Caroline Apra

MD, MSc Ciprian Enasceschu

MD Veronique Lapras

MD Gerald Raverot

PhD Emmanuel Jouanneau

Is gross total resection reasonable in adults with craniopharyngiomas with hypothalamic involvement ?

Objective: The treatment of hypothalamus-invading craniopharyngiomas, based on pediatric experience, is subtotal resection (STR) with radiotherapy. This strategy sometimes leads to uncontrollable tumor progression. In adults, with the use of endoscopic endonasal surgery (EES), does removing the hypothalamic part of the tumor -whenever possible -compromise the outcome of the patients? Methods: We included adults with craniopharyngioma treated by a first EES in 2008-2016 by E.J. Endocrine, ophtalmological and hypothalamic data were retrospectively collected, including BMI, cognitive and social status, with a systematic follow-up interview. MRI were graded according to Puget: 0 -no hypothalamic involvement, 1 -hypothalamic displacement, 2 -hypothalamic involvement. Grade 2 tumors were separated into gross total resection (GTR) or STR.

Results:

We included 22 patients, aged 18 to 79. Presenting symptoms were visual (14, 64%), endocrine dysfunction (10, 45%), BMI>30 (8, 36%), cognitive/psychiatric impairment (9, 41%). Forteen (64%) were grade 2 craniopharyngiomas. GTR was performed in 14 (64%).

Postoperatively, 12/14 (86%) cases improved visually, and 20 (91%) needed hormone replacement therapy. There was no difference in BMI evolution in the GTR versus STR group, cognitive status was stable or improved in all patients except one; 4/8 patients with STR experienced progression needing adjuvant treatment, versus no patient with GTR.

Conclusions: EES GTR of grade 2 craniopharyngiomas does not cause major hypothalamic worsening, in contrast with children operated by cranial approaches. The surgeon's experience is key in deciding when to stop the dissection. Offering GTR whenever possible aims at avoiding tumor progression and radiotherapy.

Introduction:

Craniopharyngiomas are rare suprasellar tumors which may present with hypothalamic involvement, causing dramatic symptoms such as morbid obesity, cognitive decline, feeding and sleep disturbances, in addition to endocrine and ophthalmological deficits. Besides endocrine substitution, craniopharyngiomas can be treated by surgery, radiation therapy, or "in situ" pharmacological injections such as interferon when cystic. The current strategy derives from paediatric series with subtotal resection (STR) and radiotherapy when hypothalamus is involved [START_REF] Puget | Pediatric craniopharyngiomas: classification and treatment according to the degree of hypothalamic involvement[END_REF] . This may expose to therapeutic failure if tumor volume kept in place is not responsive to radiotherapy. Several reasons made that paradigm controversial in adult, who are not tall children. First, to the best of our knowledge, there is no homogeneous adult series, except a limited one focusing on intraventricular lesions [START_REF] Forbes | Endonasal endoscopic transsphenoidal resection of intrinsic third ventricular craniopharyngioma: surgical results[END_REF] , and most results rely on mixed paediatric and adult cases. Second, childhood-onset and adult tumors are differents regarding histology and anatomy. Adamantinomatous type, which harbours CTNNB1 mutations, arises primarily in children, whereas papillary tumors, characterized by BRAF V600E mutation, are found almost exclusively in adult patients [START_REF] Hölsken | Adamantinomatous and papillary craniopharyngiomas are characterized by distinct epigenomic as well as mutational and transcriptomic profiles[END_REF] . Tumors are also different regarding their locations with more suprasellar and retrochiasmactic extensions in adults. Thirdly, consequences of hypothalamic involvement are certainly quite different in young and adults. Finally, this paradigm was promoted under the microscopic era. With the development of extended endonasal endoscopic surgery, the conditions and possibilities have changed with a better hypothalamic exposure, through a different surgical canal.

As a skull base centre with extensive surgical experience in sellar and suprasellar surgery (140 cases per year since more than 10 years), we retrospectively analysed a local series, and report the first cases of purely adult-onset craniopharyngiomas. Our therapeutical management relies on a maximal endonasal endoscopic removal of the tumor, even in patients with hypothalamic involvement. We evaluated the consequences of hypothalamic invasion in the preoperative and postoperative courses of the disease to answer the question: did removing the hypothalamic part of the tumor -whenever possible -compromise the quality of life and outcome of the patients?

Material & methods:

We retrospectively analysed our local series of adult patients who underwent a first procedure of endonasal endoscopic surgery of adult-onset craniopharyngioma between 2008 and 2016 in the Skull Base Unit of the neurosurgical department, Pierre Wertheimer Hospital of Neurology and Neurosurgery, Lyon, France. We excluded redo surgery, cranial surgery, cases lacking sufficient imaging or consistant histological findings, recent cases without follow-up and adult patients with proved childhood-onset tumors. The patients consent for retrospective analysis was obtained.

The surgical technique used was done by the senior author (EJ) consisting in an extended trans tubercular transsellar bi-nostril approach under neuronavigation. The closure technique has evolved over time consisting for the first period (2008-2012) in a multilayer technique using glue inside the suprasellar space to restore a "pseudo-arachnoid", an extradural dura mater substitute bio-absorbable (SEAMDURA®, Codman) with an artificial bone substitute (MEDPOR®, Stryker) covered by a vascularized naso-septal flap made on one side after a middle turbinectomy. The sphenoid sinus was therefore plugged by fat and a nasal plugging was done by a simple mesh removed at day 3. During the second period, a Gasket-seal technique derived from Schwartz 4 was used to close the osteo-dural defect with a piece of fascia lata and the MEDPORE still covered by the naso-septal flap. These surgical techniques have been described before [START_REF] Garcia-Navarro | Gasket seal closure for extended endonasal endoscopic skull base surgery: efficacy in a large case series[END_REF][START_REF] Zenonos | Endoscopic Endonasal Approach for a Suprasellar Craniopharyngioma[END_REF] .

Preoperative and postoperative clinical data (visual, endocrine, neurological, cognitive and social statuses, height and weight) and cranial MRI were collected in the medical record, including hypothalamic function (appetite dysregulation with weight gain or anorexia, body temperature dysregulation, cognitive impairment, in particular behavioural alteration and memory issues, psychosis, sleep-wake cycle, diabetes insipidus [START_REF] Asa | Hypothalamic Disease[END_REF] ) and the last follow-up was completed in a telephone interview (C.A.). Pituitary MRI included T1-and T2-weighted, FLAIR and gadolinium-enhanced T1 sequences. Preoperative and postoperative MRI grading for hypothalamic involvement was assessed according to Puget 1 by two authors (E.J. and C.A.): preoperatively, grade 0, no hypothalamic involvement; grade 1, the tumor abutting or displacing the hypothalamus; grade 2, hypothalamic involvement; postoperatively, our purpose was to compare the benefit or risk of hypothalamic surgery. We used the Puget classification as follows: grade 0, no hypothalamic damage; grade 1, negligible hypothalamic damage (small hole) or residual tumor displacing the hypothalamus; grade 2, significant hypothalamic damage (hole in the floor of the third ventricle, visible on MRI). In theory, potsoperative grade 1 could define either STR with residual tumor in the third ventricle, or GTR without hypothalamic damage, but in practice grade 1 defined STR in previously grade 2 whereas postoperative grade 2 was defined as a hole in the third ventricle allowing GTR. The appearance of the tumor, of the contrast enhancement and presence of a hypothalamic oedema has been collected as well.

Subjective quality of life and hypothalamic outcome (weight, cognitive functions, daily and professional activities) were studied more particularly. Statistics were performed using SPSS statistics 20.0.0 (IBM, USA).

Results:

We analysed 22 consecutive cases among 53 adults treated for craniopharyngiomas during the same period at our center. There were 7 male (30%) and 15 female (70%) patients and the mean age was 58 years, ranging from 18 to 79. All were operated on using the extended endoscopic endonasal route. Presentation, surgical complications and long-term outcome are summarized in table 1.

