Sinonasal intestinal-type adenocarcinoma (ITAC) is a rare category of malignant tumor, with a significantly higher incidence among individuals exposed to wood and leather dust (1,2). Histopathologically and immunophenotypically, ITAC resembles intestinal adenocarcinoma and shares the same immunophenotype [cytokeratin (CK)20⁺/caudal-type homeobox 2 (CDX2)⁺/villin⁺] as colorectal cancer (3). Histologically, ITAC is classified into the colonic, papillary, solid, mucinous and mixed subtypes. Well-differentiated papillary intestinal adenocarcinomas are associated with a more favorable prognosis, whereas solid and mucinous intestinal adenocarcinomas are associated with a poorer prognosis (1).

Clinically, ITAC most commonly occurs in the ethmoid sinus, followed by the nasal cavity and other sinuses (4). Early symptoms of ITAC typically include nasal congestion, rhinorrhea and localized pain. As the tumor progresses to an advanced stage, ocular symptoms may manifest, such as proptosis, diplopia and blindness. In cases where the tumor invades the cranial cavity, patients may experience headaches and nausea, and facial ulceration may occur (5).

Surgical resection combined with adjuvant therapy remains the cornerstone of ITAC management (6,7); however, the selection of the surgical approach and radiotherapy regimen varies substantially according to the stage of the tumor, the anatomical location and the extent of invasion.

With regard to surgical approaches, the endoscopic endonasal approach (EEA) is preferred for early-stage ITAC due to its benefits of reduced surgical trauma, fewer complications and a shorter period of hospitalization (8,9). Patients with T3-T4 stage tumors may still derive benefits from EEA, provided there is no extensive invasion of the skull base or orbit (9). In cases with locally advanced tumors that invade complex anatomical structures, such as the skull base, dura mater, orbit and maxillary sinus, a more intricate EEA, in conjunction with open surgery, is warranted (10).

Post-operative adjuvant radiotherapy is typically recommended to complement surgical resection for high-risk cases, with a standard dose range of 60–70 Gy (6,7). However, anatomical constraints often necessitate compromises in the radiotherapy dose. The proximity of the ethmoid sinus/cranial base area to critical structures, such as the optic nerve and brainstem, poses challenges in achieving an optimal balance between delivering an adequate dose to the target area and protecting organs at risk (OAR) using conventional radiotherapy techniques. Consequently, developing strategies to ensure sufficient dosing to the target area, while safeguarding the OAR remains an urgent issue.

There is currently no standardized systemic treatment available for an ITAC that cannot be fully resected through palliative surgery or that recurs or metastasizes post-surgery. Given the morphological and molecular similarities between ITAC and colorectal cancer, several studies have suggested the use of neoadjuvant fluorouracil-based chemotherapy regimens (4,11). Previous clinical trials have predominantly concentrated on early-stage nasal sinus adenocarcinoma, yielding favorable outcomes. Nonetheless, the median progression-free survival (PFS) time for metastatic ITAC treated with chemotherapy is only 1.2 months (12). This underscores the urgent need for more effective therapeutic options for advanced-stage ITAC.

The tumor protein p53 (TP53) gene is the most frequently mutated in ITAC, with a mutation incidence of 40–50%, and the status of the p53 protein can serve as a predictor of the tumor response to chemotherapy (13). Furthermore, KRAS proto-oncogene GTPase mutations are present in ~43% of patients with ITAC (14), while nuclear β-catenin expression is observed in 31–53% of ITAC cases (15). Consequently, targeted therapies addressing these specific mutations represent a promising avenue for future research into the treatment of advanced-stage ITAC.

Combined immunotherapy or immunotherapy alone has demonstrated promising outcomes in the treatment of various types of head and neck squamous cell carcinomas, as well as colorectal cancer (16–18). Previous research has identified that 17% of ITACs express programmed death-ligand 1 (PD-L1), suggesting the presence of an immunosuppressive environment in this malignancy (19). Although this evidence suggests that immunotherapy holds therapeutic potential, the clinical data remain limited to case reports (20,21).

