Precision Medicine in the Treatment of Malignancies Involving the Ventral Skull Base: Present and Future

Abstract

Cancers involving the ventral skull base are rare and exceedingly heterogeneous. The variety of malignant tumors that arise in the nasal cavity, paranasal sinuses, nasopharynx, and adjacent mesenchymal tissues translates into a proportionally vast spectrum of prognoses, with some histologies such as olfactory neuroblastoma being associated with rare disease-specific death to other histologies such as mucosal melanoma for which survival beyond 5 years is considered a fortunate exception. Parallel to prognosis, treatment of sinonasal cancers is complex, controversial, and deeply dependent upon the putative pretreatment diagnosis. Given their heterogeneity, cancers of the ventral skull base are particularly prone to multidisciplinary management, which is indispensable. The therapeutic options available to date for these cancers include surgery, which currently remains the mainstay of treatment in most cases, along with radiotherapy and chemotherapy. Biotherapy and immunotherapy are only anecdotally and compassionately used. For each histology, a careful selection of modalities and their timing is paramount to ensure the best chance of cure. In keeping with the principles of precision medicine, several nuances displayed by malignancies of the ventral skull base are being considered as treatment-driving characteristics. This current trend arose from the observation that a remarkable variability of behavior can be observed even within a single histology. Although evidence is lacking in this field and several potential customizations of treatment are still at a theoretical level, understanding of these cancers is rapidly evolving and practical applications of this increasing knowledge is the much-needed step forward in the management of such rare cancers. This chapter highlights the tumor characteristics that may serve as treatment-driving factors in the most relevant cancers invading the ventral skull base.

Introduction

Management of malignant tumors arising or encroaching on the ventral skull base poses a significant challenge to physicians. The density in neurovascular structures with essential functions represents a considerable part of the challenge and leads specialists to deliver the locoregional treatment (i.e., surgery and radiation therapy) with high precision, by combining an adequate control of the disease with preservation of relevant, uninvolved structures. Another factor contributing to the challenge is the wide range of histologies that can involve the skull base. While some tumors have high sensitivity to non-surgical treatment (e.g., lymphomas), others are associated with dismal prognosis if treated non-surgically (e.g., adenocarcinoma). Thus, treatment based on a reliable diagnosis is paramount to adequate management. On the other hand, a different response to treatment can also be found within the same histology (e.g., sinonasal undifferentiated carcinoma), implying the need for establishing guidance for precision treatment even beyond conventional histopathological diagnosis.

Research in the field of skull base tumors is very active and has identified several pathological features that might serve as prognostic indicators and assist in predicting the response to treatment. The present chapter aims to provide an overview of actual and potential “treatment-driving tumor characteristics” (TDTC) of ventral skull base malignancies, focusing on sinonasal, nasopharyngeal, and bony-cartilaginous tumors. TDTC denoting a more aggressive behavior of the lesion can lead to escalation of locoregional treatment and/or indicate systemic therapy. For instance, surgeons may adjust the extent of intervention by obtaining a wider margin of resection, adopting a less conservative approach towards critical structures (e.g., the orbital cavity), or performing an elective treatment of the neck. Radiation oncologists may tailor the target volume contour and dose delivery based on certain TDTC associated with aggressive local behavior. Moreover, a rational use of systemic agents might be of help even in the curative setting in high-grade malignancies of the sinonasal tract and adjacent areas. On the other hand, when TDTC suggest a more indolent behavior, treatment can be de-escalated to avoid unnecessary morbidity.

Sinonasal Tumors

The sinonasal tract harbors the widest variety of tumor histologies in the human body. Among the malignant lesions, intestinal-type adenocarcinoma (ITAC), squamous cell carcinoma (SCC), olfactory neuroblastoma, mucosal melanoma (MM), adenoid cystic carcinoma (ACC), neuroendocrine carcinomas, and sinonasal undifferentiated carcinoma (SNUC) are the most frequently encountered.

Intestinal-Type Adenocarcinoma

ITAC is a malignant epithelial tumor that mostly takes origin from the olfactory cleft (Fig. 16.1) [1]. Its etiopathogenesis is intimately associated with exposure to dust arising from hardwood, leather or cork working [2, 3]. From a clinicopathological standpoint, cancer-specific prognosis of ITAC is associated with histopathological subtype, stage, and margin status [4]. Surgery followed by adjuvant radiotherapy is the mainstay of treatment [5, 6]. Unimodal treatment with surgery alone is currently deemed adequate for early-stage, non-high-grade, completely excised ITAC [7]. Five- and 10-year rates of overall survival are 72.7 and 58.0%, respectively [4].

Fig. 16.1

Solid-subtype, sinonasal intestinal-type adenocarcinoma with intracranial extension. a, b Coronal and sagittal magnetic resonance images depicting the extension of the tumor. c Intraoperative image showing the dissection of the intracranial aspect of the tumor (T) and dura mater (D) off the brain surface (B)

From a pathological-morphological standpoint, grade and subtype are the most relevant features that serve as TDTC for ITAC. Barnes described five types of ITAC: papillary, colonic, solid, mucinous, and mixed [8]. Kleinsasser and Schroeder reported four variants: papillary-tubular cylinder cell, graded from I to III, alveolar goblet, signet-ring cell, and transitional [9]. Overall, papillary and colonic variants (roughly corresponding to papillary-tubular cylinder cell grade I and II) are associated with more favorable prognosis, whereas solid and mucinous subtypes (papillary-tubular cylinder cell ITAC grade III, alveolar goblet, and signet-ring cell) are associated with worse outcomes [4, 10,11,12,13]. However, results on the association between ITAC grade/subtype and prognosis are not univocal and this information is frequently not available prior to treatment. Hence, it is unlikely that these morphological classifications can be efficiently used as TDTC unless more reliable subtype markers are discovered. Another morphological feature associated with worse prognosis is tumor budding, a finding described in colorectal oncologic pathology as the presence of isolated single tumor cells or small clusters of up to 5 cells in the tumor stroma. Maffeis et al. and Meerwein et al. found a substantial association between tumor budding and prognosis [14, 15]. Thus, tumor budding might act as TDTC, but data on pre-treatment detectability are currently lacking.

Hermsen et al. found that the total amount of chromosomal alterations is associated with ITAC subtype, with the papillary morphology bearing a significantly lower amount of copy number alterations [16]. This might represent a more reproducible and accessible way to measure tumor aggressiveness prior to treatment. Another interesting finding has been reported by Lopez-Hernandez et al., who clustered a series of ITAC into five groups with different prognoses based on chromosomal gains and losses detected by microarray comparative genomic hybridization [17]. In particular, clusters 1 and 5 had the best and worst prognosis, respectively, while clusters 2, 3, and 4 were associated with an intermediate outcome. Moreover, Rampinelli et al. reappraised genetic alterations associated with more aggressive behavior, all of which could be used to create a more reproducible signature that stresses the need for intensified treatment [6]. More recently, Re et al. reported that miR-205 and miR-449 overexpression is associated with a higher rate of recurrence in ITAC [18].

Several molecular features of ITAC have been previously highlighted in an attempt to guide systemic treatment. Functional p53 has been demonstrated to predict the response to chemotherapy with cisplatin, 5-fluorouracil, and leucovorin by the group of the “Istituto Nazionale dei Tumori” in Milan, Italy [19,20,21]. However, this finding has not been confirmed by other authors. In view of its mutational profile, which is associated with a low rate of EGFR, HER2, KRAS, and BRAF mutations and a high rate of EGFR copy number gain, ITAC is theoretically a good candidate for anti-EGFR therapy [22,23,24]. However, real-life experience is scarce and less encouraging in this regard [25]. Since the gene MET is frequently mutated (64%), MET inhibitors potentially represent an attractive solution [26, 27]. Moreover, a small subgroup of patients with a HRAS mutation (16%) may benefit from the administration of RAS or MAPK/ERK pathway inhibitors [27]. More recently, Schatz et al. reported that EIF2S1 and EIF6, which are potentially targetable markers, are upregulated in ITAC, thus representing a putative TDTC [28]. Finally, Sánchez‑Fernández et al. reported that 8 actionable somatic mutations with a respective FDA-approved agent available were found in a series of 48 ITAC [29]. Overall, the role of predictive molecular biomarkers in ITAC is still underexplored and poorly understood, thus making them a potential TDTC although further research is needed.

