Tumor Microenvironment in Sporadic Vestibular Schwannoma: A Systematic, Narrative Review.

Although diagnosis and treatment of vestibular schwannomas (VSs) improved in recent years, no factors have yet been identified as being capable of predicting tumor growth. Molecular rearrangements occur in neoplasms before any macroscopic morphological changes become visible, and the former are the underlying cause of disease behavior. Tumor microenvironment (TME) encompasses cellular and non-cellular elements interacting together, resulting in a complex and dynamic key of tumorigenesis, drug response, and treatment outcome. The aim of this systematic, narrative review was to assess the level of knowledge on TME implicated in the biology, behavior, and prognosis of sporadic VSs. A search (updated to November 2022) was run in Scopus, PubMed, and Web of Science electronic databases according to the PRISMA guidelines, retrieving 624 titles. After full-text evaluation and application of inclusion/exclusion criteria, 37 articles were included. VS microenvironment is determined by the interplay of a dynamic ecosystem of stromal and immune cells which produce and remodel extracellular matrix, vascular networks, and promote tumor growth. However, evidence is still conflicting. Further studies will enhance our understanding of VS biology by investigating TME-related biomarkers able to predict tumor growth and recognize immunological and molecular factors that could be potential therapeutic targets for medical treatment.

Facial nerve sacrifice in lateral approaches to the skull base: Simultaneous reconstruction by graft interposition.

PURPOSE: To evaluate the outcome of facial nerve (FN) cable graft interposition in lateral skull base surgery. MATERIALS AND METHODS: A group of 16 patients who underwent FN graft interposition procedure was retrospectively considered. Postoperative FN function was evaluated using the House-Brackmann (HB) grading system, the Sunnybrook Facial Grading System (SFGS), the Facial Disability Index (FDI) and the Oral Functioning Scale (OFS) questionnaires. RESULTS: 56.2% of patients had a good postoperative FN outcome (HB grade II-III). Postoperative electromyography (EMG) showed re-innervation potentials in 60% of patients; median age of these patients was significantly lower compared to who did not manifest re-innervation (p = 0.039). CONCLUSION: FN primary reconstruction remains the advisable rehabilitative option when the nerve is interrupted during lateral skull base surgeries, allowing to satisfactory postoperative results in more than half of patients. EMG confirmed the restoring of nerve conduction and it was more frequent in younger patients. The SFGS, the FDI and the OFS are important tools especially in the setting of a rehabilitation program.

Cochlear implant in vestibular schwannomas: long-term outcomes and critical analysis of indications.

PURPOSE: To describe our institutional experience in cochlear implantation after vestibular schwannoma (VS) resection, and compare the audiological outcomes between sporadic and neurofibromatosis type 2 (NF2) VS sub-cohorts of patients, and in relation to preoperative contralateral hearing. METHODS: Seventeen patients (8 sporadic and 9 NF2-associated VSs) who had undergone VS resection and cochlear implant (CI) were analyzed retrospectively. Audiological outcomes at 24 months were correlated with preoperative clinical variables. The results according to VS type (sporadic vs. NF2-associated) and contralateral hearing (impaired vs. normal) were compared. RESULTS: Fourteen CIs were actively used by the patients (77.8%). Twenty-four months after CI activation, the median postoperative PTA (pure tone average) was 45.6 dB nHL and a measurable WRS (Word Recognition Score) was achieved by 44.4% of patients (median WRS = 40%). The median postoperative PTA in the implanted ear resulted better in the group with an impaired contralateral hearing (36.3 dB nHL vs. 78.8 dB nHL, p = 0.019). Good preoperative contralateral hearing status (A-B classes of AAO-HNS) was a negative prognostic factor for CI performance on open-set discrimination (OR = 28.0, 95% CI 2.07-379.25, p = 0.012). CONCLUSIONS: CI is a viable rehabilitative option for patients with sporadic or NF2-associated VS. A good contralateral hearing adversely affects CI outcome and should be taken into consideration for patients' selection and rehabilitation programs.

Temporal Bone Squamous Cell Carcinoma: Molecular Markers Involved in Carcinogenesis, Behavior, and Prognosis: A Systematic Review.