The present study constitutes a preliminary systematic validation of radiotherapy dose thresholds and describes a potentially promising approach combining immunotherapy with chemotherapy, followed by sequential immunotherapy as a single-agent maintenance treatment. This strategy could provide preliminary insights for the management of advanced-stage ITAC.

Sinonasal ITAC is an uncommon malignancy with a high post-operative recurrence rate, which is a major cause of treatment failure in numerous patients (23). However, to date, no consensus has been reached on the recurrence patterns of ITAC. The present case report aimed to explore the clinical course of patients with ITAC experiencing recurrence. The present study describes a detailed account of the management of a 60-year-old patient diagnosed with ITAC with cranial invasion. The patient underwent an endoscopic combined transcranial tumor resection, followed by adjuvant post-operative radiotherapy. Tumor recurrence was observed after a 12-month follow-up period, and a biopsy confirmed the pathology as ITAC. Immunohistochemical analysis revealed PD-1 positivity at 5% and a PD-L1 CPS of 5. Consequently, the treatment strategy was modified to include four cycles of chemotherapy combined with anti-PD-1 immunotherapy, followed by maintenance monotherapy with immunotherapy. At the 11-month follow-up, disease progression was observed.

The present case highlights two critical issues in the treatment of advanced intracranial infiltrative ITAC, providing valuable insight into the management of this rare neoplasm.

First, inadequate post-operative radiotherapy dosage is likely a key factor contributing to early local recurrence. Non-‘R0’ resection represents a high-risk factor for the early post-operative recurrence of ITAC (24). In the present case, the tumor was located in the ethmoid sinus and had extended to the skull and orbit, adjacent to the optic nerve and other vital structures. The anatomical complexity of this region rendered a complete ‘R0’ resection challenging, which may have contributed to the early post-operative recurrence of the patient. In an observational study, Abu-Shama et al (25) analyzed the surgical data of 13 patients with localized recurrence and found that difficulty was experienced in dissecting the cribriform plate or the lateral lamina during surgery in 11 of these patients.

An insufficient adjuvant radiotherapy dose may be associated with early local recurrence. Based on the postoperative radiotherapy doses for sinonasal intestinal-type adenocarcinoma reported in the previous literature (26–31) (Table I) and the positive surgical margins of this patient, the radiation oncologists formulated an initial radiotherapy plan with a total dose of 66 Gy. However, due to concerns about potential optic nerve damage (with the optimal maximum dose of the optic nerve recommended to be ≤54 Gy), the patient ultimately received only 25 sessions, a dose substantially lower than the planned regimen and the ≥66 Gy EQD2 generally recommended for adjuvant radiotherapy in postoperative high-risk areas (such as those with margin positivity, neural invasion or extra-peritoneal invasion) (26). Definite recurrence was observed at merely 12 months following surgery, primarily involving the bilateral ethmoid sinus margins, anterior left nasal cavity and nasal septum. These sites were within or adjacent to the original radiotherapy target volume, suggesting that an insufficient radiotherapy dose may be a key factor in the early local recurrence.

For ITACs involving complex anatomical structures adjacent to critical organs (e.g., optic nerve and brainstem), particularly those with high-risk factors, such as intracranial invasion and narrow surgical margins, achieving ‘R0’ resection margins during surgery is notably challenging. Therefore, post-operative radiotherapy should aim to deliver a curative dose. A dose of 66 Gy EQD2 is recommended, as per previous studies (26,27). The application of advanced radiotherapy modalities, including proton and heavy ion therapy, is recommended for precise dose distribution. Proton and heavy ion therapies, due to their distinctive Bragg peak effect, enable the concentration of high radiation doses within the target area, while substantially minimizing exposure to surrounding vital structures. This capability facilitates safe dose escalation and enhances tumor control (32,33). For instance, proton therapy has been shown to achieve a 43% local control rate in patients with unresectable advanced sinus tumors (34). Additionally, carbon ion therapy permits dose escalation up to 73 Gy without an increase in acute toxicity (35).

