Anal adenocarcinoma with perianal Paget's disease: A case report

Abstract

BACKGROUND

Anal canal adenocarcinoma with secondary perianal Paget’s disease (PPD) is clinically rare and exhibits atypical symptoms, often misdiagnosed as benign conditions such as hemorrhoids or perianal eczema, leading to delayed treatment. Further summarization of diagnostic and therapeutic key points, as well as reasons for misdiagnosis, is necessary to enhance clinical awareness.

CASE SUMMARY

A retrospective analysis was conducted on a 72-year-old female patient with a 2-year history of perianal moisture, pruritus, and hematochezia, who was repeatedly misdiagnosed with mixed hemorrhoids. The diagnosis of anal canal adenocarcinoma with secondary PPD was confirmed through colonoscopy, perianal skin biopsy, and immunohistochemical staining (CK7, CK20, etc.). The patient underwent 3D laparoscopic-assisted abdominoperineal resection (APR) with extended perianal skin excision, achieving negative margins and primary wound healing. No recurrence or metastasis was observed during the 12-month follow-up.

CONCLUSION

Secondary PPD has a high misdiagnosis rate. Clinicians should maintain a high index of suspicion for elderly patients with prolonged perianal symptoms (e.g., pruritus, hematochezia > 6 months) and promptly perform colonoscopy and immunohistochemical testing for definitive diagnosis. APR combined with extended perianal resection is an effective treatment, and standardized long-term follow-up is crucial for prognosis.

Key Words: Perianal Paget’s disease; Anal canal adenocarcinoma; Extramammary Paget’s disease; Hemorrhoids; Combined abdominoperineal resection; Pathology; Case report

Core Tip: Perianal Paget's disease (PPD), particularly secondary PPD associated with anal adenocarcinoma, is frequently misdiagnosed due to nonspecific symptoms resembling hemorrhoids or eczema. This case highlights a 72-year-old female with a 2-year misdiagnosis history, ultimately confirmed via colonoscopy, biopsy, and immunohistochemistry [IHC; CK7(+)/CK20(+)/CDX2(+)/CEA(+)]. Successful treatment with 3D laparoscopic abdominoperineal resection and extended perianal excision underscores the importance of early IHC testing in refractory perianal symptoms. Key takeaways: (1) Secondary PPD requires high clinical suspicion in elderly patients with chronic perianal lesions; (2) Multimodal diagnostics (endoscopy, biopsy, IHC) are critical to differentiate primary/secondary PPD; and (3) Radical resection ensures oncologic safety, while structured follow-up prevents recurrence.

INTRODUCTION

Extramammary Paget's disease (EMPD) is a rare epithelial malignancy that constitutes approximately 20%-30% of all Paget's disease cases. This condition primarily develops in regions rich in apocrine glands, particularly the external genitalia and perineal area. Within the spectrum of EMPD, perianal Paget's disease (PPD) accounts for 6.5%-10% of cases. Pathogenetically, PPD is categorized into two distinct subtypes: Primary PPD, originating from perianal epidermal apocrine glands, and secondary PPD, which is commonly associated with concurrent malignancies such as rectal adenocarcinoma, anal canal carcinoma, or urothelial carcinoma[1]. Clinically, PPD often presents with nonspecific symptoms, including perianal moisture, pruritus, erythematous plaques, erosions, superficial ulcerations, and hyperpigmentation. These manifestations frequently mimic benign anorectal disorders like hemorrhoids, anal eczema, or perianal dermatitis, leading to a high misdiagnosis rate. Studies indicate that the average diagnostic delay for PPD exceeds two years[2]. This is particularly concerning for secondary PPD cases, which often coexist with underlying gastrointestinal malignancies. Diagnostic delays in such cases may result in missed therapeutic windows, substantially compromising patient outcomes[3]. Given these clinical challenges, there is an urgent need to improve clinician recognition of PPD, enhance diagnostic precision, and develop effective strategies to prevent misdiagnosis. In the present study, we report a diagnostically complex case of anal canal adenocarcinoma with secondary PPD that was initially misdiagnosed as mixed hemorrhoids over an extended period. The patient was admitted to the General Hospital of the Southern Theater Command, People's Liberation Army of China in January 2024. Through a comprehensive analysis of the misdiagnosis causes and by distilling key diagnostic and therapeutic lessons, we aim to provide clinically relevant insights for the management of PPD.