Preoperatively, 14 patients (70%) presented with visual impairment, including visual field abnormalities or decreased visual acuity. Visual deficit was the main reason for consultation in 13 patients (65%). Endocrine status was normal in 12 patients (55%) whereas 6 (27%) presented panhypopituitarism, 2 (9%) isolated hypogonadism, 2 (9%) hyperprolactinemia, Diabetes insipidus was present in 4 (18%).

Few patients complained of neurological symptoms: 1 patient had vertigo, 2 -headaches, and 2 others -signs of elevated intracranial pressure. In contrast, 5 patients (23%) showed cognitive impairment with pseudo-dementia (decreased Mini Mental Score, amnesia and attentional troubles), with episodes of acute confusion. In 4 more patients (18%), cognitive slow-down mimicked depressive symptoms. Psychiatric expert diagnosis was not established in all cases.

The social burden of the disease was noticed in 3 of the 14 working patients (21%), who stopped, whereas 11 (79%) were still working despite their symptoms. Eight (36%) patients were retired, with varied impact on their daily activities. Concerning weight, 6 (27%) patients had a BMI<25; 8 (36%) were overweight (BMI 25-30), whereas 5 (23%) were obese (BMI 30-35) and 3 (14%) had a BMI>35.

On preoperative MRI, 1 patients (4%) was grade 0, 7 (32%) grade 1, and 14 (64%) grade 2.

Ten tumors (45%) of all grades were purely solid and 12 (55%) included both a solid and a cystic component. Fifteen (68%) were homogeneously contrast-enhanced, whereas 6 (27%) had an irregular appearance. Fifteen (68%) were associated with hypothalamic oedema. Sixteen (73%) involved the pituitary stalk. Five (23%) were associated with hydrocephalus on MRI and 8 (37%) were partly calcified.

In our series, preoperative symptoms (BMI, ophthalmological, endocrinologic or neuropsychological impairment) were not significantly correlated with the MRI grade.

However, five out of the six patients who presented with the higher BMI (BMI>31.5) had grade Postoperative data is described in table 1, and results according to the preoperative grade in figure 1. The visual function was improved in 12/14 preoperatively impaired patients (86%), was stable in preoperatively normal patients and worsened in one case (5%). On the endocrine point of view, none of the patients improved their pituitary function, with 12 new panhypopituitarism (total 18, 90%) and 9 new diabetes insipidus (total 13, 65%), still needing medication on long-term follow-up. Two patients were free of any hormonal substitution.

Preserving the pituitary stalk was not correlated with the absence of diabetes insipidus.

Concerning the hypothalamic outcome, cognitive and social statuses improved noticeably in 2 out of 5 patients (40%) and 1 patient worsened, developing psychiatric symptoms. Patients with a normal preoperative weight did not develop obesity, including two grade 2 tumors. Among 6 overweighed patients, 2 developed obesity, and among obese patients, 2 developed morbid obesity (cf figure 2). Four patients had a BMI increase by more than 2 points. Two of them had grade 1 tumors and 2 had grade 2 tumors. Two of them underwent GTR that led to a defect in the third ventricle floor, while the two others had a STR respecting the part of the tumor invading the third ventricle. Overweight issue was not correlated with the extent of resection.

Other hypothalamic symptoms were not systematically tested, but several patients did report sleep disturbances before and after surgery.

On postoperative MRI, 8 patients (36%) were grade 0, 4 (18%) grade 1, and 10 (46%) grade 2.

GTR could be performed in 14 cases (64%), comprising all grades 0-1 and half of grade 2 tumors. Histological analysis showed that 16 craniopharyngiomas were adamantinous (76%), 5 were papillary (24%), and 1 could not be specified because of artifact. No patient with GTR developed tumor recurrence or received any adjuvant treatment. Among the 8 patients with STR, 4 developed tumor progression. Six patients received stereotactic radiotherapy (3 at recurrence and 3 upfront for postoperative residual tumor, one of which recurred), and two also received local interferon therapy for cystic recurrence. The median follow-up period is 5.3 years (from 2.1 to 9.9 years) for STR and 3.7 years (from 1.7 to 9.9) for GTR.

The grading and extent of resection were not correlated with postoperative complications. Rhinorrhoea needed surgical revisions in 4 patients (18%), but the CSF leakage rate dropped after the modification of the surgical protocol as described in the methods. Two patients with severe comorbidities died in the three months following the surgery, one from rectal abcess with multi-organ failure, the other from pneumonia (cf. figure 3).

Discussion:

Craniopharyngiomas are rare tumors in adults and, to the best of our knowledge, all series tackle the issue of childhood-onset craniopharyngiomas. Puget et al. have contributed to give a precise description of postoperative course in children operated for craniopharyngiomas transcranially under microscope leading to an algorithm of treatment [START_REF] Puget | Pediatric craniopharyngiomas: classification and treatment according to the degree of hypothalamic involvement[END_REF][START_REF] Puget | Treatment Strategies in Childhood Craniopharyngioma[END_REF] . As a consequence, the strategy of STR and radiotherapy was commonly adopted for grade 2 tumors, in adults as well as in children, in order to avoid postoperative disabling hypothalamic sequelae. However, in several patients with STR, we experimented rapid tumor growth with local invasion and severe symptoms with radiotherapy failure. It led us to question this approach and to modify our strategy in order to aim to remove the tumor totally even in case of hypothalamic involvement, whenever possible. This strategy has also been discussed in a recent study in a mixed pediatricadult population, that shows that combined trans-ventricular and endonasal approach might help remove cystic craniopharyngiomas radically without causing disastrous hypothalamic lesions [START_REF] Deopujari | Combined endoscopic approach in the management of suprasellar craniopharyngioma[END_REF] . Our retrospective study focuses only on adults without previous significant surgery or radiotherapy, in order to analyze a homogeneous population, with a native tumor-hypothalamus interface.

The initial symptoms in our series are similar to those reported in the literature [START_REF] Yano | Surgical Outcomes of Endoscopic Endonasal Skull Base Surgery of Craniopharyngiomas Evaluated According to the Degree of Hypothalamic Extension[END_REF] , with visual impairment in more than two third of the population and endocrine dysfunction in more than half the population. The most important difference between our adult-onset series and mixed or childhood-onset ones 1,9,10 is the higher rate of acute hydrocephalus in children (68%, with 38% needing emergency treatment, versus chronic hydrocephalus in 10% in adults). Preoperative pituitary deficits were found in 80% of children, versus 48% in adults and visual deficits in 44% versus 70%. The global picture shows that adult craniopharyngiomas reveal more slowly, often with visual deficiencies, which actually are the most frequent reason for emergency procedures. An explanation could be the suprasellar retrochiasmatic / intrasellar location of the craniopharyngiomas in our series, without anterior and lateral extensions, a bias due to their frequency in adults and compatibility with the endonasal approach. As described in the methods, our study relies on experimented surgical techniques already described by other authors [START_REF] Garcia-Navarro | Gasket seal closure for extended endonasal endoscopic skull base surgery: efficacy in a large case series[END_REF][START_REF] Zenonos | Endoscopic Endonasal Approach for a Suprasellar Craniopharyngioma[END_REF][START_REF] Yano | Surgical Outcomes of Endoscopic Endonasal Skull Base Surgery of Craniopharyngiomas Evaluated According to the Degree of Hypothalamic Extension[END_REF][START_REF] De Divitiis | Extended endoscopic transsphenoidal approach for extrasellar craniopharyngiomas[END_REF] . Concerning the hypothalamic access in this context, the surgical field is narrow, and it cannot be seen before most of the tumor has been removed ; some authors have proposed that a relevant preoperative CT landmark is the angle between the tuberculum sellae and the optic apparatus, with a sharp angle (< 118°) predictive of difficult visualization of the suprasellar space 12 . When the access is possible, dissection is critical and differentiation between hypothalamus tissue and gliosis may be difficult, making long surgical practice mandatory. In our experience, when the tumor could be mobilized with smooth dissection, we decided to remove it ; on the opposite, when sharp dissection was needed, we decided to leave these tumor pieces. When we could not distinguish between a cyst wall in the third ventricle and the hypothalamus, we left the cyst remnant in place and it was considered as STR.

