Sinonasal (SN) malignancies are rare. Within SN adenocarcinomas, the most frequent are intestinal-type adenocarcinomas (ITACs). ITAC has been associated with wood and leather dust occupational exposure and TP53 mutations. Not much information is available regarding its characterization and treatment. The aim of this study is to characterize the clinicopathologic and prognostic factors of patients with sinonasal adenocarcinomas (SNACs) treated in our tertiary-level hospital. A retrospective, consecutive study including SNAC patients diagnosed between 2004-2023 was conducted. Clinicopathological data was collected, and p53 status was assessed in the tumor specimens. The association between p53 status and clinicopathological variables, as well as their impact on survival, was evaluated. In total, 35 were included, most of them having ITAC (91.4%) with papillary subtype (37.5%); the majority were subjected to occupational risk exposure (82.9%). Overexpression of p53 was identified in 48.6% of the tumors. Papillary and colonic subtypes were associated with higher median progression-free survival (mPFS) than mucinous and solid subtypes (mPFS 37 months, 95% CI, 20.0-54.0, vs. 9 months, 95% CI, 7.15-10.85, p=0.01); the former was also associated with higher median overall survival (mOS) (mOS 64 months, 95% CI, 37.18-90.81 vs. 14 months, 95% CI, 0-41.58, p=0.02). Histologic grade 1-2 and macroscopic complete resection were associated with higher PFS (PFS of five months of 90.9% vs. 33.3%, p=0.01; mPFS of 37 months, 95% CI, 4.93-69.07 vs. 10 months, 95% CI, 6.43-13.57, p=0.04, respectively). Disease recurrence with distant metastases was associated with lower OS (11 months, 95% CI, 6.1-15.9 vs. 53 months, 95% CI, 22.70-83.30, p=0.04). This study reinforces the importance of protective occupational measures. Future studies will be important to validate the best treatment strategy in the advanced stages of this disease and also to identify new prognostic and/or therapeutic target biomarkers in SNAC.

Despite advances in surgery and radiotherapy, the overall prognosis of sinonasal intestinal-type adenocarcinoma (ITAC) is poor, and new treatment options are needed. Recent studies have indicated alterations in cellular signaling pathways that may serve as targets for modern inhibitors. Our aim was to evaluate the frequency of mTOR and ERK pathway upregulation in a retrospective series of 139 ITAC and to test the efficacy and mechanism of action of candidate targeted inhibitors in cell line ITAC-3. An immunohistochemical analysis on p-AKT, p-mTOR, p-S6, p-4E-BP1, and p-ERK indicated, respectively, a 68% and 57% mTOR and ERK pathway activation. In vitro studies using low doses of mTOR inhibitor everolimus and ERK inhibitor selumetinib showed significant growth inhibition as monotherapy and especially as combined therapy. This effect was accompanied by the downregulation of mTOR and ERK protein expression. Our data open a new and promising possibility for personalized treatment of ITAC patients.

UNASSIGNED: Primary non-squamous cell carcinomas of the vulva are rare entities including various tumor types. Among these, primary vulvar intestinal-type adenocarcinoma (vPITA) is extremely rare. Until 2021, less than twenty-five cases have been reported in the literature.
UNASSIGNED: We report a case of vPITA in a 63 years old woman with a histopathological diagnosis of signet-ring cell intestinal type adenocarcinoma at vulvar biopsy. Accurate clinical and pathological work-up excluded secondary metastatic localization, and vPITA was diagnosed. The patient was treated with radical vulvectomy and bilateral inguinofemoral dissection. Adjuvant chemo-radiotherapy was performed because of a positive lymph node. At 20 months follow-up the patient was alive and free of disease.
UNASSIGNED:  The prognosis of this very rare disease is unclear and optimal treatment is not well established. About 40% of clinical early-stage diseases reported in literature had positive inguinal nodes, more than in vulvar squamous cell carcinomas. A proper histopathologic and clinical diagnosis is mandatory to exclude secondary disease and to recommend an adequate treatment.