CASE PRESENTATION

Chief complaints

A 72-year-old female patient was admitted due to "recurrent perianal moisture, pruritus, and hematochezia for 2 years".

History of present illness

The patient developed unexplained perianal moisture and pruritus accompanied by skin ulceration and exudation 2 years ago, which worsened at night and significantly affected sleep. Subsequently, the patient experienced progressive symptoms characterized by bright red blood streaks on toilet paper following defecation. The bleeding was not mixed with stool, and no associated prolapsed masses, dyschezia, or tenesmus were observed.

History of past illness

The patient denied any history of alternating bowel habits (constipation/diarrhea), inflammatory bowel disease, or pelvic floor disorders. During the initial 2-year diagnostic odyssey, the patient's persistent perianal symptoms were recurrently misattributed to benign conditions (''mixed hemorrhoids'' and ''anal pruritus'') at peripheral institutions. Despite undergoing two sessions of sclerotherapy, two hemorrhoidectomies, and prolonged topical therapy (suppositories/corticosteroid ointments), her symptoms not only failed to resolve but progressively exacerbated. Critically, the absence of definitive diagnostic procedures—specifically colonoscopy and histopathological evaluation—at these institutions perpetuated the diagnostic delay until ultimate referral. Over the past three months, the patient experienced worsening perianal pruritus accompanied by progressive skin erosion, exudation, and significantly aggravated hematochezia, severely impairing quality of life. To establish a definitive diagnosis, the patient was admitted to our hospital in January 2024 with preliminary diagnoses of PPD and anal canal tumor.

Personal and family history

The patient denied any significant personal or family medical history, including chronic diseases, malignancies, or hereditary disorders.

Physical examination

Physical examination revealed extensive moist erythematous lesions with erosion, hyperpigmentation, white scaling, and fissured hyperplasia encircling the anus in a circumferential pattern (approximately 4 cm in diameter). Digital rectal examination identified an irregular ulcerated mass located 1.5 cm above the dentate line on the posterior rectal wall. The lesion exhibited a soft texture, irregular surface, and poorly defined margins, with blood staining noted on the examining glove (Figure 1A).

Figure 1 Macroscopic and imaging examinations of extramammary Paget's disease. A: Preoperative anal appearance showed atypical perianal eczema-like changes; B: Enteroscopic presentation of anal canal mass, suggesting an infiltrative growth in the 1/2 circle of the posterior wall of the anal canal; C: Preoperative magnetic resonance imaging (as indicated by the white arrow): Suggesting inhomogeneous circumferential thickening of the intestinal wall (about 3/4 circle), downward extension of the anal canal, characterized by the posterior wall, with the posterior wall being thickest by about 1.2 cm, involving the upper and lower diameters of the intestinal canal of about 3.1 cm, and narrowing of the corresponding lumens.

Laboratory examinations

Routine laboratory examinations revealed no clinically significant abnormalities.