Secondly, PD-L1 expression-guided chemoimmunotherapy followed by sequential immunotherapy maintenance may hold potential clinical value for advanced recurrent sinonasal ITAC.

The pathological analysis of the biopsy tissue from the recurrence site revealed 5% PD-1 positivity and a PD-L1 CPS of 5. Although the value is at the threshold, the presence of PD-1 positive tumor-infiltrating lymphocytes may indicate potential for an enhanced immune response (36). As an anti-PD-1 monoclonal antibody, camrelizumab blocks PD-1 on immune cells to reverse PD-L1-induced immune suppression. Consequently, a combination treatment regimen consisting of albumin-bound paclitaxel, cisplatin and camrelizumab was subsequently administered in the present case. This regimen was formulated based on the following considerations: i) Chemotherapy with paclitaxel and platinum compounds is known to induce immunogenic tumor cell death and increase T-cell infiltration (37,38); and ii) platinum compounds are recognized for promoting PD-L1 expression and enhancing the sensitivity to immune checkpoint inhibitors (39). Considering the tolerability of long-term combination therapy, the treatment was subsequently adjusted to camrelizumab monotherapy maintenance. This strategy, termed ‘chemotherapy-induced combined immune maintenance’, has shown efficacy in clinical practice for various solid tumors, such as lung cancer (40). After the initiation of this regimen, the patient achieved a PFS time of 11 months (followed by disease progression) with good treatment tolerance.

Survival rates for early-stage ITAC are relatively favorable. Dallan et al (41) reported a 5-year cancer-specific survival rate of 81.7% in a cohort of 440 European patients with ITAC, which was consistent with the findings in the study by Camp et al (42). Additionally, van de Velde et al (43) documented a 5-year overall survival rate of 47.8% (95% CI, 39.4–55.6) among patients with ITAC in The Netherlands. By contrast, the prognosis of patients with advanced or metastatic ITAC remains less favorable. Sarradin et al (12) conducted a retrospective analysis on the efficacy of chemotherapy in 6 patients with advanced ITAC, revealing that 3 patients with meningeal involvement experienced rapid disease progression, with a median PFS time of only 1.2 months. In the present case, the tumor of the patient had invaded the orbit at initial diagnosis, breached the meninges, invaded the skull and recurred swiftly post-surgery, all of which are considered poor prognostic indicators. Nevertheless, the patient achieved a prolonged PFS time of 11 months following chemoimmunotherapy combined with subsequent immunotherapy maintenance. This case provides preliminary evidence supporting the potential of this therapeutic strategy for PD-1/PD-L1-positive patients with advanced or recurrent ITAC.

The present case report has several limitations. Firstly, as a single case report, the present study lacks statistical analysis and can only provide limited reference value. Secondly, due to the different positions of the patient during the radiotherapy planning CT and the PET-CT scan for recurrence diagnosis, precise registration comparison between the two could not be performed. Nevertheless, sectional images near the optic nerve (the main recurrence site) are included in Fig. S1. Thirdly, the recurrence diagnosis described in this manuscript was based on pathology reports rather than retrievable original image files, which may represent a limitation of this study. Fourthly, due to the low incidence of this tumor, there were virtually no established clinical guidelines to reference during the management of this patient. The present study merely proposes two preliminary hypotheses, and further data from other cases and studies are required to provide stronger evidence for the treatment of ITAC.

In conclusion, ITAC is characterized by local invasiveness, which poses substantial challenges to treatment, particularly when intracranial tissue is involved. The analysis of this case provides two preliminary insights: First, an adequate postoperative adjuvant radiotherapy dose (≥66 Gy EQD2) may be important for controlling local recurrence. Second, for patients with recurrent or metastatic ITAC, the assessment of PD-1/PD-L1 expression may provide a valuable reference for treatment decision-making. In patients who are PD-1-positive or exhibit a PD-L1 CPS ≥1, a treatment strategy involving chemotherapy followed by sequential immune monotherapy maintenance therapy, such as camrelizumab, may serve as a potential salvage treatment. This approach may achieve durable disease control in some cases and provide preliminary references for the treatment of advanced ITAC.