Rhabdomyosarcoma of the clivus – a case report 153

Overview

Rhabdomyosarcoma is a highly malignant mesenchymal tumor growing out of the primitive mesenchyme, which is (usually) differentiated into predominantly striated skeletal muscle. It is the most common soft tissue sarcoma in childhood, with a predilection site that occurs in the head and neck area. Multimodal approaches in treatment include surgery, chemotherapy, and radiotherapy. We present a case of a 6-year-old girl with a history of nasal obstruction and mucus secretion more on the left side, with loss of smell and headache above the left eye. Through clinical examination, a pink tumor was detected in the left nasal cavity. CT and MRI were complemented and showed a tumor mass filling the entire nasopharynx, propagated into the left sphenoid cavity, to the clivus, and to the prevertebral space; the tumor mass completely obturated both choanae. The patient underwent endoscopic endonasal resection of the skull base tumor using CT navigation. Embryonal rhabdomyosarcoma has been confirmed. In the postoperative period, the patient underwent adjuvant oncology treatment, and control biopsies at 2 and 16 months after surgery were negative. The patient is now three years after surgery – clinically free of signs of tumor recurrence. Conclusion: Rhabdomyosarcoma, like other tumors in the skull base region, is a challenge for the surgeon due to the location in which complete resection of the tumor is sometimes very difficult or impossible. Meticulous preoperative analysis of imaging examinations, as well as intraoperative use of CT/MRI navigation, make this possible. Complete removal of the tumor increases the patient‘s chance for successful treatment.

Keywords:

rhabdomyosarcoma – skull base tumor – endonasal endoscopic resection

Introduction

Rhabdomyosarcoma (RMS) is defined as a highly malignant mesenchymal tumor growing out of the primitive mesenchyme, which is (usually) differentiated into predominantly striated skeletal muscle [1]. It is the most common sarcoma of soft tissues in children, while the predilection area of occurrence in patients younger than 15 years is in the head and neck area (35–40%) [2]. According to the location of head and neck RMS, we divide it into parameningeal, orbital, and nonparameningeal. Parameningeal RMS includes the sinuses, nasal cavity, nasopharynx, parapharynx, skull base, middle ear, mastoid, fossa infratemporalis, and pterygopalatine. A multimodal approach is used in the treatment, which consists of a combination of surgical treatment, radiotherapy, and multi-agent chemotherapy.

A case study

We present a case of a 6-year-old girl who attended the outpatient clinic of the tertiary referral center in March 2021 with a 1-month history of nasal obstruction and congestion, mucus secretion more on the left side, with loss of smell, and headache above the left eye. Through rhinoendoscopic examination, stagnant mucus was detected on both sides of the nasal cavity; after suction, a pink tumor was visible in the left nasal cavity, impassable to the nasopharynx by the endoscope.

CT scan (Fig. 1) showed the bulky tumorous mass measuring 47 × 26 × 31 mm, which filled the entire nasopharynx; it propagated a little more to the left and locally destroyed the surrounding structures via osteolytic process. It propagated asymmetrically and more prominently into the left sphenoid cavity; at the back, it propagated up to the clivus and the prevertebral space at the height of the atlas; in the front, it propagated into the back half of the nasal cavity, completely obstructing the at the back. The tumorous mass completely obturated both choanae; caudally, it was bordered by the palate.

Magnetic resonance imaging (MRI) (Fig. 2) showed a vascularized tumorous lesion of the nasopharynx that spread to the nasal cavity and sphenoid sinuses, destroying the skeleton without pathological cervical lymphadenopathy. The patient underwent endoscopic endonasal navigated resection of the tumor of the skull base (clivus, sphenoid sinuses, nasopharynx, palate, septum posterior part – midline), where the tumor obturated the nasal cavity on both sides, pushed the septum to the sides, filled the nasopharynx, sphenoid sinuses, and posterior ethmoids, and insisted and marginally infiltrated the upper surface of the soft and posterior palate. We continued with the centripetal resection of the tumor; the origin of the tumor was probably in the clivus area. Part of the tumor specimen was sent in for intraoperative biopsy with the finding of an unspecified malignant undifferentiated tumor.

The postoperative course was completely uneventful. The patient received a transfusion of 1 transfusion unit of erythrocyte mass and was discharged on the 7th postoperative day. Complementary staging examinations (CT of the neck and chest, USG of the abdomen, PET/CT scan) showed no distant metastases.