There are few data on the ITAC-immune system interaction. Specifically, PD-L1 expression in the tumor and infiltrating immune cells have been reported in 17 and 33% of cases, respectively [30]. García-Marín et al. found that the density in CD8⁺ lymphocytes is associated with prognosis and concluded that, overall, ITAC is a poorly immunogenic tumor with some potential for immune checkpoint inhibitors (ICI) in well differentiated subtypes [31]. Thus, there are no sufficient data to determine a TDTC that suggests immunotherapy should be used in ITAC (Table 16.1).

Table 16.1 Potential treatment-driving tumor characteristics (TDTC) of sinonasal intestinal-type adenocarcinoma

Squamous Cell Carcinoma

The term SCC of the sinonasal tract groups together different epithelial cancers exhibiting squamous differentiation (Fig. 16.2) [33, 34]. From a pathological standpoint, they are classified into a classical variant, which is further divided into keratinizing and nonkeratinizing, and non-classical subtypes including the adenosquamous, spindle-cell, basaloid, papillary, and verrucous SCC. Surgery combined with (neo)adjuvant therapies is the mainstay of treatment [33]. A large majority of cases are treated with surgery followed by radiation therapy. Unimodal treatment is rarely indicated for well selected early-stage sinonasal SCC [4]. The role of neoadjuvant chemotherapy prior to definitive surgical and/or non-surgical treatment is debated, but there is some evidence on its beneficial role in specific clinical circumstances such as orbital encroachment [33, 35,36,37,38,39,40]. Recently, short-term prognosis was found to be improved in patients with sinonasal SCC undergoing neoadjuvant chemotherapy compared with the standard of care [41]. Five-year survival in SCC suitable for endoscopic surgery-including treatment is 66.2% [4], whereas it decreases to 39.7–44% when considering sinonasal SCC regardless of the type of surgery employed [42, 43].

Fig. 16.2

Squamous cell carcinoma of the sinonasal tract. a, b Preoperative magnetic resonance and intraoperative endoscopic appearance of a moderately differentiated squamous cell carcinoma. c–e Pre-treatment magnetic resonance imaging, hematoxylin–eosin-stained slice, and NUT immunohistochemistry of a nasoethmoidal NUT carcinoma with orbital encroachment

From a pathological standpoint, there are several features that have been shown to have a prognostic effect. Adenosquamous and spindle-cell SCC are associated with worse outcome, whereas the papillary variant shows better survival [34, 44, 45]. Degree of differentiation was also found to have an impact on prognosis, with well differentiated tumors behaving more indolently [4]. Consistently, inverted papilloma-related SCC is associated with a higher degree of differentiation and better prognosis compared with de novo SCC [46, 47]. NUT carcinoma, which is characterized by monotonous tumor cells and “abrupt” keratinization, is considered by some authors as the most dedifferentiated variant of SCC and, as such, is associated with dismal outcome regardless of treatment intensity (Fig. 16.2) [48,49,50]. However, BET inhibitors, histone deacetylase inhibitor, and small molecules are currently emerging as novel therapies that may potentially improve the prognosis of this aggressive cancer [51]. Nonkeratinizing and multiphenotypic variants associated with human papillomavirus (HPV) show a more favorable behavior, with the latter displaying noticeable local aggressiveness with limited propensity to distant metastasis [52,53,54,55,56,57]. Factors associated with nodal metastasis have also been analyzed. High-stage, involvement of the hard palate or superior alveolar ridge, microscopic lymphovascular invasion, and detection of Epstein–Barr virus (EBV) have been associated with a higher risk of nodal metastasis [58,59,60].

The fact that sinonasal SCC comprises a variety of different tumors has been previously emphasized [34]. This observation has led some authors to suggest a step forward in the way of defining sinonasal SCC, which consists of a molecular classification. Haas et al. classified sinonasal SCC in 4 types: (1) carcinogen-driven; (2) HPV-associated; (3) gene fusion-SCC (i.e., DEK-AFF2 fusion-related SCC); (4) EGFR-altered SCC [61]. Taverna et al. proposed a 6-type classification by (1) dividing HPV-related SCC in monotypic (mainly associated with HPV-16) and multiphenotypic (mainly associated with HPV-33); (2) distinguishing EGFR-altered SCC in lesions with an EGFR gene mutation (in exon 19 or 20) and those with EGFR gene amplification; and (3) reporting SCC with KRAS mutation (mostly arising from oncocytic papillomas) [62]. Besides deepening the current understanding of sinonasal SCC, these molecular classifications might partially serve as TDTC. For instance, HPV-related sinonasal SCC has been associated with favorable prognosis by several groups [52,53,54,55,56,57]. Moreover, EGFR-mutated SCC might be targeted with some tyrosine kinase inhibitors [61]. Interestingly, DEK-AFF2 fusion-related SCC shows a relatively aggressive behavior, with high propensity to metastasize in the nodal basin and at distant site, thus suggesting the need for treatment intensification [63, 64].

Several molecular features of SCC have been associated with prognosis, thus representing potential TDTC. For instance, deregulation of microRNAs showed an impact on prognosis: miR-9-5p upregulation was associated with improved survival, and let-7d downregulation and miR-137, miR-21, and/or miR-34a upregulation with decreased survival [65,66,67]. Overexpression of pS6, CA9, podoplanin and/or TrkB have also been associated with worse outcomes [68,69,70,71]. Takahashi et al. revised the most relevant prognostic biomarkers described for head and neck SCC and found that only expression of EGFR was associated with prognosis of sinonasal SCC, with EGFR-positive tumors showing worse outcomes [72].

The SCC-immune system interaction has been analyzed by some authors [73, 74]. PD-L1 expression in more than 5% tumor cells has been found in 30.2% of sinonasal SCC [75]. Similarly, Riobello et al. reported a 34% rate of membranous expression [30]. Despite being based on limited data, the overall response rate and median progression-free survival after ICI treatment were 27.2% and 4.2 months, respectively, which compares favorably with non-sinonasal SCC of the head and neck as reported by Park et al. [76]. The same authors highlighted a trend towards a better response in SCC highly expressing PD-L1, which can thus represent a TDTC (Table 16.2).

Table 16.2 Potential treatment-driving tumor characteristics (TDTC) of sinonasal squamous cell carcinoma