Temporal bone squamous cell carcinoma (TBSCC) is an uncommon malignancy with a poor prognosis in advanced cases. The dismal outcome of advanced TBSSC cases is largely due to the cancer's local aggressiveness and the complex anatomy of this region, as well as to persistent pitfalls in diagnosis and treatment. Molecular changes occur in malignancies before any morphological changes become visible, and are responsible for the disease's clinical behavior. The main purpose of this critical systematic review is to assess the level of knowledge on the molecular markers involved in the biology, behavior, and prognosis of TBSCC. A search (updated to March 2022) was run in PubMed, Scopus, and Web of Science electronic databases without publication date limits for studies investigating molecular markers in cohorts of patients with primary TBSCC. The search terms used were: "temporal bone" OR "external auditory canal" OR "ear", AND "cancer" OR "carcinoma" OR "malignancy". We preliminarily decided not to consider series with less than five cases. Twenty-four case series of TBSCC were found in which different analytical techniques had been used to study the role of several biomarkers. In conclusion, only very limited information on the prognostic role of molecular markers in TBSCC are currently available; prospective, multi-institutional, international prognostic studies should be planned to identify the molecular markers involved in the clinical behavior and prognosis of TBSCC. A further, more ambitious goal would be to find targets for therapeutic agents able to improve disease-specific survival in patients with advanced TBSCC.

Temporal bone carcinoma: testing the prognostic value of a novel clinical and histological scoring system.

PURPOSE: Our group recently proposed the novel Padova prognostic scoring system for temporal bone carcinoma (TBSCC) that considers: the revised Pittsburgh staging system; radiological dura mater involvement; non-anterior spread (medial, inferior or posterior into the temporal bone and skull base) of T4 tumors; and histological grade. The aim of the present study was to validate this prognostic TBSCC scoring system in a case series selected from the literature. METHODS: A search was run to identify studies on TBSCC reporting the variables included in our score for each patient. Then our system was applied to the data extracted. RESULTS: Only two published investigations reported all the clinical and pathological data required for our scoring system. In one series from the Gruppo Otologico in Piacenza (Italy), a significantly higher recurrence rate (p = 0.008), shorter disease-free survival (DFS) (p = 0.001), higher disease-specific mortality (DSM) (p = 0.006), and shorter disease-specific survival (DSS) (p = 0.004) were associated with scores ≥ 5. Receiver operating curve (ROC) analysis showed an AUC of 0.804 for TBSCC recurrence, and 0.832 for DSM. In a series from Kyushu University Hospital (Japan), a significantly higher DSM (p = 0.018) and shorter DSS (p = 0.021) were associated with scores ≥ 5. ROC analysis showed an AUC of 0.812 for tumor relapse and 0.790 for DSM. CONCLUSION: Our TBSCC Padova scoring system confirmed its validity when applied to the only two international TBSCC series providing the required data. These preliminary results need to be confirmed in a multi-center prospective setting.

Hearing preservation in small acoustic neuroma: observation or active therapy? Literature review and institutional experience.

BACKGROUND: Current imaging modalities enable early diagnosis of a large number of small acoustic neuromas in patients with well-preserved hearing, whose best management is still a debatable matter. METHODS: Comparing the hearing outcome of the various therapeutical approaches, including observation, radiosurgery, or resective surgery, is not easy because of the numerous classifications measuring hearing in different ways. In this review, a literature review was performed and papers selected dealing with small tumors, short- and long-term hearing, tumor control or radical resection, and effect of pre-treatment hearing and size on outcome. Two different surgical institutional series of sporadic vestibular schwannomas provided us comparative data on the outcome of observation alone. RESULTS AND CONCLUSIONS: Our experience suggests that active treatment with hearing preservation surgery, unlike observation alone, offers a better chance of hearing preservation, also enabling a more effective treatment of the tumor and an appropriate rehabilitation with hearing aids or cochlear implants.

Cortactin and phosphorylated cortactin tyr466 expression in temporal bone carcinoma.

