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Table of Contents
Year : 2022  |  Volume : 40  |  Issue : 4  |  Page : 222-230

A clinicopathological study of perianal Paget disease: A single center-based cohort study and literature review

1 Education Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
2 Department of Dermatology, National Cheng Kung University Hospital, College of Medicine; School of Pharmacy, Institute of Clinical Pharmacy and Pharmaceutical Sciences, National Cheng Kung University, Tainan, Taiwan
3 Department of Dermatology, National Cheng Kung University Hospital; Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University; Center of Applied Nanomedicine, National Cheng Kung University, Tainan, Taiwan
4 Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
5 Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan

Date of Submission07-Mar-2022
Date of Decision02-Jul-2022
Date of Acceptance05-Aug-2022
Date of Web Publication17-Nov-2022

Correspondence Address:
Dr. Julia Yu-Yun Lee
Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1027-8117.361417

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Background: Perianal Paget disease (PPD), an uncommon extramammary Paget disease, is characterized by intraepidermal pagetoid spread of atypical Paget cells in the perianal skin. PPDs can be primary or secondary. Secondary PPDs have poorer prognosis due to progression of the underlying anorectal carcinoma. Objectives: We analyzed the clinicopathological features of PPDs to determine the primary versus secondary PPD. Methods: We reviewed the clinicopathological features, including evidence of underlying anorectal carcinomas, tumor immunoprofiles, treatments, and outcomes of 8 cases of PPD diagnosed in our department during 1992–2019. Results: Colonoscopy was performed in 6 cases; rectal adenocarcinoma and anal canal adenocarcinoma were detected in 2 cases each. Three patients had local recurrence(s). Based on the detection of underlying anorectal cancers and immunoprofiles, 2 cases were classified as primary (one with perianal squamous cell carcinoma), 4 secondary, and 2 inconclusive for primary or secondary PPD. The immunoprofiles were CK7(+)/CK20(−)/GCDFP-15(−)/CDX2(−) in the primary PPDs; CK7(+/−)/CK20(+)/GCDFP-15(−)/CDX2(+) in the secondary and inconclusive PPDs. Eventually, all patients with secondary PPD died of the disease; one primary PPD and one inclusive PPD cases died of unrelated causes. Conclusion: We report the clinicopathological features of 8 cases of PPD in Taiwanese and first describe differential CK7 expression in the epidermal and dermal tumor cells in 2 cases of secondary PPDs, which may provide a clue to the diagnosis of secondary PPD. Since an underlying anorectal carcinoma in PPDs may be undetectable by colonoscopy, it is essential to consider anoscopy and/or anal canal mucosal biopsy to search for an occult anorectal carcinoma.

Keywords: Extramammary Paget disease, immunohistochemistry, occult anorectal malignancy, perianal Paget disease, primary, secondary

How to cite this article:
Hou PC, Lee CN, Wong TW, Hsu TC, Wu CL, Lee JY. A clinicopathological study of perianal Paget disease: A single center-based cohort study and literature review. Dermatol Sin 2022;40:222-30

How to cite this URL:
Hou PC, Lee CN, Wong TW, Hsu TC, Wu CL, Lee JY. A clinicopathological study of perianal Paget disease: A single center-based cohort study and literature review. Dermatol Sin [serial online] 2022 [cited 2023 Jan 29];40:222-30. Available from: https://www.dermsinica.org/text.asp?2022/40/4/222/361417

  Introduction Top

Extramammary Paget disease (EMPD) is a rare disease entity, typically occurring at apocrine gland-rich areas. Perianal EMPD accounts for around 20% of all EMPD cases,[1] usually manifesting as erythematous patches or plaques with progression to ulcerative, infiltrative, or nodular lesions over time. The histopathology of EMPD is characterized by intraepidermal proliferation of atypical pagetoid cells with pale cytoplasm, large round nuclei, and prominent nucleoli. Paget cells are distributed as solitary units with pagetoid spread, formation of nest-like or glandular structures, and extension along the adnexal structures. Although uncommon, primary Paget disease invades the dermis in more advanced stage.[2]

Perianal Paget disease (PPD) is classified into primary or secondary depending on the existence of an underlying anorectal malignancy. Secondary PPD is resulted from extension of an extracutaneous malignancy with epidermotropic spread to the perianal epidermis.[3] As secondary PPD usually has poorer prognosis due to progression of the anorectal neoplasm,[4] immunohistochemical stains are utilized to predict the possibility of an associated cancer.[5],[6],[7],[8] However, the results were inconsistent.[7],[8] Moreover, the definition of secondary PPD is not standardized. Cases with distant, noncontiguous malignancies have been regarded as secondary PPD.[9] These limitations make it difficult for physician to perform pertinent clinical evaluation and management.