The postoperative outcome in our series is beneficial on the visual point of view for 95% of patients. On the opposite, the pituitary function is clearly made worse, necessitating life-long hormonal replacement therapy. Although it has been suggested that preservation of the pituitary stalk may be associated with endocrine preservation [START_REF] Yano | Surgical Outcomes of Endoscopic Endonasal Skull Base Surgery of Craniopharyngiomas Evaluated According to the Degree of Hypothalamic Extension[END_REF][START_REF] Ordóñez-Rubiano | Preserve or sacrifice the stalk? Endocrinological outcomes, extent of resection, and recurrence rates following endoscopic endonasal resection of craniopharyngiomas[END_REF] , it does not seem compatible with GTR, as craniopharyngiomas often arise from it. Therefore, it has not been a priority in our surgical strategy. We noticed that panhypopituitarism and diabetes insipidus still developed in two patients, despite preservation of the pituitary stalk. Moreover, in series with preservation of the stalk, the recurrence rate is higher, and preservation does not guarantee preservation of the endocrinological function [START_REF] Ordóñez-Rubiano | Preserve or sacrifice the stalk? Endocrinological outcomes, extent of resection, and recurrence rates following endoscopic endonasal resection of craniopharyngiomas[END_REF] .

Hypothalamic dysfunction includes a panel of symptoms that, unfortunately, were not systematically tested in our patients, but were explored clinically. When isolated, most signs are not specific, for instance weight gain, which may be related to hypothalamus dysfunction when it occurs a few months or years before diagnosis without neither any reasons nor endocrine dysfunction. Concerning postoperative hypothalamic results, all preoperatively valid patients but one recovered their daily life or social activities without any limitations after surgery. Two patients with pseudodemential symptoms experienced a major improvement, and only one patient deteriorated. A closer discussion with his family showed that he actually presented cognitive decline for a few months that had not been mentioned preoperatively. This underlines the fact that preoperative neuropsychologic testing is necessary preoperatively when the clinical context allows it. In our small series, the extent of surgery (GTR or STR) was not correlated to the postoperative cognitive status. In terms of BMI, the only quantitative assessment of hypothalamic dysfunction we have access to, there are strikingly different populations in the different series: in our population, 8 patients (38%) initially presented with obesity (BMI > 30), versus only 2 (11%) in Yano et al. We notice that, out of the 7 more obese patients (BMI >31), 5 presented with preoperative grade 2 tumors, and 2 with grade 1.

Hypothalamic edema, which was present in 6 patients in our series (30%), was not correlated with obesity, although this has been described as a marker of hypothalamic involvement [START_REF] Yano | Surgical Outcomes of Endoscopic Endonasal Skull Base Surgery of Craniopharyngiomas Evaluated According to the Degree of Hypothalamic Extension[END_REF] .

Patients who developed obesity or morbid obesity were all overweighed preoperatively. It is worth mentionning that several obese patients did not improve despite professional dietary counselling. The extent of surgery was not correlated to the BMI progression. This suggests that the hypothalamic troubles may have been caused by the tumor itself rather than the surgery. Some grade 2 tumors could be entirely removed without causing major deterioration, even when the floor of the third ventricle was invaded. In theory, the precise radiological knowledge of the hypothalamic extent of the tumor could help predict the surgical risk but the anatomical boundaries of the hypothalamus may not be detectable on MRI, and anatomy isn't strictly correlated to the function due to plasticity. This may explain the difficulty to grade the tumors reproducibly and the clinical heterogeneity among tumors with the same apparent grade, as exampled in the two cases we present in figure 3. Moreover, STR did not guarantee that the hypothalamic symptoms would remain stable: a 64-year-old female patient had a preoperative grade 2 tumor and postoperative grade 1 tumor, with no surgical damage to the hypothalamus but a remnant which could not be totally removed. Her psychiatric symptoms improved postoperatively, but she underwent preventive radiotherapy on the remaining part, and her BMI then increased from 31.2 to 45.2, without tumor progression on MRI. When the tumor has invaded the hypothalamus preoperatively, it seems that it can be removed without causing additional damage when it doesn't stick too much to the hypothalamic wall. This points out the importance of the surgeon's experience, who must decide how far he can go during the surgery.

It is worth noticing that, in our series, invasive grade 2 craniopharyngiomas were mostly of adamantinomatous type (13/14, 93%), that are reported to arise more often in children, whereas non-invasive grade 0-1 tumors were papillary tumors (5/8, 63%) (cf. figure 1). Concerning the oncological outcome, no patient with GTR experienced tumor recurrence or needed any adjuvant treatment after a median period of 3.7 years. On the opposite, out of 8 patients with STR, 4 showed tumor growth needing radiotherapy and, in two cases, local interferon, after a period of 5.3 years. Tumor regrowth happened in the first two years after surgery. One patient severely deteriorated after radiotherapy. One more patient underwent preventive radiotherapy on the tumor residual. In all cases, STR was a matter of technical issue rather than a preoperative strategy, and surgery was stopped because the lesion could not be visualized or accessed safely.

Puget's classification based on a grade 0-1-2 description of the tumor 1 is simple to use and we chose it to analyse our series because the standard of care for treatment relies on these criteria. This classification can be confusing since the postoperative grading is not comparable with the preoperative one, especially for postoperative grade 1 tumors that can refer to both GTR and STR without major hypothalamaic damage, possibly mixing damages due to the tumor itself and to the surgical resection. More recent studies offer supplementary criteria for stratifying the risk of postoperative hypothalamic damage based on MRI findings: the position of the hypothalamus in relation to the tumor, the type of pituitary stalk distortion and the tumor shape [START_REF] Prieto | Preoperative Assessment of Craniopharyngioma Adherence: Magnetic Resonance Imaging Findings Correlated with the Severity of Tumor Attachment to the Hypothalamus[END_REF] ; the authors have also proposed a model of predictive adherence of the tumor to the hypothalamus based on pre-and peroperative characteristics: the intracranial structures attached to the tumor, the morphology of the adhesion and the adhesion strength [START_REF] Prieto | Craniopharyngioma adherence: a comprehensive topographical categorization and outcome-related risk stratification model based on the methodical examination of 500 tumors[END_REF] . These studies are helpful to anticipate the surgical difficulty of hypothalamic dissection, however we find they are not easily reproducible, they do not always provide practical information and, more importantly, that we cannot make a therapeutic decision based on these classifications.

Deciding not to offer GTR to a patient because of pejorative factors in any of these classifications could lead to a loss of complete treatment opportunity. The final decision remains up to the surgeon's peroperative experience. Indeed, our experience in this series shows that performing GTR whenever possible, even in a hypothalamus invading tumor, prevents tumor progression and additional damage due to radiotherapy, and does not worsen the quality of life of the patients, with the majority of patients coming back to life standards comparable to their preoperative status. GTR is not associated to significant clinical worsening compared to STR in patients with grade 2 tumors. The key element, in addition to the MRI findings, before planning the surgery, is the general clinical status of the patient and palliative treatment should sometimes be considered. In our series, the two patients who died in the postoperative period were in very poor general condition, with severe comorbidities and hypothalamic dysfunction (grade 2 tumors with cognitive deterioration, BMI 36 and 37.7) and, retrospectively, it would have been reasonable to offer them palliative care only. There is no evidence that age is a limiting factor, with craniopharyngiomas affecting patients older than 60 in 20% of cases (43% in our purely adult series), and even older than 80 in 2.7% [START_REF] Zacharia | Incidence, treatment and survival of patients with craniopharyngioma in the surveillance, epidemiology and end results program[END_REF] , and we think that surgery is an option if the clinical state of the patient allows it.

