A Rare Diagnosis of HPV-Positive Rectal Squamous Cell Carcinoma in a 59-Year-Old Heterosexual Woman: Implications for Screening Guidelines

Introduction

Colorectal cancer is the second leading cause of cancer-related deaths in the United States for men and women combined, with an estimated 52,900 deaths projected in 2025 [1]. Although mortality has declined among older adults, likely due to improved screening and treatment, death rates among individuals younger than 55 have increased by approximately 1% annually since the mid-2000s [1]. Human papillomavirus (HPV), a well-established cause of cervical and anal squamous cell carcinoma (SCC), has also been implicated in the rare but increasingly recognized rectal SCC, underscoring its relevance for prevention through vaccination and consideration of targeted screening in high-risk groups [2–4].

The rectal columnar epithelium renders SCC uncommon, although HPV-driven cases have been reported, possibly originating from squamous metaplasia or extension from the anal canal [5]. Previous studies have shown that anal HPV infection prevalence in women can reach 86%; this rate is highest among individuals with a history of receptive anal intercourse, multiple sexual partners, human immunodeficiency virus (HIV) infection, or prior genital HPV [6,7]. Nevertheless, heterosexual women are not routinely screened for anal or rectal HPV-related disease, which may delay diagnosis and treatment. We report a rare case of HPV-positive rectal SCC in a 59-year-old heterosexual woman, highlighting the need for greater awareness and more inclusive screening strategies regarding HPV-associated rectal malignancies in women.

Case Report

A 59-year-old heterosexual woman presented with a 3-month history of painless, intermittent rectal bleeding and altered bowel habits. The bleeding was described as bright red and mixed with stool; she also reported the onset of constipation during this period. She denied weight loss or anorexia but noted mild tenesmus and a sensation of incomplete bowel emptying over the preceding 2 months. Her medical history included hypertension and well-controlled type 2 diabetes mellitus. She had no history of inflammatory bowel disease and no personal or family history of cancer. The differential diagnoses of rectal bleeding at presentation were benign anorectal disease such as hemorrhoids and fissures, diverticulosis, angiodysplasia, inflammatory or ischemic colitis, and, most importantly, colorectal neoplasia. Initial laboratory findings, including complete blood count, renal and liver function tests, and coagulation profile, were unremarkable. Colonoscopy confirmed a fungating, non-obstructing rectal mass, partially circumferential and involving approximately one-third of the lumen (Figure 1). The carcinoembryonic antigen level was within normal limits at 2.8 ng/mL (reference range, 0.0–3.8 ng/mL). Histopathological analysis demonstrated SCC, with strong immunohistochemical positivity for squamous cell markers (cytokeratin [CK]5/6, p63), AE1/AE3 (an antibody mixture confirming epithelial origin through broad-spectrum cytokeratin staining), and cyclin-dependent kinase inhibitor 2A (p16-INK4a; a surrogate marker for transcriptionally active HPV infection). High-risk HPV subtypes 16, 18, and 33 were detected (Figures 2, 3). A Papanicolaou test conducted at the time of diagnosis revealed atypical squamous cells of undetermined significance, but the results were negative for HPV. Review of the patient’s medical records indicated that a Papanicolaou test performed 10 months earlier had shown results within normal limits and HPV negativity. Additionally, documentation confirmed that the patient had declined colonoscopy for colorectal cancer screening, instead choosing annual fecal occult blood testing; all results had been negative prior to presentation with rectal bleeding. She had also undergone multiple HIV screenings with negative results during the preceding 10 years, including at the time of rectal cancer diagnosis.

Further history revealed that the patient had engaged in occasional unprotected receptive anal intercourse with her long-term male partner but had never undergone anal cytology screening. Magnetic resonance imaging confirmed localized disease with muscularis propria invasion but no definite extension beyond the serosa or evidence of distant metastasis (T2N0) (Figure 4). She was subsequently referred to oncology for further management.