In our experience, PPDs have a high local recurrence rate, a finding strongly suggestive of the existence of an underlying anorectal carcinoma which, however, is often difficult to detect by the routine workup, including imaging and colonoscopy. In the present study, we sought to review the clinicopathological features of our cases of PPD to determine which constellation of the features may allow us to better determine primary versus secondary PPD.

  Methods Top

Case selection and clinicopathological review

In this retrospective study, we reviewed all pathologically confirmed EMPD cases diagnosed at our department during November 1992 to September 2019, after approval from the institutional review board (IRB) of National Cheng Kung University Hospital (IRB number: A-ER-109-275). The IRB has approved that informed consent forms are not required in this study. Demographic information and clinical features were collected from review of medical records and clinical pictures. PPD is defined as EMPD involving the perineal anal triangle. Patients with PPD suspicious of an underlying carcinoma were referred to colorectal surgeons for further evaluation. The underlying anorectal malignancy, when detected, was regarded as relevant based on the anatomical location and timing, specifically, tumor with anatomical proximity to the cutaneous lesion and found within 5 years.[10] Treatment modalities and clinical outcomes were also obtained from medical records and telephone interview.

Histopathological study

Histopathological features, including epidermal changes and the presence of dermal invasion, were reviewed. Immunohistochemistry (IHC) was performed on formalin-fixed paraffin-embedded sections. The procedures were done with the Bond-Max Automated IHC Stainer (Leica Biosystems Newcastle Ltd, Australia). Tissues were deparaffinized with xylene and pretreated with Epitope Retrieval Solution 2 (ethylenediaminetetraacetic acid buffer, pH 9.0) at 100°C, followed by incubation with primary antibodies [Supplementary Table 1] at room temperature. Tissues were then incubated with postprimary using the Bond™ Polymer Refine Detection Kit (Leica Biosystems Newcastle Ltd, United Kingdom), incubated with hydroperoxide blocking buffer and developed with 3,3'-diaminobenzidine chromogens. Counterstaining was done using hematoxylin.

The grading of immunoreactivity was divided into two parts: the extent of positively stained tumor cells and the intensity of positive staining. The former was graded as 0 (positive staining with any intensity in <5% tumor cells), 1+ (5%–25%), 2+ (26%–50%), 3+ (51%–75%), and 4+ (over 75%).[11] The tumor was regarded as focal positive (<50% of tumor cells stained) or diffuse positive (≥50% tumor cells stained). The intensity of immunoreactivity was graded as 1+ to 4+ by comparing with positive control. Overall, only cases with either the extent or intensity of staining graded as 3+ or 4+ were regarded as positive staining.

  Results Top

Clinical information

Our initial search of the department's database found 133 patients with pathological reports mentioning of pagetoid cells or spread. Among them, 10 cases had the diagnosis of malignant melanoma, 22 Bowen's disease or squamous cell carcinoma (SCC), 12 mammary Paget disease and 9 had other diagnoses. These cases were excluded. The remaining 80 cases had the diagnosis of EMPD, including 72 cases of nonperianal EMPD (48 penoscrotal, 14 vulvar, 6 inguinal/suprapubic, 4 axillary) and 8 cases of PPD, accounting for 10% of all EMPD cases diagnosed over 27-year period in our department.

Clinicopathological findings of these 8 cases (5 males, 3 females) were reviewed and additional IHC was performed as needed. Demographic information and clinical features were summarized in [Table 1]. The mean age at diagnosis was 68.8 years old (55–92 years old). The mean interval to diagnosis was 18.1 months (5–36 months). Clinical symptoms varied from asymptomatic to pruritus, pain or having blood-tinged stool. Physical examination revealed erythematous, eczematous patches or plaques with occasional ulceration. Colonoscopy performed in 6 patients detected rectal adenocarcinoma in two patients (Case 6, 7), anal canal adenocarcinoma in 2 (Case 5, 8) and negative finding in 2 (Case 1, 4). Of note, in Case 5, the first colonoscopy showed negative finding, but the second colonoscopy performed after an unknown interval detected an anal canal adenocarcinoma near the anal verge. In addition, 3 cases had other tumors deemed unrelated to PPD, specifically, anal SCC in Case 1 (recurrence, 15 months after the PPD diagnosis), left breast cancer in Case 2 (metachronous, 4 years before), left retro-auricular basal cell carcinoma in Case 4 (metachronous, 3 years before) and laryngeal cancer (metachronous, 9 years after) [Table 1].
Table 1: Summary of the clinical information of 8 cases of perianal Paget disease

