A review of 14 cases of perianal Paget’s disease: Characteristics of anorectal cancer with Pagetoid spread

doi:10.21203/rs.3.rs-1507489/v1

Background: Perianal Paget's disease (PPD) is intraepithelial invasion of the perianal skin and is frequently associated with underlying anorectal carcinoma. The relatively rare nature of this disease has made it difficult to develop treatment recommendations. This study aimed to clarify the clinicopathological characteristics, treatment options that allow preservation of anorectal function, and long-term results.

Methods: The National Cancer Center Hospital database was searched for all cases of perianal Paget's disease

diagnosed between 2006 and 2021. In the 14 cases identified, we reviewed the diagnosis, management, and outcomes of adenocarcinoma with Pagetoid spread, including suspected or recurrent cases.

Results: All 14 cases met the inclusion criteria. The median follow-up period after diagnosis was 4.5 (range, 0.1–13.0) years. Pagetoid spread before initial treatment was suspected in 12 cases (85.7%). Underlying rectal cancer was identified in 6 cases and no primary tumor was detected in the other 6 cases. Seven patients had recurrent disease, with median time to recurrence of 34.6 (range, 19.2–81.7) months. The time to first relapse was 3 months and that to the second relapse was 6 months. The overall 5-year survival rate was 90.0%.

Conclusions: Skin biopsy and immunohistological examination are essential to differentiate PPD with and without underlying anorectal carcinoma. If wide local excision is performed to preserve the anus, it is necessary to search carefully for distant metastasis and arrange for regular follow-up, even if recurrence occurs after a long period. Local resection may achieve long-term survival in patients with locoregional recurrence if distant recurrence does not occur within a short interval.

Pagetoid spread

extramammary Paget’s disease

anorectal cancer

CK20

GCDFP-15

CDX-2

Pagetoid spread (PS) is defined as the proliferation of individual cells in the epithelium characterized by erythema and inflammation. It can manifest as mammary or extramammary Paget’s disease (EMPD) and is described as an apocrine gland tumor that can be benign or malignant with metastatic potential. EMPD has been reported at several extramammary sites, including the axilla, thigh, groin, perineum, scrotum, vulva, and perianal area [1, 2]. When EMPD affects the perianal region, it is called perianal Paget’s disease (PPD). PPD is usually associated with an underlying malignancy, such as anal, rectal, cervical, or urinary bladder adenocarcinoma with an appearance similar to that of simple PPD without an underlying malignancy [3, 4]. The prognosis of simple PPD is relatively favorable, with overall and disease-free survival of approximately 60% at 5 years [5–7]. However, PPD associated with an underlying malignancy has been reported to have poor prognosis [5–9]. Given the rarity of PPD, only a limited number of cases have been reported, so the prognosis and appropriate treatment options remain unclear.

Immunohistochemical analysis of the skin lesion is useful for differentiating whether or not PPD is associated with underlying anorectal adenocarcinoma or carcinoma. Immunohistochemical markers that are frequently used include cytokeratin 7 (CK7), CK20, gross cystic disease fluid protein 15 (GCDFP-15), and CDX2. CK7 is a sensitive marker for almost all Pagetoid neoplasms of the breast and genital skin; however, some rectal adenocarcinomas also express CK7 and it has no practical value for distinguishing the type of PPD [10, 11]. CK20 might be expressed in colorectal carcinoma but not in simple PPD [12]. GCDFP-15, which is regarded as a specific marker for apocrine epithelium tissue, is usually positive in breast cancer and simple PPD [13–15] (Fig. 1). As mentioned above, PPD associated with anorectal carcinoma often has the CK20+/GCDFP-15- immunophenotype whereas simple PPD shows a CK20-/GCDFP-15 + pattern [16]. CDX2, which has a high positivity rate in gastrointestinal cancers, including rectal cancer, has been used [17]. However, about 17% of colorectal cancers are negative for CK20 [18]. Therefore, it is necessary to evaluate the underlying malignancy using a combination of colonoscopy and radiology [19].

Staging classification and treatment outcome

A staging classification for PPD that includes appropriate treatment for each stage has been proposed (Table 1) [9, 20]. The prognosis is good for stage I (Paget’s cells found in the perianal epidermis and adnexa without primary carcinoma) but worsens for stage II (invasive cutaneous disease penetrating the basement membrane and entering the underlying stroma and/or synchronous localized malignancies, i.e., IIa adnexal malignancy and IIb visceral malignancy), stage III (regional metastatic disease), and stage IV (distant metastatic disease).

