare intraepithelial adenocarcinoma. EMPD can be associated with an underlying malignancy of an adjacent organ, in which case the skin lesion is known as the pagetoid spread (PS) of the underlying tumor. PS, also known as secondary EMPD, has a worse prognosis than primary EMPD. The standard treatment is surgery, but the efficacy of nonsurgical treatments is unknown in inoperable cases. We present 2 cases of anal canal adenocarcinoma with PS that were treated with definitive concurrent chemoradiation therapy (CCRT). Although both cases experienced recurrence outside of the radiation field, and one died, anal function was preserved in both. In conclusion, CCRT may be a viable treatment option for inoperable anal canal cancer with PS.
Keywords: Pagetoid spread, Secondary extramammary Paget’s disease, Anal canal cancer, Concurrent chemoradiation therapy, Case report
Introduction
Extramammary Paget’s disease (EMPD) is a rare condition that affects only 1–2% of vulval malignancies [1]. EMPD is distinguished by intraepithelial skin invasion, most commonly caused by adenocarcinoma of vulva, perineum, and scrotum. About 25% of EMPD cases are associated with an underlying malignancy [1], in which case the skin lesion is referred to as the pagetoid spread (PS) of the underlying tumor. About 33–80% of perianal EMPD is associated with underlying rectal/anal canal cancer, and approximately 6% of anal canal adenocarcinoma has PS [2]. The first line of treatment for anal canal adenocarcinoma with PS is surgery, and the majority of case reports published on this disease involve surgical cases. However, when compared to anal canal cancer without PS, surgery can be extremely invasive due to the wide resection margin of skin in PS cases. Furthermore, surgery in this region frequently necessitates resection of anal sphincter muscles, resulting in a loss of anal function and a lower quality of life for the patient. We present two cases of inoperable anal canal adenocarcinoma with PS that were treated with concurrent chemoradiation therapy (CCRT) and resulted in good local control.
Case report
Case 1
A 70-year-old woman complaining of anus erosion presented with a flat red skin lesion extending from the anus to the perineal region (Fig. 1a). Skin biopsy revealed poorly differentiated adenocarcinoma with PS (Fig. 1b). The skin lesion tested positive for CK7, CK20, and CDX2 immunostaining. Contrast-enhanced CT (CECT) revealed metastasis in the left inguinal lymph node (LN) (Fig. 2). The primary lesion was undetectable on MRI, but colonoscopy revealed rough-surfaced mucosa.
Fig. 1.
a Visual presentation of the anus of case 1, with a flat red skin lesion extending from the anus to the perineum. b Hematoxylin–Eosin staining of a skin biopsy reveals the intraepidermal pagetoid spread of poorly differentiated adenocarcinoma
Fig. 2.
CECT imaging before treatment. The arrow indicates the left inguinal LN metastasis. The primary lesion was undetectable
The patient was diagnosed at stage IIIB, T3N1M0 (UICC 8th) with anal canal adenocarcinoma. The patient refused surgery and instead received chemotherapy. The chemotherapy regimens comprised modified fluorouracil and oxaliplatin (mFOLFOX), FOLFIRI (leucovorin calcium, fluorouracil, and irinotecan hydrochloride), bevacizumab, pembrolizumab, and capecitabine. 39 months after the diagnosis, left external iliac and paraaortic LN metastasis appeared. CCRT was used to achieve local control of a pelvic lesion with 58 Gy/2 Gy and capecitabine 1800 mg/day, targeting the primary lesion and the inguinal LN (Fig. 3). The treatment resulted in grade 3 radiation dermatitis (Common Terminology Criteria for Adverse Events (CTCAE) 5.0) of the anal and vulva, causing erosion and bleeding. Radiation dermatitis healed 9 months after treatment, leaving the skin with depigmentation and sclerosis (Fig. 4). The patient was administered panitumumab following chemoradiotherapy.
Fig. 3.
The treatment plan for the first CCRT of case 1. Intensity-modulated radiation therapy (IMRT) was used. 44 Gy in 22 fractions was first administered to the primary lesion, inguinal lymph node, and pelvic lymph node areas. The primary lesion and inguinal lymph node were also treated with 14 Gy in 7 fractions as boost radiation
Fig. 4.