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Histopathological features

All cases displayed characteristic features of Paget disease in the epidermis, including pagetoid spread of atypical cells with enlarged hyperchromatic, vesicular nuclei and abundant pale cytoplasm, or with scant cytoplasm indicating poor differentiation. Overall, the histopathology showed one case with signet-ring cells (12.5%; Case 7), 4 with adnexal involvement (50%; Case 5–8), and 2 with dermal invasion (25%; Case 6, 8). Their immunoprofiles are summarized in [Table 2].
Table 2: Summary of the immunoprofile of 8 cases of perianal Paget disease

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In two cases (Cases 1 and 2), the pagetoid cells were diffuse positive for CK7, negative for CK20 and GCDFP-15. CDX2 was positive with weak intensity (1+). These findings were consistent with primary PPD. Interestingly, Case 1 displayed two distinct intraepidermal components next to each other, specifically, one area with proliferation of atypical Paget cells, and another area with proliferation of atypical keratinocytes involving the entire thickness of epidermis without pagetoid feature. Tumor cells in the former were CK7, carcinoembryonic antigen positive, while the latter were diffusely p63 positive, indicating concomitant primary PPD and SCC in situ [Figure 1]. The recurrence of anal SCC in this case also supported this diagnosis.
Figure 1: Case 1: Primary perianal Paget disease with a concurrent perianal squamous cell carcinoma in situ. Biopsy specimen of the perianal lesion showed atypical intraepidermal proliferation with two different histomorphology. (a and b) One side showed prominent pagetoid spread of atypical Paget cells with pale cytoplasm and large hyperchromatic round nuclei. (c-h) Immunohistochemistry revealed that Paget cells were marked positive for CK7, CEA, weak positive for CDX2, while negative for CK20, GCDFP-15 and p63. (i and j) The other side showed more prominent epidermal hyperplasia with full-thickness proliferation of atypical cells presenting with hyperchromatic vesicular nuclei, without pagetoid morphology. (k-p) Immunohistochemistry revealed that atypical cells in this part were diffusely strong positive for p63, focally weak positive for CK7, CDX2, and negative for CK20 and GCDFP-15. These tumor cells were CEA-negative, except for some cells at the junctional zone of these two tumors. Magnification: ×100 for (a) and (i), ×200 for others.

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In the remaining 6 cases (Cases 3-8), the intraepidermal tumor cells were positive for CK20, CDX2 and negative for GCDFP-15. The intraepidermal pagetoid cells were CK7 positive, except for Case 5. Interestingly, the 2 cases with invasive disease (Cases 6 and 8), the epidermal and dermal components showed different histomorphology and immunoprofiles. In Case 6, the epidermis part displayed typical Paget cell morphology with abundant clear cytoplasm, while the component in the lower reticular dermis and lymphatics demonstrated high nuclear-to-cytoplasm ratio with scant cytoplasm. Both tumor components were diffuse positive for CK20 and CDX2, negative for GCDFP-15. However, CK7 was only positive in the epidermal component. The features of poorly differentiated tumor cells in the dermis with an immunoprofile of CK7(−)/CK20(+)/CDX2(+) were identical to that of the underlying rectal adenocarcinoma. In Case 8, CK7 was diffusely positive in the epidermal component but negative in the dermal part. The patient developed a recurrent poorly differentiated anal adenocarcinoma one year later, and the tumor displayed an immunoprofile identical to the dermal component of the initial PPD biopsy [Figure 2].
Figure 2: Case 8: Secondary perianal Paget disease with underlying anal adenocarcinoma. (a) Section of the initial biopsy specimen of perianal Paget disease showed epidermal hyperplasia with atypical pagetoid cells infiltrating the epidermis. (b-e) Immunohistochemistry showed that epidermal pagetoid cells were positive for CK7, CK20, CDX2, but negative for GCDFP-15. (f) The same section also showed diffuse infiltration of atypical cells with round vesicular nuclei, prominent nucleoli and pale cytoplasm in the dermis. (g-j) Immunohistochemistry showed that dermal tumor cells were positive for CK20 and CDX2, but negative for CK7 and GCDFP-15. (k) Section from the recurrent poorly differentiated anal adenocarcinoma demonstrated atypical cells with hyperchromatic nuclei and scant cytoplasm diffusely invading the dermis and subcutaneous tissue. (l-o) Immunohistochemical stains showed that atypical tumor cells were positive for CK20 and CDX2, but negative for CK7, GCDFP-15, identical to the dermal pagetoid cells (g-j) in the original biopsy specimen of perianal Paget disease. Magnification: ×200.