The treatment options for PPD depend on local (extent and depth of invasion) and regional (lymph node involvement) factors and the extent of systemic disease. Local excision (with macroscopic clearance of surgical margins) has been performed as a treatment for non-invasive PPD but was associated with a high local recurrence rate (40%) [19]. Wide local excision (WLE, > 1 cm microscopic clearance of surgical margins) with a sphincter-saving technique was later proposed as the treatment of choice for PPD due to the higher survival rate in patients treated with WLE than in those treated with local excision and due to the better chance of cure and normal survival. The standard treatment for PPD associated with the anorectal canal is abdominoperineal resection (APR) [9, 20]. However, it is recommended that adenocarcinoma of the anal canal be managed in the same way as rectal cancer [21, 22], and transanal local excision is appropriate for selected early-stage rectal cancers [22, 23]. Therefore, even in cases of PPD associated with anal canal cancer, combined transanal local excision and WLE may be an alternative to APR.

The distinction between PPD with and without underlying anorectal cancer is essential [3, 24–26] because of the differences in treatment methods and the prognosis [4]. Due to the rarity of PPD, few cases have been reported [25–28], and long-term outcomes of treatment for PS are unknown. This study aimed to elucidate the natural history and treatment outcomes of PPD associated with anorectal carcinoma.

A search of the National Cancer Center Hospital database identified 14 cases of PPD diagnosed between 2006 and 2021. Cases of adenocarcinoma of the rectum or anal canal with Pagetoid spread, including suspected and recurrent cases, were retrospectively reviewed for age, sex, tumor size, presence or absence of preoperative endoscopic findings, presence or absence of mapping biopsy, treatment methods, and long-term prognosis.

All 14 patients met the inclusion criteria. Eight patients (57.1%) were male and 7 (50.0%) were female(Table 2). The median age was 74 (range, 55–84) years. Twelve patients (85.7%) suspected having PS before initial treatment. The most commonly used immunostaining for differentiation was CK7+/CK20+/GCDFP-15-/CDX2+. These 12 patients were clinically and radiologically evaluated for underlying anorectal carcinoma, which was identified in 6 cases. The median size of the primary tumor was 52 (9–110) mm. No primary lesions were detected in the other 6 cases. There were no distant metastases at the initial diagnosis; however, 1 patient had metastasis to the lateral lymph nodes, and another had metastasis to the inguinal lymph nodes.

The median follow-up period after diagnosis was 4.5 (range, 0.1–13.0) years. At the last follow-up, 7 patients were alive with no evidence of disease, 4 were alive with recurrent disease, 1 had transferred to another hospital, and 2 had died of disease.

Seven patients (50%) developed recurrence, with a median time to recurrence of 34.6 (range 19.2–81.7) months. Three patients had local recurrence, and 4 (28.6%) had a recurrence in the inguinal lymph nodes. One patient had distant metastases. The time to first relapse was 3 months and that to the second relapse was 6 months. The 5-year overall survival rate was 90.0%.

The initial treatment in the 6 patients with no detectable primary lesion was WLE alone (n=4, 66.7%), APR + WLE (n=1, 16.7%), and radiotherapy (n=1, 16.7%). The outcomes in the 4 patients who underwent WLE alone were as follows: alive with no evidence of disease (n=2), alive with lung metastasis (n=1), and died after inguinal lymph node metastases at first relapse and liver and bone metastases at second relapse (n=1).

The initial treatment of the 6 patients in whom anorectal carcinoma was detected was APR + WLE (n=3, 50%), transanal local excision + WLE (n=2, 33.3%), and referral to another hospital (n=1, 16.7%). The outcomes in the group that underwent APR + WLE were as follows: alive with no evidence of disease (n=2) and died (n=1). The outcomes in the group that underwent transanal local excision + WLE were as follows: alive with no evidence of disease (n=1) and alive with recurrent disease (n=1). Mapping biopsy was performed in 5 (45.4%) of the 11 patients who underwent surgical resection, and 4 (80.0%) had positive margins. In the 6 cases without mapping biopsy, 2 (33.3%) had positive margins.

