Perianal Paget’s disease with concomitant rectal cancer: A case report

Abstract

BACKGROUND

Perianal Paget’s disease (PPD) is a rare condition with a predisposition to anal and colorectal malignancies. Due to its subtle location and the nonspecific nature of its symptoms, PPD is often misdiagnosed or diagnosed late.

CASE SUMMARY

We present the case of a 75-year-old male patient who sought medical attention for “anal pain for more than 4 years”. Clinical examination revealed perianal skin thickening with ulceration, and biopsy pathology showed adenocarcinoma with Paget’s disease. The patient underwent radical surgical treatment, and postoperative pathology confirmed PPD with concomitant rectal cancer. Postoperative pathology showed an infiltrative ulcerative tubular adenocarcinoma with Paget’s disease involving the rectum, anal canal and perianal skin. The lesion measured 7.0 cm × 4.8 cm with a maximum thickness of 0.9 cm. Immunohistochemistry showed mismatch repair protein retention and BRAF negativity, and molecular testing showed no typical KRAS, NRAS, BRAF or PIK3CA mutation. Furthermore, we employed high-throughput sequencing on both the surgical and blood specimens to investigate genetic mutations in the cancer tissue and differential gene expression between cancerous and normal tissues, aiming to explore the molecular mechanisms underlying the disease's development and progression.

CONCLUSION

Persistent perianal ulceration requires biopsy and anorectal evaluation to exclude PPD with concomitant malignancy.

Key Words: Perianal Paget’s disease; Rectal cancer; Adenocarcinoma; Abdominoperineal resection; Case report

Core Tip: Perianal Paget’s disease is rare and may mimic benign perianal disorders, resulting in delayed diagnosis. This case highlights the need for biopsy of persistent perianal ulceration and complete anorectal evaluation. The resected specimen confirmed rectal adenocarcinoma with Paget’s disease. Immunohistochemistry showed retained mismatch repair proteins and negative BRAF expression, and molecular testing revealed no typical KRAS, NRAS, BRAF, or PIK3CA mutations.

INTRODUCTION

Extramammary Paget’s disease is a rare neoplastic condition of apocrine gland-bearing regions[1,2]. The most frequently affected site is vulva, followed by perineal, perianal, scrotal and penile skin. Perianal Paget’s disease (PPD) involving perianal skin or anal mucosa accounts for less than 20% of extramammary Paget’s disease[3]. In this report, we present a case of PPD with concomitant rectal cancer, which was treated with radical surgery. The pathogenesis of this disease remains unclear. Using molecular diagnostic techniques, we conducted an in-depth exploration of the molecular mechanisms underlying the disease from multiple perspectives. This included revealing genetic and epigenetic alterations, as well as analyzing gene expression abnormalities. Our findings aim to provide new insights and approaches for the diagnosis, treatment, and personalized management of this disease.

CASE PRESENTATION

Chief complaints

A 75-year-old male patient presented to our hospital with a complaint of “anal pain for more than 4 years”.

History of present illness

Four years ago, he underwent surgery for “hemorrhoids” at a local hospital. Following the procedure, he developed a sharp, stabbing pain in the anal region, which worsened during defecation. The patient has bowel movements 1-2 times per day, with small stool volume and difficulty passing stools. He occasionally experiences fresh red blood in the stool, as well as mucus, accompanied by a sensation of anal heaviness and incomplete evacuation. He also reports perianal moisture and itching.

History of past illness

The patient has no significant past medical history, no underlying diseases, and no previous surgical history other than the prior hemorrhoid surgery.

Personal and family history

The patient was retired and had no notable occupational exposure. He denied long-term residence in epidemic areas and denied a relevant smoking, alcohol or toxin exposure history. He was married and had children. His father had died, but the detailed cause was unavailable. He denied a family history of hereditary tumors or infectious diseases.