A definitive histopathological examination confirmed a highly malignant small blue cell sarcoma. The phenotype favored the diagnosis of poorly differentiated vs. embryonal rhabdomyosarcoma (Fig. 3). Genetic examination confirmed a negative status of the fusion of the investigated genes.

According to the multidisciplinary tumor board recommendation, the patient was referred for adjuvant chemotherapy treatment. According to the Frontline and Relapsed Rhabdomyosarcoma Protocol (FaR-RMS), the patient was in subgroup A (tumor size under 5 cm, age under ten years, N0, fusion status – negative). Intravenous VA-V-V-VA chemotherapy (vincristine + actinomycin D, 16 cycles in total) was administered to the patient at weekly intervals. After the first four cycles, there was a 3-week therapeutic break, during which control biopsies were scheduled. On the follow-up MRI in April 2021, there was a finding of irregularity of the contour of the clivus with indicated inhomogeneity, where a possible residue couldn’t be excluded, and there were postoperative changes of the dorsal wall of the nasopharynx, cystic lesions of the sphenoid sinuses, and maxillary sinusitis on the left. In May 2021, the patient underwent endoscopic revision with resection of suspected persistence and control biopsies – definitive histological examination confirmed only chronic inflammatory changes and non-specific granulation tissue without tumor infiltration. The patient subsequently continued with adjuvant chemotherapy, completed in September 2021. During further outpatient check-ups, the patient was doing well; the local finding was no signs of recurrence; and the control MRI was performed every 3–6 months and showed no signs of tumor recurrence (Fig. 4). The last control biopsies 16 months after the surgery were also negative. The patient continued to be regularly monitored in the ENT and Children‘s Hemato-oncology clinics.

 

Discussion

Malignancies in childhood are less common than in adults and differ in the prevalence of individual histological subtypes. While epithelial tumors (carcinomas) predominate in adults, mesenchymal tumors such as lymphomas and sarcomas (rhabdomyosarcoma) are most common in children [3]. Rhabdomyosarcomas make up 4.5–7% of all childhood malignancies and 40–50% of soft tissue sarcomas [4, 5]. Although most cases of RMS occur sporadically, they can develop due to various genetic mutations, such as in Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, von Recklinghausen‘s disease, cardiofaciocutaneous syndrome, Noonan syndrome, and Costello syndrome [4, 6]. The association of RMS with these syndromes has made RMS genetics an area of intense study. Decades of targeted sequencing and microarray methods led to the discovery of loss of heterozygosity at 11p15.512; mutations are in TP53, 13 NRAS, KRAS, HRAS, 14 PIK3CA, CTNNB1,15, and FGFR416; and characteristic translocations involve the PAX3 or PAX7 genes with FOXO1, which defined the genomic characteristics often associated with the histological and clinical features of this disease [6]. Next-generation sequencing studies have confirmed that RMS should not be diagnosed by histology alone, but by the presence (fusion-positive RMS) or absence (fusion-negative RMS) of a PAX3/7 gene fusion [7].

Based on the location of head and neck RMS, we divide it into parameningeal, orbital, and nonparameningeal. Parameningeal location is considered an unfavorable prognostic factor for frequent infiltration of the central nervous system (CNS) and worse surgical resectability [1, 4, 8]. RMS in this area is also treacherous in that, due to the lack of symptoms, it is diagnosed later and often already at an advanced stage. Orbital RMS affects the area of the orbit and eyelashes. Nonpara- meningeal RMS affects the parotid region, scalp, cheeks, oral cavity, oropharynx, hypopharynx, larynx, thyroid and parathyroid glands, and neck.

The fourth edition of the WHO classification distinguishes four histological types of rhabdomyosarcoma: embryonal, alveolar, spindle cell/sclerosing, and pleomorphic. In this classification, the botryoid variant of RMS was classified under the typical embryonal type [9, 10]

