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.

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.

Respiratory epithelial adenomatoid hamartoma: a diagnostic challenge in sinonasal lesions.

Respiratory epithelial adenomatoid hamartoma (REAH) is a rare lesion in nasal cavity first reported by Wenig and Heffner in 1995. Most commonly seen in men in third to ninth decade of life. Majority of cases presents as a polypoidal mass in one or both nasal cavities. We experienced such a case of REAH originating from the nasal septum, in posterior aspect, treated by endoscopic approach. It is important to differentiate REAH from other sinonasal pathologies like inverted papilloma and low grade sinonasal adenocarcinoma. Complete surgical resection is the treatment of choice.

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.

Sinonasal hemangiopericytoma caused hypophosphatemic osteomalacia: A case report.

RATIONALE: Tumor-induced osteomalacia (TIO) is a rare, paraneoplastic syndrome featured with fibroblast growth factor 23 (FGF23) secretion primarily by benign mesenchymal tumors and sometimes by malignancies. TIO diagnosis and treatment is often delayed because TIO usually has nonspecific generalized bone pain and weakness, and location of TIO tumor is quite challenging. Very few TIO caused by sinonasal hemangiopericytoma have been reported in the literature. PATIENT CONCERNS: A 40-year-old Chinese woman presented with diffuse bone pain for more than 1 year. Laboratory examination showed hypophosphatemia, hyperphosphaturia, hypocalcemia, an elevated serum alkaline phosphatase (ALP) level and bone-specific ALP level. Imaging studies revealed low bone mineral density (BMD) and multiple pseudofractures at the ribs. F-18 fluorodeoxyglucose positron emission tomography was negative in searching for tumors. Because no tumor was located, the patient was treated with oral phosphate, calcium, and alfacalcidol, and achieved great relief in her symptoms and improvement in BMD. Six years later, the patient had breast cancer surgery and received chemotherapy, and still had hypophosphatemia. During this time, nasopharyngo-fiberscope showed nasal mass in her left nasal cavity. Then she had her nasal polyps removed and surprisingly the serum phosphate became normal. DIAGNOSES AND INTERVENTIONS: The patient had the nasal mass resected, and pathological diagnosis of the nasal mass was sinonasal hemangiopericytoma. Immunohistochemical analysis was positive for FGF23. Thus the final diagnosis was osteomalacia induced by sinonasal hemangiopericytoma. Phosphate supplementation and alfacalcidol were discontinued. OUTCOMES: The patient had normal serum phosphate after 6-month follow-up. LESSONS: By presenting this case, we hope to remind clinicians that in patients with osteomalacia with undetermined reason and intranasal polypoid mass, sinonasal hemangiopericytoma should be suspected.

A case of squamous cell carcinoma of the nasal cavity in a patient with granulomatosis with polyangiitis (Wegener granulomatosis).

We report a rare case of squamous cell carcinoma (SCC) of the nasal cavity arising in a patient with granulomatosis with polyangiitis (GPA). The patient was a 35-year-old man who had been diagnosed 15 years earlier with GPA and treated medically for sinonasal, pulmonary, and renal involvement. He presented to us with left-sided orbital and cheek pain and nasal obstruction. Endoscopy detected a friable, exophytic mass that involved the left lateral nasal wall and septum. Biopsy analysis identified the mass as an SCC. A definitive endoscopic resection was performed, followed by chemoradiation, but the patient exhibited progression of disease 2 months after the cessation of therapy. He then underwent an open craniofacial resection and a second round of chemoradiation. At 7 months of follow-up, he remained disease-free. Sinonasal symptoms in GPA are consistent with those in chronic rhinosinusitis, but the presence of unilateral symptoms may suggest a neoplastic process. Immunosuppressants are implicated in the pathophysiology of this malignancy, but equally plausible is the oncogenic role of chronic inflammation.

Clinical manifestations and STK11 germline mutations in Taiwanese patients with Peutz-Jeghers syndrome.