Physical examination

The vital signs were stable. Body temperature was 36.5 °C, pulse rate was 69 beats/minutes, respiratory rate was 16 breaths/min and blood pressure was 136/74 mmHg. A specialized examination was performed with the patient in the left lateral decubitus position. Examination revealed perianal skin thickening with ulceration, which appeared dark red in color and was associated with erosion and exudation (Figure 1). Upon digital rectal examination, the anal canal and distal rectum were narrow, barely accommodating one finger. The rectal tumor was located in the lower rectum, with its distal margin approximately 3 cm from the anal verge. The patient experienced severe pain during the examination, but no blood was noted on the examining finger upon withdrawal. Due to the intense pain, the patient refused to undergo anoscopy.

Figure 1  Image of perianal lesions before surgical treatment.

Laboratory examinations

Relevant laboratory tests were conducted, with the carcinoembryonic antigen level found to be 6.09 ng/mL, while other test results were unremarkable.

To further clarify the nature of the lesion, a preoperative perianal skin biopsy was performed. Histopathological examination revealed moderately differentiated adenocarcinoma with Paget’s disease.

Imaging examinations

To exclude other lesions or distant metastasis, a series of imaging studies were conducted. Chest and abdominal computed tomography scans revealed no abnormalities. Pelvic magnetic resonance imaging showed mild thickening and signal changes in the lower rectum and anal canal wall, most notably on the posterior right wall, which was considered possibly malignant. The lesion involved the internal anal sphincter and the intersphincteric space, with suspected involvement of the right external anal sphincter. Enlarged left inguinal lymph nodes were also noted. Colonoscopy revealed smooth mucosa with clear vascular patterns in the ascending colon, hepatic flexure, transverse colon, splenic flexure, descending colon, and sigmoid colon. In contrast, the rectal mucosa near the anal canal was thickened, reddened, rough in texture, with ulceration covered by purulent exudate, and surrounding erythema (Figure 2A).

Figure 2 Preoperative examination and surgical procedure. A: Preoperative colonoscopy showing abnormal rectal mucosa near the anus; B: Complete surgical excision of the rectum, anus, and perianal skin; C: Radical excision and perineal suturing; D: Sigmoid colostomy.

FINAL DIAGNOSIS

Postoperative pathology revealed that the tumor was an infiltrating, ulcerative tubular adenocarcinoma with Paget’s disease. The tumor was located in the rectum and anal canal and involved the perianal skin. The lesion measured 7.0 cm × 4.8 cm with a maximum thickness of 0.9 cm, and was approximately 13.5 cm from the proximal resection margin and 3.0 cm from the distal resection margin. The tumor invaded perirectal tissue and adjacent striated muscle. Lymphovascular invasion and perineural invasion were present, tumor budding was grade 3, and all examined regional lymph nodes were negative for metastasis. The proximal, distal, perianal skin and mesorectal margins were negative. Immunohistochemistry of the resected specimen showed HER2 (2+), CK (+), Syn (-), MSH6 (+), MSH2 (+), MLH1 (+), PMS2 (+) and BRAF (-). Molecular testing showed no typical KRAS, NRAS, BRAF or PIK3CA mutation. The postoperative pathological diagnosis and immunohistochemical findings were verified against the original institutional pathology report.

TREATMENT

A comprehensive evaluation of the patient's condition was conducted, and there were no contraindications for surgery. The patient underwent laparoscopic abdominal-perineal resection (Miles procedure). During the surgery, thorough dissection was performed to excise the rectum, anus, and perianal skin, and the specimen was removed (Figure 2B). The perineum was closed in layers (Figure 2C), and a sigmoid colostomy was performed to divert the fecal stream (Figure 2D).

OUTCOME AND FOLLOW-UP

The patient had a good postoperative recovery, and follow-up at 2 months showed no local recurrence of the lesion.