In 1 of our patients (case 13), PS was detected in a postoperative specimen but not before surgery. In another patient (case 14), heterogeneous local recurrence resulted in a recurrence with PS.

In case 13, after chemotherapy for unresectable anal canal cancer with multiple inguinal lymph node metastases, the patient underwent perineal rectal amputation, bilateral lateral dissection, and inguinal lymph node dissection as a conversion resection. The pathological specimen showed PS, which had not been recognized preoperatively. Resection margins for skin lesions were negative. The pathological diagnosis was bilateral inguinal lymph node metastasis, and adjuvant chemoradiation was performed.

Case 14 developed a recurrence of a skin lesion caused by PS 13 years after endoscopic treatment for anal canal cancer. WLE was performed, and the patient remains under observation.

PPD is usually associated with an underlying malignant anorectal tumor and has a relatively poor prognosis [24] with a high risk of local recurrence [29]. The rate of malignancy associated with PPD ranges from 33% to 86% [30]. Immunohistological examination alone is not sufficient to differentiate whether or not PPD is associated with underlying anorectal cancer in half of the cases, and endoscopic and radiologic evaluation is mandatory to confirm the presence or absence of underlying malignancy.

In the present study, primary anorectal carcinoma could not be identified preoperatively in half of the patients, and APR was performed in only 1 case. There was 1 death in the WLE group. However, only half of the patients with anorectal cancer underwent APR + WLE to preserve the anus, although there were cases of recurrence-free survival of more than 5 years after WLE. Further investigations are needed to identify cases in which APR should be pursued aggressively and those in which WLE (with or without transanal local excision) can be considered.

The 2 deaths occurred in a patient without an identified primary tumor who underwent WLE alone as the initial treatment (case 1) and in a patient with a primary tumor identified preoperatively who underwent APR + WLE (case 7).

Case 1 was found to have a dermal invasion in a WLE specimen and suspected to have underlying anorectal cancer based on histological and immunohistological findings. Five years after surgery, the patient was found to have multiple distant metastases (inguinal lymph nodes, liver, and bone) and died 1 year later. Patient 7 had a mucinous (muc/sig) adenocarcinoma of the anal gland with the invasion of the external anal sphincter and a positive surgical margin. This patient received postoperative chemoradiotherapy (FOLFOX + radiotherapy at 50.9 Gy/33 Fr) but had the first relapse in the inguinal lymph nodes about 6 months later and underwent inguinal lymph node dissection. Three months later, he had a second relapse in the pararenal lymph nodes and underwent further chemotherapy (FOLFIRI + panitumumab). After an additional 3 months, he had another relapse in the pararenal aortic lymph nodes and received another course of chemotherapy (FOLFIRI + panitumumab). However, he developed multiple liver, lung, and bone metastases and died 2 years after surgery.

Both these fatal cases had immunohistological findings in a preoperative skin biopsy suggestive of underlying anorectal carcinoma, inguinal lymph node metastasis as the first relapse, and distant metastasis several months later. If WLE is performed to preserve the anus, a careful search for distant metastasis and regular follow-up are essential, even if recurrence occurs after a long period.

In terms of initial treatment, there were 4 recurrences after WLE (with or without transanal local excision), 2 after APR, and 1 after radiotherapy. There were 2 recurrences in lymph nodes (with or without distant metastasis) after initial APR + WLE and 2 local recurrences plus 2 lymph node recurrences in the initial WLE group. All 6 cases of recurrence after surgical resection had positive resection margins at the initial surgery. Chemoradiotherapy or radiotherapy was performed in 2 cases after APR and in all 4 cases after WLE. WLE was performed for local recurrence in 3 patients, 2 of whom (cases 6 and 12) developed distant metastasis as a second recurrence and are alive and under treatment more than 4 years after their initial diagnosis. One of the patients with local recurrence (case 3) had a third recurrence and survived for more than 5 years. Lymph node dissection was performed in 4 patients with recurrence limited to the inguinal or lateral lymph nodes. Two patients (cases 1 and 7) died of distant metastasis after a second recurrence, and 2 patients were alive without recurrence (cases 2 and 9). Local resection was performed in patients with locoregional (local or lymph node) recurrence. Long-term survival may be possible if distant recurrence does not occur within a short interval.