BACKGROUNDS: Clinical manifestations and molecular basis of Taiwanese patients with Peutz-Jeghers syndrome (PJS) were investigated to add the knowledge of phenotype and genotype of the disease. METHODS: Based on the Pathology Data Bank and the Colorectal Cancer Register, we collected their clinical data. The entire coding sequence of the STK11 gene was amplified and analyzed by sequencing using the genomic DNA. RESULTS: Fifteen patients diagnosed with PJS from 11 unrelated families were collected until 2015. The median age at the onset of symptoms was 19 years with intussusception as the most frequent presenting symptom. Ten patients developing 11 cancers at various anatomical sites, including two cases of sinonasal cancer, two lung cancers, two breast cancers, two rectal cancers, two gynecological cancers and one small bowel cancer. Five of the deceased patients had died of cancers. The median age of diagnosis of first cancer in the probands was 32 years. Seventy patients (7 of 10) diagnosed before age of 40. Mutations found in eight families included five novel mutations (exon 6, c.843 ins G; exon 8, c.2065 delete A; exon 8, c.G923A, nonsense; exon 6, c.748dupA; and mTOR c.5107dupA) and three previously reported mutations. The other three PJS families without detectable STK11 mutations did not develop malignancies so far. CONCLUSION: This is the first comprehensive study of patients with Peutz-Jeghers syndrome in the Taiwanese. We have demonstrated that the phenotype of Peutz-Jeghers syndrome varies greatly among the patients. Patients with detectable STK11 mutations have very high risk of developing cancers.

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 papillomas of the sinonasal tract. A comprehensive review.

Papillomas are uncommon tumors of the sinonasal tract histologically derived from the Schneiderian membrane. Three distinctive variants are described, the exophytic, the inverting and the oncocytic types. On physical examination, their appearance varies from exophytic-fungiform seen in the exophytic variant, to polypoid-papillary in both the inverting and oncocytic variant. The presence of an asymptomatic mass or epistaxis and unilateral nasal obstruction are the typical presenting symptoms. Clinically they tend to recur and, although benign, they may erode the bone laminas by pressure, especially the inverting type, causing proptosis and other co-morbidities. Malignant transformation is seen both synchronously, on a pre-existing papilloma, and metachronously after several recurrences of papilloma. Schneiderian papillomas are at a date a topic of controversy regarding their etiology, pathogenesis and biological behavior. Furthermore, histologic criteria to assess dysplasia and malignant transformation are ill-defined. The present study aims to comparatively review the histologic types of papillomas, their etiology, the currently available criteria for malignant transformation, their treatment and prognosis.

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.

A Peutz-Jeghers syndrome family associated with sinonasal adenocarcinoma: 28 years follow up report.

Peutz-Jeghers syndrome (PJS) is a rare hereditary disorder characterized by hamartomatous polyps in both of the gastrointestinal tract and mucosal pigmentation. It could increase in risk of intestinal and extra-intestinal neoplasms. We here described three cases of sinonasal polyposis in a PJS family and two developed sinonasal type adenocarcinoma. Genetic study revealed a germline STK11/LKB1 mutation on codon 179 (c.C536G, p.P179R) of exon 4. LOH analysis of the LKB1 locus confirms this to be a deleterious mutation. Sinonasal polyposis with malignant transformation could be encountered in PJS patients. Regular follow-up was recommended for the risk of malignant changes in nasal polyps.

RUNX3 is oncogenic in natural killer/T-cell lymphoma and is transcriptionally regulated by MYC.

RUNX3, runt-domain transcription factor, is a master regulator of gene expression in major developmental pathways. It acts as a tumor suppressor in many cancers but is oncogenic in certain tumors. We observed upregulation of RUNX3 mRNA and protein expression in nasal-type extranodal natural killer (NK)/T-cell lymphoma (NKTL) patient samples and NKTL cell lines compared to normal NK cells. RUNX3 silenced NKTL cells showed increased apoptosis and reduced cell proliferation. Potential binding sites for MYC were identified in the RUNX3 enhancer region. Chromatin immunoprecipitation-quantitative PCR revealed binding activity between MYC and RUNX3. Co-transfection of the MYC expression vector with RUNX3 enhancer reporter plasmid resulted in activation of RUNX3 enhancer indicating that MYC positively regulates RUNX3 transcription in NKTL cell lines. Treatment with a small-molecule MYC inhibitor (JQ1) caused significant downregulation of MYC and RUNX3, leading to apoptosis in NKTL cells. The growth inhibition resulting from depletion of MYC by JQ1 was rescued by ectopic MYC expression. In summary, our study identified RUNX3 overexpression in NKTL with functional oncogenic properties. We further delineate that MYC may be an important upstream driver of RUNX3 upregulation and since MYC is upregulated in NKTL, further study on the employment of MYC inhibition as a therapeutic strategy is warranted.

A case of radiation-induced mucosal melanoma in an immunohistochemically S-100-negative patient.

