Primary sinonasal adenocarcinoma is a rare tumor, accounting for less than 1% of all head and neck cancers (Sarradin et al. 2018). In the 5th edition of the World Health Organization (WHO) classification, primary sinonasal adenocarcinoma is divided into two subtypes: intestinal-type sinonasal adenocarcinoma (ITAC) and non-intestinal-type sinonasal adenocarcinoma (non-ITAC) (Thompson et al. 2022). Non-ITAC is an extremely rare adenocarcinoma that lacks both intestinal and salivary features (Purgina et al. 2015a).Non-ITAC can be classified as low-grade or high-grade non-ITAC, the low-grade non-ITAC appears as a well-defined mass with heterogeneous enhancement on contrast-enhanced CT or MRI, High-grade non-ITAC may have more aggressive features such as invasion of adjacent structures, destruction of bony structures and lymphadenopathy. Imaging findings alone may not be sufficient to make a definitive diagnosis and histopathological examination is required. Low-grade non-ITAC has a specific subset of mucinous adenocarcinoma with focal fusion growth or infiltration (El-Naggar et al. 2017). High-grade non-ITAC is even rarer and has rarely been reported in the national and international literature. It is an invasive tumor with low differentiation, marked atypia and greater tissue diversity. Most high-grade non-ITACs present as solid sheet-like structures, sometimes accompanied by scattered glandular or papillary growth, with fewer glandular lumens, which may not be obvious or may appear as small vacuoles (Stelow et al. 2011). Tumor cells are of moderate size with clear or slightly acidophilic cytoplasm. They show high pleomorphism, increased mitotic activity and may show signs of necrosis. They infiltrate the surrounding soft and bone tissues and often involve blood vessels and nerves (Agaimy et al. 2021). High-grade non-ITAC may have many overlapping features with other malignancies in this region. Therefore, pathologists should strive to exclude other tumours before making this diagnosis. In addition, due to the morphological heterogeneity of the lesion, it is important to consider the possibility of metastatic malignancy (Stelow et al. 2011 Jul).Low-grade non-ITAC often stains positive for S100 protein, SOX10, and DOG1, whereas high-grade non-ITAC may show immunohistochemical changes. High-grade non-ITAC may also express focal neuroendocrine markers (Purgina et al. 2015b). Recently, SATB2 has been identified as a potential diagnostic biomarker that is highly specific for differentiating ITAC from non-ITAC (Skalova et al. 2018). There are few reports on genetic analysis of nasal non-ITAC. It has been reported in the literature that some high-grade non-ITAC may be associated with an ETV6 gene rearrangement, usually an ETV6-NTRK3 gene fusion (Klubíčková et al. 2023 Aug).

The main clinical manifestations of non-ITAC are nasal congestion and epistaxis, and pain caused by tumor growth compressing other tissues. Median survival is 5.5 months (range: 2 months to 5 years), with higher-grade tumours having a worse prognosis than lower-grade tumours (Franchi et al. 2005). High-grade tumours mainly affect the nasal cavity and maxillary sinuses, while low-grade tumours mainly affect the nasal cavity and ethmoid sinuses (Perez-Ordonez 2009; Bracigliano et al. 2021). Due to the rarity of these tumours, their histological diversity and their proximity to important structures such as the orbit, skull base and brain, diagnosis and treatment of these tumours are challenging. Surgery is the first-line treatment for sinonasal adenocarcinoma of the nasal cavity and paranasal sinuses (Meccariello et al. 2016; Nicolai et al. 2011). Research has reported that bilateral ethmoidectomy can minimise the occurrence of secondary tumours, as tumor nests in healthy mucosa away from the tumor have been demonstrated in these regions (Bussi et al. 2002). In recent years, the range of endoscopic procedures has expanded with the development of endoscopic techniques. However, these procedures have mainly focused on smaller and lower stage tumours (Kassam et al. 2005; Gerven et al. 2011). Currently, the gold standard treatment for primary sinonasal adenocarcinoma is surgical removal of the tumor with negative margins followed by radiotherapy, which is suitable for most patients (Poorten and Jorissen 2020). Antognoni P reported a study of 30 cases of intestinal-type sinonasal adenocarcinoma treated with endoscopic resection followed by adjuvant radiotherapy. The retrospective analysis suggested that endoscopic surgery combined with postoperative radiotherapy may be considered a safe, minimally invasive, and highly effective option for the treatment of specific ITAC of the paranasal sinuses (Antognoni et al. 2015). Tachino H reported the first case of successful cure of locally advanced low-grade non-intestinal-type sinonasal adenocarcinoma in a patient treated with concurrent chemoradiotherapy, achieving complete pathological and clinical remission. This study suggested that the regimen of super-selective intra-arterial injection of cisplatin (CDDP) combined with conventional fractionated radiotherapy followed by salvage surgery may be beneficial for the treatment of sinonasal adenocarcinoma (Tachino et al. 2020). Bossi compared the prognosis of two groups of patients: one group received postoperative radiotherapy (group A) and the other group received platinum-based induction chemotherapy followed by standard treatment (group B). The study found that the 5-year overall survival (OS) rate was 42% in group A and 70% in group B (P = 0.041), and the 5-year disease-free survival (DFS) rate was 40% in group A and 66% in group B (P = 0.009). These results suggest that preoperative induction chemotherapy may be beneficial for the prognosis of ITAC (Bossi et al. 2013).

