Stereotactic radiosurgery for distant brain metastases secondary to esthesioneuroblastoma: a single-institution series.

OBJECTIVE: Esthesioneuroblastoma (ENB), also known as olfactory neuroblastoma, is a rare, malignant tumor of neuroectodermal origin that arises from the olfactory neuroepithelium. In this study the authors present the first series in the literature on distant brain metastases (BMs) secondary to ENB that were treated with stereotactic radiosurgery (SRS), to evaluate the safety and effectiveness of SRS for this indication. METHODS: A retrospective analysis of clinical and radiological outcomes of patients with ENB who underwent CyberKnife (CK) SRS at a single center was conducted. The clinical and radiological outcomes of patients, including progression-free survival, overall survival, and local tumor control (LTC) were reported. RESULTS: Between 2003 and 2022, 32 distant BMs in 8 patients were treated with CK SRS at Stanford University. The median patient age at BM diagnosis was 62 years (range 47-75 years). Among 32 lesions, 2 (6%) had previously been treated with surgery, whereas for all other lesions (30 [94%]), CK SRS was used as their primary treatment modality. The median target volume was 1.5 cm3 (range 0.09-21.54 cm3). CK SRS was delivered by a median marginal dose of 23 Gy (range 15-30 Gy) and a median of 3 fractions (range 1-5 fractions) to a median isodose line of 77% (range 70%-88%). The median biologically effective dose was 48 Gy (range 21-99.9 Gy) and the median follow-up was 30 months (range 3-95 months). The LTC at 1-, 2-, and 3-year follow-up was 86%, 65%, and 50%, respectively. The median progression-free survival and overall survival were 29 months (range 11-79 months) and 51 months (range 15-79 months), respectively. None of the patients presented adverse radiation effects. CONCLUSIONS: In the authors' experience, SRS provided excellent LTC without any adverse radiation effects for BMs secondary to ENB.

Comprehensive analysis of HPV infection, EGFR exon 20 mutations and LINE1 hypomethylation as risk factors for malignant transformation of sinonasal-inverted papilloma to squamous cell carcinoma.

Different risk factors are suspected to be involved in malignant transformation of sinonasal papillomas and include HPV infection, tobacco smoking, occupational exposure, EGFR/KRAS mutations and DNA methylation alterations. In our study, 25 inverted sinonasal papillomas (ISPs), 5 oncocytic sinonasal papillomas (OSP) and 35 squamous cell carcinomas (SCCs) from 54 patients were genotyped for 10 genes involved in EGFR signalling. HPV-DNA detection was performed by in-situ hybridisation and LINE-1 methylation was quantitatively determined by bisulphite-pyrosequencing. High-risk HPV was observed only in 13% of ISP-associated SCC and in 8% of de novo-SCC patients. EGFR mutations occurred in 72% of ISPs, 30% of ISP-associated SCCs and 17% of de novo-SCCs. At 5-year follow-up, SCC arose in only 30% (6/20) of patients with EGFR-mutated ISPs compared to 76% (13/17) of patients with EGFR-wild-type ISP (p = 0.0044). LINE-1 hypomethylation significantly increased from papilloma/early stage SCC to advanced stage SCC (p = 0.03) and was associated with occupational exposure (p = 0.01) and worse prognosis (p = 0.09). In conclusion, our results suggest that a small subset of these tumours could be related to HPV infection; EGFR mutations characterise those ISPs with a lower risk of developing into SCC; LINE-1 hypomethylation is associated with occupational exposure and could identify more aggressive nasal SCC.

Role of the Akt/mTOR signaling pathway in human papillomavirus-associated nasal and sinonasal inverted papilloma.