We report a case of radiation-induced mucosal melanoma in a 41-year-old woman with a history of childhood rhabdomyosarcoma of the nasal cavity that had been treated with radiotherapy. During the workup for the melanoma, the patient was found to be negative for S-100 protein on immunostaining. While many melanotic markers for the histologic confirmation of melanoma exist, they can be negative in some cases, such as ours. To the best of our knowledge, only 1 case of radiation-induced melanoma has been previously reported in the English-language literature, and in that case the patient was S-100-positive. Although our case is rare, it suggests another possible long-term adverse effect of radiotherapy. We also describe the morphologies and histology associated with diagnosing melanoma in an S-100-negative patient.

Intestinal-type sinonasal adenocarcinomas: The road to molecular diagnosis and personalized treatment.

BACKGROUND: Sinonasal intestinal-type adenocarcinomas (ITACs) are epithelial tumors of the nasal cavity and the paranasal sinuses, often related to professional exposure to organic dust, mainly wood or leather. It is a rare cancer. If resectable, surgery is the treatment of choice. Postoperative radiotherapy is often indicated to increase local control. Systemic treatment (chemotherapy, targeted agents, or immunotherapy) of irresectable ITACs and/or metastasized disease is less standardized. METHODS: Articles on ITAC histopathology, molecular profile, and current treatment options of this specific tumor were identified and reviewed, using the electronic databases Pubmed, Medline, Cochrane, and Web of Science. RESULTS: This article reviews what is currently known on the histopathology, tumorigenesis, molecular characteristics, and standardized treatment options of ITAC. CONCLUSION: More translational research is needed to identify druggable targets that may lead to a personalized treatment plan in order to improve long-term outcome in patients with locally advanced and/or metastasized ITAC. © 2016 Wiley Periodicals, Inc. Head Neck 38: First-1570, 2016.

Sinonasal inverted papilloma: From diagnosis to treatment.

Inverted papilloma is a rare sinonasal tumor that mainly occurs in adults during the 5th decade. Three characteristics make this tumor very different from other sinonasal tumors: a relatively strong potential for local destruction, high rate of recurrence, and a risk of carcinomatous evolution. Etiology remains little understood, but an association with human papilloma virus has been reported in up to 40% of cases, raising the suspicions of implication in the pathogenesis of inverted papilloma. Treatment of choice is surgery, by endonasal endoscopic or external approach, depending on extension and tumoral characteristics. Follow-up is critical, to diagnose local relapse, which is often early but may also be late. The seriousness of this pathology lies in its association with carcinoma, which may be diagnosed at the outset or at recurrence during follow-up. It is important to diagnose recurrence to enable early treatment, especially in case of associated carcinoma or malignancy. A comprehensive review of the international literature was performed on PubMed and Embase, using the following search-terms: "sinonasal" [All Fields] AND ("papilloma, inverted" [MeSH Terms] OR ("papilloma" [All Fields] AND "inverted" [All Fields]) OR "inverted papilloma" [All Fields] OR ("inverted" [All Fields] AND "papilloma" [All Fields])). We reviewed all articles referring to sinonasal inverted papilloma published up to January 2015. The present article updates the state of knowledge regarding sinonasal inverted papilloma.

Human papillomavirus infection and the malignant transformation of sinonasal inverted papilloma: A meta-analysis.

A growing number of molecular epidemiological studies have been conducted to evaluate the association between human papillomavirus (HPV) infection and the malignancy of sinonasal inverted papilloma (SNIP). However, the results remain inconclusive. Here, a meta-analysis was conducted to quantitatively assess this association. Case-control studies investigating SNIP tissues for presence of HPV DNA were identified. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by the Mantel-Haenszel method. An assessment of publication bias and sensitivity analysis were also performed. We calculated a pooled OR of 2.16 (95% CI=1.46-3.21, P<0.001) without statistically significant heterogeneity or publication bias. Stratification by HPV type showed a stronger association for patients with high-risk HPV (hrHPV) types, HPV-16, HPV-18, and HPV-16/18 infection (OR=8.8 [95% CI: 4.73-16.38], 8.04 [95% CI: 3.34-19.39], 18.57 [95% CI: 4.56-75.70], and 26.24 [4.35-158.47], respectively). When only using PCR studies, pooled ORs for patients with hrHPV, HPV-16, and HPV18 infection still reached statistical significance. However, Egger's test reflected significant publication bias in the HPV-16 sub-analysis (P=0.06), and the adjusted OR was no longer statistically significant (OR=1.65, 95%CI: 0.58-4.63). These results suggest that HPV infection, especially hrHPV (HPV-18), is significantly associated with malignant SNIP.

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.