PURPOSE: Cortactin is a multidomain protein engaged in several cellular mechanisms involving actin assembly and cytoskeletal arrangement. Cortactin overexpression in several malignancies has been associated with increased cell migration, invasion, and metastatic potential. Cortactin needs to be activated by tyrosine or serine/threonine phosphorylation. The role of cortactin and phosphorylated cortactin (residue tyr466) was investigated in temporal bone squamous cell carcinoma (TBSCC). MATERIALS AND METHODS: Immunohistochemical expression of cortactin and phosphorylated cortactin (residue tyr466) was assessed in 27 consecutively-operated TBSCCs. RESULTS: Several clinicopathological variables correlated with recurrence (pT stage, dura mater involvement), and disease-free survival (DFS) (cT stage, pT stage, pN status, dura mater involvement). Twenty-three of 24 immunohistochemically evaluable TBSCCs were cortactin-positive. Median cortactin expression was 75.0%. Cortactin reaction in the cytoplasm was more intense in carcinoma cells than in normal adjacent tissue. Recurrence and DFS rates did not correlate with cortactin and phosphorylated cortactin (residue tyr466) expression in TBSCC specimens. CONCLUSIONS: Cortactin upregulation in TBSCC supports the conviction that inhibiting cortactin functions could have selective effects on this malignancy. Multi-institutional studies should further investigate the role of cortactin and phosphorylated cortactin in TBSCC, and their potential clinical application in integrated treatment modalities.

Observation and partial targeted surgery in the management of tympano-jugular paraganglioma: a contribution to the multioptional treatment.

The objective of this study was to assess the value of a limited tumor excision in tympano-jugular paragangliomas treated with observation with the goal of preventing, or repairing, a neural (VII cranial nerve) or brain damage and continue an otherwise correct observation. This is a retrospective case review. Each patient was submitted to a complete neuro-radiological work-up for diagnosis including CT, MRI, and angiography if needed of tympano-jugular paraganglioma class C. All the cases were submitted to observation and in 16 cases partial targeted surgery was performed. In 10 cases, the procedure involved a targeted removal of the tumor growing in contact with, or invading, the Fallopius. In four cases, the procedure was a petro-occipital trans-sigmoid approach to remove the intradural portion of tumor producing the picture of brain stem compression. In two cases, there was the excision of the bleeding tumor surfaces in the outer ear canal. Follow-up ranged from 4 to 20 years. Success was considered the maintenance of observation without the change of class of tumor extension. In 13 over 16 cases, the observation could be continued, as it still was the more favorable option between natural and surgical morbidity. In the other three cases, a newly installed paralysis of the 9-10 cranial nerves due to tumor growth involved a correction of the strategy to a radical procedure. Partial targeted surgery was directed to cases submitted to observation. It allowed to prevent, or repair, an impending, or actual damage to the facial nerve or the brain stem and to continue the abstentional treatment by keeping the balance between natural and therapy morbidity in favor of observation.

Temporal bone carcinoma: a first glance beyond the conventional clinical and pathological prognostic factors.

Temporal bone squamous cell carcinoma (TBSCC) is an uncommon, aggressive malignancy with a poor prognosis in advanced cases. The dismal outcome is partially related to: the lack of reliable clinical or pathological prognostic factors and the largely unstandardized surgical and integrated treatments adopted. There is an undeniable need for novel diagnostic/therapeutic strategies to improve the prognosis. The purpose of this critical review was to explore the level of available knowledge concerning the molecular markers involved in the biology of TBSCC that have a prognostic potential. The Pub-Med and Scopus electronic databases were searched without publication date limits for studies investigating molecular markers in cohorts of patients with primary TBSCC. The search terms used were: "temporal bone cancer", "temporal bone carcinoma", "temporal bone malignancy", "ear cancer", "ear carcinoma", and "ear malignancy". We decided preliminarily not to consider series with less than five cases. Nine retrospective case series of TBSCC were found in which different analytical techniques had been used to study the role of several biomarkers (HPV, vimentin, transforming growth factor ß, CD105, RECK, matrix metalloproteinase-9, MASPIN, EBV, p16, TP53 mutation, pSTAT3, relaxin-2). CD105 expression (in tumor vessel endothelial cells) and MASPIN cytoplasmic expression (in carcinoma cells) were, respectively, found directly and inversely related with the neoplasm's recurrence rate. CD105 expression was also inversely related with disease-free survival in TBSCC. A future goal of such analyses should be to ascertain the radio- and chemo-sensitivity profiles of individual TBSCCs, enabling truly personalized therapies. A further, more ambitious goal will be to find targets for therapeutic agents that might prove crucial in improving the disease-specific survival for patients with advanced TBSCC.