Of the 5 patients in this study who underwent mapping biopsy, 4 had positive margins, 1 had local recurrence, 3 had lymph node recurrence, and 2 had a recurrence of distant metastasis. Accurate histological examination by four-quadrant biopsy or multiple sharp punch biopsies of the lesion’s periphery has been recommended as a prerequisite for mapping the lesion preoperatively. Intraoperative frozen section analysis of the resection margin has been proposed to reduce the possibility of borderline invasion and minimize the local recurrence rate [19]. However, frozen section analysis of surgical margins in PPD can be misleading and dangerous because it may appear negative intraoperatively but become permanently positive on subsequent histological analysis. It is believed that permanent margin status is not a predictor of local recurrence and that a minimally invasive carcinoma measuring <1 mm probably does not have an adverse prognosis, whereas a deeply invasive carcinoma behaves as a fully malignant adenocarcinoma [31].

In this study, 1 patient (case 3) received radiotherapy, and another (case 13) received preoperative chemoradiotherapy. It is difficult to identify the extent of excision in EMPD because of skip lesions [19]. It may be necessary to devise a method such as mapping biopsy, which is similar to surgical excision, for areas in which a skin lesion has been irradiated. Although there are no definite opinions on the treatment of adenocarcinoma of the anal canal with PS at present, there are some case reports of radiotherapy for PPD [32, 33], and it may become an option in the future.

Although skin biopsy and immunohistological diagnosis are useful for distinguishing underlying malignancy in patients with PPD, endoscopic and radiologic evaluation is mandatory. If WLE is performed to preserve the anus, a careful search for distant metastasis and close follow-up are essential, even if recurrence occurs after a long period. In the cases of locoregional recurrence, local resection may achieve long-term survival if distant recurrence does not occur in a short interval.

CI, confidence interval; EMPD, extramammary Paget’s disease; HR, hazard ratio; PPD, perianal Paget’s disease; PS, Pagetoid spread.

Ethics approval and consent to participate

Ethics approval was obtained from our hospital’s review board (NCC2017437).

Consent for publication

Not applicable.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Competing interests

The authors declare that they have no competing interests.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Authors’ contributions

JI and KM designed the report, analyzed the data, and wrote the manuscript. ST, YT, MI, and YK collected the patient’s clinical data and coordinated and drafted the manuscript. All authors read and approved the final manuscript.

Acknowledgments

The authors thank Sigeki Sekine, all of whom served as staff members at the National Cancer Center Hospital.