A multimodal approach is used in the treatment, which consists of a combination of surgical treatment, radiotherapy, and multi-agent chemotherapy. This approach significantly increased patient survival [1, 4, 8, 11–15]. As with other types of tumors, the goal of surgical treatment for RMS is to remove the tumor completely. Radical resection with histopathologically-confirmed negative margins guarantees a favorable prognosis, and at the same time, the possibility of avoiding adjuvant radiotherapy [11, 12, 14, 16–18]. Due to the variability of the primary tumor locations, complete resection is often difficult. These are mainly tumors in parameningeal locations that can grow for a long time without clinical symptoms, tumors with larger dimensions reaching the base of the skull, and with the presence of intracranial spread [4, 8]. In our patient, we chose endoscopic trans-nasal tumor resection with CT navigation. This approach is a minimally invasive approach that allows the removal of various pathologies in the sella turcica and skull base [19]. Orbital RMS has a very good prognosis after treatment with chemotherapy and radiotherapy; surgical treatment offers no advantage over chemotherapy and radiotherapy in terms of survival and is therefore limited to diagnostic biopsy [11, 20]. This combined modality is a treatment modality for orbital RMS, thus avoiding significant morbidity from eye loss [17]. Chemotherapy is an integral part of multimodal therapy for RMS. For newly diagnosed pediatric patients, multimodal chemotherapy regimens are currently assigned according to the classification of patients into clinical groups according to risk factors (Tab. 1). The drugs used are combinations of long-established cytotoxic agents, including alkylating agents, vincristine, and actinomycin D. Within the concept of a multimodal treatment approach, radiotherapy is also an important part of the treatment. It depends on the location of the primary tumor, the extent of the disease after initial surgical treatment, and the histological subtype of the tumor. Patients with a completely resected embryological type of RMS do not require radiotherapy [12], but it is indicated in patients with a completely resected alveolar type of RMS [16, 21]. Radiotherapy is generally reserved for patients with histologically unfavorable, unresectable tumors and as adjuvant therapy after resection with positive surgical margins [22]. Our patient had an R0 resection, the embryonal subtype of the tumor, so radiotherapy was not indicated for her.

The staging system was developed as a modified TNM, similar to the classification used by the Union for International Cancer Control (UICC) (Tab. 1) [15]. During the development of the Intergroup Rhabdomyosarcoma Study Group (IRSG) protocols, it became clear that it is necessary to adopt a preclinical staging system that does not depend on the surgeon‘s decision on how much tissue to remove or on the pathological evaluation of the specimen. TNM staging before treatment is based on the location, invasiveness, and size of the tumor, along with possible involvement of regional nodes and distant metastases (Tab. 1) [15].

A surgical-pathologic classification system categorizes patients according to the extent of the disease remaining after initial surgery, but before chemotherapy and radiotherapy are initiated. The staging system categorizes patients according to the amount of residual disease after initial surgery; external radiotherapy is administered according to each patient‘s group and histological subtype (Tab. 2) [23].

Currently, staging systems and classification into clinical groups (Clinical Grouping Classification, Intergroup Rhabdomyosarcoma Study Group, IRSG) as well as the histological subtype of the tumor or fusion status – presence or absence of PAX 3/7 gene fusion with FOXO1, are used to decide on treatment. Most alveolar RMS contains these translocations, and its presence is considered an unfavorable prognostic factor. Patients are categorized according to predicted survival using a staging system and histological subtype; different combinations of chemotherapy drugs are given accordingly. Patient survival has improved significantly over the past decades, from 25% in the 1970s to more than 70–91.3% today [1, 4, 8, 13]. This is mainly due to the multimodal approach in the treatment of these patients.

According to the Frontline and Relapsed RhabdoMyoSarcoma protocol (FaR-RMS protocol), EpSSG – European Pediatric Soft Tissue Sarcoma Group, our patient was assigned to a low-risk group (Subgroup A), and based on this protocol, underwent adjuvant chemotherapy (VA- V-V-VA, vincristine + actinomycin D, a total of 16 cycles) [24].

 

Conclusion

Rhabdomyosarcoma, like other tumors in the skull base region, is a challenge for the surgeon due to the location in which complete resection of the tumor is sometimes very difficult or impossible. Meticulous preoperative analysis of imaging examinations, as well as intraoperative use of CT/MRI navigation, make this possible. Successful complete tumor removal, together with adjuvant oncological therapy, increases the patient‘s chance for successful treatment. Regular follow-up after treatment is important for patients to track possible recurrence or metastatic spread.

Conflict of interest statement

The author declares that there is no conflict of interest related to the topic, development, or publication of this article, and that neither the preparation nor the publication of the article was supported by any pharmaceutical company. This statement also applies to all co-authors.