Table 1: Preoperative and postoperative characteristics of the patients operated for endoscopic endonasal surgery of craniopharyngioma (n=22) Figure 1: Comparison of the preoperative and postoperative charcateristics of the patients according to the craniopharyngioma hypothalamic involvement (Puget's grading). Preoperative grades 0-1 craniopharyngiomas are distant from the hypothalamus or displace it without invading the floor of the third ventricle (left column). Grade 2 tumors involve the hypothalamus, which is not clearly identifiable (right column). In the postoperative period, grade 1 tumors refer to subtotal resection without hypothalamic damage whereas grade 2 to hypothalamic damage as created by the tumor in order to achieve gross total resection. There is major hypothalamic worsening in the patients with grade 2 tumors, after STR or GTR. STR : subtotal resection, GTR : gross total resection, BMI : body mass index. A-B) Case 1 was an active 30-year-old woman, preoperative BMI 32.9, who presented with hyperprolactinemia. On preoperative MRI, she had a grade 2 solid flocculent craniopharyngioma arising from the pituitary stalk. After GTR, she developed panhypopituitarism, and her BMI was 36.9 but decreased to preoperative level after dietetic mesures. She remained normal on a cognitive point of view and kept working as previously. C-D) Case 2 was an active 63-year-old male who also presented with a grade 2 solid flocculent tumor. He had visual field abnormalities, mild cognitive impairment with psychiatric symptoms, and a BMI of 29.6. After GTR, he developed obesity (BMI 34.5), and his cognitive and psychiatric functions worsened, impeding his quality of life. He is the only patient in the series who deteriorated on a cognitive point of view. E-F) Case 3 was a 58-year-old retired woman, preoperative BMI 22.7, who presented with right visual deterioration and headache. On preoperative MRI, she had a grade 2 solid craniopharyngioma invading the third ventricle. After GTR, she developed panhypopituitarism with diabetes insipidus, but her visual function improved, her BMI was stable and she was able to resume all her daily activities. MRI follow-up is normal after 3 years. G-H) Case 4 was a 68-year-old retired man with preoperative morbid obesity (BMI 37.7), bilateral visual abnormalities, erectile dysfunction and cognitive decline with depression. On preoperative MRI, he had a grade 2 solid and cystic craniopharyngioma. After GTR, he developed panhypopituitarism without diabetes insipidus, and hydrocephalus. He died from infectious pulmonary disease in the intensive care department three months after the surgery, after having developed postoperative ventriculitis.

These cases illustrate that MRI is not predictive of hypothalamus damage and that clinical and surgical evaluation remain central in making therapeutical decisions. GTR: gross total resection, BMI: body mass index.

Preoperative grades 0-1 Preoperative grade 2

Figure 1: Comparison of the preoperative and postoperative charcateristics of the patients according to the craniopharyngioma hypothalamic involvement (Puget's grading). Preoperative grades 0-1 craniopharyngiomas are distant from the hypothalamus or displace it without invading the floor of the third ventricle (left column). Grade 2 tumours involve the hypothalamus, which is not clearly identifiable (right column). In the postoperative period, grade 1 tumours refer to subtotal resection without hypothalamic damage whereas grade 2 to hypothalamic damage as created by the tumour in order to achieve gross total resection. There is major hypothalamic worsening in the patients with grade 2 tumours, after STR or GTR. STR : subtotal resection, GTR : gross total resection, BMI : body mass index. Figure 3: pre-and post-operative MRI, coronal, gadolinium-enhanced T1 sequence, for illustrative cases with preoperative grade 2 craniopharyngiomas, and postoperative grade 2 with GTR. A-B) Case 1 was an active 30-year-old woman, preoperative BMI 32.9, who presented with hyperprolactinemia. On preoperative MRI, she had a grade 2 solid flocculent craniopharyngioma arising from the pituitary stalk. After GTR, she developed panhypopituitarism, and her BMI was 36.9 but decreased to preoperative level after dietetic mesures. She remained normal on a cognitive point of view and kept working as previously. C-D) Case 2 was an active 63-year-old male who also presented with a grade 2 solid flocculent tumor. He had visual field abnormalities, mild cognitive impairment with psychiatric symptoms, and a BMI of 29.6. After GTR, he developed obesity (BMI 34.5), and his cognitive and psychiatric functions worsened, impeding his quality of life. He is the only patient in the series who deteriorated on a cognitive point of view. E-F) Case 3 was a 58-year-old retired woman, preoperative BMI 22.7, who presented with right visual deterioration and headache. On preoperative MRI, she had a grade 2 solid craniopharyngioma invading the 3rd ventricle. After GTR, she developed panhypopituitarism with diabetes insipidus, but her visual function improved, her BMI was stable and she was able to resume all her daily activities. MRI follow-up is normal after 3 years. G-H) Case 4 was a 68-year-old retired man with preoperative morbid obesity (BMI 37.7), bilateral visual abnormalities, erectile dysfunction and cognitive decline with depression. On preoperative MRI, he had a grade 2 solid and cystic craniopharyngioma. After GTR, he developed panhypopituitarism without diabetes insipidus, and hydrocephalus. He died from infectious pulmonary disease in the intensive care department three months after the surgery, after having developed postoperative ventriculitis. These cases illustrate that MRI is not predictive of hypothalamus damage and that clinical and surgical evaluation remain central in making therapeutical decisions. GTR: gross total resection, BMI: body mass index.

Figure 2 :

 2 Figure 2: Individual evolution of preoperative (first point) and postoperative (second point) BMI A) for all patients, B) for patients with postoperative grade 0-1 tumors, C) for patients with postoperative grade 2 tumors, i.e. with a defect in the floor of the third ventricle. There is no increase of BMI worsening in patients with GTR involving the hypothalamic part of the tumor. GTR: gross total resection, BMI: body mass index.

Figure 3 :

 3 Figure 3: pre-and postoperative MRI, coronal, gadolinium-enhanced T1 sequence, for illustrative cases with preoperative grade 2 craniopharyngiomas, and postoperative grade 2 with GTR.

Figure 2 :

 2 Figure 2: individual evolution of preoperative (first point) and postoperative (second point) BMI A) for all patients, B) for patients with postoperative grade 0-1 tumors, C) for patients with postoperative grade 2 tumors, i.e. with a defect in the floor of the third ventricle. There is no increase of BMI worsening in patients with GTR involving the hypothalamic part of the tumor.

Table 1 . Preoperative and postoperative characteristics of the patients operated for endoscopic endonasal resection of craniopharyngioma (n=22)

 1

			Our series
	Parameter		(n=22)
			n	%
	Population
	Sex	Male	7	30
		Female	15	70
	Age (years), median		58 (18-79)
	Preoperative characteristics
	Visual status (n=20)	Normal	6	30
		Visual field abnormalities	11	55
	Unilateral decreased visual acuity	7	35
	Bilateral decreased visual acuity	5	23
	Visual impairment as main complaint	13	65
	Endocrine status	Normal	12	55
		Panhypopituitarism	6	27
		Isolated hypogonadism	2	9
		Isolated hyperprolactinemy	2	9
		Diabetes insipidus	4	18
	Neurological status	Vertigo	1	5
	Signs of elevated intracranial pressure	2	9
		Headaches	2	9
	Cognitive status	Cognitive impairment	5	23
	Slow-down or signs of depression	4	18
	Social status	Working	11	50
		Retired	8	36
		Work stoppage	3	14
	Weight	BMI < 25	6	27
		BMI ]25 ; 30]	8	36
		BMI ]30 ; 35]	5	23
		BMI > 35	3	14
	Height	Female	161+/-3
		Male	176+/-5
	MRI grading	Grade 0	1	4
		Grade 1	7	32
		Grade 2	14	64
	Postoperative course (n=22)
	Complete resection		14	64
	Mortality (after 3months)		2	9
	Complications	Death	2	9
		Meningitis	5	23
	Surgical closure for rhinorrhea	4	18
		Severe hyponatremia	1	5
	Need for internal ventricular drainage		4	18
	MRI grading (n=22)	Grade 0	8	36
		Grade 1	4	18
		Grade 2	10	46

Conclusions:

In our experience, endonasal endoscopic GTR of craniopharyngiomas does not cause major worsening of preoperative hypothalamic syndrome, even if the lesion invades the third ventricle, suggesting that hypothalamic damage may be caused by the tumor itself. Severe preexisting hypothalamic syndrome, in particular morbid obesity in patients with major comorbidity, seems to be a contraindication for surgery because of the high risk of neurological and general complications. There is a need for a systematic thorough hypothalamic evaluation preoperatively and postoperatively in order to determine the optimal strategy in these patients, since it seems that favouring STR in patients with aggressive preoperative MRI findings is not appropriate in all cases.