Discussion

This case represents a rare but increasingly recognized clinical presentation of HPV-positive rectal SCC in a heterosexual, immunocompetent woman without prior anal pathology [6,7]. Colorectal cancer is the third most common malignancy and second leading cause of cancer-related mortality worldwide, with increasing incidence in younger populations [1,8]. Ninety percent of rectal cancers are adenocarcinomas, whereas pure rectal SCC is rare, representing only 0.3% of cases [9]. Epidemiological disparities in colorectal cancer across populations are largely attributable to heterogeneous exposures to lifestyle and environmental factors implicated in its pathogenesis [8]. Key risk factors for colorectal cancer include advancing age, male sex, family history, inflammatory bowel disease, a history of high-risk adenomas, hereditary syndromes such as familial adenomatous polyposis or Lynch syndrome (hereditary nonpolyposis colorectal cancer), obesity, tobacco use, alcohol consumption, pelvic radiotherapy, and diets rich in red or processed meat [2,8,10,11]. However, rectal SCC is increasingly recognized as a distinct clinical entity, characterized by unique etiologies, molecular features, and risk factors, including the rising incidence of HPV-associated cancers, in contrast to adenocarcinoma, the predominant type of colorectal cancer [9].

The pathogenesis of rectal SCC remains poorly understood [2,4]. Although HPV is a recognized cause of cervical, anal, and oropharyngeal cancers, its association with rectal SCC has only recently received attention; high-risk genotypes such as HPV-16 and HPV-18 have been implicated in anorectal and genital malignancies [9,12]. Compared with anal cancer, studies have demonstrated similar HPV prevalences and molecular profiles between rectal and anal SCC [13]. In our case, the pathology report confirmed the presence of superficial fragments of non-keratinizing SCC in situ, with strong immunohistochemical positivity for squamous markers (AE1/AE3, CK5/6, p63), p16-INK4a (a biomarker for HPV-driven cancers), and high-risk HPV types 16, 18, and 33. This profile is consistent with HPV-driven squamous neoplasia and supports a causal role for high-risk HPV infection in tumor pathogenesis. The patient’s immunohistochemical profile was similar to that of three previously reported cases of primary rectal SCC evaluated for high-risk HPV using immunohistochemistry for p16-INK4a, in situ hybridization, and polymerase chain reaction [14]. All three tumors displayed HPV type 16 positivity – the most common oncogenic HPV subtype – according to polymerase chain reaction testing. Additionally, the tumors exhibited strong, diffuse p16 expression and characteristic nuclear staining patterns on in situ hybridization, supporting HPV-driven carcinogenesis [14].

Notably, HPV was absent at typical entry sites such as the cervix in our patient, similar to findings in another reported case of rectal SCC [15]. Nonetheless, a prior oral or anogenital infection cannot be excluded as the original source of viral dissemination. High-risk HPV genotypes, particularly HPV-16 and HPV-18, exhibit tropism for squamous epithelium. Rectal SCC remains rare because of columnar epithelium predominance in the rectal mucosa; however, HPV-associated cases may arise through squamous metaplasia of the rectal epithelium or by contiguous extension from the anal canal [5]. Persistent infection with high-risk HPV genotypes contributes to carcinogenesis through the expression of E6 and E7 oncoproteins, which functionally inactivate the tumor suppressors p53 and Rb. Thus, detection of E6/E7 mRNA indicates active oncogenic activity and substantiates a causal role for the virus in tumorigenesis, beyond mere viral presence. These mechanisms have been well established in cervical and anal cancers and are increasingly recognized in rectal SCC [15,16].

Anal or rectal HPV transmission is not limited to men who have sex with men or individuals living with HIV, although it is more frequently documented in these groups [17–19]. Heterosexual women, particularly those engaging in receptive anal intercourse, also face increased risk. Epidemiological data indicate a rising incidence of anal and potentially rectal cancers in recent decades, with higher risk observed among women reporting receptive anal intercourse [6,20]. One study showed that anal HPV prevalence in heterosexual women may approach 20–25%, and persistent infection was identified even in women without a history of anal intercourse [6]. In multivariable analysis, persistent anal HPV-16 infection was significantly associated with concurrent cervical HPV-16, alcohol use, anal contact during sexual activity, recent anal intercourse, and absence of condom use during anal sex [21].

Although direct evidence remains limited, current data suggest that screening for and treating high-risk HPV-associated lesions in the anal and perianal region, particularly in high-risk populations, may reduce overall cancer risk, including SCC of the rectum, which shares anatomical and histological characteristics with anal canal tumors [22]. Additionally, some rectal cancers may be misclassified or overlap with anal SCC; the similar epidemiologic patterns of rectal SCC, particularly among individuals living with HIV, suggest a shared sexually transmitted etiology, such as high-risk HPV [18]. Routine HPV screening in high-risk individuals could also incidentally identify precancerous lesions that might otherwise progress in the rectal transition zone [18]. Current screening guidelines for anal or rectal HPV-related malignancies remain limited to high-risk populations such as men who have sex with men; individuals living with HIV; transgender women; those with a history of cervical or vaginal high-grade squamous intraepithelial lesion (HSIL) or cancer, perianal warts, and/or persistent (>1 year) cervical HPV-16 infection; immunosuppressed individuals; and organ transplant recipients [23]. Recommended screening modalities include anal cytology and high-risk HPV testing, followed by high-resolution anoscopy for abnormal results [14,23–26]. This gap is further compounded by the absence of standardized screening protocols for anal cytology or HPV testing in women.