Nasal and sinonasal inverted papilloma (NSIP) is a benign tumor in which surface epithelial cells grow downward into the underlying supportive tissue with varying degrees of metaplasia. Human papillomavirus (HPV) has been proposed as the causal agent in the pathogenesis of this disease. Many studies have shown that HPV can activate the Akt/mechanistic target of rapamycin (mTOR) signaling pathway, but the role of this pathway in HPV-associated NSIP is largely unknown. In this study, we enrolled 40 control tissue samples and 80 NSIP tissue samples. HPV genotyping showed that 47 of the 80 examined cases of NSIP were HPV-positive (58.8%), and the most common subtype was HPV11 (20/53, 37.7%). The immunohistochemistry showed statistically significant differences in phosphorylated Akt and phosphorylated S6 ribosomal protein staining among control samples, HPV-positive NSIP and HPV-negative NSIP. The HPV11 L1-L2 plasmid increased the proliferation of normal human nasopharyngeal epithelial NP69-SV40T cells and human nasopharyngeal cancer CNE1 cells. Meanwhile, rapamycin, an mTOR inhibitor, reversed the increased cell proliferation induced by the HPV11 L1-L2 plasmid. Western blot analysis showed that Akt/mTOR/S6 were overexpressed in NP69-SV40T cells and CNE1 cells infected with the HPV11 L1-L2 plasmid. These data demonstrate that HPV promotes cell proliferation through the Akt/mTOR signaling pathway in NSIP.

The Rapid Development of Squamous Cell Carcinoma on the Nasal Dorsum of a Patient Receiving Immunosuppressive Therapy.

The risk of cancer is significantly increased in patients undergoing renal transplant surgery than in the general population. In particular, skin cancer is the most commonly occurring cancer in these patients.A 34-year-old man underwent living renal transplantation for focal segmental glomerulosclerosis. After 18 months, he developed a lesion on the nasal dorsum, approximately 1 cm in size, and the lesion rapidly expanded to cover the entire dorsum.Owing to its rapid expansion, the lesion was suspected to be a malignant tumor and wide excision was planned.We removed the lesion with a 6-mm margin. Squamous cell carcinoma was diagnosed through intraoperative rapid pathological examination. The nasal bone and septum were invaded by the tumor and, as a result, the entire external nose was removed. The patient's nose was subsequently reconstructed using a free forearm flap for lining, iliac bone graft for the nasal frame, and a scalping forehead flap for skin coverage.Selective target radiotherapy was administered at the closest margin around the lesion, and the dosage of immunosuppressants was reduced.At >2 years postoperatively, the patient showed good cosmetic results with no relapse or metastasis of the tumor.We report the unusual case of a young man who developed a rapidly progressing squamous cell carcinoma on his nasal dorsum after 18 months of immunosuppression. Squamous cell carcinoma in organ transplant recipients may be more aggressive and may progress differently than in regular patients. Therefore, special attention is required for patients who take immunosuppressive drugs after renal transplant surgery.

RADIATION THERAPY COMMUNICATION-REIRRADIATION OF A NASAL TUMOR IN A BRACHYCEPHALIC DOG USING INTENSITY MODULATED RADIATION THERAPY.

A 5-year-old spayed female Shih Tzu was referred for evaluation of a nasal transitional carcinoma. A total lifetime dose of 117 Gy was delivered to the intranasal mass in three courses over nearly 2 years using fractionated intensity modulated radiation therapy (IMRT) to spare normal tissues. Clinically significant late normal tissue side effects were limited to bilaterally diminished tear production. The patient died of metastatic disease progression 694 days after completion of radiation therapy course 1. This case demonstrates that retreatment with radiation therapy to high lifetime doses for recurrent local disease may be well tolerated with IMRT.

Workers exposed to wood dust have an increased micronucleus frequency in nasal and buccal cells: results from a pilot study.

Wood dust is recognised as a human carcinogen, based on the strong association of wood dust exposure and the elevated risk of malignant tumours of the nasal cavity and paranasal sinuses [sino-nasal cancer (SNC)]. The study aimed to assess genetic damage in workers exposed to wood dust using biomarkers in both buccal and nasal cells that reflect genome instability events, cellular proliferation and cell death frequencies. Nasal and buccal epithelial cells were collected from 31 parquet layers, installers, carpenters and furniture workers (exposed group) and 19 non-exposed workers located in Switzerland. Micronucleus (MN) frequencies were scored in nasal and buccal cells collected among woodworkers. Other nuclear anomalies in buccal cells were measured through the use of the buccal micronucleus cytome assay. MN frequencies in nasal and buccal cells were significantly higher in the exposed group compared to the non-exposed group; odds ratio for nasal cells 3.1 [95% confidence interval (CI) 1.8-5.1] and buccal cells 1.8 (95% CI 1.3-2.4). The exposed group had higher frequencies of cells with nuclear buds, karyorrhectic, pyknotic, karyolytic cells and a decrease in the frequency of basal, binucleated and condensed cells compared to the non-exposed group. Our study confirms that woodworkers have an elevated risk for chromosomal instability in cells of the aerodigestive tract. The MN assay in nasal cells may become a relevant biomonitoring tool in the future for early detection of SNC risk. Future studies should seek to standardise the protocol for MN frequency in nasal cells similar to that for MN in buccal cells.