Disclosure & Funding:

The authors declare no conflict of interest. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.


Kentaro Watanabe
email: kentarow31@gmail.com

Ali R Zomorodi

Moujahed Labidi

Shunsuke Satoh

Sébastien Froelich

M.D, D.M.Sc Takanori Fukushima

Visualization of Dark Side of Skull Base with Surgical Navigation and Endoscopic Assistance: Extended Petrous Rhomboid and Rhomboid with Maxillary Nerve-Mandibular Nerve Vidian Corridor

Keywords: extended anterior petrosal approach, endoscopic assistance, clivus, jugular foramen, hypoglossal, condyle, middle fossa approach arcuate eminence, BS, brains stem, CL, clivus, Cdy: condyle, CT: Computed tomography, CTA: computed tomography angiogram, CTV: computed tomography venous angiography, EP: epipharynx, FO: foramen ovale, FR: foramen rotundum, GdT1W: T1 with gadolinium contrast, GPN: greater petrosal nerve, HC: hypoglossal canal, IAC: Internal auditory canal, ICA: internal carotid, IPS: inferior petrosal sinus, IJV: internal jugular vein, JB: jugular bulb, JF: Jugular foramen, JT: jugular tubercle, Mid: midline, MMA: middle meningeal artery, MF: middle fossa, MRI: magnetic resonance imaging, PF: posterior fossa, PLL: petroligngual ligament, RS: Retrosigmoid, ShpS: sphenoid sinus, SPS: superior petrosal sinus, T1WI: T1 weighted image, T2WI: T2 weighted image, V2: maxillary nerve, V3: mandibular nerve, VN: vidian nerve,

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Introduction

Lesions located at the petrous apex, cavernous sinus, clivus, medial aspect of the jugular foramen, or condylar regions are still difficult to fully expose using the operating microscope. While approaches to this region through the middle cranial fossa have been described before, these approaches afford only a limited visualization. The authors confirmed a transcranial infratemporal fossa combined microsurgical and endoscopic access to the petrous apex, clivus, medial aspect of the jugular foramen and occipital condyle. This article presents a microanatomical cadaver dissection study and its clinical application.

Materials and Methods

Ten latex injected cadaveric specimens (twenty sides) underwent dissection with navigational guidance to achieve an extended anterior petrosal approach combined with a far vidian corridor approach (between the foramen rotundum (FR) and foramen ovale (FO)). We performed anatomical dissections to confirm the surgical anatomy, as well as the feasibility and limitations of this approach. Anatomical dissections were performed in the skull base laboratory of Lariboisière Hospital and Duke University Medial Center.

This approach was then applied to some clinical cases.

Result

The combination of the microscope and endoscope, aided by surgical navigation, was extremely effective and provided a wide view of the petrous rhomboid, the entire clivus, and the medial condylar regions. The extended extradural anterior petrosal approach provides a large corridor to petrous and clival lesions. The endoscopic assistance offers a wide and deep exposure of the middle to lower clivus, epipharyngeal space, and bilateral condylar regions. This approach successfully provided adequate surgical access for resection of tumors located in these regions.

The depth of the medial aspect of the jugular foramen (JF) was 16.3±1.2 mm deep from the geniculate ganglion. The emerging point of the inferior petrosal sinus (IPS) in the jugular foramen is 16.5 ±1.8 mm deep from the geniculate ganglion. The hypoglossal canal (HC) is 21.6 ± 2.2 mm deep from the geniculate ganglion. The foramen magnum was located 31.5±2.4 mm deep from the gasserian ganglion. The IPS was found to be a reliable landmark to identify the medial portion of the jugular bulb (JB). The introduction of the endoscope through the middle fossa rhomboid enabled visualization of the medial aspect of the JB, which is hampered by the internal auditory canal (IAC) under the microscope.

Conclusion

Following the microscopic exposure of the middle fossa rhomboid neuronavigational endoscopic assistance facilitated visualization of the ventral cavernous region, petrous apex, retropharyngeal space, middle and inferior clivus, down to the medial aspect of the jugular bulb and condyle regions. Additional V2-V3 vidian corridor visualization provides lateral transsphenoidal approach to upper clivus lesions.

Introduction

Over the past 30 years, skull base surgeons have developed extended skull base techniques to access difficult anatomic areas [START_REF] Day | Microanatomical study of the extradural middle fossa approach to the petroclival and posterior cavernous sinus region: description of the rhomboid construct[END_REF] . Even with these techniques, and with advanced microscopic visualization, there are still areas of the skull base such as the ventral cavernous sinus, petrous apex, clivus, or the medial aspect of the jugular bulb and condylar regions that remain hidden to the microscope. Recently, transnasal approaches through the sphenoid and maxillary sinuses, transpterygoid, and/or transclivus approach have been used successfully to treat lesions in the medial jugular and lower clivus condylar lesions. Despite these developments we sometime still realize a benefit of the transcranial approaches as these do not share some of the limitations of even extended endoscopic exposures -e.g. lesions that extend above and below the lateral cavernous sinus.

Over the past five years, our group has been aiming to visualize these hidden areas using high-resolution 4 mm rigid endoscopic techniques from transcranial approaches. We have found unique profit in anatomical visualization by combining these techniques with our previously described extended skull base approaches. This article presents a navigational endoscopic study using cadaveric head specimens and clinical applications, focusing on the extended anterior petrosal approach.

The purpose of this study was to perform a morphometric analysis of the extended middle fossa rhomboid and additional V2-V3 vidian corridor to the middle and lower clivus around the medial jugular bulb and condyle with cadaveric head models (Fig. 1, 2) and to report on our clinical experience with these approaches.

Material and Method

Ten fixed cadaveric heads dissected with a microscope (OPMI pico; Carl Zeiss, Inc., Oberkochen, Germany) and endoscope (Karl Storz GmbH, Tuttlingen, Germany) were used for dissections and photography. For the endoscopic approaches, we used an 18 cm long, 4 mm diameter endoscopes with 0°, 30° and 70° lenses. Endoscope Images were recorded and stored with the Karl Storz Aida system (Karl Storz GmbH, Tuttlingen, Germany). Measurement of the exposure thus obtained was performed with a surgical navigation system (Medtronic, Minneapolis, MN, US). Microsurgical cadaveric dissections were performed to achieve an extended anterior petrosal approach and additionally combined anterior petrosal approach and the V2-V3 vidian corridor approach.

Anatomical dissections were performed in the anatomical laboratory for skull base surgery at Duke University Hospital and Lariboisière Hospital.

Positioning and surgical technique

The head was fixed in a Mayfield head holder (Integra life science corporation, USA) and turned 70° with 5° of extension. The posterior border of the temporal muscle was incised and detached from the temporal bone using the retrograde dissection technique to protect the deep temporal nerve and arteries by the temporal muscle fascia. A 5cm x 5cm craniotomy was performed and the middle fossa was accessed extradullary. The foramen spinosum (FS) was identified following the middle meningeal artery (MMA) and was coagulated and cut. The FO and FR were also identified. A small incision of the dura mater above the FO was made and the dura propria was elevated. Dissection over the greater petrosal nerve (GPN) was performed in a posterior to anterior fashion to protect the nerve. The arcuate eminence (AE) and GPN and petrous ridge were exposed completely. The rhomboid area (Kawase triangle with post-meatal area) [START_REF] Fukushima | Extradural total petrous apex resection with trigeminal translocation for improved exposure of the posterior cavernous sinus and petroclival region[END_REF][START_REF] Kawase | Anterior transpetrosal-transtentorial approach for sphenopetroclival meningiomas: surgical method and results in 10 patients[END_REF][START_REF] Kawase | Transpetrosal approach for aneurysms of the lower basilar artery[END_REF][START_REF] Kawase | Middle fossa transpetrosal-transtentorial approaches for petroclival meningiomas. Selective pyramid resection and radicality[END_REF][START_REF] Aristegui | Surgical anatomy of the extended middle cranial fossa approach[END_REF][START_REF] Borghei-Razavi | Anterior petrosal approach: The safety of Kawase triangle as an anatomical landmark for anterior petrosectomy in petroclival meningiomas[END_REF][START_REF] Maina | The middle cranial fossa: morphometric study and surgical considerations[END_REF] defined by the posterior border of the V3, the GPN, the AE and the petrous ridge were exposed.