Shepherd V, Davidson EJ, Davies-Humphreys J. Extramammary Paget's disease. BJOG 2005;112:273–279.
Jones RE Jr., Austin C, Ackerman AB. Extramammary Paget's disease. A critical reexamination. Am J Dermatopathol. 1979;1:101–132.
Chumbalkar V, Jennings TA, Ainechi S, Lee EC, Lee H. Extramammary Paget's disease of anal canal associated with rectal adenoma without invasive carcinoma. Gastroenterology Res. 2016;9:99–102.
Liao X, Mao W, Lin A. Perianal Paget's disease co-associated with anorectal adenocarcinoma: Primary or secondary disease. Case Rep Gastroenterol. 2014;8:186–192.
McCarter MD, Quan SH, Busam K, Paty PP, Wong D, Guillem JG: Long-term outcome of perianal Paget's disease. Dis Colon Rectum. 2003;46:612–616.
Sarmiento JM, Wolff BG, Burgart LJ, Frizelle FA, Ilstrup DM: Paget's disease of the perianal region–an aggressive disease? Dis Colon Rectum. 1997;40:1187–1194.
Marchesa P, Fazio VW, Oliart S, Goldblum JR, Lavery IC, Milsom JW. Long-term outcome of patients with perianal Paget's disease. Ann Surg Oncol. 1997;4:475–480.
Goldman S, Ihre T, Lagerstedt U, Svensson C. Perianal Paget's disease: report of five cases. Int J Colorect Dis. 1992;7:167–169.
Shutze WP, Gleysteen JJ. Perianal Paget's disease. Classification and review of management: report of two cases. Dis Colon Rectum. 1990;33:502–507.
Smith KJ, Tuur S, Corvette D, Lupton GP, Skelton HG. Cytokeratin 7 staining in mammary and extramammary Paget's disease. Mod Pathol. 1997;10:1069–1074.
Lundquist K, Kohler S, Rouse RV. Intraepidermal cytokeratin 7 expression is not restricted to Paget cells but is also seen in Toker cells and Merkel cells. Am J Surg Pathol. 1999;23:212–219.
Chu P, Wu E, Weiss LM. Cytokeratin 7 and cytokeratin 20 expression in epithelial neoplasms: A survey of 435 cases. Modern Pathol. 2000;13:962–972.
Ansai S, Mitsuhashi Y, Kondo S, Manabe M. Immunohistochemical differentiation of extra-ocular sebaceous carcinoma from other skin cancers. J Dermatol. 2004;31:998–1008.
Goldblum JR, Hart WR. Perianal Paget's disease: a histologic and immunohistochemical study of 11 cases with and without associated rectal adenocarcinoma. Am J Surg Pathol. 1998;22:170–179.
Kohler S, Smoller BR. Gross cystic disease fluid protein-15 reactivity in extramammary Paget's disease with and without associated internal malignancy. Am J Dermatopathol. 1996;18:118–123.
Ohnishi T, Watanabe S. The use of cytokeratins 7 and 20 in the diagnosis of primary and secondary extramammary Paget's disease. Br J Dermatol. 2000;142:243–247.
Zeng HA, Cartun R, Ricci A Jr. Potential diagnostic utility of CDX-2 immunophenotyping in extramammary Paget's disease. Appl Immunohistochem Mol Morphol. 2005;13:342–346.
Bayrak R, Haltas H, Yenidunya S. The value of CDX2 and cytokeratins 7 and 20 expression in differentiating colorectal adenocarcinomas from extraintestinal gastrointestinal adenocarcinomas: cytokeratin 7-/20 + phenotype is more specific than CDX2 antibody. Diagn Pathol. 2012;7:9.
Kyriazanos ID, Stamos NP, Miliadis L, Noussis G, Stoidis CN. Extra-mammary Paget’s disease of the perianal region: A review of the literature emphasizing the operative management technique. Surg Oncol. 2011;20:e61-e71.
Mehta NJ, Torno R, Sorra T: Extramammary Paget's disease. South Med J. 2000;93:713–715.
Benson AB, Venook AP, Al-Hawary MM, Cederquist L, Chen Y-J, Ciombor KK, Cohen S, Cooper HS, Deming D, Engstrom PF, Grem JL, Grothey A, Hochster HS, Hoffe S, Hunt S, Kamel A, Kirilcuk N, Krishnamurthi S, Messersmith WA, Meyerhardt J, Mulcahy MF, Murphy JD, Nurkin S, Saltz L, Sharma S, Shibata D, Skibber JM, Sofocleous CT, Stoffel EM, Stotsky-Himelfarb E, Willett CG, Wuthrick E, Gregory KM, Freedman-Cass DA. Anal Carcinoma, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2018;16:852–871.
Hashiguchi Y, Muro K, Saito Y, Ito Y, Ajioka Y, Hamaguchi T, Hasegawa K, Hotta K, Ishida H, Ishiguro M, Ishihara S, Kanemitsu Y, Kinugasa Y, Murofushi K, Nakajima TE, Oka S, Tanaka T, Taniguchi H, Tsuji A, Uehara K, Ueno H, Yamanaka T, Yamazaki K, Yoshida M, Yoshino T, Itabashi M, Sakamaki K, Sano K, Shimada Y, Tanaka S, Uetake H, Yamaguchi S, Yamaguchi N, Kobayashi H, Matsuda K, Kotake K, Sugihara K, Japanese Society for Cancer of the Colon and Rectum. Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2019 for the treatment of colorectal cancer. Int J Clin Oncol. 2020;25:1–42.
Benson AB, Venook AP, Al-Hawary MM, Cederquist L, Chen Y-J, Ciombor KK, Cohen S, Cooper HS, Deming D, Engstrom PF, Grem JL, Grothey A, Hochster HS, Hoffe S, Hunt S, Kamel A, Kirilcuk N, Krishnamurthi S, Messersmith WA, Meyerhardt J, Mulcahy MF, Murphy JD, Nurkin S, Saltz L, Sharma S, Shibata D, Skibber JM, Sofocleous CT, Stoffel EM, Stotsky-Himelfarb E, Willett CG, Wuthrick E, Gregory KM, Gurski L, Freedman-Cass DA. Rectal Cancer, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2018;16:874–901.
Kubota K, Akasu T, Nakanishi Y, Sugihara K, Fujita S, Moriya Y. Perianal Paget's disease associated with rectal carcinoma: a case report. Jpn J Clin Oncol. 1998;28:347–350.
Yamaura M, Yamada T, Watanabe R, Kawai H, Hirose S, Tajima H, Sato M, Uchida Y, Suganuma D, Yamamoto Y, Moriwaki T, Hyodo I. Anal canal adenocarcinoma with neuroendocrine features accompanying secondary extramammary Paget disease, successfully treated with modified FOLFOX6: a case report. BMC Cancer. 2018;18:1142.
Yukimoto R, Fujino S, Miyoshi N, Ogino T, Takahashi H, Uemura M, Tanemura A, Matsuda C, Yamamoto H, Mizushima T, Doki Y, Eguchi H. A case report of anal canal cancer with pagetoid spread requiring differential diagnosis. Int J Surg Case Rep. 2020;75:198–202.
Suenaga M, Oya M, Ueno M, Yamamoto J, Yamaguchi T, Mizunuma N, Hatake K, Kato Y, Muto T. Anal canal carcinoma with Pagetoid spread: report of a case. Surg Today. 2006;36:666–669.
Shimizu T, Inozume T, Takaki M, Ohnuma T, Sano S, Kawamura T, Shimada S. Case of anal adenocarcinoma in situ with pagetoid spread but without macroscopic abnormality in anal mucosa. J Dermatol. 2017;44:1076–1077.
Jensen SL, Sjølin KE, Shokouh-Amiri MH, Hagen K, Harling H. Paget's disease of the anal margin. Br J Surg. 1988;75):1089–1092.
Kanitakis J. Mammary and extramammary Paget's disease. J Eur Acad Dermatol Venereol. 2007;21:581–590.
Goldblum JR, Hart WR: Vulvar Paget's disease: a clinicopathologic and immunohistochemical study of 19 cases. Am J Surg Pathol. 1997;21:1178–1187.
Brown RS, Lankester KJ, McCormack M, Power DA, Spittle MF. Radiotherapy for perianal Paget's disease. Clin Oncol (R Coll Radiol). 2002 Aug;14(4):272–84.
Velenik V, Segedin B, Anderluh F, Oblak I, Strojan P. Radiotherapy for perianal Paget's disease: a case report. Tumori. 2008 Sep-Oct;94(5):750–3.