Olfactory Neuroblastoma

Olfactory neuroblastoma (ONB) arises from the olfactory neuroepithelium. Hence, it is most frequently located in the olfactory cleft, even if rare cases of ectopic ONB have been reported (Fig. 16.3) [77]. The grade of ONB is classified according to Hyams and substantially affects prognosis [78,79,80]. Moreover, prognosis of ONB is negatively impacted by advanced age, male gender, locally advanced stage, nodal involvement, and positive margins [4, 81,82,83,84,85,86]. Classification of local extension is more controversial in contrast to the previously mentioned cancers. Originally described by Kadish et al. in 1976, the classification of ONB local extension has been thoroughly studied and refined [86,87,88,89]. Treatment of ONB is based on surgery and adjuvant radiotherapy [4, 86, 90]. Overall, ONB is associated with better prognosis than other sinonasal cancers [4]. This fact substantially affects the type of surgery performed for ONB, which is currently performed with an endoscopic technique in most cases: in early-stage tumors, surgical strategies including unilateral nasoethmoidal resection and/or dura-sparing ablation have been developed [91, 92]; in advanced-stage diseases the threshold to define the tumor as suitable for surgical resection has been pushed to include brain invasion [93, 94]. Adjuvant RT has a positive effect on prognosis in most published series [4, 81, 82, 86]. Intensity-modulated particle beam radiotherapy (IMPT), either alone or as an adjuvant treatment, is being used in several centers for ONB, but no long-term follow-up data are currently available [95,96,97]. Meerwein et al. performed an individual patient data meta-analysis on 128 patients treated with surgery alone and concluded that carefully selected low-grade, early-stage, and completely excised ONB could be managed unimodally [98]. The indication to elective neck irradiation is still debated, with a remarkable rate of regional failure (including the retropharyngeal site) as the main argument in favor and the absence of positive prognostic effect in terms of overall survival and high percentage of salvageable recurrent cases as main arguments against [86, 90, 99, 100]. The role of chemotherapy is controversial. On the one hand, there is evidence that high-grade ONB display a more frequent response to neoadjuvant chemotherapy [101], while on the other hand recent publications report hints of a potential null-to-negative therapeutic effect of chemotherapy in patients receiving surgery-including treatment [102,103,104]. Interestingly, Topcagic et al. found some immunohistochemical biomarkers of sensitivity or resistance to chemotherapeutic agents [105]. In particular, ERCC1 underexpression was associated with sensitivity to cisplatin, TOPO1 overexpression with sensitivity to irinotecan, TUBB3 overexpression with resistance to vincristine, and MRP1 overexpression with multidrug resistance. Of note, the recent evidence that ONB frequently expresses the somatostatin receptor (SSTR-2 in 75–99% and SSTR-5 in 7.5%) [106,107,108,109] serves as a rationale to include radioactive somatostatin-analogues (i.e., peptide receptor radionuclide therapy) in the spectrum of treatment options for ONB, which has been shown to be effective in the recurrent/metastatic setting [86, 110].

Fig. 16.3

Olfactory neuroblastoma. a, b Coronal and sagittal magnetic resonance images depicting the extension of a Hyams grade 2 olfactory neuroblastoma. c Intraoperative image showing the dissection of the intracranial aspect of the tumor (T) and dura mater (D) off the brain surface (B)

A commendable step forward in the understanding of ONB was recently published by Classe et al., who presented a thorough, multi-omic analysis of 59 cases [111]. Their study integrated information on exome sequencing, transcriptomics, protein expression-based clustering, methylomics, and immune environment analysis. By comprehensively assessing these data, Classe et al. proposed to subdivide ONB into the “neural” and “basal” types. Neural ONB are not associated with recurrent mutations and are usually well differentiated with a low proliferation index, hypomethylation of neural enhancers, and low density of tumor-infiltrating lymphocytes. Basal ONB can bear TP53 and IDH2 gene mutations, which is associated with the CpG island methylator phenotype, cytokeratin (i.e., cytokeratin AE1/AE3) expression, high proliferation index, DNA hypermethylation, and a high density of tumor-infiltrating lymphocytes. Most importantly, the prognosis of basal ONB is significantly worse than neural ONB. Thus, reliable markers of basal versus neural subtype could serve as TDTC to tailor treatment of ONB. For instance, Wu et al. confirmed that IDH2 mutation is associated with worse prognosis and can be reliably detected with either immunohistochemistry or real-time polymerase chain reaction [112]. Romani et al. profiled the gene expression of 32 ONB and found that some deregulated pathways (i.e., TGF-beta binding, epithelial-mesenchymal transition, UV response, allograft rejection, IFN-alpha response, angiogenesis, IL-2-STAT5, and IL-6-JAK-STAT3 signaling) were associated with reduced disease-free survival [113]. Moreover, they found that ONB with expression of cytokeratin, which could be considered a surrogate of the basal subtype, were associated with E2F targets, MYC targets, and KRAS hallmark pathways alongside with BUB1 gene upregulation, all of which potentially represent a rationale for targeted therapy. Turri-Zanoni et al. reviewed the prognostic biomarkers of ONB and reported that alteration in the PI3K/mTOR signaling pathway, CDK-dependent cell cycle regulation, CCND1 amplification, FGFR3 amplifications, and DMD gene deletions may have a role in the pathogenesis of ONB [106]. In this regard, Spengler et al. recently reviewed the use of biological agents in ONB and found that sunitinib, cetuximab, bevacizumab, imatinib, everolimus, and pazopanib were all active in adequately selected cases [114].

As for other sinonasal cancers, a number of molecular features of ONB were found to be associated with tumor grade, which is established based on histomorphological features, and thus have prognostic implications. Since grading is subjectively determined and hence flawed by potentially low inter-rater agreement, there is a strong need for prognostic biomarkers associated with grade that would be usable as TDTC. Ki67 proliferation index ≥25% and low microvascular density are associated with high grade and worse survival [115,116,117]. SATB2 was found to reliably segregate grade 4 versus grade 1–3 ONB according to Hyams [118].

The interaction between ONB and the immune system is still poorly understood. Friedman et al. reported that ONB is associated with a low tumor mutational burden, hence suggesting a limited utility of immunotherapy [119]. However, there is evidence that both primary and metastatic ONB tissue express PD-L1 and display an associated tumor and stromal infiltrate of PD-1-positive and CD8-positive lymphocytes [120]. Interestingly, the higher the density in tumor-infiltrating lymphocytes the worse the prognosis [111], which places ONB in the minority of tumors, such as renal cell carcinoma, with an inverse relationship between immune infiltrate and prognosis [121]. To date, there is still insufficient evidence to support the use of immunotherapy in ONB (Table 16.3).

Table 16.3 Potential treatment-driving tumor characteristics (TDTC) of olfactory neuroblastoma

Mucosal Melanoma

Sinonasal MM is one of the most aggressive tumors in the wide spectrum of sinonasal malignancies (Fig. 16.4). This is clearly witnessed by the experience of the Memorial Sloan Kettering Cancer Center (New York, US): Flukes et al. recently showed that treatment outcomes remained stable over the last 2 decades despite the increasing use of immunotherapy [122]. T staging of this tumor reflects its intrinsic aggressiveness, with T3 representing the minimum category attributable to any MM of the head and neck. Of note, even an in situ (i.e., intraepithelial) MM is classified as T3 according to the latest TNM criteria. The detrimental prognostic effect of paranasal sinus involvement is well known, and Lechner et al. proposed a revision of T classification, with tumors involving the epithelium or submucosa of paranasal sinuses with no bony-cartilaginous, deep soft tissue or skin invasion to be classified as T4a instead of T3 [123]. Similarly, Moya-Plana et al. suggested that anatomical criteria applied to stage non-melanoma sinonasal cancers could be useful for MM [124]. Surgery is considered the mainstay of treatment and there is evidence that can be safely performed through an endoscopic transnasal approach if adequately indicated and as long as negative margins can be achieved [4, 125,126,127,128,129,130,131]. The role of adjuvant radiotherapy is debated. While some studies have demonstrated an increased local control in patients treated with surgery and adjuvant radiotherapy, no clear evidence of benefit on overall survival is currently available [132,133,134,135,136,137,138]. Grant-Freemantle et al. recently published a meta-analysis on 2489 patients with MM and found that adjuvant radiotherapy had a significant positive effect on local control and overall survival when considering head and neck sites together, whereas this effect was lost when the analysis focused on sinonasal localizations [139]. Neoadjuvant treatment with hyperfractionated radiotherapy and concomitant chemotherapy with weekly cisplatin followed by surgery has been proposed by Hafström et al. [140]. They reported a 5-year overall survival rate of 70% in patients with MM stage IVA. However, this represents a single-center experience and further research is required to establish whether this treatment sequence confirms to have an advantage on survival. Interestingly, the Japan Carbon-Ion Radiation Oncology Study Group reported a 2-year overall survival of 69.4% in a series of 260 patients affected by head and neck MM treated with definitive carbon-ion therapy [141], which compares favorably with other large series on patients who underwent curative treatment including surgery [4, 122, 137]. Of note, in the Japanese study a multivariable-confirmed positive prognostic effect of concomitant chemotherapy with DTIC, with/without nimustine hydrochloride and vincristine, was demonstrated, with 2-year overall survival increasing to 75.8% (of note, these MM either were deemed unresectable or patients refused surgery) [141]. This benefit came at the cost of an increased mucosal toxicity, though no patient interrupted radiotherapy because of mucositis.

