Clinical features of pagetoid spread: Analysis of perianal lesions associated with anal canal adenocarcinoma and perianal primary extramammary Paget disease

Secondary extramammary Paget disease (s‐EMPD) represents anal canal and rectal, bladder, and gynecological cancers, which horizontally extend within the epidermis of the anal and vulvar skin. It is necessary to distinguish this condition from primary extramammary Paget disease (p‐EMPD), which occurs primarily in genital and perianal areas. This study aimed to investigate the clinical and histopathological features of these two conditions in the perianal skin and to identify useful features for differentiation. We retrospectively analyzed 16 patients who visited Shinshu University Hospital from 2009 to 2022 and presented with perianal skin lesions and suspected EMPD. Six patients had p‐EMPD and 10 had s‐EMPD derived from anal canal adenocarcinoma. Regarding clinical features, nine of 10 (90%) of the s‐EMPD cases had symmetric skin lesions, whereas all of the p‐EMPD cases had asymmetrical lesions (p = 0.0004). Furthermore, assessment of symmetry around the anus showed that s‐EMPD had a significantly smaller coefficient of variation than p‐EMPD (0.35 and 0.62, respectively; p = 0.048), suggesting that s‐EMPD was more symmetric around the anus. The frequency of raised lesions, such as foci or nodules, was nine of 10 (90%) for s‐EMPD and one of six (16%) for p‐EMPD (p = 0.003). Well‐defined tumor borders on the lateral margins were identified in s‐EMPD (5/10, 50%); however, they were not identified in p‐EMPD (0/6, 0%). The borders tended to be clearer in s‐EMPD; however, the difference was not significant (p = 0.078). Based on these findings, we recommend consideration of s‐EMPD when anal skin lesions are symmetrical, well‐defined, or raised.

study aimed to investigate the clinical and histopathological features of these two conditions in the perianal skin and to identify useful features for differentiation. We retrospectively analyzed 16 patients who visited Shinshu University Hospital from 2009 to 2022 and presented with perianal skin lesions and suspected EMPD. Six patients had p-EMPD and 10 had s-EMPD derived from anal canal adenocarcinoma. Regarding clinical features, nine of 10 (90%) of the s-EMPD cases had symmetric skin lesions, whereas all of the p-EMPD cases had asymmetrical lesions (p = 0.0004). Furthermore, assessment of symmetry around the anus showed that s-EMPD had a significantly smaller coefficient of variation than p-EMPD (0.35 and 0.62, respectively; p = 0.048), suggesting that s-EMPD was more symmetric around the anus. The frequency of raised lesions, such as foci or nodules, was nine of 10 (90%) for s-EMPD and one of six (16%) for p-EMPD (p = 0.003). Well-defined tumor borders on the lateral margins were identified in s-EMPD (5/10, 50%); however, they were not identified in p-EMPD (0/6, 0%). The borders tended to be clearer in s-EMPD; however, the difference was not significant (p = 0.078). Based on these findings, we recommend consideration of s-EMPD when anal skin lesions are symmetrical, well-defined, or raised.

K E Y W O R D S
anal canal adenocarcinoma, extramammary Paget disease, pagetoid spread, raised appearance, symmetrical spread, well-defined margin

| INTRODUC TI ON
Secondary extramammary Paget disease (s-EMPD) represents anal canal and rectal, bladder, and gynecological cancers, which extend horizontally within the epidermis of the anal and vulvar skin. 1 It is necessary to distinguish this condition from primary extramammary Paget disease (p-EMPD), which occurs primarily in genital and perianal areas and occasionally extends to the urethra, vagina, or anus.
p-EMPD and s-EMPD have different causes and require different treatment and management. However, clinical features of p-EMPD and s-EMPD remain to be fully elucidated. This study aimed to investigate the clinical and histopathological features of these two conditions in the anorectal region and to identify useful features for differentiation.