DISCUSSION

PPD is a rare form of intraepithelial adenocarcinoma, typically localized to the area below the dentate line, centered around the anus, within a 6.0 cm diameter region. The diagnosis of PPD is usually delayed, with a slow-growing erythematous plaque with sharp demarcation that can either be eczematous, crusting, scaling or ulcerated. Patients report symptoms of prolonged anal pruritis, pain, a burning sensation or bleeding[4]. The reported delay in diagnosis can be as long as 3 years, as it is often confused with other anal diseases[5].

Histologically, PPD is characterized by scattered or clustered Paget cells within the epidermis. Due to its extremely low incidence and the lack of specific biochemical markers, the disease is easily misdiagnosed as eczema, hemorrhoids, or chronic inflammation. A definitive diagnosis requires biopsy and pathological examination. If a perianal ulcer persists despite 6-8 weeks of standard treatment with no significant improvement, biopsy should be considered. PPD is often associated with colorectal malignancies, particularly in the anal canal and rectum. Studies have shown that up to 60% of cases of PPD are associated with colorectal tumors[6]. Therefore, once diagnosed with PPD, a colonoscopy should be routinely performed to exclude the presence of a concomitant malignancy. Furthermore, patients diagnosed with rectal or anal canal cancer should undergo regular examination for perianal defects.

Recent clinicopathological studies have further clarified the relationship between PPD and anorectal carcinoma. Tateishi et al[7] reviewed 11 cases of perianal Paget disease with a rectal phenotype and found that most cases contained an invasive carcinoma component, with tubular adenocarcinoma being the most common histological type. Their findings emphasized the pathological heterogeneity of this condition and the importance of careful pathological and immunohistochemical evaluation. Imaizumi et al[8] analyzed 14 patients with perianal Paget disease and identified underlying rectal cancer in six patients. Recurrent disease was observed in several patients, supporting the need for complete anorectal evaluation and prolonged postoperative surveillance. More recently, Ishii et al[9] reviewed 89 reported cases of PPD or anorectal carcinoma with pagetoid spread and highlighted the clinical and pathological heterogeneity of this rare condition, as well as the importance of individualized treatment and long-term follow-up.

The present case shares several features with these reports, including persistent nonspecific perianal symptoms, delayed diagnosis, and coexistence with anorectal adenocarcinoma. However, the lesion in our patient was extensive, measuring 7.0 cm × 4.8 cm and involving the rectum, anal canal, and perianal skin. Lymphovascular invasion, perineural invasion, and Grade 3 tumor budding were present, although the examined regional lymph nodes and resection margins were negative. Because of the extensive involvement of the anorectal region and perianal skin, abdominoperineal resection was performed. In addition, the present case provides exploratory transcriptomic and whole-exome sequencing findings, which may offer further insight into the potential molecular characteristics of this rare disease.

In general, surgical resection with adequate surgical margins is the preferred treatment for PPD, as it helps achieve low postoperative recurrence rates. In the previously reported cases, the adopted treatments include a local excision and abdominoperineal resection. Whether to perform a local excision or abdominoperineal resection depends on the stage of the associated anorectal cancer[10]. Systemic chemotherapy is recommended for cases of distant metastases. Long-term postoperative follow-up is needed to rule out local recurrence and associated cancers.

In this case, exploratory molecular analyses were performed to provide additional insight into the potential biological features of PPD with concomitant rectal cancer. Transcriptome sequencing of cancerous and adjacent non-cancerous tissues identified 644 differentially expressed messenger RNAs, including 260 upregulated and 384 downregulated genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that these genes were mainly associated with cellular processes, immune response, metabolism, cancer-related pathways, sulfur metabolism, fructose and mannose metabolism, efferocytosis, and the hypoxia-inducible factor-1 signaling pathway (Figure 3). Whole exome sequencing of cancer tissue and blood samples further demonstrated somatic mutation differences, with single nucleotide variants (SNV) being the predominant mutation type and C>T/G>A substitutions being the most frequent. Copy number variation analysis also revealed chromosomal-level differences between cancer tissue and blood samples (Figure 4). These findings suggest that transcriptomic alterations and chromosomal copy number changes may be involved in the tumorigenesis and progression of this rare disease.