Fig. 16.4

Sinonasal mucosal melanoma. a T1-weighted magnetic resonance image demonstrating the spontaneous hyperintensity displayed by certain melanotic mucosal melanomas. b Endoscopic appearance of a melanotic mucosal melanoma of the right nasal cavity. c, d Preoperative magnetic resonance imaging and main surgical specimen of a case of mucosal melanoma of the right nasal cavity. LN, limen nasi; LW, lateral wall of the nasal cavity; NS, nasal septum; T, tumor

The remarkable rate of distant metastasis regardless of the stage at presentation [4, 142] makes MM similar to a systemic tumor, leading several authors to conclude that systemic therapy should be part of the future standard of care even in the curative setting [143]. Since tumor volume has been demonstrated to predict the risk of distant metastases and death, then it could be employed as a TDTC to implement systemic therapy in initial treatment [141, 144]. Currently, chemotherapy has a limited role in the management of MM, especially in the curative setting [145]. However, in a phase II randomized clinical trial by Lian et al., the temozolomide and cisplatin adjuvant chemotherapy outperformed surgery alone and surgery followed by adjuvant IFN therapy, with 2-year recurrence-free survival of 41.0, 0.0, and 11.7%, respectively [146]. This study corroborated the concept that systemic therapy has a substantial role in determining the prognosis of MM patients, as emphasized by other authors [147]. Several biotherapeutics and immunotherapies are emerging as potential systemic agents for MM [148]. Among these, imatinib [149] and binimetinib (although evidence exists for skin melanoma) [150] in KIT-mutated and NRAS-mutated MM, respectively, are the most promising ones. In terms of frequency, NRAS is more often mutated compared to KIT and BRAF (22–30% versus 5–12.5% and 0–8%, respectively) and is associated with poorer survival [131, 151,152,153]. A recent study found a higher rate of BRAF mutation (32%) [154]. The use of immunotherapy is controversial. The majority of data on immunotherapy for sinonasal MM are gathered from recurrent/metastatic cases. Recently, Ganti et al. published a National Cancer Database study demonstrating that immunotherapy had a positive prognostic effect in patients with metastatic disease [155]. In their study, they included all patients registered in the National Cancer Database between 2004 and 2015. Since ICI were approved for solid tumors by the FDA in 2012, a considerable proportion of patients included in their study received a non-ICI-based immunotherapy, which is most likely represented by IFN therapy. Subsequently, Klebaner et al. published a National Cancer Database study that narrowed the inclusion period to 2012–2015, so that most patients who received immunotherapy were treated with ICI [156]. Surprisingly, they did not demonstrate a positive prognostic effect of immunotherapy on metastatic sinonasal MM patients. Therefore, one could hypothesize that the beneficial role of IFN therapy outweighs that of ICI in MM patients. Consistently, Sun et al. demonstrated increased survival in patients treated with subdermal injection of either the bacillus Calmette–Guérin, or IL-2 or IFN-α-2b [157]. However, Lechner et al. recently published a multi-institutional study on 505 sinonasal MM patients and demonstrated that therapies including ICI conferred the highest survival rate in the recurrent/metastatic setting [123]. When focusing on specific agents and their combination, the most relevant data come from the pooled analysis by D’Angelo et al., who reported an objective response rate to nivolumab, ipilimumab, and their combination of 23.3, 8.3, and 37.1%, respectively (versus 40.9, 21.2, and 60.4% in skin melanoma, respectively) [158]. However, response can be dissociated, as described by Chao et al., who reported on 4 patients with distant metastases at presentation treated with immunotherapy, out of which 2 had a response and 1 stability of the distant metastases but all had progression of disease at the primary site [159]. On the other hand, Philipp et al. reported a case of initial pseudoprogression with subsequent complete response to combined ipilimumab and nivolumab in a patient affected by an inoperable sinonasal MM [160]. Intrinsic or acquired resistance to immunotherapy is poorly understood in MM but a recent publication reported 3 cases with switch of oncogenic driver (i.e., from KRAS, KIT, or no driver to NRAS) as the mechanisms determining acquisition of resistance to ICI [161]. Thus, the role of ICI remains controversial, and more studies are needed to determine whether they can provide a prognostic advantage.

Elective treatment of the neck is another controversial aspect of MM. A recent publication from the MD Anderson Cancer Center (Houston, Texas, US) on 198 patients treated over a 31 year timespan demonstrated that the rate of nodal recurrence in initially node-negative patients was 17 and 18% in patients receiving elective neck adjuvant radiotherapy and in those who did not, respectively [162]. In a meta-analysis on 939 patients, De Virgilio et al. found a similar 17.0% regional recurrence rate in patients with clinically negative, untreated neck [163].

Despite the prognosis of MM is overall poor, some pathologic and molecular prognostic markers have been identified. Ki67 proliferation index >30% and lymphovascular invasion have been associated with decreased survival [164]. Overexpression of PARP1 and IDO1 were found to have a negative effect on overall survival, which lead to hypothesize the use of PARP1- and/or IDO1-inhibitors in this subset of MMs [165]. Similarly, overexpression of phosphorylated Akt1 has been associated with increased cancer-specific mortality [166]. In turn, the Akt pathway was found to be inhibited by the miR-4633-5p molecule, whereof loss of expression was associated with an increased risk of metastasis [167]. Mutations in the NF1 gene (found in 33% of MM) have also been associated with decreased survival [168].

Recent studies have contributed to increase the understanding of the crosstalk between immune system and sinonasal MM. Yin et al. performed a comprehensive analysis of 44 MM and found that immunotype was substantially associated with prognosis [147]. They classified tumors in terms of tumor-infiltrating immune cell density, according to Erdag et al. [169], and found that cases with complete depletion of immune cells (32% of their series) had dismal prognosis, those with diffuse immune cell infiltration (18% of their series) were all progression-free, and those with immune cells mainly concentrated in the stroma and perivascular tissue (50% of their series) had an intermediate prognosis, which is consistent with the fact that “brisk” tumor-infiltrating lymphocytes have been associated with improved outcome by other authors [164, 170]. They also found that CD8⁺ T cells and NK cells were positively associated with prognosis, and Th2 T cells and M2 macrophages with disease progression [147]. Interestingly, expression of PD-L1 was not associated with prognosis [171].

As a final remark, despite some TDTC can be hypothesized for MM, the dismal outcomes associated with this tumor should orient research towards the identification of therapeutic strategies that are capable of improving the overall prognosis, whereas a precision medicine-approach has to be more realistically postponed until a more effective standard of care is available (Table 16.4).

