Inclusion. Case reports/series describing primary colonic SCC with adequate diagnostic work−up to exclude metastasis or adenosquamous carcinoma; English full text (or extractable case−level data from included citations); adults (≥ 19 years); reports containing clinical, pathologic, treatment, or outcome data.

Exclusion. Pediatric cases; secondary colonic involvement by non−colonic SCC; squamous differentiation within adenocarcinoma (i.e., not pure SCC); non−English without extractable case data.

We searched PubMed (last accessed September 30, 2025) using combinations of: “squamous cell carcinoma of the colon,” “primary SCC,” “squamous cell carcinoma,” “treatment,” and “case report.” Filters: English, adults, case reports, free full text. Reference lists of retrieved articles were hand−searched for additional cases. No publication year limits.

Two reviewers independently screened titles/abstracts and full texts. Extracted variables included: age/sex; tumor stage; laterality/location; CEA; surgery; systemic therapies and regimens; and outcomes (overall survival, recurrence, progression−free survival when available). When treatment information was not reported, it was assumed absent; when adjuvant therapy was described without explicit surgery, surgery was inferred. These assumptions were applied consistently and acknowledged as limitations.

Data from 33 cases were abstracted from Linardoutsos et al. (2020) and supplemented with individual case details were available. Attempts were made to contact corresponding authors for missing long−term outcomes. (Table 2).

Given rarity and heterogeneity, we performed descriptive synthesis. Treatments were analyzed by stage and modality (surgery, chemotherapy, radiation). Case−level data were tabulated to facilitate pattern recognition.

The literature on primary SCC of the colon remains limited to single−patient case reports and a few small series, reflecting both the rarity of the disease and the lack of uniform reporting guidelines. Our review adds to this field by synthesizing 62 published cases from 1955 to September 2025. This dataset, spanning 70 years, has a broad temporal window that captures significant evolution in diagnostic capability and treatment approaches. In earlier decades, imaging was less advanced (e.g., PET/CT scans became available in 2010) and long−term follow−up was infrequent; more recent reporting provides greater detail on surgical pathology, immunohistochemistry, and systemic therapies.

Across cases, the majority of patients presented with abdominal pain (≈70%), followed by altered bowel habits, weight loss, or anemia. A particularly notable and recurring pattern is the frequency of obstructive symptoms, with several cases requiring urgent decompression or emergent surgery. Fewer than 10% of cases were diagnosed during routine screening colonoscopy, emphasizing the need for vigilance when encountering unusual or non−adenomatous features endoscopically.

Age at diagnosis is typically clustered between 50–75 years, although younger presentations have been described, including individuals in their third and fourth decades, often in association with underlying inflammatory bowel disease. Older females were slightly more represented in left−sided tumors, similar to our index patient.

Historically, the right colon (cecum and ascending colon) appeared overrepresented in case reports, though more recent literature reveals a more even distribution with increasing recognition of sigmoid and left−sided tumors mirroring advancements in colonoscopy and diagnostic accuracy (3, 9). Most patients were diagnosed at stage II or III, with nodal metastases documented in 30–50% of cases and distant metastases most commonly to liver, lung, or peritoneum in 10–20%.

Poor differentiation was predominant across reports, reinforcing the aggressive phenotype of SCC in the colon. Perforation and abscess formation were recurrent complications, raising the possibility that the inflammatory tumor microenvironment may contribute to the pathologic process.

Use of PET/CT has significantly increased since 2010, improving clinicians’ ability to confirm colonic primary origin by excluding more common SCC primaries (gynecologic, pulmonary, cutaneous). Likewise, widespread adoption of IHC including p40/p63 has strengthened diagnostic confidence, reducing historical uncertainty regarding whether early cases truly represented SCC rather than poorly differentiated adenocarcinoma.

Survival outcomes are inconsistently reported across the literature, with historical cases demonstrating high mortality, often within 1–3 years of diagnosis. More recent reports, reflecting advances in multimodality therapy, describe long-term survival exceeding 10 years, as observed in our patient. Interpretation of these trends is limited by short follow-up durations and incomplete outcome reporting, particularly in earlier case reports. When survival duration or recurrence data were not explicitly reported, outcomes were recorded as unavailable rather than inferred, and these cases were included in the descriptive synthesis but excluded from longitudinal interpretation. Although attempts were made to contact corresponding authors for missing long-term outcomes, substantial gaps remained. Consequently, reported long-term survival reflects a subset of cases with extended follow-up, introducing survivorship bias and requiring cautious interpretation of apparent improvements over time.

Collectively, these findings highlight the need for standardized documentation and follow−up for future cases. Prospective registry−based reporting would substantially enhance understanding of this entity.