Physical presentation of the anus 31 months after the start of the initial CCRT. Although depigmentation and sclerosis of the skin can be seen, there is no visible remnant of the skin lesion
CT scanning performed 10 months after the start of the chemoradiotherapy revealed that the lesions included in the radiotherapy target had a complete response, but it also revealed enlargement of paraaortic LN metastasis and emergence of the mediastinal LN metastasis. PET-CT was performed, and FDG uptake was detected in the paraaortic and mediastinal LN. A salvage CCRT of 60 Gy/2 Gy to paraaortic and mediastinal LN metastasis with capecitabine was carried out 11 months after the first chemoradiotherapy. The patient has been treated with panitumumab for 20 months following the second chemoradiotherapy and has had no loco-regional recurrence or further metastasis. Her anal function is intact.
Case 2
A 69-year-old woman had itches and skin erosion in her anus for 4 years before visiting her doctor with complaints of anal and left inguinal mass. Physical examinations revealed a flat red mass that extended from the anus to the left buttocks (Fig. 5a). The mass was accompanied by a flat red skin lesion that spread to both buttocks, perineum, and left inguinal region. Skin biopsy revealed adenocarcinoma with PS (Fig. 5b).
Fig. 5.
a Visual presentation of the anus of case 2. A flat red mass that extends from the anus to the left buttocks is shown. b Hematoxylin–Eosin staining of a skin biopsy from case 2 reveals intraepidermal pagetoid spread of adenocarcinoma
A contrast-enhanced (CE) CT scan and a MRI revealed a mass that extended from the rectum to the anus, as well as a mass in the inguinal region. PET-CT imaging revealed that both the anal mass and the skin lesion had high FDG uptake (Fig. 6). Colonoscopy revealed a protruding lesion, primarily in the lower rectum near the dentate line. The patient was comprehensively diagnosed with stage IIIC, T3N1M0 (UICC 8th) anal canal adenocarcinoma. The lesion was deemed inoperable due to its size and wide extension, and the patient received CCRT of 66 Gy/2 Gy with capecitabine 3000 mg/day. The treatment caused grade 3 diarrhea and grade 3 radiation dermatitis of the anal. Radiation dermatitis caused erosion of the anal skin, which healed within a year but left the skin with depigmentation and telangiectasia (Fig. 7).
Fig. 6.
PET-CT before treatment of case 2. Arrows depict the primary lesion of the anal canal as well as the extension of the pagetoid spread within the skin, demonstrating the continuity of the lesion
Fig. 7.
Physical presentation of the anus 16 months after the start of the initial CCRT. Although the skin has depigmented, there are no visible remnants of the skin lesion
The patient received adjuvant chemotherapy for 3 months following the CCRT. The adjuvant chemotherapy regimens included FOLFOX, Bevacizumab, Oxaliplatin, and S-1. The disease initially went undetected, but relapse in the thoracic LNs was detected 1 year after the start of the initial treatment. Salvage radiation therapy (RT) of 60 Gy/2 Gy was given 19 months after the initial treatment. 3 months after the second radiation therapy, the patient experienced dyspnea which was at first diagnosed as radiation pneumonitis and treated with prednisolone 0.5 mg/kg, but the symptom prevailed. The thoracic LNs showed reduction at first, but CT scanning performed 4 months after the second radiation therapy showed regrowth and progression. Although the patient died due to dyspnea resulting from progression of the thoracic LN swelling 24 months after the initial treatment, the primary lesion of the anal canal was relatively well controlled, and her anal function was preserved for life.
Discussion
Anal canal adenocarcinoma with pagetoid spread has a worse prognosis than those without PS, with 5-year OS of 45 and 52–60% respectively [2]. There are currently no treatment guidelines for anal canal cancer with PS. Shutze et al. [3] propose surgery as the standard treatment for perianal Paget’s disease, with or without underlying malignancy. In inoperable cases due to lesion extension and patient refusal, alternative treatment options are unclear. According to Snast et al.’s systemic review of nonsurgical treatment modalities for EMPD [4], RT in conjunction with imiquimod is the most effective. However, the systemic review focuses on primary EMPD cases.