Angiofibroma of inferior turbinate as an unusual complication of CO2 laser turbinoplasty.

Angiofibroma is a benign vascular tumor that usually occurs in the nasopharynx, and extranasopharyngeal angiofibromas are rarely reported. We report the first case of an angiofibroma arising from the inferior turbinate after CO2 laser turbinoplasty. Endoscopic excisional biopsy was performed, but the tumor recurred after 2 months of surgery. The mass was excised by endoscopic approach including surrounding normal mucosal tissue. Histologic examination suggested the diagnosis of angiofibroma. The patient was asymptomatic, and there was no evidence of recurrence after 1 year of the second surgery.

Risk factors for nasal malignancies in German men: the South-German Nasal cancer study.

BACKGROUND: There are few studies of the effects of nasal snuff and environmental factors on the risk of nasal cancer. This study aimed to investigate the impact of using nasal snuff and of other risk factors on the risk of nasal cancer in German men. METHODS: A population-based case-control study was conducted in the German Federal States of Bavaria and Baden-Württemberg. Tumor registries and ear, nose and throat departments provided access to patients born in 1926 or later. RESULTS: Telephone interviews were conducted with 427 cases (mean age 62.1 years) and 2.401 population-based controls (mean age 60.8 years). Ever-use of nasal snuff was associated with an odds ratio (OR) for nasal cancer of 1.45 (95% confidence interval [CI] 0.88-2.38) in the total study population, whereas OR in smokers was 2.01 (95% CI 1.00-4.02) and in never smokers was 1.10 (95% CI 0.43-2.80). The OR in ever-smokers vs. never-smokers was 1.60 (95% CI 1.24-2.07), with an OR of 1.06 (95% CI 1.05-1.07) per pack-year smoked, and the risk was significantly decreased after quitting smoking. Exposure to hardwood dust for at least 1 year resulted in an OR of 2.33 (95% CI 1.40-3.91) in the total population, which was further increased in never-smokers (OR 4.89, 95% CI 1.92-12.49) in analyses stratified by smoking status. The OR for nasal cancer after exposure to organic solvents for at least 1 year was 1.53 (1.17-2.01). Ever-use of nasal sprays/nasal lavage for at least 1 month rendered an OR of 1.59 (1.04-2.44). The OR after use of insecticides in homes was 1.48 (95% CI 1.04-2.11). CONCLUSIONS: Smoking and exposure to hardwood dust were confirmed as risk factors for nasal carcinoma. There is evidence that exposure to organic solvents, and in-house use of insecticides could represent novel risk factors. Exposure to asbestos and use of nasal snuff were risk factors in smokers only.

Epidemiology and pathogenesis of nasal NK/T-cell lymphoma: a mini-review.

Nasal NK/T-cell lymphoma (NKTCL) frequently presents with necrotic, granulomatous lesions in the upper respiratory tract, and usually shows a highly aggressive clinical course. Thus, it was initially included in the clinical condition of lethal midline granuloma. Recently, the disease has been recognized as a neoplastic proliferation of NK/T cells. The disease is much more frequent in Asian and Latin American countries than in Western countries, and is universally associated with Epstein-Barr virus (EBV) infection. Analyses of gene mutations, especially p53 and c-kit, revealed the different frequencies by district. Abnormalities of other genes have also been reported. Case-control studies showed that the exposure to pesticides and chemical solvents could be causative of NKTCL. Further studies including HLA antigen typing of patients is necessary to further clarify the disease mechanism.

[The contribution of surveillance systems of occupational diseases and mesothelioma in environmental health studies]. / Il contributo dei sistemi di registrazione delle malattie professionali e dei mesoteliomi negli studi su ambiente e salute.