Table 16.4 Potential treatment-driving tumor characteristics (TDTC) of mucosal melanoma

Sinonasal Undifferentiated Carcinoma and SWI-SNF-Deficient Sinonasal Carcinomas

SNUC was first described by Frierson et al. in 1986, and represents one of the most fascinating entities in the field of sinonasal pathologies (Fig. 16.5) [172]. Being a diagnosis of exclusion, SNUC initially served as a basket entity so that several tumors that were difficult to define by histopathology were misdiagnosed as SNUC [173]. Treatment outcomes of patients affected by SNUC have been historically poor, but reached a first turning point with the evidence that multimodal therapy was key in improving prognosis [174,175,176,177,178,179,180,181,182]. More recently, the seminal paper by Amit et al. reported that response to neoadjuvant chemotherapy is the most reliable factor in selecting the definitive treatment strategy [183]. In their study, the authors from MD Anderson Cancer Center (Houston, Texas, US) included 95 treatment-naïve patients affected by SNUC, all treated with neoadjuvant chemotherapy followed by either definitive chemoradiation or surgery and adjuvant (chemo)radiotherapy. They found that in the group of responders to chemotherapy (n = 64, 67%), 5-year disease-specific survival was 81% in patients treated with definitive chemoradiation and 54% in those treated with surgery and adjuvant (chemo)radiotherapy. Thus, definitive non-surgical treatment is associated with significantly better outcomes in responders. In contrast, in the group of non-responders to chemotherapy (n = 31, 33%), 5-year disease-specific survival was 0 and 39% in patients treated with definitive chemoradiation and those treated with surgery and adjuvant chemoradiation, respectively. Hence, the majority of patients benefit most from induction chemotherapy followed by chemoradiation, but 1 out of 3 patients should be treated with upfront surgery and subsequent chemoradiotherapy to confer the highest chance of survival. In this sense, response to neoadjuvant chemotherapy is the most relevant TDTC in SNUC and several other oncologic centers have conformed with a neoadjuvant chemotherapy-driven approach [4, 184]. Takahashi et al. discovered that a 24-gene signature is able to predict response to chemotherapy with cisplatin and etoposide in SNUC [185]. The potential practical implications of this signature would be of high interest in non-responders (i.e., patients to be treated with surgery and adjuvant therapy according to the response-driven paradigm), who could avoid the non-negligible toxicity of neoadjuvant chemotherapy and directly undergo locoregional treatment. Whether responders could skip neoadjuvant chemotherapy and be sent directly to chemoradiation remains doubtful, as this would mean de-escalating the treatment schedule that led to the aforesaid outcomes [183]. Of note, Lehrich et al. published a National Cancer Database study on 440 SNUC patients demonstrating that neoadjuvant chemotherapy does not have an impact on survival, which could suggest that if chemotherapy does not lead to response-driven selection of definitive treatment, then the benefit of its employment is lost [186]. On the other hand, a French multi-institutional study demonstrated that neoadjuvant chemotherapy is an independent protective factor in terms of recurrence-free survival [187]. Regarding neck management, there is evidence that the elective treatment of the nodal basin significantly reduces the rate of regional recurrence from 26.4 to 3.7% [188].

Fig. 16.5

Sinonasal undifferentiated carcinoma and SWI-SNF-deficient carcinomas. a, b Pre-treatment and post-neoadjuvant chemotherapy magnetic resonance images showing a partial response in a case of sinonasal undifferentiated carcinoma with no association to specific molecular identifier. The patient was treated with definitive chemoradiation with complete response. c–e Pre-treatment magnetic resonance imaging, hematoxylin–eosin-stained slice, and SMARCB1 immunohistochemistry of a fronto-orbital SMARCB1-deficient carcinoma

A subset of SNUC, accounting for 20–47% of tumors, is associated with HPV-16 and shows increased survival in one study [189, 190]. Several authors found mutations in the IDH1/2 genes in SNUC, with a prevalence ranging between 35 and 82% [191]. This genetic characteristic, particularly for the IDH2 gene, has been associated by some authors with a more favorable outcome compared to IDH2-wild type SNUC [192,193,194]. Libera et al., however, found that IDH2-mutation was associated with decreased survival in a series of 53 poorly differentiated sinonasal carcinomas including 6 SNUC [195]. SWI/SNF-deficiency has been discovered as the genetic hallmark of a very aggressive group of tumors originally considered as a subset of SNUC (Fig. 16.5) [196,197,198,199,200]. In particular, SMARCB1-deficient and SMARCA4-deficient carcinomas are two malignancies that were initially described under the umbrella of SNUC but displaying an exquisitely aggressive behavior, which might lead them to be considered as separate entities with respect to “true SNUC” [201, 202]. Interestingly, targeting EZH2 and CDK4/6 proved effective in preclinical models of SWI/SNF-deficient ovarian and lung cancer [203, 204]. Moreover, there is evidence that SWI/SNF-deficiency is associated with remarkably increased response to ICI in patients with colorectal cancer [205]. These findings could drive future research and lead to the discovery of systemic agents to effectively target SWI/SNF-deficient sinonasal carcinomas.

Takahashi et al. demonstrated that the ERBB2 gene is amplified and HER2 overexpressed and phosphorylated in SNUC [206]. They also showed that lapatinib efficiently inhibits HER2 signaling pathway in a SNUC cell line. Bell et al. reported that BRCA1 is overexpressed in SNUC, thus demonstrating a biological rationale for the use of PARP inhibitors in this cancer [207].

There are no substantial data on the use of immunotherapy for SNUC. However, a case of metastatic SNUC with complete response to nivolumab has been reported [208]. Interestingly, PRAME, which is a candidate target for immunotherapy, was found to be overexpressed in SNUC (Table 16.5) [207].

Table 16.5 Potential treatment-driving tumor characteristics (TDTC) of sinonasal undifferentiated carcinoma

Sinonasal Neuroendocrine Carcinomas

Neuroendocrine neoplasms of the sinonasal tract are rare and poorly understood tumors. Their rarity alongside with the fact that several other sinonasal malignancies can display neuroendocrine features has contributed to the heterogeneity in different series [209,210,211]. The nomenclature of sinonasal tumors will be revised in the upcoming 5^th Edition of the World Health Organization Classification of Head and Neck Tumors [212]. Specifically, neuroendocrine neoplasms of the upper aerodigestive tract and salivary glands will be classified into well differentiated (referred to as “neuroendocrine tumors” and further classified in grade 1–3 according to mitotic activity) and poorly differentiated (referred to as “neuroendocrine carcinomas” and further classified in “small cell” and “large cell”). A proportion of neuroendocrine neoplasms, which can be as high as 44.4% in areas characterized by endemic nasopharyngeal carcinoma, is represented by post-irradiation cancers [213]. Anecdotally, neuroendocrine carcinoma has been reported as part of a collision tumor including either SCC or exocrine adenocarcinoma [214, 215].

Prognosis of sinonasal neuroendocrine neoplasms is poor, with 3-, 5-, and 10-year overall survival of 42.4, 38.9, and 34.0%, respectively, according to the MUSES study [4]. Van der Laan et al., however, showed that well and moderately differentiated neuroendocrine carcinomas are associated with a 5-year disease-specific survival of 70.2%, in contrast to 46.1% in the small cell variant, which is consistent with what reported by other authors (Fig. 16.6) [210, 216]. Moreover, small cell neuroendocrine carcinoma of the sinonasal tract showed better survival outcomes compared with other sites of the head and neck [217]. Large cell neuroendocrine carcinoma of the sinonasal tract is exceedingly rare and a possible relation with HPV infection has been reported [218]. Interestingly, Dogan et al. recently surmised that large cell neuroendocrine carcinoma and IDH2-mutated SNUC constitute a phenotypic spectrum of the same tumor entity [193]. There is consensus on the fact that treatment of sinonasal neuroendocrine neoplasms should be multimodal [219,220,221,222,223]. However, the best sequence of treatment and the indication for (neo)adjuvant non-surgical therapies are debated. Response to neoadjuvant chemotherapy is a strong positive prognostic factor [220]. Turri-Zanoni et al. showed that patients treated with neoadjuvant chemotherapy, which was indicated in poorly differentiated neuroendocrine carcinomas, had a 5-year overall survival rate of 88.8% compared to 9.3% in those who were not [210]. On the other hand, van der Laan et al. did not find a benefit of chemotherapy in the treatment of sinonasal small cell neuroendocrine carcinomas [216]. As for other tumors with neuroendocrine phenotype, use of ⁶⁸Ga-DOTATATE PET-CT and ¹⁷⁷Lu-DOTATATE has been reported for staging and treatment purposes, respectively [224, 225].

Fig. 16.6

Sinonasal small cell neuroendocrine carcinoma. a–c Pre-treatment magnetic resonance imaging, hematoxylin–eosin-stained slice, and chromogranin immunohistochemistry of a nasoethmoidal small cell neuroendocrine carcinoma

Overall, neuroendocrine neoplasms of the sinonasal tract are poorly understood and the best treatment strategy is still matter of research. Thus, no TDTC can be currently determined for this histology.