Table 1 Perianal Paget's disease classification and accompanying suggested therapy

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

APR abdominal perineal rectal dissection, WLE wide local excision,

Table 2 Clinicopathologic Characteristics

Characteristic		Value	(n=14)
Age, madian (IQR), y		74	(67.5-78.5)
Gender
	Male, No. (%)	7	(50%)
	Female, No. (%)	7	(50%)
Preoperative diagnosis of pagetoid spread, No. (%)
	diagnosed	2	(14%)
	not diagnosed	12	(86%)
Identification of underlying anorectal cancer, No. (%)
	Not found	6	(43%)
	Syncronous	7	(50%)
	Metachronous	1	(7%)
Primary tumor site, No. (%)
	anal canal	7	(50%)
	lower rectum	1	(7%)
	unknown	6	(43%)
Immunohistochemistry, No. (%)
	Not confirmed	2	(14%)
	CK20+/CK7+	7	(50%)
	CK20+/CK7-	4	(29%)
	CK20-/CK7+	0	(0%)
	CK20-/CK7-	1	(7%)
	GCDFP15-*	8	(100%)
	CDX2+	11	(92%)
Histology*, No. (%)
	adenocarcinoma (grade unknown)	7	(50%)
	tub1/2	1	(7%)
	por/sig	4	(933%)
	muc	3	(600%)
Tumor size, median (IQR), cm		53.5	(26.3-87.5)
Depth of invasion, No. (%)
	M	3	(21%)
	SM	1	(7%)
	MP	2	(14%)
	A	1	(7%)
	AI	1	(7%)
	invasive (WLE)	1	(7%)
	non-invasive (WLE)	2	(14%)
Lymph node metasatases at initial treatment, No. (%)
	negative	4	(29%)
	Lateral lymph node	1	(7%)
	Inguinal lymph node	2	(14%)
	unknown (clinically negative)	7	(50%)
Initial treatment, No. (%)
	WLE (±transanal local excision	7	(50%)
	APR (±WLE)	5	(36%)
	Radiation	1	(7%)
	unknown**	1	(7%)
Mapping biopsy***, No. (%)
	done	5	(42%)
	none	7	(58%)
Resection status***, No. (%)
	R0		(0%)
	R1		(0%)
	R2		(0%)
Follow-up time, median (IQR), mo		4.5	(158.7-7.4)
Recurrence, No (%)		7	(50%)
Time to reccurence, median (IQR), mo		34.6	(18.2-81.7)
5 year Recurrence Free Survival		55.9%
Mortality, No. (%)		2	(14%)
5 year Overall Srvival		90.0%
*There are duplicates.
**Referred to another hospital
*** excluded: non-surgical 2 cases
Abbreviation:
	IQR, inerquartile range,
	WLE, Wide local excsiion
	RT, Radiotheray
	LE, Local Excision,
	APR, Abdominoperineal Resection