National surveillance systems of occupational diseases may contribute to evaluate the work-related component of diseases investigated in SENTIERI Project. For a description of SENTIERI, refer to the 2010 Supplement of Epidemiology & Prevention devoted to SENTIERI Project. The National Workers Compensation Authority (INAIL) archives all occupational diseases claims (more than 230 000 in the period 2000-2007) and is in charge of their compensation. The Italian National Mesothelioma Register (ReNaM) and the Sinonasal Cancer Register (ReNaTuNS) record high occupational etiological fraction neoplasms (i.e. mesothelioma and sinonasal cancers). The former has identified more than 10 000 mesothelioma cases until now, and covers almost the whole country; the latter is active only in three Italian regions, Piemonte, Lombardia and Toscana. The monitoring of cancer sites at lower occupational etiological fraction is based on a record-linkage procedure between population-based cancer registries and employment history data, available at the Italian National Institute for Social Security (INPS). Finally, the informative system Mal.Prof collects and classifies all the diseases possibly related to the work environment reported by the Prevention Services of the Local Health Units.

[Extranodal NK/T-cell lymphoma, nasal type, developed in a patient with rheumatoid arthritis].

It is well known that patients with rheumatoid arthritis (RA) have a higher risk of developing malignant lymphoma (ML) than the general population. Most of these lymphomas occur in patients receiving immunosuppressive (IS) agents such as methotrexate (MTX). Spontaneous regression of tumors is often observed after the discontinuation of IS drugs, especially in patients with Epstein-Barr virus-positive lymphoma. Here we encountered an RA patient who developed extranodal NK/T-cell lymphoma, nasal type during treatment of RA with MTX and etanercept. Despite the discontinuation of MTX and etanercept, the tumor did not show any regression. Complete response was achieved after treatment with concurrent chemoradiotherapy. ML of NK-cell origin is extremely rare, while the majority of ML cases associated with RA are of B-cell origin. This report describes extranodal NK/T-cell lymphoma, nasal type case associated with RA. Such cases should be accumulated to evaluate the mechanism of onset and clinical characteristics of NK/T-cell lymphoma associated with RA.

Mutations in TP53 tumor suppressor gene in wood dust-related sinonasal cancer.

The causal role of work-related exposure to wood dust in the development of sinonasal cancer has long been established by numerous epidemiologic studies. To study molecular changes in these tumors, we analyzed TP53 gene mutations in 358 sinonasal cancer cases with or without occupational exposure to wood dust, using capillary electrophoresis single-strand conformation polymorphism analysis and direct sequencing. A significant association between wood-dust exposure and adenocarcinoma histology was observed [adjusted odds ratio (OR) 12.6, 95% confidence interval (CI), 5.0-31.6]. TP53 mutations occurred in all histologies, with an overall frequency of 77%. TP53 mutation positive status was most common in adenocarcinoma (OR 2.0, 95% CI, 1.1-3.7; compared with squamous cell carcinoma), and mutation positivity showed an overall, nonsignificant association with wood-dust exposure (OR 1.6, 95% CI, 0.8-3.1). Risk of TP53 mutation was significantly increased in association with duration (> or =24 years, OR 5.1, 95% CI, 1.5-17.1), average level (>2 mg/m(3); OR 3.6, 95% CI, 1.2-10.8) and cumulative level (> or =30 mg/m(3) x years; OR 3.5, 95% CI, 1.2-10.7) of wood-dust exposure; adjustment for formaldehyde affected the ORs only slightly. Smoking did not influence the occurrence of TP53 mutation; however, it was associated with multiple mutations (p = 0.03). As far as we are aware, this is the first study to demonstrate a high prevalence of TP53 mutation-positive cases in a large collection of sinonasal cancers with data on occupational exposure. Our results indicate that mutational mechanisms, in particular TP53 mutations, are associated with work-related exposure to wood dust in sinonasal cancer.

Do viscid secretions have a role in nasal polyp formation?