Adenoid Cystic Carcinoma

ACC is a rare and capricious cancer that arises from major and minor salivary glands. For its almost invariable tendency to perineural spread, management of ACC represents a challenge in a nerve-dense area such as the skull base (Fig. 16.7). Grade is intimately associated with prognosis and depends upon the presence and proportion of a solid histological architecture within tumor tissue [226,227,228,229]. Whenever feasible, surgical resection followed by adjuvant radiotherapy is considered the standard of care [5]. A variant with squamous differentiation features and predilection for involvement of the sinonasal tract and skull base, called “metatypical ACC”, has been recently described, with diagnosis of ACC being corroborated by the identification of the fusion between MYB/MYBL1 and NFIB, which is typical of this cancer [230, 231]. Even if only 3 cases have been described, this variant seems to behave more aggressively. ACC with “high-grade transformation” is another distinct entity, characterized by faster progression and propensity to metastasize to the neck [232]. The sinonasal tract is among the most frequent sites of origin of this variant [232].

Fig. 16.7

Sinonasal and nasopharyngeal adenoid cystic carcinoma. a, b Preoperative magnetic resonance imaging of a nasoethmoidal solid-type adenoid cystic carcinoma with involvement of the sphenoid sinuses and right cavernous sinus. c, d Preoperative magnetic resonance imaging of a nasopharyngeal cribriform-type adenoid cystic carcinoma with abutment of the petrous internal carotid artery. e, f Pre- and post-treatment magnetic resonance imaging of a cribriform-type nasopharyngeal adenoid cystic carcinoma with involvement of the external carotid and jugular foramina (asterisk). The patient was treated with proton beam radiotherapy. T, tumor

The University of Pittsburgh (Pittsburgh, Pennsylvania, US) group judiciously stated that the realistic aim of surgery in sinonasal/nasopharyngeal ACC is gross total resection rather than microscopically clear margin resection, which can be rarely achieved in this histology [233]. This approach is consistent with the evidence that margin status does not appear to be an independent factor associated with survival in ACC of the minor salivary glands of the head and neck and sinonasal tract [234, 235]. On the other hand, this aspect is debated and the philosophy of the University of Pittsburgh group should not be misinterpreted: whenever negative margins can be realistically achieved while avoiding unreasonable morbidity they should be pursued as for any other cancer deemed suitable to curative surgery [236, 237].

The role of adjuvant radiotherapy is debated. Unsal et al. published a study on 694 patients collected from the National Cancer Database, reporting that patients treated with surgery alone had better prognosis compared to those treated with surgery and adjuvant radiotherapy [238]. However, this result was not assessed with a multivariable model, and is potentially biased by the fact that patients for whom adjuvant radiotherapy was indicated could bear risk factors associated with worse prognosis, such as advanced stage [239]. Overall, surgery followed by adjuvant radiotherapy is the most frequent and effective treatment strategy, at least in terms of local control, according to a systematic review with meta-analysis and single-center series [240,241,242]. While intensity-modulated particle therapy has shown encouraging results, the duration of follow-up of published series is not sufficient to draw clear conclusions on its added value in ACC treatment [243,244,245,246,247].

Song et al. showed that elective irradiation of the neck conferred no benefit in terms of overall and progression-free survival in a cohort of 166 sinonasal ACC [248]. Wang et al. reported a similar finding with a propensity score matching approach, similar to the International Head and Neck Scientific Group review of 774 patients [249, 250]. Likewise, elective neck dissection did not show to provide a prognostic advantage [251]. On the contrary, elective neck treatment has been suggested for ACC with “high-grade transformation” [252].

Given the remarkably high recurrence rate, disease-specific mortality, and occurrence of distant metastases, several efforts have been performed to identify effective systemic treatments. Atallah et al. reviewed the relevant literature and reported that the following targeted agents have been tested to date: axitinib, bortezomib, cetuximab, dovitinib, everolimus, gefitinib, imatinib, lapatinib, sorafenib, sunitinib, vorinostat, crenigacestat, and lenvatinib [253]. Although a considerable rate of stable disease has been observed with some of these drugs (up to 85–90% with sunitinib, vorinostat, or cetuximab), the pooled rate of patients with partial response was only 18/438 (4.1%). In the same review, the pooled rate of responders to chemotherapy was 32/222 (14.4%). The NOTCH pathway was found to be frequently altered in ACC, particularly in those not bearing a MYB-involving fusion [254]. The genes NOTCH1-3 and SPEN are the most frequently mutated [255]. From a genetic standpoint, Ho et al. classified ACC in 4 clusters: (1) ACC with both MYB and NOTCH1 mutated, (2) ACC with MYB mutated and NOTCH1 wild type, (3) ACC with MYB wild type and TERT mutated, and (4) ACC with MYB wild type and NOTCH1 mutated [256]. Wang et al. demonstrated that the solid component of ACC, which predicts poor prognosis [226,227,228,229, 257], is intimately associated with NOTCH pathway deregulation, which could represent the key mechanism of aggressive clone selection in this cancer [255]. Consistently, Xie et al. showed that the NOTCH1-HEY1 pathway is associated with epithelial–mesenchymal transition of ACC [258]. Thus, one could hypothesize that using NOTCH inhibitors is critical in improving outcomes of ACC patients. However, objective response has been observed in only 0–17% patients treated with drugs targeting the NOTCH pathway [259, 260]. Moreover, with an immune-excluded microenvironment, M2-polarized macrophages, high density of myeloid-derived suppressor cells, and low mutational load, ACC is also an unpromising candidate to immunotherapy [261]. Indeed, unsatisfactory response rates to ICI have been reported [262]. Overall, there is currently no effective systemic therapy for ACC, since the large majority of molecular alterations found in this cancer are not actionable and the proportion of patients eligible for effective targeted therapy is currently low [256, 263].

In conclusion, ACC of the sinonasal tract represents a distinct challenge and the current potential TDTC are limited to those characteristics associated with more aggressive behavior or an unusual propensity to nodal metastasis (Table 16.6).

Table 16.6 Potential treatment-driving tumor characteristics (TDTC) of sinonasal and nasopharyngeal adenoid cystic carcinoma

Nasopharyngeal Tumors

Nasopharyngeal carcinoma (NPC), with its 3 variants according to the World Health Classification (nonkeratinizing SCC, keratinizing SCC, basaloid SCC), is by far the most common malignancy involving this area. Other histologies, such as carcinomas originating from minor salivary glands and the entity called “low-grade nasopharyngeal papillary adenocarcinoma” (LGNPPA) are only rarely observed [264].

It is well established that the treatment of choice for NPC is radiotherapy alone, preferably in the form of intensity-modulated radiotherapy (IMRT), in stage I–II disease and chemo-radiotherapy in stage III–IVA. The selection of patients to receive chemotherapy as induction or adjuvant treatment is a therapeutic area that is currently being explored [265]. Surgery can have a role in the treatment of selected persistent/recurrent lesions as an alternative to re-irradiation. A recent multicenter, randomized, phase 3 trial including 200 patients with recurrent NPC confined to the nasopharyngeal cavity, post-naris or nasal septum, superficial parapharyngeal space, or the base wall of the sphenoid sinus, has shown that endoscopic surgery significantly improved overall survival compared with IMRT [266]. In the present chapter, the discussion will focus on those tumors whose treatment is less standardized compared to NPC, in view of their rarity and the variable response to (chemo)radiation.