Radiologic imaging is pivotal not only for identifying colonic SCC but also for differentiating it from more common colorectal malignancies and for staging to exclude alternative primaries. In our review, contrast−enhanced CT was used in nearly all reported cases and typically demonstrated an infiltrative, sometimes necrotic mass involving the bowel wall, with potential extension into adjacent fat planes or peritoneum (21, 23). Obstructing lesions were not uncommon, with a subset presenting emergently due to large bowel obstruction (9). CT was also crucial for detecting complications such as contained perforation, abscess, or fistulization, which have been documented more frequently in SCC than adenocarcinoma in some reports.

Colonoscopy remains the first−line diagnostic modality, often revealing a fungating or ulceroproliferative mass that may hinder complete luminal assessment (9). In cases with obstructive tumors, stent placement or diverting procedures have been performed prior to definitive surgical management (15).

PET/CT serves an essential role in excluding alternative SCC primaries, given the colon is an atypical site for primary squamous disease. Its use has expanded in recent literature, particularly as a confirmatory tool when biopsy shows squamous morphology. PET/CT can detect clinically occult metastases in up to one−third of advanced cases and may influence operability decisions (7, 8).

MRI has been selectively used in tumors with suspected pelvic involvement or to assess depth of invasion when CT is equivocal (4). This may be particularly relevant in rectosigmoid tumors, where precise staging influences whether neoadjuvant therapy should be considered a strategy occasionally extrapolated from anal SCC protocols.

Overall, multimodal imaging facilitates accurate diagnosis, appropriate staging, and surveillance of primary colonic SCC, contributing to postoperative monitoring for recurrence especially during the first five years when relapse risk is highest.

Serum tumor markers such as CEA and CA 19−9 have shown inconsistent results in colonic SCC. Although markedly elevated CEA has been reported in isolated cases (4), many remain within normal limits (24), limiting its sensitivity and utility as a standalone marker (9). As such, routine markers commonly used for colorectal adenocarcinoma should not be relied upon to triage suspected SCC.

In contrast, IHC is indispensable. Nuclear p63 and p40 positivity was observed in the majority of published cases (4, 8, 10, 11, 26) is highly supportive of squamous differentiation. CK5/6 positivity further strengthens this characterization (10, 11). Frequently, tumors demonstrate high proliferation indices (e.g., Ki−67 >70%), correlating with aggressive histologic features (4, 8, 11, 26).

Markers typical of intestinal lineage (CK20, CDX2) are typically negative or only focally expressed in pure SCC, allowing distinction from adenocarcinoma with squamous differentiation (9, 11). Neuroendocrine markers (chromogranin A, synaptophysin, CD56) are likewise negative, preventing misclassification as high−grade neuroendocrine carcinoma (26).

Select reports have described PD−L1 expression, with implications for experimental use of checkpoint inhibitors in advanced or refractory disease (8). The majority of tumors tested remain microsatellite stable (MSS/pMMR) (4, 8), consistent with the poor correlation between high−level genomic instability and squamous differentiation in this context.

Finally, while HPV−driven oncogenesis is a hallmark of anal SCC, HPV testing has been negative in most primary colonic SCC cases, including our own (4), arguing against viral contribution in the colon. The occasional p16 expression in some cases likely reflects cell−cycle dysregulation rather than viral etiology (11).

Histological diagnosis of primary SCC of the colon relies on recognition of features characteristic of squamous differentiation. These include: Keratinization with keratin pearls, intercellular bridges between tumor cells, eosinophilic cytoplasm, marked nuclear atypia and mitotic activity (25, 51).

Most reported cases, including ours, describe moderately to poorly differentiated tumors (4, 11, 21), consistent with historically adverse prognosis. Areas of necrosis and infiltrative growth patterns are also frequently noted, reflecting the tumor’s aggressive nature.

A major pathological distinction must be made between primary pure SCC and adenosquamous carcinoma, the latter demonstrating both glandular and squamous components. This is crucial because treatment principles and biological expectations differ. In our case, the absence of glandular morphology and negative CK20/CDX2 staining confirmed a pure SCC phenotype.

To ensure accurate classification, pathologists follow Williams et al. diagnostic criteria (6), which exclude: 1. Squamous−lined fistula tracts 2. Metastatic SCC from an extra−colonic primary 3. Direct extension from anal canal SCC.

Contemporary reports emphasize that this diagnostic rigor be supported by comprehensive imaging (CT/PET) and complete clinical history. Additionally, tumor staging particularly identification of T4 disease and nodal involvement, is paramount for prognostication and selection of adjuvant therapy (30).