OBJECTIVES: We compared histologic findings on light microscopy of viscid secretions found in association with nasal polyps with those found in patients with chronic sinusitis without polyposis (CSWP). The differences might further understanding of nasal polyp pathogenesis. METHODS: In a prospective controlled study, viscid secretions found in association with nasal polyps were collected at endoscopic sinus surgery. Retained secretions in patients with CSWP acted as a control group. Both were fixed in 10% formalin, processed, and examined with a light microscope. RESULTS: Viscid secretions were encountered among nasal polyps in 25 of 132 patients (18.9%). Polyps containing multiloculated cysts filled with viscid secretions were found in 2 of them. Histologic examination of viscid secretions showed variable histologic pictures, ranging from a homogeneous material infiltrated with inflammatory cells, newly formed blood vessels, and bundles of collagen fibers to a well-developed connective tissue core covered with a respiratory epithelium in some areas. Histologic examination of retained secretions in patients with CSWP revealed amorphous material infiltrated with inflammatory cells with no further maturation or epithelial coverage. CONCLUSIONS: Viscid secretions, originating from ruptured mucosal cysts, might represent the initial step in nasal polyp pathogenesis. The variable histologic pictures detected possibly reflect different stages in nasal polyp formation from these secretions. Factors postulated in nasal polyp etiopathogenesis might trigger maturation and changes in the morphological structure of these secretions.

[Systematic surveillance of occupational cancer: the Lombardy Sinonasal Cancer Registry]. / Ricerca sistematica dei tumori professionali: il Registro Tumori dei Seni Nasali e Paranasali della Lombardia.

BACKGROUND: Sinonasal cancer (SNC) includes uncommon tumours that are characterized by a high occupational etiologic component. For this reason they are an easy target for systematic surveillance by setting up a specific disease registry. The National Registry of these tumours is located at the Italian Institute for Occupational Safety and Prevention (ISPESL) and is based on data from Regional Operating Centres (ROCs). In the Lombardy Region a ROC was established in 2008 at the Clinica del Lavoro "Luigi Devoto" in Milan aimed at making surveillance systematic and thus provide adequate support for scientific research and prevention measures in the high risk work sectors. OBJECTIVES: To estimate the incidence of SNC, to define different sources of occupational exposure both known (wood, leather, nickel, chromium) and unknown. METHODS: The Registry collects all the new incident cases of epithelial SNC occurring among residents ofthe Lombardy Region. The Regional Registry is managed in accordance with the specific National Guidelines and uses the experience already acquired with the organizational and operational management of the Regional Mesothelioma Registry. RESULTS: During the first period of activity (1.1.2008-30.9.2009) 556 cases of suspected SNC were reported to the Registry; only 62 (11.2%) of these actually complied with the inclusion criteria of the Registry and were mainly adenocarcinoma and squamous carcinoma. Occupational exposure to wood or leather dust was ascertained in 50% of cases. CONCLUSION: Data collected up to now confirm that occupational exposure to wood and leather dusts are the most significant risk factors for SNC. The study of occupational sectors and job tasks in cases with as yet undefined exposure might suggest new etiologic hypotheses.

Carcinosarcoma Arising from Inverted Papilloma in a Patient with History of Radiotherapy for Sinonasal Squamous Cell Carcinoma.

BACKGROUND Carcinosarcoma of the sinonasal tract is an extremely rare malignant neoplasm; it is often designated as carcinoma with spindle cell or sarcomatoid features. We report a case of carcinosarcoma arising in a pre-existing inverted Schneiderian papilloma in the left maxillary antrum and nasal cavity of a 72-year old male patient. CASE REPORT The patient had a significant history of radiotherapy for squamous cell carcinoma in the sinonasal area, 3 decades ago. The patient presented with chief complaints of left nasal blockage, nasal discharge, anosmia, and occasional epistaxis. Computed tomography scan displayed a lobular soft tissue mass resulting in narrowing of the nasopharyngeal airway with massive destruction of palatal tissue. The lesion was resected via endoscopic surgery. Macroscopically, a white fleshy appearance with necrosis was noted in the submitted specimen. Microscopically, the tumor was composed of pleomorphic epithelial and spindle cells with numerous mitoses and remarkable tissue necrosis. Residual inverted papilloma (IP) with high-grade dysplasia, and minimal foci of moderately differentiated squamous cell carcinoma (SCC) component was present at the tumor margin. A distinct zone of transition of SCC to spindle cell carcinoma (SpSCC) was noted and confirmed by focal positivity of p63 in epithelial and sacromatoid components. The pleomorphic sarcomatoid tumor was positive for vimentin with Ki67 highlighting 70% of tumor cells. A final diagnosis of sinonasal spindle cell carcinoma associated with residual inverted papilloma was rendered. CONCLUSIONS Due to the rarity of such cases, the prognosis and response to treatment is unclear. No effective directed treatment has been developed. Unfortunately, the patient refused any further treatment and died of persistent disease. To the best of our knowledge, only one case of sinonasal carcinosarcoma arising from dysplastic inverted papilloma has been reported. The distinct possibility of previous radiotherapy contributing to development of sarcomatoid features in this neoplasm should also be considered.