According to the largest single-institution study on 28 patients, LGNPPA affects subjects with an average age of 41.5 years, with a preference for females [267]. A consistent number of LGNPPA is pathologically characterized by a papillary growth, and may mimic papillary thyroid carcinoma, thus being called “thyroid-like” LGNPPA. Evidence of a transition from the mucosal surface to the tumor, predominance of stratified nuclei, negativity for thyroglobulin, and absence of thyroid lesions at imaging studies are all criteria favoring a diagnosis of thyroid-like LGNPPA [268]. The continuity of LGNPPA tumor cells with positive cytokeratin staining indicates that the lesion arises from the surface mucosal epithelium rather than from submucosal seromucinous glands [269]. In view of its tendency to present as a polypoid lesion with superficial growth, and no spread to regional lymph nodes and distant sites, LGNPPA is ideally amenable to surgery, and many of the cases reported in the literature have been successfully treated with transnasal endoscopic surgery [267]. The role of radiotherapy is questionable. Mutations in KRAS, NRAS, BRAF, EGFR, and ALK have been so far excluded [267].

Among minor salivary gland cancers, ACC, adenocarcinoma not otherwise specified, and mucoepidermoid carcinoma (MEC) are the most frequent histologies [270].

Similar to sinonasal localizations, ACC of the nasopharynx invariably presents at an advanced local stage, with frequent radiologic signs of perineural spread, bony permeation of the clivus and temporal bone, and critical relationships with the internal carotid artery (Fig. 16.7). In view of these features, radical resection can be rarely achieved so that surgery, if technically feasible, generally leaves behind microscopic or macroscopic disease. However, a population-based analysis of 383 patients with minor salivary gland cancers extracted from the Surveillance, Epidemiology, and End Results Program (165 of which were ACC) demonstrated that any form of treatment schedule including surgery provided high 5-year disease-specific survival [270]. Of note, as in any retrospective large dataset analysis, the bias of treatment selection in relation to tumor extent should not be neglected. In a recent retrospective review on the role of endoscopic transnasal surgery in treatment of 30 patients with ACC of the sinonasal tract and nasopharynx, the University of Pittsburgh (Pittsburgh, Pennsylvania, US) group concluded that tumor grade has a significant impact on prognosis [233]. They recommended endoscopic resection followed by radiotherapy for low-grade tumors and suggested that intermediate/high grade tumors might benefit from novel treatment strategies. Regarding radiotherapy, there is a need to demonstrate the superiority of particle therapy over IMRT, in terms of local control of the disease as well as morbidity, with a high level of evidence. For medical therapy, the limited effect of chemotherapeutic agents is well known, while there is still a lack of drugs effectively targeting the numerous molecular alterations, as described in the section on sinonasal tumors (Table 16.6).

MEC is classically divided into low-grade, intermediate-grade, and high-grade, with grading having a significant impact on prognosis. The tumor is frequently associated with a t(11;19)(q14–21;p12–13) translocation that creates a CRTC1-MAML2 fusion gene. This feature is known to have a favorable prognostic effect, and not unexpectedly is found more frequently in low/intermediate grade lesions than in high-grade tumors [271]. However, many other alterations have been identified in MEC. Morita et al. recently looked for CRTC1/3-MAML2 fusions and gene alterations in EGFR, RAS family (KRAS, HRAS and NRAS), PIK3CA, BRAF, and AKT1 in 101 MEC cases [272]. They also searched for mutations in TP53. CRTC1/3-MAML2 fusions were found in 62.4% of cases. KRAS, HRAS and PIK3CA mutations were detected in 6.9, 2.0, and 6.9%, respectively, but other EGFR pathway genes were not mutated. In total, gene mutations (RAS/PIK3CA) in the EGFR pathway were detected in 14.9% of cases, and TP53 mutations in 20.8%. CRTC1/3-MAML2 fusions were associated with better prognosis and RAS/PIK3CA mutations with worse prognosis, and both were selected as independent prognostic factors for the overall survival. TP53 mutations had no prognostic impact. CRTC1/3-MAML2 fusion-positive rates were inversely associated with the patient age and fusions were found in 82% of patients aged <30 years. There has been no phase II study exclusively evaluating MEC. Targeted therapies investigating MEC together with other histologies included cetuximab [273], nintedanib [274], and sorafenib [275], but no subgroup analysis was performed. Isolated cases of favorable response of high-grade MEC to pembrolizumab have been reported [276, 277]. In a patient with an extensive high-grade lesion of the parotid gland, pembrolizumab was used as “first-line” therapy and complete pathologic response was achieved [276]. In another two patients with distant metastasis from parotid high-grade MEC, prolonged partial response to pembrolizumab was observed [277].

In conclusion, the treatment of choice for glandular malignancies of the nasopharynx is still based on the combination of surgery and radiotherapy. The role of chemotherapy, biotherapy, and immunotherapy need to be further elucidated, in light of improved understanding of their molecular profile.

Non-epithelial Skull Base Cancers

A variety of non-epithelial cancers can arise from mesenchymal tissues of the skull base, among which chondrosarcoma and chordoma are the histologies that have raised the greatest interest over the last decades. Of note, diagnosis of these cancers is frequently based on imaging findings and histological information is not always available prior to treating the patient. This fact should be taken into account when considering pathological and biological prognostic factors as potential TDTC.

Chondrosarcoma

Chondrosarcoma of the skull base is a rare tumor that arises from cartilaginous areas dispersed throughout the cranial base, mostly represented by synchondrosis (Fig. 16.8). It can be either sporadic or associated with hereditary enchondromatosis such as Maffucci syndrome and Ollier disease [278, 279]. Raza et al. reported that the petroclival synchondrosis is the most frequently affected site (49%), followed by the sphenoethmoidal (18.4%) and intersphenoidal (12.2%) synchondroses [280]. From a histological standpoint, chondrosarcomas can be conventional (further classified in grades I–III), mesenchymal, clear cell, myxoid, and dedifferentiated [281]. Surgery consisting of “maximum safe resection” is the mainstay of treatment and can be performed through an endoscopic transnasal approach in adequately selected cases [282,283,284,285,286,287,288,289,290].

Fig. 16.8

Chondrosarcoma and chordoma of the ventral skull base. a–c Preoperative magnetic resonance imaging of a left sphenoethmoidal grade 2 chondrosarcoma. d–f Preoperative magnetic resonance imaging of a chondroid chordoma involving the lower and middle clivus, prevertebral muscles, and left petroclival junction

Adjuvant radiotherapy is thought to provide advantages in terms of local control and the possibility to avoid it in selected cases is a matter of discussion. In fact, some authors suggest to reserve radiotherapy as a potential salvage option in grade I–II chondrosarcomas initially treated with “maximum safe resection” [291,292,293]. When progression-free survival is stratified by grade, only grade II and III are associated with a prognostic benefit when treated with adjuvant radiotherapy [290]. Given the strict adjacency to vital skull base structures, the dose distribution provided by intensity-modulated radiation therapy and particle radiotherapy is particularly effective in chondrosarcoma [294,295,296,297,298,299]. For instance, Holtzman et al. reported that proton beam radiotherapy on primary or residual post-surgical chondrosarcoma resulted in 4-year overall survival and local control of 95 and 89%, respectively [300]. However, compared to surgery only, surgery followed by proton beam radiotherapy increased 10-year progression-free survival from 58.2 to 87.5%, but did not improve disease-specific survival [301]. Overall, proton beam radiotherapy was more effective compared with photon radiotherapy in a National Cancer Database study on 736 sinonasal and skull base chondrosarcomas [302]. A systematic review with meta-analysis including 243 patients treated with surgery and postoperative carbon ion radiotherapy reported local control in 88% of cases with an overall survival of 79% at 10 years after treatment and grade ≥3 toxicity seen in 0–4% of patients [303]. Preclinical experiments on grade III chondrosarcoma have shown that the PARP inhibitor olaparib may serve as a radiosensitizer, particularly for particle therapy [304].

Mesenchymal and dedifferentiated chondrosarcomas are thought to have increased chemosensitivity [305]. Indeed, Raza et al. reported that the use of neoadjuvant (4 cases) or adjuvant (1 case) chemotherapy with vincristine, adriamycin, and ifosfamide increased progression-free and distant recurrence-free survival in mesenchymal and dedifferentiated chondrosarcomas [290].