Figure 3 Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis with volcano and scatter plots of differentially expressed mRNAs between cancer and adjacent tissues. A: Gene Ontology (GO) classification; B: GO enrichment. X-axis label represents rich factor, Y-axis label represents GO term. Size, shape and color of the bubble represent amount of differentially expressed (DE) mRNAs, classification and enrichment significance, respectively; C: Kyoto Encyclopedia of Genes and Genomes (KEGG) classification; D: KEGG enrichment. X-axis label represents rich factor, Y-axis label represents pathway. Size, and color of the bubble represent amount of DE mRNAs and enrichment significance, respectively; E: Up-regulated and down-regulated mRNAs were showed by the volcano plot; F: The differential expression of mRNAs between cancerous and adjacent normal tissues was evaluated using a scatter plot. Red points indicate up-regulated mRNAs, and blue points indicate down-regulated mRNAs. GO: Gene Ontology; KEGG: Kyoto Encyclopedia of Genes and Genomes; DE: Differentially expressed; T: Tumor; N: Adjacent normal tissue.

Figure 4 Whole exome sequencing results of cancer tissue and blood samples. A: Somatic mutations detected in both tissue types, highlighting significant genomic differences; B: Copy number variations observed in the cancer tissue and blood samples. InDel: Insertion/deletion; T: Tumor; CNV: Copy number variations; SNV: Single nucleotide variants.

For other similar cases, treatment should be individualized according to lesion extent, sphincter involvement, resection margin status and the presence or absence of underlying anorectal carcinoma. Wide local excision may be considered for localized noninvasive disease when anal function can be preserved. Abdominoperineal resection is appropriate when disease involves the anal canal, sphincter complex or rectum, or when an associated rectal or anal canal carcinoma is present. Radiotherapy, chemotherapy or systemic therapy may be considered for unresectable, recurrent or metastatic disease, although standardized treatment remains limited because of disease rarity.

In this study, we performed differential gene expression analysis of both cancerous and adjacent non-cancerous tissues from the patient using high-throughput sequencing, and explored the mutational characteristics through whole exome sequencing. The differential expression analysis identified 644 mRNAs with significant differences in expression, with transmembrane protein 51 (FC = -1.108688; P = 0.000101) being the most significantly different gene. GO and KEGG pathway analysis revealed that the differentially expressed genes were primarily involved in key biological processes and pathways, including cellular processes, immune response, metabolism, and cancer. Notably, the genes were enriched in pathways related to sulfur metabolism, fructose and mannose metabolism, phagocytosis, and the HIF-1 signaling pathway, providing insights into the potential mechanisms associated with the disease. Whole exome sequencing showed significant somatic mutation differences between cancer tissues and blood samples. SNV-dominant mutation types and C>T/G>A mutations predominated, reflecting significant changes in the genome. Additionally, copy number variations analysis showed marked differences between the cancer tissue and blood samples across multiple chromosomal regions. These findings further suggest that chromosomal-level changes in PPD with concomitant rectal cancer may be closely linked to the onset and progression of the disease.

This case has several limitations. It represents a single patient, and the follow-up period was short. Functional outcomes and long-term recurrence risk require continued surveillance. In addition, molecular sequencing results were exploratory and should not be overinterpreted without validation in larger cohorts.

CONCLUSION

Based on our case and the literature, we suggest that a high index of suspicion, prompt and early diagnosis, and aggressive surgical treatment are crucial for the successful management of PPD. We identified significant differential mRNA expression and specific gene mutation types in the cancer tissue of PPD with concomitant rectal cancer. The results of this study provide important genomic evidence for understanding the pathogenesis of PPD associated with rectal cancer and offer potential molecular targets for the diagnosis and targeted therapy of this condition.