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Clinicopathological correlation

Based on the presence or absence of an underlying anorectal malignancy and immunohistochemical profiles, the 8 PPD cases were categorized into 3 groups, specifically, primary PPD (Cases 1, 2), secondary PPD (Cases 5–8), and PPD, inconclusive for primary or secondary disease (Cases 3, 4) [Table 2]. According to previous reports, primary PPDs are generally CK7(+)/CK20(−)/GCDFP-15(+)/CDX2(−), while secondary PPDs are mostly CK7(+/−)/CK20(+)/GCDFP-15(−)/CDX2(+).[7],[8] Therefore, Case 1 and 2 were classified as primary PPD, whereas Case 5 to 8 were deemed secondary PPD. For Case 3 and 4, their immunophenotypes fitted secondary disease, but no anorectal malignancy was found in the routine workup, so they were regarded as PPD, inconclusive for primary or secondary disease.

Based on the aforementioned diagnoses, the positive expression rate for each marker was as follows: 100% for CK7, 0% for CK20 and GCDFP-15, and 50% for CDX2 in primary PPDs (n = 2); 75% for CK7, 100% for CK20, 0% for GCDFP-15, and 100% for CDX2 in secondary PPDs (n = 4); 100% for CK7, CK20, and CDX2, and 0% for GCDFP-15 in the inconclusive PPD cases (n = 2).

Treatment and outcome

Treatment modalities in the eight patients included wide local excision (3 with split thickness skin graft) in 4 cases (50%), radiotherapy in 4 (50%), photodynamic therapy in 2 (25%), and chemotherapy in 3 (37.5%) [Table 1]. Follow-up of 8 cases showed that 3 cases (Case 3, 4, 7) encountered local recurrence in 5–24 months (mean 11.3 months). In the 2 primary PPD cases, one died of cardiac arrest, and one had complete remission without recurrence. As for the 2 inconclusive cases, one died of unknown cause, and one is still alive with multiple episodes of local recurrence. In contrast, all 4 secondary PPD cases died of underlying anorectal malignancies. Regarding the metastatic status, only three patients with secondary PPD (Cases 6–8) had extracutaneous metastases, specifically, lymph nodes (n = 3), one to the lung, and one to the liver and left rib [Table 1]. Overall, the disease-specific mortality rate was 50% of all 8 cases, whereas 100% in the secondary PPD subgroup.

  Discussion Top

The new WHO book classifies anal adenocarcinoma as primary if arising from the mucosal glandular epithelium, which shares the same immunoprofile of CK7(+/−)/CK20(+)/CDX2(+), as in colorectal adenocarcinomas, or from the anal gland, which shares identical immunoprofiles as skin adnexal carcinomas.[12] Primary PPD is indolent, whereas secondary PPD has poorer prognosis due to the progression of concurrent anorectal malignancies. In the present study, the 8 cases of PPD accounts for 10% of the 80 EMPD cases diagnosed during 27-year period in our department. All four patients with secondary PPD died of disease, while those without detectable underlying anorectal neoplasms generally had longer lifespan and their death was attributed to other medical events.

In our clinicopathological observation, primary PPDs often remain in the status of in situ carcinoma in the epidermis with or without downward extension along the adnexal structure, and without true dermal invasion for long time. On the contrary, secondary PPDs seem more likely to show both intraepidermal and invasive dermal components in the initial biopsy [Table 2]. Though the number of such cases are limited, it may be worthwhile to pay attention to this feature in the future studies. To improve the differentiation between primary and secondary PPDs, expressions of selected markers by IHC have been reported to predict the existence of an underlying malignancy in PPDs.[5],[7],[8] Although characteristic immunophenotypes have been described for primary and secondary PPDs, there were inconsistency in the results, thus failing to reach a 100% consensus. Previously, GCDFP-15, a marker of sweat gland differentiation, was found almost exclusively expressed in primary PPDs with a sensitivity range of 30%–100%.[5],[7],[8],[13] But it was all negative in our cases of primary PPDs. This implies that GCDFP-15 may be a marker with low sensitivity for detecting a primary disease, and a negative GCDFP-15 stain does not indicate a definite diagnosis of secondary PPD.