The standard of care for advanced non-ITAC sinus cancer remains radical surgery and adjuvant radiotherapy using a multimodality approach. Advances in imaging, surgical and endoscopic techniques, radiotherapy techniques (intensity modulated radiotherapy, volumetric modulated arc therapy, and heavy particle beam radiotherapy) and strategies involving neoadjuvant chemotherapy have shown promising results in improving prognosis(Leivo et al. 2021). However, the prognosis for advanced non-ITAC sinus cancer remains poor. To assess the prognosis of sinonasal adenocarcinoma, Veuger J conducted a systematic review analysing 21 studies investigating the impact of biomarkers on the prognosis of sinonasal non-ITAC. The study found that expression of the mucin antigen sialosyl-Tn, C-erbB-2 tumor protein, TIMP3, TP53, vascular endothelial growth factor, ANXA2, MUC1 and histological subtypes of mucinous tissue had a significant negative impact on survival. A comprehensive understanding of the biomarkers associated with ITAC/non-ITAC prognosis may provide therapeutic targets to improve treatment strategies (Veuger et al. 2023).

Immunotherapy, which harnesses the immune system to recognise and eliminate cancer, has become one of the mainstays of cancer treatment. In the past decade, immunotherapy has significantly improved survival in many cancer patients (Dagher et al. 2023). In a study of 30 cases of high-grade sinonasal cancer, including 2 cases of non-ITAC, they examined the expression of major histocompatibility complex molecules, leukocyte infiltration and chemokine expression. They found that the chemokines CXCL8 and CXCL5 were up-regulated in high-grade sinonasal cancer, affecting leukocyte activation and trafficking, angiogenesis, metastasis and cancer cell proliferation. On the other hand, some chemokines such as CCL28 and CCL14 were downregulated in high-grade neuroendocrine carcinoma compared to normal tissue. Targeting migration-associated chemokines and their receptors in sinonasal tumours may be beneficial for immunotherapy (Bell et al. 2020). Currently, there are no guidelines recommending immunotherapy for high-grade non-ITAC. A large phase II trial of nivolumab and ipilimumab in patients with rare tumours, including squamous cell carcinoma and adenocarcinoma of the sinonasal region (NCT02834013), is underway and is expected to provide more detailed and accurate descriptions of treatment outcomes.

We reported for the first time a case of high-grade non-ITAC of maxillary sinus origin treated with postoperative radiotherapy followed by immunocombination chemotherapy and then targeted therapy. The patient was clinically diagnosed as high-grade non-ITAC of the maxillary sinus with cervical lymph node and bone metastasis, and the patient was treated with local radiotherapy and then with 6 cycles of “immunocombination chemotherapy” protocol after endoscopic resection of the tumor. The specific regimen of which was carilizumab + docetaxel + cisplatin. The immuno-maintenance therapy of carilizumab was continued until the tumor progressed one year after the operation (new bone metastatic foci and suspected lung nodal foci increased in size, and tumor metastases were taken into consideration), and the genetic test showed mutations of EGFR and TP53, and the targeted therapy of gefitinib was given. After treatment, the metastatic foci in the lungs were smaller than before. Currently, the disease is in a stable state.