Imaging examinations

Colonoscopic examination (covering the rectum, sigmoid colon, descending colon, and ascending colon) revealed a semi-circumferential friable and bleeding tumor extending from 3 cm above the anal verge to the anal canal, with multiple biopsies obtained. Pathology of the rectal mucosal biopsy showed atypical glands arranged in papillary and micropapillary patterns, consistent with villous-tubular adenoma with malignant transformation - moderately to well-differentiated adenocarcinoma. Perianal skin biopsy demonstrated nests of atypical cells within squamous epithelium, consistent with EMPD with adenocarcinoma infiltration (Figure 1B). Immunohistochemistry (IHC) results were CEA(+), CK7(+), CK20(+), CDX2(+), MUC2 (focal+), SATB2 (partial+). Pelvic magnetic resonance imaging (MRI) revealed heterogeneous circumferential wall thickening (approximately 3/4 of the lumen) at 3.1 cm from the anal verge, extending to the anal canal (predominantly posterior wall; maximal thickness: 1.2 cm; longitudinal extension: 3.1 cm), with luminal narrowing. The tumor showed penetration beyond the muscularis propria to suspicious serosal layer without mesorectal involvement, suggesting low rectal cancer (T3Nx), showing no signs of regional lymph node metastasis, and the clinical staging was T3N0M0 (Figure 1C).

MULTIDISCIPLINARY EXPERT CONSULTATION

The multidisciplinary team (MDT) comprising general surgery, oncology, and pathology departments conducted a comprehensive evaluation. Given the patient's concurrent malignancy and PPD, abdominoperineal resection (APR) combined with extended perianal lesion excision was ultimately prioritized as the treatment of choice.

FINAL DIAGNOSIS

The patient's final preoperative diagnosis was "anal canal adenocarcinoma with secondary PPD (cT3N0M0)".

TREATMENT

Following comprehensive preoperative evaluation, the patient underwent three-dimensional laparoscopy-assisted APR with extended perianal lesion excision under general anesthesia. Intraoperatively, primary reconstruction and closure of the pelvic peritoneum were performed without requiring perianal skin flap transplantation. The perineal wound was primarily repaired and reconstructed (Figure 2A). The resected specimen was submitted for pathological examination. Both gross and histopathological evaluations confirmed negative surgical margins, achieving an R0 resection. Postoperative pathological examination revealed: (Rectoanal tumor and perianal skin) moderately to well-differentiated adenocarcinoma infiltrating the superficial muscular layer (flat-type lesion, approximately 4 cm × 3 cm in size). Microscopic examination of the perianal grayish-white rough area demonstrated nests of atypical cells within squamous epithelium, consistent with EMPD (approximately 7 cm × 1.5 cm in size). Immunohistochemical staining showed: MLH1(+), PMS2(+), MSH2(+), MSH6(+), Ki67 approximately 80%(+), PD-1 lymphocytes approximately 20%(+), and PD-L1(-; Figure 2B and C). The patient recovered well postoperatively without perioperative complications, achieving primary healing of both perianal and perineal wounds, and was successfully discharged on postoperative day 10.

Figure 2 Postoperative appearance, specimen and postoperative immunohistochemistry. A: Postoperative view of the anal appearance after perineal stage I reconstruction following extended excision of perianal skin; B: Surgical excision specimen, showing rectoanal and perianal extended excised tissues; C: Postoperative immunohistochemistry, Hematoxylin-eosin-stained blood (200 ×) to microscopically visualize the morphology of Paget's cells.

OUTCOME AND FOLLOW-UP

After comprehensive evaluation by the MDT comprising general surgery, medical oncology, radiology, and pathology disciplines, adjuvant chemoradiotherapy was not recommended based on the final pathological staging (pT2N0M0 with R0 resection) and absence of high-risk features such as lymph node metastasis. The patient was advised to undergo regular follow-up evaluations every 3 months, consisting of comprehensive physical examinations, serum tumor marker assessments (CEA, CA19-9, and CA-125), contrast-enhanced pelvic MRI, and thoracoabdominal computed tomography scans, supplemented by annual colonoscopic surveillance. At the 12-month follow-up assessment, the patient maintained favorable overall health status with complete resolution of the perianal wound. All measured tumor markers persisted within normal physiological ranges, while serial imaging evaluations conclusively demonstrated absence of both local disease recurrence and distant metastatic spread. Importantly, no stoma-associated complications (including parastomal hernia formation) or perineal/pelvic floor herniation were clinically evident, and the patient consistently reported preserved quality of life parameters throughout the follow-up period.

