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Extra-mammary Paget's disease rising from a non-invasive rectal adenoma

  • M. Harb
    Correspondence
    Contact Dr Martin Harb.
    Affiliations
    Department of Gastroenterology and Hepatology, Liverpool Hospital, Liverpool, NSW, Australia

    South Western Sydney Clinical School, University of NSW, Liverpool, NSW, Australia
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  • D.S. Prince
    Affiliations
    Department of Gastroenterology and Hepatology, Liverpool Hospital, Liverpool, NSW, Australia
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  • M. Bassan
    Affiliations
    Department of Gastroenterology and Hepatology, Liverpool Hospital, Liverpool, NSW, Australia

    South Western Sydney Clinical School, University of NSW, Liverpool, NSW, Australia
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  • S. Mackenzie
    Affiliations
    Department of Colorectal Surgery, Liverpool Hospital, Liverpool, NSW, Australia

    Liverpool School of Medicine, Western Sydney University, Liverpool, NSW, Australia
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  • S.J. Connor
    Affiliations
    Department of Gastroenterology and Hepatology, Liverpool Hospital, Liverpool, NSW, Australia

    South Western Sydney Clinical School, University of NSW, Liverpool, NSW, Australia

    Ingham Institute for Applied Medical Research, Liverpool, NSW, Australia
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  • T. Rutland
    Affiliations
    Department of Anatomical Pathology, Liverpool Hospital, Liverpool, NSW, Australia

    Discipline of Pathology, School of Medicine, Western Sydney University, Liverpool, NSW, Australia