We did a literature review of reports of PPDs with immunohistochemical data from 1996 to 2021 and found a total of 159 cases. Based on the classification in individual reports, there were 70 primary and 89 secondary PPDs cases, and our present series added another 6 cases (2 primary and 4 secondary PPDs; 2 inconclusive cases were not included) [Table 3]. Further analyses revealed that CK7 was expressed in 89% (48/54) of primary PPD cases, but only in 68% (54/79) of secondary PPD cases, partly reflecting the CK7(−) nature of most anorectal cancers. Although CK20 and CDX2 were predominantly expressed in secondary PPD, 90% (77/86) and 93% (41/44), respectively, about a third of primary PPDs still demonstrated the positivity of CK20 (20/67, 30%) and/or CDX2 (11/41, 27%). These particular findings suggest that there may be a subgroup of PPDs with an immunoprofile of secondary PPDs whose primary anorectal malignancy remained unidentified at the time of initial diagnostic workup. As for GCDFP-15, its expression was generally negative in secondary cases while its positivity only accounted for 61% (35/57) of the primary cases, reiterating its high specificity but low sensitivity for primary PPDs.
Table 3: Summary of the immunoprofile of the primary (n=72) versus secondary (n=93) perianal Paget disease in the literature with 6 of our cases combined

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Overall, CK20(−)/GCDFP-15(+)/CDX2(−) is likely an immune signature for primary PPDs, while CK20(+)/GCDFP-15(−)/CDX2(+) for secondary PPDs. The positive predictive values for primary versus secondary diseases are: (a) CK7: 0.47 versus 0.53, (b) CK20: 0.21 versus 0.79, (c) GCDFP-15: 0.97 versus 0.03, (d) CDX2: 0.21 versus 0.79 [Table 3]. Yet, there are limitations in interpreting these data, including variations in defining positive staining of each IHC markers, and clinical and pathologic judgments as well as the extent of clinical workups in individual cases. Another confounding factor is that some authors regarded cases of PPD with noncontiguous colon cancers as secondary PPD.[14],[15],[16]

The inconsistency of immunoprofiles of PPDs for predicting the presence of an underlying anorectal cancer has raised the uncertainty of interpreting pathological findings for clinicians. However, the possibility of missing a clinically occult tumor in the anal canal by colonoscopy cannot be totally excluded,[17] as illustrated in Case 5. Possible explanations for overlooking the tumor include small tumor size (<10 mm), presence of multiple polyps, and infiltrative neoplasms in the anorectal wall without obvious protrusion or ulceration.[17] Of note, anal canal cancer generally presents as infiltrating ulcer with mildly elevated margins and rarely manifests as an apparent polypoid lesion.[18] Besides, colonoscopy is not as effective in detecting anal canal lesions as high-resolution anoscope,[18] thus increasing the chance of missing the tumor.

Some authors commented on the issue of occult anorectal primaries in PPDs. Goldblum and Hart reported two PPD cases with immunoprofile of CK7(+)/CK20(+)/GCDFP-15(−). Despite the negative colonoscopy, the authors speculated that there might be occult anorectal cancers, because of the presence of intraluminal necrosis and signet-ring cells.[5] Shimizu et al. described a case of PPD with an immunoprofile favoring a secondary disease, but colonoscopy, anoscopy and radiologic examinations all failed to find evidence of an underlying neoplasms. The authors resorted to anal mucosal biopsy and identified an occult anal canal carcinoma in situ.[19] Al Hallak and Zouain also reported a case with negative sigmoidoscopy, colonoscopy, and computed tomography findings. An underlying invasive adenocarcinoma was eventually detected after wide local excision of the perianal lesion.[20] These reports support our viewpoint that a diligent search for an occult anorectal malignancy is warranted in cases of PPD with an immunophenotype typical of secondary PPD, despite negative results by colonoscopy. A thorough or high-resolution anoscopy and/or anal canal biopsy can be very helpful or essential for such cases. Likewise, in cases of PPD with CK7(+)/CK20(−)/CDX2(−), the same approach is recommended to look for an underlying anal gland adenocarcinoma with pagetoid spread, despite its rarity,[21],[22] since anal gland carcinoma shares the same immunoprofile as skin adnexal carcinomas and primary PPDs.