DISCUSSION

PPD represents a rare subtype of EMPD, comprising about 20% of EMPD cases yet fewer than 1% of all anorectal conditions[4-6]. In contrast to vulvar or scrotal EMPD, PPD demonstrates more aggressive biological behavior, with invasive disease present at diagnosis in nearly half of cases. Additionally, local recurrence occurs in over one-third of patients, and the disease shows marked potential for lymph node involvement and distant metastasis, collectively contributing to its unfavorable prognosis[5,6]. Recent multicenter data indicate PPD primarily affects patients aged over 65 years, with a male predominance (male-to-female ratio approximately 2.4:1). The average disease duration exceeds two years, and the misdiagnosis rate remains alarmingly high (72.2%), with recent data suggesting that delayed referral and overreliance on clinical impression without biopsy contribute significantly to this trend[2,7]. PPD is frequently misdiagnosed as eczema (48.4%), hemorrhoids (12.9%), or chronic dermatitis (6.4%), with many patients receiving multiple unsuccessful treatments before accurate diagnosis[8]. A JAMA dermatology study reported an average diagnostic delay of 35.7 months, attributed to nonspecific symptoms and the perianal region's anatomical concealment that hinders self-examination[9].

PPD demonstrates varied clinical presentations, most commonly including refractory pruritus, pain, erythematous plaques, erosions, and localized white scaling[10]. The pathognomonic "strawberry-and-cream" appearance may be observed in classic presentations[11]. Histologically, the disease is defined by intraepidermal Paget cells exhibiting large vesicular nuclei and abundant pale cytoplasm, frequently arranged in nests that complicate accurate margin assessment[12-14]. Secondary PPD (representing 18.1% of cases) predominantly arises from concomitant malignancies in the rectum, anal canal, or urogenital tract[5]. IHC is indispensable for differentiation: Primary PPD typically expresses CK7(+)/GCDFP-15(+) but lacks CK20, while secondary PPD shows CK7(+)/CK20(+)/CDX2(+) with GCDFP-15(-), indicating likely colorectal adenocarcinoma origin[15-17]. However, IHC alone has diagnostic limitations, necessitating a multimodal assessment—including pelvic MRI, endoscopy, and digital rectal examination—to detect potential underlying malignancies[18]. The staging and management of PPD still follow the 1990 Shutze and Gleysteen classification system (Table 1), which remains the basis for treatment decisions[19]. Although surgical resection is the primary treatment, recurrence rates depend not only on surgical technique but also on adverse prognostic factors, such as advanced age, male sex, perianal/rectovaginal involvement, extensive subclinical spread, lymphovascular invasion, adnexal infiltration, and high p53 expression. Wide local excision carries a high recurrence rate (37.5%), whereas Mohs micrographic surgery, with its superior margin control, reduces recurrence to 11%-22%[20]. In secondary PPD with concurrent anal or rectal carcinoma, extended APR combined with perianal skin excision provides definitive radical treatment[21]. A study confirm that this combined approach significantly lowers local recurrence and improves long-term survival in secondary PPD[22]. Although T2N0M0-stage tumors are generally candidates for sphincter-preserving procedures, this case necessitated APR due to circumferential anal canal involvement and extensive PPD infiltration. Secondary Paget's disease requires wider surgical margins (typically 3-5 cm beyond standard adenocarcinoma resection) and generally contraindicates sphincter-sparing approaches. Furthermore, the coexistence of secondary Paget's disease with rectal adenocarcinoma may signify more aggressive tumor biology and/or advanced disease staging, which is strongly associated with adverse clinical outcomes including diminished survival rates and elevated recurrence risk[3]. Given the significantly elevated recurrence risk in such cases, intensified postoperative surveillance is mandatory. In recent years, molecular targeted therapies have become important treatment options for advanced or recurrent PPD. HER2 (ERBB2) gene amplification is detected in 30%-60% of PPD cases, with HER2-positive tumors showing favorable responses to trastuzumab-based regimens[23]. Additionally, immune checkpoint inhibitors targeting PD-1/PD-L1 have demonstrated promising efficacy in advanced PPD, further expanding therapeutic options[24-26].