The constellation of findings in our patient- poor differentiation, T4a invasion, and negative lymph nodes informed subsequent management decisions and correlated with her favorable long−term outcome.

This case highlights several diagnostic and therapeutic themes that recur across the published literature on primary colonic SCC. First, the clinical presentation of nonspecific abdominal pain and iron−deficiency anemia in the absence of changes in bowel habits or overt gastrointestinal bleeding mirrors many reported cases and underscores why diagnosis is often delayed until colonoscopy and tissue sampling are performed (1, 3). In our patient, the lack of prior screening colonoscopy likely contributed to presentation at a locally advanced T4a stage, a scenario commonly observed in narrative reviews and single−institution experiences (12).

Second, the pathological and immunophenotypic profile is representative of pure squamous histology. The strong p63 positivity, coupled with negative CK7 and neuroendocrine markers and only weak CK20/CDX2, supports squamous differentiation and effectively argues against colorectal adenocarcinoma, adenosquamous carcinoma, and neuroendocrine carcinoma (8–10). Anal cell cancer tends to be HPV positive as noted by p16 or ISH positivity. In contrast, our case demonstrated HPV negativity (p16-/ISH-), a finding reported in the majority of published primary colonic SCC cases (4 of 5 references). This consistent HPV-negative profile reinforces the emerging consensus that primary colonic SCC is biologically distinct from HPV-driven anal SCC (p16/ISH+), despite overlapping squamous markers (8, 11).

Third, with respect to staging and exclusion of mimics, our diagnostic pathway adhered to the Williams criteria through systematic anatomic and metabolic imaging to rule out alternate primaries and direct extension (6). The incorporation of PET/CT used in several contemporary reports adds confidence in establishing colonic origin by surveying typical squamous primary sites (gynecologic, pulmonary, cutaneous) and detecting otherwise occult disease (3, 7, 8).

From a therapeutic standpoint, this case informs the practical question of adjuvant chemotherapy in stage II colonic SCC. In colorectal adenocarcinoma, T4 invasion is a recognized high−risk feature for which adjuvant therapy is often recommended. While colonic SCC lacks randomized data, the pattern of care in modern reports suggests increasing use of FOLFOX−based regimens in stage II disease with high−risk features and in nearly all stage III cases (12–14). Our patient’s durable >12−year disease−free survival following mFOLFOX−6 adds to this signal and supports a stage−adapted, risk−stratified approach in which T4a pathology justifies postoperative chemotherapy even in the absence of nodal involvement.

The role of radiotherapy remains selective. While some node−positive or locally advanced presentations have received chemoradiation (e.g., with 5−FU/mitomycin C or platinum−taxane backbones) (16, 62), routine use for completely resected, node−negative colon primaries is not supported by current case−based evidence and is generally reserved for margin−threatened disease or pelvic fixation. In our patient, negative margins and absence of nodal or perineural/lymphovascular invasion argued against adjuvant radiation.

Emerging data regarding immunotherapy in MSS/pMMR colonic SCC are intriguing but preliminary. Case reports describe partial responses to PD−1 blockade combined with chemotherapy in metastatic or unresectable settings (17, 18), suggesting that PD−L1 expression and other tumor−immune features may have future relevance in selected patients (8). At present, however, these observations should be viewed as hypothesis−generating and not as standards of care.

Finally, this case emphasizes the importance of structured, long−term surveillance. Many historical reports suffer from abbreviated follow−up; recurrences, when documented, tend to occur within the first few years. Our patient’s >12−year remission demonstrates the curative potential of margin−negative resection plus appropriately selected adjuvant therapy in high−risk stage II disease. The trajectory of surveillance we employed—more intensive during the first 3–5 years, followed by annual assessments—mirrors patterns used in colon adenocarcinoma and appears reasonable for colonic SCC in the absence of disease−specific guidelines.

In summary, this case reinforces several pragmatic points for clinicians: (1) maintain diagnostic vigilance for SCC when endoscopic and histologic findings are discordant with adenocarcinoma; (2) apply a multimodal diagnostic work−up to establish primary colonic origin; (3) consider adjuvant FOLFOX for stage II T4a tumors after R0 resection; and (4) adopt a prolonged surveillance schedule given uncertainties about late recurrence. These principles, while derived from limited evidence, are consistent with patterns across 62 published reports and provide a rational framework for decision−making until higher−level data become available.

Progress hinges on collaborative registries and pooled data. Molecular profiling and next−generation sequencing could reveal targetable pathways or viral associations. Immunotherapy particularly checkpoint blockade in PD−L1−positive or MSI−high tumors warrants systematic evaluation. AI−assisted pathology and radiomics may refine diagnosis, staging, and risk stratification, moving care toward precision oncology.