Respiratory Epithelial Adenomatoid Hamartoma is Frequent in Olfactory Cleft After Nasalization.

OBJECTIVES: To assess the site and histopathology of polyps at the first revision surgery for recurrent nasal polyposis (NP) after radical ethmoidectomy (nasalization). STUDY DESIGN: Retrospective study. METHODS: Between January 2008 and December 2015, a total of 62 patients having undergone revision surgery for recurrent NP after nasalization were included. The site and histology of the recurrence of polyps were analyzed according to operative and pathological reports. RESULTS: Histology showed classical inflammatory nasal polyps (CINP) in 91% of nasal cavities at primary surgery versus respiratory epithelial adenomatoid hamartoma (REAH) or REAH associated to CINP in 54.8% at revision surgery (P < .0001). Polyps were principally observed in the ethmoidal complex in 70% of nasal cavities during primary surgery and in the olfactory clefts in 88.7% during revision surgery (P < .0001). The mean interval between nasalization and first revision surgery was 8.8 ± 4.4 years (0.4-21.7 years). This interval was significantly shorter for grade 3 polyps, polyps removed from both ethmoidal complex and olfactory cleft at primary surgery, association of CINP and REAH at primary surgery, and when primary surgery had preserved the middle turbinates. CONCLUSION: Polyp recurrences after nasalization were mainly observed in the olfactory clefts and can be different histological features: inflammatory polyps, respiratory epithelial adenomatoid hamartoma, or a combination of both. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:2098-2104, 2020.

[Acromegaly-associated lesions of the nasal mucosa. Case report]. / Mit Akromegalie assoziierte Veränderungen der Nasenschleimhäute. Fallbericht.

Acromegaly is a rare disease caused by a growth-hormone-secreting pituitary adenoma. Symptoms include enlargement of the hands, feet, and jaw with growing dental interspaces, as well as hypertrophy of the tongue and nasal and sinusoidal mucosa. The two latter symptoms are mostly responsible for the accompanying obstructive sleep apnea syndrome. Besides these "cosmetic" symptoms, the disease is associated with hypertension and diabetes mellitus, as well as with an increased risk for adenomas and carcinomas of the colon. The average time span from first symptom to diagnosis is well over 6 years; a single determination of insulin-like growth factor 1 in serum can confirm the disease. The treatment of choice remains surgical resection of the adenoma in suitable patients, whereas in extensive disease with invasion of surrounding tissue, drug therapy and/or radiotherapy may be necessary.

A retrospective study of chronic nasal disease in 75 dogs.

Chronic nasal disease is a common problem in dogs. To determine the aetiology, a retrospective study in 75 dogs with persistent and chronic nasal disease was done. All dogs were evaluated by means of survey nasal radiographs, antegrade and retrograde rhinoscopy, bacterial and fungal cultures, and histopathology. A definitive diagnosis was made in 74/75 cases (98.6%). Nasal neoplasia was the most common diagnosis (46.7%), median age 108 months, followed by lympho-plasmacytic rhinitis (20%), median age 112 months, and fungal rhinitis (10.7%), median age 53.5 months. Other diagnoses included nasal foreign body (5.3%), median age 51 months, and primary bacterial rhinitis (6.7%), median age 116.5 months. Rare aetiologies identified were nasal polyps, granulomatous rhinitis, oro-nasal fistula and naso-pharyngeal stenosis. This study showed that by using a structured combination of survey radiography, rhinoscopy, cultures and histopathology, a diagnosis could be made in dogs with chronic nasal disease.