    Graduate School of Medicine, University of Wollongong, Wollongong, NSW, Australia
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Published:February 16, 2022DOI:https://doi.org/10.1016/j.pathol.2021.11.011
      To the Editor,
      Extra-mammary Paget's disease (EMPD) is a chronic erythematous dermatological condition which can be classified as either primary or secondary. Primary EMPD is thought to arise from skin adnexal apocrine glands, whereas, secondary tends to arise from visceral carcinomas, such as a colorectal or gynaecological source.
      • Heymann W.R.
      Extramammary Paget's disease.
      ,
      • Shepherd V.
      • Davidson E.J.
      • Davies-Humphreys J.
      Extramammary Paget's disease.
      EMPD developing from a non-invasive colorectal adenoma is incredibly rare, with very few documented cases in the current literature. As such, there is very little guidance on treatment and prognosis, although reports suggest these patients may have better outcomes.
      • Hutchings D.
      • Windon A.
      • Assarzadegan N.
      • Salimian K.J.
      • Voltaggio L.
      • Mongtomery E.A.
      Perianal Paget’s disease as spread from non-invasive colorectal adenomas.
      Thus, it is critical for a clinical pathological consensus to avoid over treatment. This case report presents an incidental finding of EMPD in a patient with a rectal tubulo-villous adenoma (TVA).
      A 70-year-old woman presented for assessment of mild rectal bleeding in the context of known sigmoid diverticular disease. She had no history of malignancy and her only past history was a previous hysterectomy performed decades prior. She had a family history of colorectal cancer (first degree relative). Her laboratory investigations including full blood count and iron studies were within normal limits.
      Her index colonoscopy revealed a 6 mm pedunculated polyp at the dentate line that was resected with cold snare polypectomy. Histology revealed a TVA with low grade dysplasia. A surveillance procedure performed one year later revealed tumour recurrence at the site of previous resection and a new 12 mm lesion (Fig. 1A). This, and surrounding tissue were removed with combined cold and hot snare polypectomy. Histology revealed the same findings as the original polyp.
      Fig. 1
      Fig. 1Macroscopic appearance. (A) Endoscopy, first recurrence. (B) Perianal appearance.
      A second surveillance procedure six months later revealed ongoing recurrence with an 8 mm pedunculated lesion at the dentate line. Cold snare polypectomy was again performed. Given the ongoing recurrence, submucosal fibrosis, and the difficult endoscopic location, she was referred for an endoscopic mucosal resection. A 15 mm polypoid lesion was completely resected using endoscopic submucosal dissection. Histology revealed a TVA with a focal area of high grade dysplasia that was clear of the inked margin (Fig. 2A–C). Adjacent to the adenoma, there was a small fragment of attached squamous mucosa that showed large atypical cells in a pagetoid spread, containing intracytoplasmic mucin. Immunohistochemistry showed that both the adjacent adenoma and these cells were positive for cytokeratin (CK)7, CK20, CDX-2 and SATB2, indicating an intestinal phenotype (Fig. 2D–F). Gross cystic disease fluid protein (GCDFP)-15, oestrogen receptor, GATA-3 and mammaglobin were negative.
      Fig. 2
      Fig. 2(A) Non-invasive rectal adenoma with intraepithelial neoplastic cells in the adjacent squamous epithelium (haematoxylin and eosin), with areas of high grade dysplasia (B,C). (D,E,F) Immunohistochemistry shows an intestinal phenotype: (D) CK7, (E) CK20, (F) SATB2 pictured.
      She was referred for gynaecological and colorectal evaluation. Speculum examination of the vaginal vault did not reveal evidence of anterior extension of disease. Serum tumour markers were negative and contrast enhanced computed tomography of the chest, abdomen and pelvis did not reveal a distant primary tumour. There was no evidence of local invasion seen on pelvic magnetic resonance imaging. Examination under anaesthesia (EUA) revealed subtle macroscopic changes including mild induration and oedema from 7 o'clock to 1 o'clock which were consistent with Paget's (Fig. 1B). The biopsies showed extensive disease, confined to the epithelium, with the same intestinal phenotype as the original case. The final pathological diagnosis was EMPD arising from a rectal adenoma. The patient has been reviewed by a multi-disciplinary team and planned for regular surveillance with repeat EUA and biopsy.
      Secondary EMPD usually arises when there is intraepithelial invasion (pagetoid spread) of an underlying or contiguous visceral carcinoma. The most common sites are the lower gastro-intestinal or urogenital tract. Differential diagnoses for the microscopic appearance in these areas include melanoma and pagetoid Bowen's disease;
      • Shepherd V.
      • Davidson E.J.
      • Davies-Humphreys J.
      Extramammary Paget's disease.
      however, these can readily be differentiated with an appropriate immunohistochemical (IHC) panel. Primary perianal Paget's is rare, whilst secondary Paget's disease makes up to 60% of perianal cases.
      • Lam C.
      • Funaro D.
      Extramammary Paget’s disease: summary of current knowledge.
      Presentations include itch and irritation of the peri-anal area, as well as ulceration and a palpable mass.
      • Liao X.
      • Liu X.
      • Fan X.
      • Lai J.
      • Zhang D.
      Perianal Paget’s disease: a clinicopathological and immunohistochemical study of 13 cases.
      Distinguishing primary from secondary EMPD involves both immunohistochemistry and exclusion of an underlying carcinoma. Immunohistochemically, primary tumours arising from adnexal structures tend to have the following IHC markers: CK7+, CK20−, GCDFP+
      • De Nisi M.C.
      • D’Amuri A.
      • Toscano M.
      • Lalinga A.V.
      • Pirtoli L.
      • Miracco C.
      Usefulness of CDX2 in the diagnosis of extramammary Paget disease associated with malignancies of intestinal type.
      and may also express HER2 and androgen receptors. In contrast, secondary EMPD of anorectal origin tends to be CK7−, although this is not specific, and CK20+
      • Ohnishi T.
      • Watanabe S.
      The use of cytokeratins 7 and 20 in the diagnosis of primary and secondary extramammary Paget’s disease.
      ,
      • Battles O.E.
      • Page D.L.
      • Johnson J.E.
      Cytokeratins, CEA, and mucin histochemistry in the diagnosis and characterization of extramammary Paget’s disease.
      can also express a range of antigens dependent on the underlying tumour. Of note CDX2 is a specific lower gastrointestinal adenocarcinoma associated EMPD supportive marker.
      • De Nisi M.C.
      • D’Amuri A.
      • Toscano M.
      • Lalinga A.V.
      • Pirtoli L.
      • Miracco C.
      Usefulness of CDX2 in the diagnosis of extramammary Paget disease associated with malignancies of intestinal type.
      However, not all secondary EMPDs follow these patterns of expression, such as certain gynaecological and breast carcinomas. Hence, the diagnosis needs to be made in conjunction with the clinical findings and exclusion of other causes.
      Unlike Paget's disease of the nipple associated with ductal carcinoma in situ, EMPD arising from a non-invasive colorectal adenoma is unusual. Very few cases have been reported in the current literature. In a series of 11 cases of perianal Paget's disease, five of the patients had documented synchronous rectal adenocarcinoma and they were CK7+, CK20+, and GCDFP−. Of the six patients who did not have rectal adenocarcinoma, four were CK7+, CK20−, and GCDFP+. The other two cases were CK7+, CK20+ and GCDFP−, similar to our case. In both cases there was evidence of recurrence after wide local excision, and one was subsequently treated with radiotherapy.
      • Goldblum J.R.
      • Hart W.R.
      Perianal Paget's disease: a histologic and immunohistochemical study of 11 cases with and without associated rectal adenocarcinoma.
      In their case series of 13 patients, Liao and colleagues also found that GCDFP was only positive in patients with primary peri-anal disease, and CDX2 was only positive in secondary disease, whilst CK20 was present in both primary and secondary disease. Eight of the 13 cases also had a synchronous carcinoma, whilst one had an adenoma with high grade dysplasia.
      • Liao X.
      • Liu X.
      • Fan X.
      • Lai J.
      • Zhang D.
      Perianal Paget’s disease: a clinicopathological and immunohistochemical study of 13 cases.
      The largest case series to date of EMPD associated with colorectal adenomas published by Hutchings et al. included four cases. Similar to our case, all four had evidence of high grade dysplasia with no evidence of invasion or an invasive adenocarcinoma elsewhere and IHC markers were CK7+, CK20+, GCDFP− and CDX2 +, where available. Only one patient required adjuvant treatment after excision. One had recurrence at 8 months and another was found to have a mucinous adenocarcinoma 36 months after presentation.
      • Hutchings D.
      • Windon A.
      • Assarzadegan N.
      • Salimian K.J.
      • Voltaggio L.
      • Mongtomery E.A.
      Perianal Paget’s disease as spread from non-invasive colorectal adenomas.
      In summary, secondary EMPD is a rare condition, especially arising from non-invasive rectal adenomas such as in our case. As such, it is important that pathologists are aware of this condition. Thorough clinical assessment in addition to IHC markers are essential to determine (1) whether these are invasive or non-invasive lesions, and (2) whether these are primary or secondary lesions. Due to the limited number of cases, the optimal treatment strategy following excision of the primary lesion remains uncertain. In any case, after careful assessment and exclusion of a malignant primary, regular surveillance appears to be a reasonable follow-up strategy in order to avoid undue harm from over treatment. However, clinicians need to be aware that recurrence and metachronous malignancy may still occur in these patients.

      Conflicts of interest and sources of funding

      The authors state that there are no conflicts of interest to disclose.

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