Then, through the rhomboid, an anterior petrosectomy was achieved towards the petrous apex and ventral cavernous sinus wall. The petrous bone was drilled from the petrous apex anteriorly to the anterior border of the superior semicircular canal posteriorly. The dura of the internal auditory canal (IAC) was completely exposed. Inferiorly, the inferior petrosal sinus (IPS) was able be exposed on the inferior petrosal sinus groove. Normally, the IPS is a landmark of the inferior limit of the petrous bone removal. When the tumor extends to the clivus and/or condyle, the tumor provides a tumor corridor across the IPS.

The IPS leads to the medial aspect of the jugular bulb and location of the jugular complex.

A partial clivectomy could be performed by removing bone around the JF (Fig. 3). To visualize below the IAC, the endoscopic assisted visualization is necessary.

In order to continue to remove the clivus and condyle below the IPS, the addition of the V2-V3 corridor helped with visualization and lighting. In addition, the far lateral triangle (V2-V3 corridor) was exposed. The V2-V3 vidian corridor defined as the space between the maxillary nerve (V2)-mandibular nerve (V3) and medial to the vidian nerve, was exposed in the farlateral triangle [START_REF] Wanibuchi | Photo atlas of skull base dissection : techniques and operative approaches[END_REF][START_REF] Yasuda | Microsurgical anatomy and approaches to the cavernous sinus[END_REF] . The bone located in the V2-V3 vidian corridor, which is the pterygoid process (or root of pterygoid) was drilled until the epipharynx was reached inferiorly and the sphenoid sinus (ShpS) medially. (Fig. 2).

Working through the V2-V3 vidian corridor, navigational assisted endoscopic examination of the posterior clinoid and dorsum sella, petrous apex, ventral cavernous sinus, and contralateral condylar space was done. This maneuver was performed on 20 sides of 10 fixed human cadaveric heads and was then performed on 26 clinical cases without endoscope and 4 cases with endoscope assistance.

Result

Extended extradural anterior petrosal approach provides a look down surgical trajectory from the middle fossa to medial aspect of the jugular foramen and condyle region inferiorly. The IPS can be followed to the medial aspect of the jugular foramen and condyle. Between the pharyngeal wall and posterior fossa dura, the bone corridor provides a narrow but usable extradural corridor to clivus removal. The inferior extension of the petrous rhomboid drilling can provide exposure of the medial condyle complex up to the level of the hypoglossal canal. Laterally and anteriorly, the posterior wall of the retropharyngeal mucosa was found behind the ICA. Inferiorly and posteriorly, the mid and lower clivus were exposed up to the level of the foramen magnum. Also, additional bone removal of the root of pterygoid through the V2-V3 vidian corridor (Fig. 2) gives us an access route to the upper and middle clivus posteroinferiorly. The space left by drilling in the V2-V3 vidian corridor can be used to insert the endoscope and gain visualization into the sphenoid sinus and sphenoclival junction. Dorsally, the V2-V3 vidian corridor leads to the upper lateral epipharynx wall. Posteroinferiorly, at the level of the mid and lower clivus, it follows to posterior wall of epipharynx.

Morphometric analysis

Middle Fossa Rhomboid (Fig. 2,3)

The GPN length from its exit from the geniculate ganglion to its entrance point under the trigeminal nerve was found to be on average 17.2 ± 3.8 mm. The mean IAC length from the geniculate ganglion to the petrous ridge was 13.3 ± 0.8 mm. The petrous ridge length from the IAC's anterior dural limit to the trigeminal nerve posterior edge was found to be 18.5 ± 1.5 mm, on average. The mean trigeminal nerve (V3) posterior edge length from the GPN to the petrous edge was 13.4 ± 2.6 mm. The average rhomboid area in the specimens studied was 228.8 ± 23.3 mm 2 . Anterior translocation of the trigeminal nerve by 5mm provided additional space, measured to be 69.9 ± 7.1 mm 2 , with a maximal surface of 297.6 ± 30.4 mm 2 . (Fig. 3E)

Posterior view from the rhomboid corridor

The jugular foramen and hypoglossal canal in the lateral clivus from the petrous rhomboid (Fig. 3,4)

The IPS's emergence from the jugular bulb was found, on average, to be 16.3 ± 1.2 mm deep from the geniculate ganglion. The superior aspect of the 9 th cranial nerve was 16.5 ± 1.8 mm deep from the geniculate ganglion, on average (Fig. 3E). The IPS originates from the posterior cavernous sinus and tracks down in the posterior fossa dura towards the jugular bulb (Fig. 3A,B,E). Below the 9 th and 10 th cranial nerves complex, the hypoglossal canal is found (Fig. 3C). The hypoglossal canal is located 21.6 ± 2.2 mm deep from the geniculate ganglion (Fig. 3E). The distance between the inferior edge of the clivus and the midpoint of the GPN was found to be 31.5 ± 2.4 mm, on average. This approach was also found to reach the contralateral lower clivus, at the level of the foramen magnum.

Posteroinferiorly deep view from the rhomboid corridor

Intradural anatomical structures and relationship of the jugular foramen and hypoglossal canal (Fig. 3) These figures show the endoscopic view of the medial wall of the jugular foramen and condylar region through the middle fossa rhomboid. The 9 th and 10 th cranial nerves are seen at their origin from the postolivary sulcus of the upper medulla and the hypoglossal nerve at its exit from the medulla in the preolivary sulcus (Fig. 3D,E). Drilling of the petrous bone, followed by drilling of the medial jugular region and condyle, allowed for exposure of the IPS in its entire length. After cutting the IPS and opening the dura of the posterior fossa, a downward view on the lateral pons and medulla can be obtained.

Anterior view from the rhomboid corridor (Fig. 4A,B,C)

The petrous apex and upper clivus can be removed under visualization of the endoscope.

The inferior wall of the cavernous sinus superiorly, posterior fossa dura mater medially, ICA petrous segment and epipharyngeal superior wall laterally, can be exposed (Fig. 4A,B,C). The IPS is a landmark for the junction between the petrous bone and the clivus.

The sphenoid sinus and vidian corridors can be connected (Fig. 5) and used to visualize the upper clivus (Fig. 5B), mid and lower clivus until ipsilateral and contralateral condyle (Fig. 5D,E).

V2-V3 corridor to clivus

(Fig. 5)

The VN was found at a mean depth of 8.0 ± 1.2 mm below and parallel to the V2 through the space between V2 and V3. This corridor leads to the region of the ventral cavernous sinus to mid-inferior clivus posteriorly. The direction of the V2-V3 corridor posteroinferiorly is aimed at the lower clivus and contralateral condyle, between the posterior constrictor muscle of the posterior wall of epipharynx and posterior fossa dura mater (Fig. 2). The contralateral lower clivus at the level of the foramen magnum can also be exposed by adjusting the angle of the surgical trajectory (Fig. 5). Endoscopic assistance can be used to visualize structures and pathology inside and through the sphenoid sinus. This way, the contralateral vidian nerve can be seen.

Clinical illustration

Before endoscopic surgery development, we approached middle fossa, petrous, and extended cavernous sinus tumors through the anterior petrosal approach. In our clinical material, we identified 18 cases treated via the anterior petrosal approach without endoscopic assistance. Then, 4 cases were treated via the anterior petrosal approach with endoscopic assistance. Case 1. Extended middle fossa rhomboid with endoscopic assistance (Fig. 6,7)

A 37 year old patient, who initially presented with hearing disturbance and facial weakness, had an MRI that revealed a large lesion in the petrous apex and extending to the lower clivus and C1 condyle. (Fig. 6A,B,C) Tumor extension into the intradural space was also suspected. The preoperative presumptive diagnosis was chordoma, and we elected to proceed through an extended anterior petrosal approach. The tumor was soft and was removed mostly with the aspiration under the microscope. We identified the IPS and medial wall of the jugular bulb and followed the tumor until the hypoglossal canal was exposed. (Fig. 7A-F) The condyle was drilled to remove the tumor-invaded bone.