Historical development of the treatment of skull base tumours.

Surgery has evolved greatly over the last decades thanks to the more sophisticated and conservative surgical approaches and also thanks to the progress of diagnostic imaging. An added value is represented by the increased experience of the professionals and the close multidisciplinarity of the procedures including neurosurgeons, otolaryngologists and maxillo-facial surgeons. One of the most recent developments is the endoscopic surgery allowing for more conservative and cosmetically satisfactory outcomes. Radiation therapy has greatly changed over the last decades thanks to the technology advances related both to the availability of new imaging modalities and techniques of radiation delivery. Delivery of radiation evolved from three-dimensional conformal techniques to stereotactic and intensity-modulated radiation therapy. Particle therapy has the potential to further improve in the near future thanks to the progress of technology. Proton therapy allows for optimization of dose deposition in the target with lesser dose in the healthy tissues and ion therapy, currently using carbon ions, has been more recently introduced with the advantage of more effective treatments in case of less radio-sensitive tumours thanks to a higher biological effectiveness. A relevant concept that can significantly improve the results is that of interaction and integration of different disciplines not only within the surgical field. The cooperation between surgeons of various disciplines, radiation oncologists and medical oncologists together with professionals from other disciplines, such as pathology and radiology is nowadays required in an effort to customize and optimize the treatment in each single patient.

Treatment of endolymphatic sac tumour (Papillary adenocarcinoma) of the temporal bone.

AIM: To define a better treatment of sporadic endolymphatic sac tumours (ELST) analysing our experience and literature available data. BACKGROUND: ELST can arise as sporadic case (rare) or as a part of von Hippel-Lindau (VHL) disease. It is a low grade malignancy with local spread by continuity. MATERIALS AND METHODS: we described our experience with 7 cases with up to date follow up. RESULTS: Five cases were free of disease after first surgical procedure. One case had recurrence in the temporal lobe after 12 years. One case had two surgical procedures followed by irradiation and died five years after radiotherapy with a slow disease progression. CONCLUSION: With increasing expertise in the skull base surgery, complete tumour excisions are achieved in majority of the more recent cases and appear to be the treatment of choice. External irradiation is also used as palliative measures with doubtful effectiveness. Some recent reports showed encouraging results with gamma knife radiosurgery.

Temporal bone carcinoma: Classical prognostic variables revisited and modern clinico-pathological evidence.

AIM: Prognostic factors, rational management, and the ongoing investigations regarding temporal bone squamous cell carcinoma (TBSCC) have been critically reviewed. BACKGROUND: TBSCC is an uncommon, aggressive malignancy. Although some progress has been made in treating this aggressive tumor, the prognosis in advanced cases remains poor. MATERIALS AND METHODS: A systematic search of the literature for articles published between 2009 and October 2014 was performed using the PubMed (http://www.pubmed.gov) electronic database. RESULTS: Given the particular anatomical site of TBSCC, its prognosis is significantly influenced by any direct involvement of nearby structures. The extent of the primary tumor is generally considered one of the most important prognostic factors and it is frequently related to prognosis even more strongly than N stage. For TBSCC, biomarker investigations in surgical specimens are only just beginning to appear in the oncological literature. CONCLUSION: Given the particular features of TBSCC, the sub-specialty of otologic oncology seems to be emerging as a defined area of practice involving multidisciplinary team comprising oto-neurosurgeons, head and neck surgeons, plastic surgeons, oncologists, radiotherapists, dedicated radiologists, and pathologists.

Recurrent squamous cell carcinoma of the temporal bone: critical analysis of cases with a poor prognosis.