Table 3 A summary of cases attended

Case

gender

Initial Treatment

immunohistological findings

Primary

histology*

LN mets

Mapping Biopsy

1st Relapse

Outcome

age

lymph node dissection

CK7

CK20

GCDFP15

CDX2

maximum diameter

Depth of invasion

location of LN

Resection status

inteval

treatment

Fllow up time (primary)

No detectable primary lesion

1

M

WLE

-

+

NA

+

unknown

Adenocarcinoma

negative

done

ILN

ILND

Dead of disease

76

none

55mm

invasie

R1

61mo

6 years

2

M

WLE

+

-

+

unknown

Adenocarcinoma

NA

done

ILN

ILND

Alive with no evidence of disease

55

none

30mm

non-invasive

R1

34mo

13 years

3

F

RT

-

+

-

unknown

Adenocarcinoma

NA

none

Local

Medication

Alive with 2nd relapse

78

none

NA

87mo

12 years

4

F

APR with WLE

+

-

+

unknown

Adenocarcinoma

negative

none

NA

Alive with no evidence of disease

73

D2

74mm

MP

R0

5 years

5

F

WLE

-

NA

-

unknown

muc

positive

done

NA

Alive with no evidence of disease

63

ILND

80mm

invasie

inguinal

R0

2 years

6

M

WLE

+

-

unknown

Adenocarcinoma

negative

none

Local

WLE

Alive with 2nd relapse

80

none

50mm

invasie

R0

25mo

5 years

Detectable underlying anorectal carcinoma

7

M

APR with WLE

-

+

NA

+

P

muc/sig

positive

none

ILN

ILND

Dead of disease

68

D3,LLND

110mm

AI

lateral pelvic

R1

7mo

2 years

8

M

Transanal LE with WLE

-

+

-

+

P

tub1

NA

none

NA

Alive with no evidence of disease

72

none

9mm

SM1

R0

5 years

9

F

APR with WLE

+

-

+

P

tub1/por/sig

negative

done

LD/ILN

LLND

Alive with no evidence of disease

80

D2

90mm

MP

R1

13mo

ILND

2 years

10

M

APR with WLE

+

NA

+

P

Adenocarcinoma

negative

none

NA

Alive with no evidence of disease

66

D2

106mm

M

R0

3 years

11

F

NA

+

-

+

Rb

NA

unknown

69

none

unknown

3 years

12

F

Transanal LE with WLE

+

-

+

P

por2/tub2/muc

NA

done

Local

WLE

Alive with no evidence of disease

84

none

52mm

M

R1

36mo

4 years

No preoperative diagnosis of pagetoid spread

13

M

Trans anal LE*

NA

P

tub2/por

NA

Local

WLE

Alive with 2nd relapse

74

none

10mm

SM

159mo

13 years

14

F

Chemoterapy

NA

+

P

por/sig

positive

none

NA

Alive with

74

D3, LLND, ILND

25mm

A

inguinal

positive

1 year

APR abdominal perineal rectal dissection, WLE wide local excision, LLND Latral lymph node dissection, ILND Inguinal lymph node dissection

No competing interests reported.

A review of 14 cases of perianal Paget’s disease: Characteristics of anorectal cancer with Pagetoid spread

Status:

Journal Publication

Version 1

Abstract

Figures

Background

Staging classification and treatment outcome

Methods

Results

Discussion

Conclusions

Abbreviations

Declarations

References

Tables

Additional Declarations

Status:

Journal Publication

Version 1