Then, the endoscope provided additional visualization of the medial wall of the jugular foramen and inferior aspect of the hypoglossal canal, which are hidden to the microscope by the internal auditory canal and hypoglossal canal. (Fig. 7D,E,F) Also, the tumor compartment, which extended intradurally was removed under endoscopic view through the petrous rhomboid. Postoperative MRI demonstrated gross total resection of the tumor.

(Fig. 6E,F) The histopathology showed chondroid chordoma. Case 2. Combined extended rhomboid with V2-V3 vidian corridor approach (Fig. 8)

The second patient was a 51 year old male who presented with nasal congestion. The MRI demonstrated a large tumor located in the infratemporal and clival region. There was extensive petrous and clivus bone erosion and invasion into the cavernous sinus. (Fig. 8A,B,C,D) Most of the tumor was removed under microscopic visualization, from the rhomboid and vidian corridors. The ICA was already occluded and resected. (Fig. 8E)

The endoscope improved the working view under the trigeminal nerve, in the areas of the petrous apex, the inferior wall of cavernous sinus and mid to lower clivus. (Fig. 8F) Also, the tumor compartment located in the medial jugular and medial condyle region, below the IAC, came well into endoscopic view and was completely resected. The postoperative course was uneventful, with no new cranial nerve deficit. The combination of the vidian triangle and extended rhomboid approach was thus useful in this case, with endoscopic assistance providing a better downward view on parts of the tumor not seen with the microscope. The histopathology showed chondroid tumor. Case 3. Extended middle fossa rhomboid case (Fig. 9) A 73 year old male patient presented with right abducens nerve palsy. The MRI showed a mass located in the right petrous apex and extending toward the carotid canal in the petrous bone and inferiorly in the upper clivus (Fig. 9A,B,C). An extended anterior petrosectomy was performed with endoscope assistance. After exposure of the GPN, petrous ridge and lateral wall of the cavernous sinus, including V3 (Fig. 9D), The posterior border of V3 was dissected and transposed approximately 5mm anteriorly.

Anterior petrosectomy was performed and the tumor was identified. The petrous bone was drilled until its apex, next to Dorello's canal and where the IPS emerges from the cavernous sinus inferiorly. Also, the petrous segment of the carotid artery was exposed and followed until its entrance in the cavernous sinus, at the petrolingual ligament (inferior wall of the cavernous sinus) (Fig. 9E). The view is similar to the anatomical dissection shown in Fig. 5A. The tumor, which extended into the petrous carotid canal and upper clivus, was seen under the visualization of the endoscope and removed with the suction and angled curettes (Fig. 9F). The histopathology was chondrosarcoma.

Discussion

Although many skull base techniques and approaches have been developed to gain access to the central skull base [START_REF] Goel | Extended middle fossa approach for petroclival lesions[END_REF][START_REF] Goel | Middle fossa sub-Gasserian ganglion approach to clivus chordomas[END_REF][START_REF] Grt | The subtemporal, transcavernous, anterior transpetrosal approach to the upper brain stem and clivus[END_REF][START_REF] House | Middle cranial fossa approach to acoustic tumor surgery[END_REF][START_REF] House | The middle fossa transpetrous approach to the anterior-superior cerebellopontine angle[END_REF][START_REF] Pensak | Transpetrosal access to meningiomas juxtaposing the temporal bone[END_REF] , the exposure provided by traditional open techniques remains quite limited in the area of the lower and lateral clivus [START_REF] Suslu | Anatomical and morphometrical evaluation of the jugular tubercle[END_REF] .

In the last decade, the endoscopic endonasal approach has been developed as a new and rational "workhorse" corridor to certain lesions located in the midline skull base [START_REF] Dehdashti | Expanded endoscopic endonasal approach for treatment of clival chordomas: early results in 12 patients[END_REF][START_REF] Fraser | Endoscopic endonasal transclival resection of chordomas: operative technique, clinical outcome, and review of the literature[END_REF][START_REF] Fatemi | Endonasal microscopic removal of clival chordomas[END_REF][START_REF] Jho | Endoscopic endonasal transsphenoidal surgery: experience with 50 patients[END_REF][START_REF] Komatsu | Endoscopic far-lateral approach to the posterolateral craniovertebral junction: an anatomical study[END_REF][START_REF] Morera | Far-medial" expanded endonasal approach to the inferior third of the clivus: the transcondylar and transjugular tubercle approaches[END_REF][START_REF] Pirris | Corridor surgery: the current paradigm for skull base surgery[END_REF] . The reach of the endonasal approach has been rapidly expanded to allow a more direct access to deep and hidden skull base areas, such as the medial aspect of the clival bone and foramen magnum [START_REF] Morera | Far-medial" expanded endonasal approach to the inferior third of the clivus: the transcondylar and transjugular tubercle approaches[END_REF] . Surgical access to infratemporal fossa and pterygopalatine fossa lesions can also be gained through an endoscopic endonasal approach [START_REF] Zanation | Endoscopic endonasal surgery for petrous apex lesions[END_REF] . However, some major issues are still associated with the endonasal route; including the loss of quality of life related to mucosal trauma, the risks of CSF leak [START_REF] Jiang | Endoscopic resection of chordomas in different clival regions[END_REF] , and ICA injury or infection [START_REF] Maira | Surgical treatment of clival chordomas: the transsphenoidal approach revisited[END_REF] . In case of intradural extension of the resection, the closure is challenging, requiring complex reconstruction technique with their own morbidity (Nasoseptal flap) with a reported rate of postoperative CSF leak ranging from 5 to 20%. Kassam et Gardner et al. (Ref).

Although the majority of sinonasal complaints are transient and resolve within months, symptoms can persist longer in more complex surgeries and when there is more extensive mucosal trauma.

Similarly, several publications have explored the role of endoscopic-assisted microsurgery through either a conventional craniotomy or a "keyhole" craniotomy [START_REF] Komatsu | Endoscopic far-lateral approach to the posterolateral craniovertebral junction: an anatomical study[END_REF][START_REF] Komatsu | Endoscopic extradural subtemporal approach to lateral and central skull base: a cadaveric study[END_REF][START_REF] Komotar | The endoscopeassisted ventral approach compared with open microscope-assisted surgery for clival chordomas[END_REF] .

In this paradigm shift, authors have tried to combine the different sets of advantages associated with these two modalities [START_REF] Komatsu | Endoscopic extradural subtemporal approach to lateral and central skull base: a cadaveric study[END_REF] .

Extended transnasal approaches are most useful in lesions located in the midline and paramedian skull base. However, in recurrent cases or small tumor remnants, which are located in lateral or deep regions, a lateral transcranial approach may be required.

Multiple previous operations sometimes mandate using a new corridor to reduce the risk of neurological morbidity or CSF leak. Skull base surgeons should have several options to approach these deep regions and prefer the corridor that allows complication avoidance and minimal invasiveness each time.

Classical middle fossa technique is matured and controllable technique. The endoscopic assist and navigational assist provides the wide visualization of the hidden area and show the safety corridor to the classical open surgery. Hassanbelliu et al. [START_REF] Hasanbelliu | Expanded Anterior Petrosectomy Through the Transcranial Middle Fossa and Extended Endoscopic Transphenoidal-Transclival Approaches: Qualitative and Quantitative Anatomic Analysis[END_REF] compared the transcranial middle fossa approach and the transsphenoidal-transclival approach to the ventral portion of the pons. They reported that the extended middle fossa approach provided an adequate corridor to lesions in the upper ventrolateral pons. The extended endonasal corridor is better suited for lesions in the midline and is limited when the approach needs to extend laterally, beyond the 6 th cranial nerve or the foramen lacerum segment of the ICA.