PURPOSE: Temporal bone squamous cell carcinoma (TBSCC) is an uncommon, aggressive malignancy with a significant recurrence rate. We reviewed our experience with recurrent TBSCCs. MATERIALS AND METHODS: Clinicopathological and therapeutic variables potentially associated with disease-free survival (DFS) and disease-specific survival (DSS) were assessed in 17 TBSCC patients who died of their disease after treatment. RESULTS: TBSCC recurrences were treated with surgery in 12 cases (palliative in 11, with curative intent in 1) and palliative chemotherapy in 5; the median DFS and DSS were 6 and 16 months, respectively. The mean DFS and DSS were longer in patients who had primary lateral temporal bone resection (LTBR) rather than subtotal temporal bone resection (STBR) (p=0.0173 and p=0.03, respectively). Patients given non-surgical palliative treatment for recurrences had a longer mean DSS than those who underwent surgery (trend toward significance, p=0.09). CONCLUSIONS: Our results reflect the aggressive nature of TBSCC recurrences. Our findings seem to support the use of non-surgical treatments (chemotherapy, radiotherapy, or specialist palliative care) in patients with loco-regionally advanced recurrent TBSCC. Salvage surgery might be considered for early recurrences when radicality is still achievable. Precise guidelines for the rational follow-up of surgically-treated TBSCCs need to be shared between tertiary centers.

Bilateral chondrosarcoma of the jugular foramen: literature review and personal experience.

Chondrosarcomas (CS) are slow-growing malignant cartilaginous tumors with locally invasive behavior. They account for only 0.15% head and neck neoplasia. There have been no reports in the management of bilateral skull base CS in the literature to date. The synchronous presentation of bilateral CS of the jugular foramen (JF) was diagnosed in a 22-year-old woman with right abducens nerve palsy. Once evaluated the collateral intracranial venous discharge, the lesions were removed in two surgical stages through a bilateral petro-occipital trans-sigmoid (POTS) approach performing a bilateral closure of sigmoid sinus. The patient is disease free 15 years after surgery. No complications occurred. Diplopia improved after excision of the tumor on the right side. A review of relevant English literature was performed. The POTS approach to the JF proved to be safe and effective. Staged radical surgery alone, assessing intracranial venous flow at all stages of surgery, was a valid strategy for bilateral CS, achieving long-term disease control, avoiding early adjuvant radiotherapy, and carrying no complications.

Relaxin-2 expression in temporal bone carcinoma.

Temporal bone squamous cell carcinoma (TBSCC) is an uncommon, aggressive malignancy with a significant local recurrence rate even in patients with postoperative pathology reports of free surgical margins. This raises the question of how "free" negative margins should be to be oncologically safe, especially in bone tissue. A potential role for relaxin-2 hormone in tumor-driven osteolysis has recently been reported. The aim of this study was to assess the prognostic role of relaxin-2 expression in TBSCC tissue specimens and pathologically negative bone margins. Relaxin-2 immunohistochemical expression was assessed in 25 consecutively operated TBSCC patients. Several pathological variables correlated with recurrence rate (pT stage, dura mater involvement), disease-free survival (DFS) (pT stage, pN status, grade, and dura mater involvement), and disease-specific survival (DSS) (pT stage, pN status, grade, and dura mater involvement). The recurrence rate, DFS, and DSS did not correlate with relaxin-2 expression in TBSCC specimens or pathologically negative bone margins. Although local recurrence in TBSCC could relate to neoplastic bone invasion not apparent on conventional pathological investigations, the present preliminary findings seem to rule out any role of relaxin-2 in mediating this local aggressiveness. Molecular mechanisms of TBSCC recurrence after curative treatment should be further investigated.

Microsurgery in carotid body paraganglioma.

Objectives: In carotid paraganglioma surgery, magnification is crucial to properly evaluate the anatomical relationships between mass, carotid wall, cranial nerves, tumour vascular supply and fascial envelope. The aims of this study are to describe the microsurgical technique, along with the underlying microsurgical anatomy, and to assess outcomes in terms of disease control, complications and functional results. Methods: Twenty-six patients, accounting for 29 carotid paragangliomas, treated with microsurgery by the same senior surgeon over a 35-year period, were included. Results: No carotid injury requiring repair, nor peri- or post-operative stroke occurred in this series. No surgical injury of the main trunk of VII to XII cranial nerves occurred. Complete excision was obtained in all cases and no recurrence was observed during follow-up. Conclusions: The small study size and its retrospective nature suggests caution; however, our results show that microsurgery can allow a safe and precise dissection of the carotids and nerves.

Expression of the tumour-suppressor maspin in temporal bone carcinoma.