Histopathologically, Paget disease can mimic other types of skin cancer, most importantly melanoma in situ and pagetoid Bowen's disease, which may also show atypical pagetoid cells with pagetoid spread.[23] Notably, reports of the concomitant occurrence of SCC in situ and EMPD are rare.[24] Several staining markers can be used for differential diagnosis; for instance, CEA, BerEP4 for Paget disease and CK14, p63 for SCC in situ.[24],[25] However, in cases where histology was dominated by features of EMPD, the component of Bowen's disease may be overlooked, as in our Case 1, in which only PPD was diagnosed in the initial perianal biopsy. The SCC in situ component, located to one side of the PPD, lacked clear cytoplasm or pagetoid morphology. Initially, these features were interpreted as poorly differentiated Paget cells. After an overt SCC was diagnosed in this patient later on, the original biopsy specimen was reviewed. The nonpagetoid component was shown to be p63-positive, confirming the diagnosis of concurrent SCC in situ and PPD in the initial biopsy specimen. The two different malignant entities were usually separated with a transitional collision zone,[24],[26] as seen in our case.

CK7 expression is generally positive in the lung and breast epithelia but negative in the colorectal and prostatic glandular epithelia.[27] However, CK7 positivity is shown in a few cases of colorectal cancer. A recent study comparing the percentage and general outcome between CK7(+) and CK7(−) colorectal adenocarcinoma found that CK7 was more commonly expressed in poorly differentiated, invasive, and metastatic diseases.[27] In the present series, Case 6 and Case 8 were secondary PPDs with infiltrative dermal component. Interestingly, CK7 was expressed solely in the intraepidermal component and not in the dermal component, however, the intraepidermal tumor cells had more abundant cytoplasm, implying better differentiation. To the best of our knowledge, the differential expression of CK7 in the epidermal and dermal tumor cells in secondary PPDs has not been documented previously. Possible explanations include the followings: (a) the epidermal microenvironment may be more inducive to the CK7 expression in primary anorectal tumor cells when the tumor develops pagetoid spread, similar to the Paget cells in primary PPD that generally express CK7.[5] (b) It is not uncommon that different clones develop as cancers progress. CK7 is not uniformly expressed in the epidermal Paget cells of primary EMPD. Likewise, different clones may develop in secondary PPD during the process of epidermal spreading.

  Conclusion Top

We report the clinicopathological features of 8 cases of PPD in Taiwanese (accounting for 10% of EMPD in the study period), and first describe the finding of differential CK7 expression in the epidermal and dermal tumor cells in secondary PPDs, which may provide a clue to the diagnosis of secondary PPD. We also emphasize that an occult anorectal malignancy might be overlooked despite a negative colonoscopic exploration, especially when the perianal tumor displays an immunoprofile favoring secondary PPD. In such cases, a diligent search for an occult anorectal malignancy by anoscopic examination (especially high-resolution anoscopy), and/or anal canal mucosal biopsy are warranted for further investigation.


The study is financially supported by the Ministry of Science and Technology, Taiwan MOST-109-2327-B-006-005, MOST110-2314-B006-086-MY3, National Cheng Kung University Hospital, Grant/Award Number: NCKUH-11006002, and the Center of Applied Nanomedicine, National Cheng Kung University from the Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education in Taiwan to TWW.

Financial support and sponsorship

The study is financially supported by the Ministry of Science and Technology, Taiwan MOST-109-2327-B-006-005, MOST110-2314-B006-086-MY3, National Cheng Kung University Hospital, Grant/Award Number: NCKUH-11006002, and the Center of Applied Nanomedicine, National Cheng Kung University from the Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education in Taiwan to TWW.

Conflicts of interest

Prof. Julia Yu-Yun Lee, an editorial board member at Dermatologica Sinica, had no role in the peer review process of or decision to publish this article. The other authors declared no conflicts of interest in writing this paper.

  Supplementary Material Top

  References Top

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  [Figure 1], [Figure 2]

  [Table 1], [Table 2], [Table 3]


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