The V2-V3 corridor is a safe pathway to lesions located ventral of the cavernous sinus and sphenoid sinus. In this study, we have shown that it can provide a wide and comfortable access to the bilateral lower clivus. Through the sphenoid sinus, and with the aid of endoscopic assistance, the contralateral vidian nerve and internal carotid artery can also be accessed. This combined transcranial extended anterior petrosectomy and additional V2-V3 corridor is useful and does not require the sacrifice of any normal structure, except for additional extradural bone work. In cases of chordomas or chondrosarcomas, this extradural work and additional bone removal is actually desirable from a tumor control standpoint, all the while improving visualization [START_REF] Dehdashti | Expanded endoscopic endonasal approach for treatment of clival chordomas: early results in 12 patients[END_REF][START_REF] Saito | Surgical results of an endoscopic endonasal approach for clival chordomas[END_REF][START_REF] Stippler | Endoscopic endonasal approach for clival chordomas[END_REF] .

To gain access to the medial inferior clivus and medial condyle, previous publications have described the use of the endonasal approach to the hypoglossal canal and medial aspect of the jugular foramen [START_REF] Benet | Comparative analysis of the transcranial "far lateral" and endoscopic endonasal "far medial" approaches: surgical anatomy and clinical illustration[END_REF] . We have used this route in many lower clival and upper cervical cases, especially in primary bony lesions, including chordomas and chondrosarcomas 34 .

The sphenoid sinus provides enough working space for the endoscope, although it requires significant dissection and resection of normal structures. In particular, when exposing the region of the medial aspect of the jugular foramen and condyle dissection and sometimes resection of the Eustachian tube may be required. The Eustachian tube opens into the pharyngeal space and is located just under the sphenoclival junction. Its resection can cause chronic serous otitis and pain that can negatively impact patients' quality of life. Simal-Julian et al. [START_REF] Simal-Julian | Full endoscopic endonasal extreme far-medial approach: Eustachian tube transposition[END_REF] reported a technique in which they transposed and preserved the Eustachian tube with endoscopic endonasal extreme far-medial approach.

This could be another option, but it is not always possible, and exposure is limited laterally when the Eustachian tube is preserved. The transnasal transsphenoidal approach has also been used to access lesions of the petrous apex 36 37,38 . In this corridor, the main element to consider is the exact location and trajectory of the ICA, at its paraclival and lacerum segments [START_REF] Van Gompel | Anterior inferior petrosectomy: defining the role of endonasal endoscopic techniques for petrous apex approaches[END_REF] . The risk of ICA injury is not insignificant in this approach as ICA transposition is sometimes required to improve visualization in the petrous region [START_REF] Van Gompel | Anterior inferior petrosectomy: defining the role of endonasal endoscopic techniques for petrous apex approaches[END_REF][START_REF] Mortini | Exposure of the petrous segment of the internal carotid artery through the extradural subtemporal middle cranial fossa approach: a systematic anatomical study[END_REF] .

Approach selection

The most important point in approach selection is concordance between the tumor plane and the surgical axis. Anterior petrosectomy follows an oblique axis, which is neither horizontal nor vertical. This way, in a tumor extending from the middle fossa down to the craniocervical junction area, anterior petrosectomy can provide a reasonable surgical corridor on condition that the axis of the tumor is congruous. On the contrary, when a tumor extends in the anteroposterior plane, the transnasal endoscopic approach is preferred if the lateral limits of the tumor can be reached.

When a tumor of the petrous apex has both lateral and anterior extensions, an anterior petrosectomy is usually insufficient as it is limited by the petrous ICA, V3 and the cavernous sinus. Opening the V2-V3 corridor helps to gain additional exposure anteriorly and laterally.

Complications avoidance

The most important pitfalls and complications of infratemporal fossa approach are temporal swelling and contusion, ICA injury, IPS bleeding, CSF leak, and trigeminal nerve injury.

In our clinical cases, temporal lobes were found to be intact on the postoperative imaging in all cases. IPS bleeding and cavernous sinus bleeding from the rhomboid approach is more troublesome and needs to be thought out in advance. At least one of the two petrosal sinuses should be preserved. In case of tumor invasion of the IPS, we take care of preserving a patent SPS. However, in most cases, the IPS is larger than SPS and hemostasis is harder to achieve if it is violated.

As in standard middle fossa approach, the petrous ICA can also be injured in the area under V3. 3D-CTA and CTV are recommended to prepare for this approach. The surgical navigation system is a valuable tool to identify these structures. CSF leak is also a concern in this corridor, and closure of the posterior fossa dura can be challenging. We recommend using a free fat graft and vascularized pericranial and fascial flap in order to close the dura.

Conclusion

The corridor developed from the combination of the rhomboid and vidian triangles is potentially a valuable option when dealing with lesions located inferiorly to the cavernous sinus and in the medial inferior clivus.

The combination of endoscopic and microscopic techniques provides several possibilities. The use of the surgical navigational is helpful in identifying anatomical landmarks such as the IPS, jugular foramen, hypoglossal canal, etc. However, a precise understanding of the 3D surgical anatomy related to this approach is crucial. Skull base neurosurgeons must remain flexible when they devise their surgical strategies and be able to offer the surgical approach most suited for each lesion; endoscopic endonasal, conventional and advanced microscopic, and combined endoscopic and microscopic approaches. Fig. 3B The horizontal segment of the ICA was skeletonized and followed posteriorly to the vertical segment of the ICA, close to the JB. Fig. 3C The IPS was cut, exposing the medial wall of the jugular foramen. The jugular tubercle is located between the jugular foramen and hypoglossal canal. Under the hypoglossal canal, the condyle and foramen magnum can be accessed .

Table

Figures

  Figures

Figure. 1

 1 Figure.1

  Superior view of the skull base with directions of the vidian corridor (in red) and extended anterior petrosal approach (in blue).

Figure. 2

 2 Figure. 2

Figure 3 Fig

 3 Figure 3

Fig. 3D

 3D Fig.3DThe dura mater of the posterior fossa was opened. The cranial nerves VII, VIII,

Fig. 3E ,

 3E Fig. 3E, 3F Schematic drawing showing a posterior view onto the medial part of the

Figure 4

 4 Figure 4

Fig. 4A

 4A Fig. 4A Endoscopic anterior view through the petrous rhomboid corridor after removing

Fig. 4B

 4B Fig. 4B Inside view into the sphenoid sinus from the petrous rhomboid. Upper clival bone

Fig. 4C

 4C Fig. 4C Schematic drawing showing an anterior view throw the anterior petrosal corridor

Figure 5

 5 Figure 5

Fig. 5B

 5B Fig. 5B Entrance of the vidian corridor into the sphenoid sinus between the right vidian

Fig. 5D

 5D Fig. 5D Inferior view from the vidian corridor after drilling of the clivus. The posterior

Figure 6 Fig

 6 Figure 6

Fig. 6B :

 6B Fig. 6B: Coronal T2WI MRI showing tumor extension at the level of C1.

Fig. 6C :

 6C Fig. 6C: CT scan image showing the osteolysis in the petrous bone.

Fig. 6D :

 6D Fig. 6D: Postoperative CT scan image. An anterior petrosal corridor reaching down to the

Fig. 6F :

 6F Fig. 6F: Postoperative T2WI MRI. The tumor was removed down to the level of the

Figure 7 Fig

 7 Figure 7

Fig. 7B

 7B Fig.7B After removing the tumor, the IPS indicates the location of the jugular bulb. The

Fig. 7C

 7C Fig.7CThe tumor infiltration into the condyle was removed.

Fig. 7D

 7D Fig.7D Intraoperative endoscopic view through the petrous rhomboid.

Fig. 7E

 7E Fig.7E Below the ICA, the posterior wall of the epipharyngeal mucosa was exposed and

Fig. 7F

 7F Fig. 7F Posterior view with a 30°endoscope visualizing the tumor located in the jugular

Figure 8 Fig

 8 Figure 8

Fig

  Fig.8C, D

Fig. 8E

 8E Fig.8EThe infratemporal fossa was exposed and most of the tumor was removed under

Fig. 8F

 8F Fig. 8F Endoscopic visualization provided a view below V3 and the medial jugular

Figure 9 Fig

 9 Figure 9

Fig

  Fig. 9D V3 was translocated anteriorly, thus widening the access to the tumor in the

Fig

  Fig. 9E Endoscopic view below V3. The petrous apex, which is invaded by the tumor,

Fig

  Fig. 9F Postoperative CT scan image. An anterior petrosal corridor reaching until petrous