Villous adenoma is a benign neoplasm with an exceptional presentation in the renal pelvis, hence very few cases have been reported. Herein we present the case of a patient who presented with left flank pain clinically suggestive of complicated pyelonephritis, culminating in simple nephrectomy with a villous adenoma in the renal pelvis as histopathological finding associated to the presence of a microscopic focus of intestinal-type adenocarcinoma.

BACKGROUND: The periurethral mass in the female is a rare clinical entity and most of the lesions are benign. We present an unusual case of a periurethral mass found to be intestinal-type adenocarcinoma which has not been previously reported in the literature.
METHODS: A 58-year-old woman was referred to our hospital with acute urinary retention. She complained of frequency, urgency and progressive obstructive urinary symptoms for the last 3 months. A pelvic magnetic resonance imaging scan showed a soft tissue mass of 5 × 4 cm surrounding the entire urethra. A needle biopsy was done and revealed adenocarcinoma with intestinal-type features. The tumor was removed by a simultaneous laparoscopic abdominal and transperineal approach. The pathological results showed a positive surgical margin and urethra and vagina wall invasion. The neoplastic cells were positive for CK20, CDX-2, CerbB-2, MSH2, MSH6, MLH1, PMS2 and P53. The patient received adjuvant systemic chemotherapy comprising S-1 and oxaliplatin. Follow-up with pelvic MRI 6 months after surgery showed no signs of local recurrence.
CONCLUSIONS: We have reported the first case of the primary periurethral adenocarcinoma of intestinal type. There are currently no standardized protocols for the diagnosis, clinical course, and treatment of this rare tumor. This case study can aid decision-making regarding the diagnosis and treatment of this tumor.

Sinonasal intestinal-type adenocarcinoma (ITAC) is strongly related to occupational exposure to wood and leather dust, however, little is known on the genetic alterations involved in tumor development and progression. The aim of this study was to identify tumorigenic signaling pathways affected by gene mutations and their relation to clinical features. We applied whole exome sequencing of 120 cancer-related genes in 50 ITACs and analyzed the signaling activity of four specific pathways frequently affected by mutations. Genes involved in DNA damage response showed somatic mutations in 30% of cases, including four tumors that also harbored germline mutations. Genes in Wnt, MAPK and PI3K pathways harbored mutations in 20%, 20% and 24% of cases, respectively. Mutations and copy number gains in receptor tyrosine kinases possibly affecting MAPK and PI3K pathways occurred in 44% of cases. Expression of key pathway proteins showed no correlation to mutations in these pathways, except for nuclear β-catenin and APC/CTNNB1 mutation. No specific gene mutation, mutated pathway, nor pathway activity level showed correlation to clinical data or survival. In addition, a similar mutational profile was observed among histological subtypes. The wide spectrum of gene mutations suggests that ITAC is a genetically heterogeneous without specific characterizing gene mutations.

BACKGROUND: Intestinal-type adenocarcinoma (ITAC) is a rare tumour occurring in the ethmoid sinus. Recent years have brought advances in endoscopic surgery and precision radiotherapy; however, five-year overall survival has not improved and remains at 35-80%, depending on tumour stage and histology. Therefore, there is a need for new therapeutic options.
METHODS: We evaluated CD8+ tumour-infiltrating lymphocytes (TILs) and tumour microenvironment immune type (TMIT, combining CD8+ TILs and PD-L1) as predictive biomarkers for immunotherapy in a series of 133 ITAC. All results were correlated to clinical and follow-up data.
RESULTS: The presence of intratumoural CD8+ TILs was low in 57% of cases and high in 8% of cases. Tumoural PD-L1 positivity was observed in 26% of cases. CD8+ TILs and TMIT correlated with the histological subtype of ITAC and with better overall survival. The presence of stromal PD-L1-positive macrophages was related to intratumoural CD8+ TILs. PD-L1 expression on tumour cells or macrophages did not show prognostic value.
CONCLUSIONS: TMIT classification did not have additional prognostic value over CD8+ TILs alone. The modest percentage of CD8high/PD-L1pos cases indicates that ITAC is a lowly immunogenic tumour type. Nevertheless, a proportion of ITAC, especially the papillary and colonic subtypes, could benefit from therapy with immune checkpoint inhibitors.

