Introduction

Craniofacial (sinonasal) malignancies affecting skull base structures are rare diseases accounting 3—5% of malignancies of the head and neck and 0.2—0.8% of all tumors [1]. These tumors are usually epithelial and, accordingly, characterized by unfavorable prognosis. Craniofacial (sinonasal) malignancies include squamous cell carcinoma, adenocarcinoma, undifferentiated cancer, neuroendocrine cancer, sinonasal undifferentiated carcinoma (SNUC), adenocystic cancer, etc. [2—3].

Most reports devoted to the treatment of skull base malignancies often combine different histological types of tumors and various treatment strategies. Therefore, unified protocols for these patients are absent [4—5] and decision making on optimal treatment strategy is difficult [6].

TNM international classification is used to predict the outcomes in patients with craniofacial primary malignancies. This system is applied for classification of stages of malignant neoplasms [7], since invasion of surrounding structures such as dura mater, cranial nerves, orbit and sphenoid bone is predictor of worse results. Moreover, Ziai H. et al. reported dura mater invasion in more than 50% of patients with craniofacial primary malignancies affecting skull base even if similar neuroimaging data are absent [8—9]. In addition, surgical strategy and consequent application of surgery, chemo- and radiotherapy are based on TNM classification too. However, there are currently no clear standards and recommendations.

Incidence of local lymph node metastases is up to 20% despite the use of all modern methods of treatment of the primary lesion [10]. Local or distant metastases can occur several years after treatment [11].

Some authors reported better outcomes of treatment of skull base squamous cell carcinoma [12—13] in patients with human papillomavirus (HPV). Unfortunately, its presence is not currently taken into account in the choice of treatment strategy.

This review is devoted to the most common craniofacial malignancies: squamous cell carcinoma, adenocarcinoma, sinonasal undifferentiated carcinoma, esthesioneuroblastoma, adenocystic cancer, sinonasal adenocarcinoma.

Squamous cell carcinoma

Squamous cell carcinoma is the most common primary craniofacial malignancy and accounts 89% of all types of these cancers [14—15]. This cancer can arise either de novo from the epithelium of paranasal sinuses and nasal cavity or in combination with inverted papillomas (10%) [16]. However, transformation from papillomas does not affect the outcomes of treatment [17—18].

Sinonasal squamous cell carcinoma affecting skull base structures was traditionally operated through open approaches (combined transfacial and/or transcranial accesses for en-bloc resection) [19—20]. Overall 5-year survival of patients with squamous cell cancer after open surgery and adjuvant therapy was 43—59% [9, 19, 21—24].

The role of endoscopic endonasal approach for resection of these malignancies has been studied in several centers over the past decade [25—28]. It was shown that partial resection results similar outcomes although conventional principle of en-bloc resection is unattainable in endoscopic surgery [20]. However, endoscopic technologies do not imply restrictions on the volume of resection, and, in addition, allow symptomatic treatment and cytoreductive surgery prior to chemoradiotherapy [29]. Currently, the generally accepted treatment strategy for squamous cell carcinoma of skull base and nasal cavity is precisely endoscopic resection of tumor and possible combination with open procedures (in case of spread to the orbit, infratemporal fossa, anterior cranial fossa), radio- and chemotherapy [14, 17, 30].

The University of Pittsburgh presented endoscopic treatment of 34 patients. T3—T4 tumors prevailed (85%). Complete endoscopic endonasal approach was used in 25 patients, combination of transcranial/transfacial and endoscopic endonasal accesses — in 9 cases. Total resection was made in 27 patients, cytoreductive surgery — in 7 cases. Recurrence-free and overall survival was 62% and 78%, respectively [17]. De Almeida J. R. et al. reported CSF leakage followed by meningitis as the only more common complication of endoscopic endonasal surgery for squamous cell carcinoma of skull base and other cancers of this zone (CSF leakage 21%, meningitis 9%) [17]. Dura mater invasion was also determined as unfavorable predictor of long-term survival in various researches [5, 31].

Recently, targeted therapy in the treatment of squamous cell carcinoma of the head and neck has been actively developing. Widespread application of targeted drugs is based on their high selective activity against tumor cells compared with normal tissue cells, targeted effect against carcinogenesis factors and lower treatment toxicity profile [32—33]. These drugs include epidermal growth factor inhibitors, growth factor inhibitors, signaling pathway blockers, drugs for cell growth control, protein synthesis and angiogenesis inhibition [34]. To date, high efficiency of tumor growth factor inhibitors is confirmed in multiple trials.

One of the most perspective drugs for the treatment of malignancies in particular squamous cell carcinoma of the head and neck is cetuximab. It is chimeric monoclonal antibody targeted against epidermal growth factor receptor (EGFR). The level of this factor is abnormally elevated in epithelial tumors including squamous cell carcinoma of the head and neck [35—36]. Cetuximab is currently approved for the treatment of platinum-resistant metastatic or locally advanced squamous cell carcinoma of the head and neck [37]. The targeted drug nivolumab as antibody to PD-1 (Programmed cell death protein 1) is also approved [38].

Platinum-based adjuvant chemoradiotherapy is usually used after surgery only in cases of positive resection margin and confirmed invasion of lymphovascular and nerve structures [1]. Induction chemotherapy was followed by promising results in the treatment of low-grade squamous cell carcinoma stage T3 – T4. This is initial course of treatment for highly or moderately sensitive tumor if other treatment strategies are impossible. These methods mainly include a combination of Taxane and Platinum followed by surgery and adjuvant chemoradiotherapy (partial or complete response was observed in 67% of patients) [39].