To our knowledge, there have been 3 published cases of definitive RT or CCRT for anal canal adenocarcinoma with PS (Table 1). One patient received CCRT of 40/2 Gy and doxifluridine 800 mg and had a showed complete response, was disease-free after 9 months, and their anal function remained intact [5]. Another case was treated with RT of 60/2 Gy and adjuvant FOLFIRI, but there was no mention of anal function preservation [6]. The third case underwent CCRT of 54/1.8 Gy with oral capecitabine, followed by adjuvant 12 cycles FOLFOX [7]. This case was reported to be disease-free at a 1-year follow-up, and while there was a complaint of defecation proctalgia, it was successfully managed effectively with perianal Botox injection. These cases, along with ours, demonstrate the potential role of CCRT in local control or, in some cases, definitive treatment while preserving anal function.
Table 1.
Case reports of anal canal adenocarcinoma with pagetoid spread treated with CCRT or RT
| Author (year of publication) | Patient sex, age (years) | Radiation dose | Chemotherapy | Follow-up duration (months) | Outcome | Anal function |
|---|---|---|---|---|---|---|
| Sakata et al. (1994) [5] | M, 86 | 40 Gy/2 Gy | Concurrent doxifluridine 800 mg + 5-FU ointment | 9 | NED | Preserved |
| Shimizu et al. (2003) [6] | M, 59 | 60 Gy/2 Gy | Adjuvant FOLFIRI | 5 | AWD | Not mentioned |
| Apikotoa et al. (2022) [7] | F, 76 | 54 Gy/1.8 Gy | Concurrent capecitabine, adjuvant FOLFOX | 12 | NED | Preserved |
M male, F female, NED no evidence of disease, AWD alive with disease, CCRT concurrent chemoradiation therapy
While the optimal chemotherapeutic agent for CCRT is unclear due to small number of reported cases, utilizing capecitabine seems promising and tolerable from our 2 cases and the case reported from Apikotoa [7]. Moreover, because anal canal adenocarcinoma is commonly treated with similar strategies to rectal cancer [8], and since capecitabine is the standard chemotherapeutic agent used for perioperative CCRT in rectal cancer [9], utilizing capecitabine for CCRT seems decent. As for dose fractionation, doses greater than or equal to 60 Gy have been shown to be effective when treating EMPD. This recommendation is based on a systemic review of mainly primary EMPD cases, and it is unclear whether it can be applied to secondary EMPD [10].
Over the last decade, surgical techniques have advanced to the point where sphincters can be spared in mid to low-risk rectal cancers [11], avoiding permanent stomas. However, abdominoperineal resection (APR) is required in T3 or 4 anal canal cancer [12], so permanent stomas cannot be avoided. Patients with permanent stomas are known to have a lower quality of life (QOL) [13]. Furthermore, patients with anal canal adenocarcinomas accompanied by PS require a wider surgical margin than patients with non-PS accompanying anal canal adenocarcinomas [14], and the impairment of QOL is even greater. Meanwhile, anal function was preserved in both of our 2 cases presented, as well as all of the related cases shown in Table 1, except for the case that made no mention of anal function.
While surgery remains the primary standard treatment, in cases of inoperable disease or when the patient refuses surgery, CCRT may be the next option to consider.
Data availability
The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request. Data are located in controlled access data storage at Shiga General Hospital.
Declarations
Conflict of interest
The authors did not receive support from any organization for the submitted work.
Ethical approval
This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Shiga General Hospital (Date March 14, 2025/No. 250314-01).
Informed consent
Informed consent was obtained from all individual participants included in the study.
Consent to participate/publish
Patients signed informed consent regarding publishing their data and photographs.
Footnotes
Publisher's Note
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Change history
6/24/2026
A Correction to this paper has been published: 10.1007/s13691-026-00881-3
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request. Data are located in controlled access data storage at Shiga General Hospital.