AIMS: Although it accounts for fewer than 0.2% of all head and neck tumours, temporal bone squamous cell carcinoma (SCC) is an aggressive malignancy with a poor prognosis in advanced cases. Novel therapeutic strategies should be developed focusing on specific targeted therapies. Maspin is a serpin showing tumour-suppressing activity which has therapeutic potential. The present study is the first to investigate maspin expression in temporal bone SCCs, using a series of 29 cases. METHODS AND RESULTS: Cytoplasmic maspin expression was significantly higher in the group of patients whose SCC did not recur than in the group experiencing recurrences (P = 0.029), and in G1-G2 SCCs than in G3 cases (P = 0.001). cT correlated with recurrence rate (P = 0.05), disease-free survival (DFS) (P = 0.008) and disease-specific survival (DSS) (P = 0.0043), and pT and pathological regional lymph node status correlated with recurrence rate (P = 0.008 and P = 0.03, respectively), DFS (P = 0.017 and P = 0.0049, respectively) and DSS (P = 0.008 and P = 0.0009, respectively). CONCLUSIONS: Although further studies using larger series are required, our preliminary findings suggest that cytoplasmic maspin expression has promise as a prognostic indicator of disease recurrence in temporal bone SCC, and that reactivating maspin functions in association with apoptosis-inducing or anti-angiogenic chemotherapeutic agents might be an important goal in the treatment of temporal bone SCC.

The contribution of oncological lateral skull base surgery to the management of advanced head-neck tumors.

BACKGROUND: Lateral skull base is a complex area between the brain and the neck that is characterized by a large anatomic variability in narrow spaces and wide heterogeneity of tissues. The complexity of the anatomy makes it more difficult to accurately identify tumor spread and surgical planning is here particularly demanding. AIMS: Oncological skull base surgery is conceived for malignant lesions originating in, secondarily infiltrating, or in close proximity to the lateral skull base. It is also conceived for selected aggressive or benign lesions of the parapharyngeal space and infratemporal fossa abutting the skull base, or crossing it from above downwards to the neck. This paper is focused on the role that oncological skull base surgery plays to resect tumors in this area. METHODS AND RESULTS: Three main types of head and neck lesions can be identified as paradigms of the philosophy of oncological lateral skull base surgery, and are herein presented: (i) primary malignant tumors of the ear; (ii) advanced malignant parotid tumors; (iii) primary malignant or locally aggressive tumors of the infratemporal fossa-parapharyngeal space. The en-bloc lateral and subtotal temporal bone resections, the en-bloc temporo-parotid resection and the combined subtemporal-transcervical-transparotid resection are described, respectively. CONCLUSIONS AND SIGNIFICANCE: Different histologies are found in the lateral skull base and adjacent areas, and each histology has its own pattern of growth and undetected spreading in a difficult-to-reach surgical area. The leading principle is to create a wide access through soft tissues and bone removal far enough from the tumor to obtain a complete resection, en-bloc radical resection in malignancies. The entity of dissection is obviously modulated on the tumor triad (histology, pattern of growth, extent) and is achieved through the en-bloc and combined approaches that are here described.

Contemporary Perspectives in Pathophysiology of Facial Nerve Damage in Oto-Neurological and Skull Base Surgical Procedures: A Narrative Review.

During the last decades, neuro-otological surgery has progressively reduced functional morbidity, including facial nerve damage. However, the occurrence of this sequela may significantly impact on patients' quality of life. The aim of this narrative review is to provide an update on the patho-physiological and clinical issues related to facial nerve damage in oto-neurological and skull base surgery, in the light of a comprehensive therapeutic and rehabilitative approach to iatrogenic disfunctions. The narrative review is based on a search in the PubMed, Scopus, and Web of Science databases. In this surgical setting, the onset of intraoperative facial nerve damage is related to various aspects, mainly concerning the anatomical relationship between tumor and nerve, the trajectory of the surgical corridor, and the boundaries of the resection margins. Mechanisms related to stretching, compression, devascularization, and heating may play a role in determining intraoperative facial nerve damage and provide the patho-physiological basis for possible nerve regeneration disorders. Most of the studies included in this review, dealing with the pathophysiology of surgical facial nerve injury, were preclinical. Future research should focus on the association between intraoperative trauma mechanisms and their clinical correlates in surgical practice. Further investigations should also be conducted to collect and record intraoperative data on nerve damage mechanisms, as well as the reports from neuro-monitoring systems.