Intestinal-type adenocarcinoma (ITAC) of sinonasal tract is a rare malignant tumor with strong morphological, immunophenotypical, and molecular similarities to colorectal adenocarcinoma (CRC). Tumor budding (TB) is a well-established adverse prognostic marker in CRC and some head and neck tumors, with features of epithelial-mesenchymal transition (EMT). The aim of this study was to assess TB in ITAC and to evaluate its possible association with EMT markers in this setting. We selected 32 surgically resected specimens of non-mucinous/non-signet ring ITAC and evaluated them for TB according to the international recommendations developed for CRC. The expression of the EMT markers E-cadherin, ZEB1, ZEB2, SLUG, and SNAIL was evaluated by immunohistochemistry (IHC). Results were stratified using clinical and follow-up data (2/32 patients had metastatic disease and 4/32 died of disease). We observed TB in 13/32 (40.6%) ITAC cases including the 7 patients with relapse (p = 0.0005) and the 4 patients dead of disease (p = 0.02). Lymphovascular invasion was associated with TB (p = 0.008). Absence of TB was associated with low ZEB2 expression (p = 0.003). No other association with EMT markers emerged. Occupational exposure to wood and leather dust was not related to the presence of TB. TB interobserver concordance was substantial (proportion of agreement = 87%; Cohen\'s kappa = 0.73). This work suggests that TB is associated with a worse prognosis in ITAC, but our findings do not seem to support the involvement of EMT in this specific setting. Further larger studies are needed to address this point.

A case of a sinonasal undifferentiated carcinoma occurring 2 years after a successfully surgically treated intestinal-type adenocarcinoma has never been reported. Treatment modality of paranasal sinus cancer strictly depends on histology so it is important to recognize a different tumor type in the follow-up of these patients.

Introduction: Data regarding treatment and survival outcome of patients with adenocarcinoma of the head and neck are limited to case reports and case series. As a consequence of lacking evidence, treatment guidelines do not exist. We aimed to analyze the effect of a bimodal irradiation regime with intensity modulated radiotherapy (IMRT) and carbon ion boost on local control (LC) and survival in adenocarcinoma patients for a large patient collective. Materials and Methods: Patient records of eighty consecutive patients treated between 2009 and 2018 were analyzed retrospectively and Kaplan-Meier estimates for LC, overall survival (OS) and progression-free survival (PFS) were compared among patients with salivary gland adenocarcinoma (SGAC), salivary duct adenocarcinoma (SDAC), and intestinal-type adenocarcinoma (ITAC) according to the World Health Organization (WHO). Prognostic factors were identified using the log-rank test and cox-regression modeling. Toxicity was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE). Results: Median follow-up was 41 months. The 3-year and estimated 5-year Kaplan-Meier rates for all patients were 83 and 75% for LC, 74 and 50% for OS and 60 and 53% for PFS, respectively. While bimodal RT for ITAC resulted in a significantly decreased 3-year LC rate of 50 vs. 93% for each SGAC and SDAC (p < 0.01), no statistical significant survival differences could be identified across the three groups regarding OS (p = 0.08) and PFS (p = 0.063). 3-year OS was 88% for SGAC, 78% for SDAC and 67% for ITAC and 3-year PFS was 72% for SGAC, 53% for SDAC and 44% for ITAC, respectively. Nevertheless, in subgroup analysis, OS for ITAC was significantly worse compared to SGAC (p = 0.024). In multivariate analysis, bilateral tumor side (vs. unilateral) solely could be identified as independent negative prognostic factor for LC (p < 0.01). Treatment was well-tolerated with 21% acute (n = 17) and 25% (n = 20) late grade ≥3 toxicities. Conclusion: Radiotherapy including active raster-scanning carbon ion boost for relatively radio resistant adenocarcinomas of the head and neck resulted in favorable survival outcome for salivary gland and salivary duct adenocarcinomas with moderate toxicity. However, local control and prognosis for bilateral intestinal-type adenocarcinomas (ITAC) seem to remain low even after dose-escalation.