Age >35/40 years and encasement of >2 major arteries (defined as ≥25% contact with the carotid, basilar or vertebral artery wall) were found to significantly predict progression of disease [306, 307]. The mesenchymal, clear cell, and dedifferentiated subtypes were demonstrated to predict progression of disease, as well as grade II and III [290, 302, 308,309,310,311]. SOX4 overexpression, which is related to miR-30a and miR-335 downregulation, was found to be associated with worse prognosis [312,313,314].

Tatman et al. demonstrated that phosphorylation of the following kinases is associated with recurrence: FES, FER, SRC family kinases, PKC, and ROCK, along with members of the mitogen-activated protein kinase pathway (JNK, ERK1, p38) [315]. The authors highlighted that several of these enzymes can be targeted with FDA-approved agents such as bosutinib, sunitinib, dasatinib, and nilotinib. In turn, even if the Hedgehog pathway was found to be upregulated in chondrosarcoma, Hedgehog pathway inhibitors do not provide significant clinical benefit [316, 317]. PD-L1 is not expressed in conventional chondrosarcoma, whereas it was detected in certain cases of dedifferentiated subtype, which also showed increased tumor-infiltrating lymphocytes and HLA class I expression [318]. Indeed, partial response to ICI has been reported in a case of dedifferentiated chondrosarcoma [319].

While the paucity and heterogeneity of data prevent drawing clear indications to customize treatment of chondrosarcoma, some potential TDTC alongside with patient-related factors can be hypothesized based on the available evidence (Table 16.7).

Table 16.7 Potential treatment-driving tumor characteristics (TDTC) of ventral skull base chondrosarcoma

Chordoma

Chordoma is a malignant tumor taking origin from remnants of the notochord and is classified in conventional, chondroid, sarcomatoid, or dedifferentiated types [320]. Recently, a SMARCB1-deficient poorly differentiated chordoma has been identified and considered as a further subtype [321]. Cranial chordomas are most frequently centered along the uppermost portion of the embryonal position of the notochord, from the craniocervical junction to the sella turcica (Fig. 16.8). Surgery consisting of gross total resection is the mainstay of treatment and less-than-total resection is independently associated with worse outcome [322, 323]. Given their central, midline position in the cranial base, chordomas are most frequently addressed through an endoscopic transnasal approach [324, 325]. Of note, surgery performed outside of a multidisciplinary setting was independently associated with decreased survival [326].

Overall, adjuvant radiotherapy is considered an essential part of treatment. Bai et al. demonstrated that postoperative radiotherapy should be delivered as adjuvant treatment following macroscopically complete surgery rather than salvage therapy after evidence of recurrence [327]. Radiation dose up to 78 Gy in 39 fractions proved beneficial over lower doses (<74 Gy) in terms of local control [328]. Both proton beam and carbon ion radiotherapy have shown remarkable efficacy in the postoperative treatment of chordomas, with 5-year local control exceeding 70% in most series [303, 329,330,331,332].

Chemotherapy has a limited role in the treatment of chordoma [333]. Interestingly, a computational drug repositioning study on FDA-approved agents identified cytarabine and tretinoin as drugs with a potential effect on chordoma, thus suggesting that their efficacy should be investigated in a preclinical setting to evaluate their potential clinical utility [334].

Akinduro et al. systematically reviewed the targeted therapy agents employed in clinical trials for chordoma [335]. They reported that 9-nitro-camptothecin, sunitinib, imatinib (with/without cyclophosphamide, with/without everolimus), lapatinib, sorafenib, dasatinib, nilotinib, and apatinib have been tested in a clinical setting, with objective response rates ranging between 0 and 25%. Meng et al. suggested that targeted therapy for chordoma should be driven by gene mutation screening or immunohistochemistry by assessing the PDGFR, EGFR, VEGFR, and mTOR pathways [336].

The dedifferentiated, poorly differentiated (i.e., SMARCB1-deficient), and sarcomatoid subtypes have been associated with poorer disease-specific survival, whereas the chondroid variant had more favorable progression-free survival [321, 323, 327, 337,338,339].

If one considers the group of rare malignancies of the skull base from a molecular and genetic perspective, chordoma is among the most extensively explored lesions [314]. Zuccato et al. presented a comprehensive, methylomic-driven analysis of 68 chordomas and identified 2 clusters of hypomethylated tumors [340]. The first was associated with deregulation of immune- and transcription/translation-related pathways (referred to as “immune-infiltrated”), and the second with cell-to-cell interaction, extracellular matrix, angiogenesis, and metabolic pathways (referred to as “cellular”). Interestingly, the first cluster had significantly worse prognosis and cluster classification could be reliably performed non-invasively based on plasma cell-free DNA. The load of chromosomal deletions of 1p36 and 9p21 in the cellular population of chordoma has been found to predict progression-free survival [341]. This biomarker was found also to deeply impact the response to adjuvant radiotherapy in an analysis of 152 clival chordomas [342]. In macroscopically resected chordomas with low-to-intermediate chromosomal deletion burden, adjuvant radiotherapy did not increase progression-free survival, whereas it did in less than totally resected tumors with intermediate burden and in those with high burden irrespective of the degree of resection. Moreover, deregulation of ERK and HPGD expression was found to increase resistance to radiotherapy [343]. When considering molecular prognostic biomarkers, upregulation of asparagine synthetase, overexpression of c-Cbl, Cbl-b, PDGFR-β, TGF-α/β, VEGFR1/2, survivin, and ERK, and underexpression of SMARCB1, HPGD, and PTEN were associated with poor prognosis [339, 343,344,345,346,347,348,349,350,351]. On the other hand, duplication and overexpression of Brachyury (also called T gene) has an ill-defined prognostic role, but is thought to be involved early in chordoma development and was implicated in familial chordomas [314, 352, 353]. The prognostic effect of miRNA deregulation in chordoma is not fully elucidated and mostly relies on series including both cranial and spinal tumors [354].

Of note, as demonstrated by the Beijing Neurosurgical Institute’s experience, several patient-related peripheral blood indexes have been associated with prognosis of chordoma patients. For instance, systemic immune-inflammation index, which summarizes the count of neutrophils, platelets, and lymphocytes, prognostic nutritional index, which includes serum albumin and lymphocytes count, and fibrinogen-albumin score have been associated with survival outcomes [355, 356]. Similarly, platelet and red cell distribution width was found to correlate with overall survival [357, 358].

The interaction between chordoma and the immune system is still far from being fully elucidated, but some inherent data have supported the design of immunotherapy clinical trials [359]. PD-L1 expression in non-tumor cells and high density of macrophages, regulatory T cells, and “exhausted” tumor-infiltrating lymphocytes were associated with more rapid progression of the disease and worse prognosis [349, 360, 361]. Currently, a number of clinical trials are assessing the potential benefit of ICI and Brachyury vaccine in patients affected by chordoma [362]. Of note, a phase I trial on MVA-BN-brachyury-TRICOM vaccine showed some form of benefit in 5/10 patients affected by chordoma, with stable disease and partial response in 4 and 1 cases, respectively [363]. On the other hand, a phase II, double blind, placebo-controlled trial showed that yeast-Brachyury vaccine does not provide additional effect in patients with unresectable chordomas treated with standard-of-care radiotherapy [364]. Though evidence is limited to the preclinical setting, B7-H3 has been identified as a potential target for CAR-T cell therapy (Table 16.8) [365].

Table 16.8 Potential treatment-driving tumor characteristics (TDTC) of ventral skull base chordoma

Conclusions

Malignant neoplasms that arise from or encroach on the ventral cranial base comprise a large group of different entities, each one with different behavior. The understanding of these cancers is rapidly evolving and is providing a wealth of information with potential therapeutic implications. The large majority of TDTC that were discussed in this chapter are based on theoretical grounds, and evidence of their value in the clinical setting is still lacking. However, several promising paths of treatment customization, which need to be appropriately validated, can be foreseen. Based on the complexity of the pathologies that we have reviewed in this chapter, the logical conclusion is that both research and clinical management should be performed at institutions with dedicated, multidisciplinary facilities.