Cervical screening programs have been highly effective in reducing cervical cancer mortality through early detection of HPV-related lesions [27]. A similar approach could be considered for at-risk women with anal HPV exposure. Although there is no widespread consensus regarding inclusion of heterosexual women who practice anal intercourse in routine anal HPV screening guidelines, several authors have advocated for behavior-informed risk stratification, proposing that screening should be based not only on identity but also on sexual practices and HPV-related risk factors, such as anal intercourse, multiple partners, and prior genital HPV infection [6,7].

Routine anal HPV or cytology screening for heterosexual women who practice receptive anal sex without additional high-risk features, such as a history of cervical or vaginal HSIL or cancer, is currently considered unlikely to be cost-effective compared with cervical or colorectal screening [28,29]. However, epidemiological data demonstrate increasing rates of anal and possibly rectal cancers, with elevated risk among women reporting receptive anal intercourse [6,7,20]. Over time, targeted screening may prove cost-effective by preventing cancer and reducing the substantial costs of advanced-stage treatment. Similar to cervical screening, it addresses an HPV-driven disease, and akin to colorectal screening, it illustrates how early detection of precancerous lesions can offset the greater burden of late-stage management. From a public health perspective, even rare cancers may warrant preventive strategies when high-risk groups can be clearly identified. The extension of anal HPV screening to these women could be supported as an approach targeting high-risk behaviors, rather than cancer incidence alone [7]. Anal HPV-related screening modalities, including self-collected samples for HPV testing, may provide scalable models for early detection of HPV-associated anogenital malignancies and serve as potential surrogates for identifying individuals at risk of HPV-driven rectal cancer [30]. Additional longitudinal and modeling studies are needed to determine the utility of this approach in high-risk women.

Furthermore, this case raises important considerations regarding HPV vaccination policies and age limitations. The patient, now 59 years old, had never received the HPV vaccine; her sexual history had not prompted anal cytology or anoscopy for high-risk HPV detection or cancer screening. Current Centers for Disease Control and Prevention guidelines recommend routine HPV vaccination through age 26 and shared decision-making for individuals aged 27 to 45; however, vaccination is not typically offered to older women who may remain at risk [31,32]. Given the rising incidence of HPV-associated anal and rectal cancers and the expanding indications for HPV vaccination, there is a growing need to reconsider existing screening frameworks.

HPV testing in gastrointestinal tumors is not routinely performed, which may contribute to underrecognition of virally mediated rectal cancers [33]. The incorporation of HPV genotyping into the diagnostic evaluation of rectal SCC may enhance understanding of tumor biology and facilitate tailored treatment strategies [34]. Rectal SCC presents in a manner similar to rectal adenocarcinoma, most often with rectal bleeding, followed by altered bowel habits, pain, or weight loss. Definitive diagnosis requires colonoscopy with biopsy of suspicious lesions [2]. Definitive chemoradiotherapy is increasingly recognized as the preferred treatment for primary rectal SCC, offering a curative approach while preserving organ function. This modality has demonstrated favorable outcomes, including complete clinical responses and avoidance of surgical intervention in select cases [9,35–37]. Given the rarity of rectal SCC, treatment approaches are frequently extrapolated from anal SCC protocols, where chemoradiotherapy is the established standard of care [9]. Salvage surgery is typically reserved for cases with persistent or recurrent disease after chemoradiotherapy; it is considered only when histological confirmation of residual or recurrent disease is present and no distant metastasis is detected [36].

Conclusions

This case of HPV-positive rectal SCC in an immunocompetent heterosexual 59-year-old woman without additional high-risk features, such as a history of cervical or vaginal HSIL or cancer, underscores the evolving landscape of HPV-related malignancies and the need for more nuanced, behavior-informed screening strategies. Education concerning high-risk sexual practices, careful sexual history assessment, and updated screening guidelines are essential to improve early detection and outcomes in this underrecognized population. Future studies should quantify the prevalence of HPV-positive rectal SCC across diverse populations, including those with a history of anal intercourse, to better define population-specific disease burden and inform targeted screening strategies.