Table 1 Shutze and Gleysteen staging system and treatment recommendations for perianal Paget's disease.

Stage	Description	Treatment recommendation
I	Paget cells confined to perianal dermis and its appendages without carcinoma in situ	WLE
II	Paget's disease of epidermis with associated appendageal carcinoma	WLE
III	Paget's disease with concurrent rectal/anal canal carcinoma	APR
IV	Paget's disease with regional lymph node metastasis	APR + regional lymphadenectomy
V	Paget's disease with distant organ metastasis	Chemoradiotherapy + local palliative therapy

WLE: Wide local excision; APR: Abdominoperineal resection.

The patient in this case was misdiagnosed for two years, primarily due to the nonspecific nature of the presenting symptoms (perianal moisture, pruritus, and hematochezia), which are commonly attributed to hemorrhoids or eczema. This diagnostic oversight was further compounded by clinicians' limited familiarity with PPD and their failure to perform fundamental examinations, particularly digital rectal evaluation. Moreover, the absence of timely colonoscopy and skin biopsy at referring institutions, coupled with repeated unnecessary hemorrhoid procedures, significantly prolonged the diagnostic process, while the patient's inadequate health literacy delayed appropriate specialist referral. To mitigate such diagnostic errors, a comprehensive multilevel approach is imperative: (1) Heightening clinical suspicion for PPD (especially in malignancy-associated cases) by systematically including it in the differential diagnosis for elderly patients presenting with refractory perianal symptoms lasting more than three months; (2) Implementing standardized diagnostic workflows that incorporate early digital rectal examination, colonoscopy, tissue biopsy, and immunohistochemical profiling (utilizing CK7/CK20/CDX2/CEA/GCDFP-15 markers) to distinguish between primary PPD and secondary manifestations (particularly those of gastrointestinal origin); (3) Establishing MDT collaboration to integrate specialized knowledge from proctology, pathology, and other relevant disciplines; (4) Improving accessibility to advanced pathological and immunohistochemical testing capabilities in primary care settings; and (5) Enhancing patient education initiatives to promote early recognition of warning signs and facilitate prompt specialist consultation.

The clinical insights from this case further underscore that PPD diagnosis necessitates comprehensive pathological evaluation and immunohistochemical analysis, whereas secondary PPD demands radical resection with wide margins (e.g., APR coupled with extensive perianal skin excision). The patient's 12-month recurrence-free survival postoperatively validates the safety of this surgical approach. Implementing a rigorous long-term follow-up protocol (quarterly to biannually during the initial 3 years, transitioning to annual surveillance for a minimum of 5 years) is paramount for early detection of recurrence and metastasis, ultimately enhancing prognostic outcomes. In summary, optimizing PPD management requires the synergistic integration of distinctive pathological characteristics, standardized surgical techniques, and a systematic follow-up regimen, with effective physician-patient communication and multidisciplinary collaboration serving as pivotal components in translating knowledge into clinical practice.

CONCLUSION

In conclusion, the experience of this case suggests that clinicians need to enhance the early recognition of PPD, strictly standardize the diagnosis and treatment process, and strengthen multidisciplinary cooperation to effectively avoid misdiagnosis and mistreatment of the disease, and maximize the improvement of the patient's prognosis and quality of life.

ACKNOWLEDGEMENTS

We appreciate the help of the RCA citation tool (https://www.referencecitationanalysis.com/) in improving our article. We appreciate the valuable contributions of the general surgery specialists at General Hospital of Southern Theater Command.