Neck irradiation should be considered for locally advanced lesion (T3—T4) due to fairly frequent (23%) metastasis to cervical lymph nodes [1].

All of these protocols are currently being studied in the ECOGACRIN protocol 3163 (EA3163), a randomized clinical trial on comparison of the protocols neoadjuvant chemotherapy + surgery + irradiation and surgery + irradiation in terms of orbit preservation.

Adenocarcinoma

Adenocarcinoma usually occurs in mucosa of ethmoid cells (85%) and olfactory zone (13%).This tumor is 4 times more common in men than in women that is due to professional activity of certain group of specialties associated with exposure to wood dust [40]. These features also determine possible multifocal growth of tumors. Therefore, bilateral resection of ethmoidal labyrinth is recommended [40—41].

Surgical treatment is the main approach for early (T1—T2) cancer. Adjuvant intensity modulated radiotherapy is applied for T3—T4 tumor (high-tech 3D radiotherapy technique for delivery of precise dose to a malignant tumor). This method results very accurate distribution of irradiation dose around the target (tumor) with complex shape with delivery of high dose to the entire volume neoplasm [42]. In 2000, it was shown that endoscopic endonasal resection of craniofacial adenocarcinomas is followed by better outcomes and less incidence of complications [27,29]. In later series, overall survival near 72.7% was reported after endoscopic transnasal resection followed by adjuvant radiotherapy [41]. Nicolai P. reported the largest series of 169 patients with sinonasal adenocarcinomas. Overall and recurrence-free survival rates were 68.9% and 63.6%, respectively [3]. Similar 5-year overall survival was observed by Camp (68%, n=123) and Vergez (62%, n=159) in 2014. As a result of these data, endoscopic transnasal resection with or without adjuvant radiotherapy became preferable for sinonasal adenocarcinomas instead of open procedures. The last ones are applied only in patients with invasion of anterior cranial fossa and frontal sinus.

Preventive irradiation of the entire brain may be considered at the late stages if invasion of cerebral meninges is suspected [3]. Cervical lymph node metastases are observed only in 7% of cases. Therefore, their irradiation is not routinely performed [1]. The protocol involving induction chemotherapy based on cisplatin, fluorouracil and leucovorin and subsequent surgery and radiotherapy was effective and perspective for T3—T4 tumors with functionally active p53 protein [43].

Sinonasal undifferentiated carcinoma (SNUC)

This highly aggressive carcinoma of uncertain histogenesis with or without neuroendocrine differentiation. This caner usually manifests as a widespread tumor with greater ability to metastasize compared to conventional squamous cell carcinoma [44]. Neoadjuvant chemotherapy followed by either chemoradiotherapy or surgical treatment with further postoperative irradiation shows fairly good outcomes even at the late stages of disease [45–46].

Histopathological features of undifferentiated carcinoma of paranasal sinuses are similar to those of olfactory neuroblastoma and neuroendocrine carcinoma [44]. The nuances of differentiation of these neoplasms are not purely methodological, since there are significant differences in prognosis and treatment strategies. However, none of these strategies is completely accepted. Al-Mamgani et al. reported 21 patients who were divided into the groups depending on treatment protocol (chemoradiotherapy, neoadjuvant chemotherapy or surgery) [47]. Multivariate analysis of local growth control was compared considering invasion grade and treatment strategy. The best survival rate was reported in this sample of patients (74%). Therefore, individual approach is preferable over any generally accepted strategy.

Sinonasal adenocarcinoma

Sinonasal adenocarcinoma is characterized by high tendency to perineural spread (for example, along trigeminal nerve) and bone invasion, that may be followed by significant destruction of skull base structures and intracranial spread including cavernous sinus and middle cranial fossa. Like other tumors of this group, sinonasal adenocarcinoma originates from the mucosa of paranasal sinuses. Surgery combined with postoperative irradiation results better overall survival [48].

Lee Y. C. et al. analyzed 47 patients with advanced adenocystic carcinomas and reported a fairly good overall survival rate (61.7%) [49]. The best outcomes were obtained in patients who underwent surgical treatment with subsequent adjuvant radiotherapy. At the same time, the role of cisplatin-based chemotherapy is still not comprehensively defined in the treatment of this pathology.

Postoperative radiotherapy may be carried out using conventional photon irradiation or recently introduced proton therapy. The last one has shown favorable local growth control not only in postoperative period, but also in inoperable cases [50]. PET with glucose is advisable in these patients to predict the effectiveness of therapy with heavy particles [51].

Overall 5-year survival in patients with sinonasal adenocarcinomas is better (77.3%) compared with other craniofacial cancers although recurrence is observed in almost 65% of patients [48, 52].

Esthesioneuroblastoma

Olfactory neuroblastoma (esthesioneuroblastoma) is a rare malignancy originating from olfactory neuroepithelium and accounting for 3—5% of all nasal cancers [53–55]. There are currently no generally accepted treatment strategies for esthesioneuroblastoma due to small incidence of this tumor. The main approach is surgery with subsequent radiotherapy and with or without chemotherapy [56—58]. Comparable results of endoscopic procedures and craniofacial resection were shown like in other malignant sinonasal neoplasms affecting skull base [56].

According to various data, overall 5- and 10-year survival of patients with neuroblastomas is 85—93 and 57—75%, respectively, regardless of surgical approach [59—60]. Xiaolin Peng reported significantly higher overall survival of males compared with females [61].

Cervical lymph node metastases are observed in 5—12% of cases during initial examination. However, neck irradiation during the treatment of primary tumor should be considered due to higher incidence of metastases in the follow-up period (up to 39% within 40 months [62]) [63—64].