| ME THODS
We retrospectively analyzed perianal skin lesions in 16 patients who were suspected as EMPD in Shinshu University Hospital between 2009 and 2022. This study was approved by the ethics committee of the Shinshu University School of Medicine (#5676) and was conducted in accordance with institutional review board guidelines. Six patients were diagnosed with p-EMPD, and 10 were diagnosed with s-EMPD derived from anal canal adenocarcinoma. We performed CK-7, CK-20, GCDFP-15, and CDX-2 immunostaining. Clinical and histopathological features were collected through electronic medical records. The differences between the two conditions were compared at the following perspectives: protuberance, continuity to the mucosa, circumscription, symmetry of perianal skin lesions, boundary clarity (dermal side), and association of depigmentation.
Protuberant lesion was defined as those with nodules or foci, not limited to a percentage of the lesion. A skin rash was defined as circumscribed type if it was present in more than 90% of the 360° directions centered on the anus. We have not included depigmentation in our determination of whether or not the circumscribed.

| RE SULTS
There were more males in both cohorts, and the s-EMPD cohort had a higher proportion of males. The p-EMPD cohort had a longer disease duration than the s-EMPD cohort (average duration of 27.3 and 9.7 months, respectively). Skin symptoms, such as itchiness and pain, were observed in two of six (33%) of the patients with p-EMPD and one of 10 (10%) of the patients with s-EMPD. Defecation disturbance, such as constipation and bleeding during defecation, were observed in five of 10 (50%) of the patients with s-EMPD and zero of six (0%) of the patients with p-EMPD (Table 1).
Six and 10 of the perianal lesions associated with p-EMPD and s-EMPD, respectively, were analyzed by their characteristics, including circumference, symmetry, radiality, surface characteristics, prominence, and border distinctiveness. A previous study reported circumferential and symmetrical perianal distribution, a focal or papillomatous elevation of the margins of the rash, and a clear cutaneous border of the tumor as characteristics of s-EMPD. 2 The present study, however, found no significant difference in the circumference of the rash between the two groups (p = 0.55; Table 1). On the other hand, nine of 10 (90%) patients with s-EMPD had symmetric perianal skin lesions, whereas all patients with p-EMPD had asymmetric skin lesions (p = 0.0004) ( Table 1; Figure 1). When perianal symmetry between the two groups was compared, s-EMPD had a smaller coefficient of variation of length in four directions from the anus (average = 0.35) than p-EMPD (average coefficient of variation = 0.62; p = 0.048) ( Figure 2); thus, these findings suggest that s-EMPD was more symmetric around the anus. The percentage of patients with raised lesions, such as foci or nodules, was nine of 10 (90%) for s-EMPD and one of six (16%) for p-EMPD (p = 0.003; Table 1). Welldefined tumor borders on the lateral margin were identified in five of 10 (50%) s-EMPD cases, and zero of six (0%) of p-EMPD borders tended to be clearer in s-EMPD; however, the difference was not significant (p = 0.078; Table 1 (Table 1).
In histopathological findings, a previous study reported that fibroepithelioma with Pinkus-like changes and peripheral nuclear palisading is characteristic of s-EMPD and that the coexistence of subepidermal mucin deposition with fibroepithelioma is specific for s-EMPD. 3 In this study, similar epithelial changes were observed in five of 10 (50%) patients with s-EMPD; however, they were not observed in p-EMPD (Table 1) p-EMPD (data not shown), which is consistent with the previous study. 3 In addition, subepidermal mucus retention was observed in five of six (83.3%) p-EMPD cases and three of 10 (30%) s-EMPD cases; thus, our findings suggest that it was not characteristic of s-EMPD.
In conclusion, we propose that s-EMPD should be considered when anal skin lesions are raised and well defined, as well as in cases of symmetrical spread from the anus.

CO N FLI C T O F I NTER E S T S TATEM ENT
None declared. F I G U R E 2 Coefficient of variation in the four directions of secondary extramammary Paget disease (s-EMPD) and primary extramammary Paget disease (p-EMPD). Box plots were created based on the coefficient of variation, which was calculated from the lengths in the four vertical and horizontal directions from the anus. The averages of s-EMPD and p-EMPD were 0.35 and 0.62, respectively (p = 0.048).