Extracranial metastasis of recurrent glioblastoma to the parotid gland: a case report and review of the literature

Abstract

Background

Glioblastomas are the most common and highly malignant primary brain tumors in adults with a median survival of 15 months even with appropriate treatment. Extracranial metastases are extremely rare due to the poor prognosis not allowing sufficient time to spread. We report an extremely rare case of extracranial metastasis of supra-tentorial glioblastoma involving the skin, subcutaneous and muscular layers, periauricular region and parotid gland, and review the literature. A total of 13 glioblastoma parotid gland metastases cases have been hitherto described.

Main body of the abstract

A 42-year-old man underwent surgery for right temporal glioblastoma and received 60 Gy/30 fractions radiotherapy together with temozolomide at 75 mg/m². Seven months later, the tumor relapsed and the patient underwent a second surgery while chemotherapy continued. Fifteen months later, he complained of swelling in the right neck region. Fine needle aspiration and tru-cut biopsy revealed a high-grade malignant tumor infiltration within the parotid gland. Despite salvage chemotherapy and adjuvant radiotherapy, in his follow-up after 6 months neck swelling increased. The patient declined any treatment modality and continues his life 39 months after the primary diagnosis of intracranial glioblastoma.

Short conclusion

Due to the recurrence rate of intracranial glioblastoma and its malignant nature; close imaging follow-up is highly crucial. The increase in reported cases of its extracranial metastases is generally due to the modern diagnostic tools and prolonged survival attributed to the improvement in treatment modalities where now radical surgery with adjuvant radiotherapy and chemotherapy is standard protocol. Patients with glioblastomas presenting with swelling in the cervical region should be investigated to rule out parotid gland metastasis.

Background

Glioblastoma are the most common and aggressive primary brain tumor in adults. Histopathologically, it is characterized by necrosis and endothelial proliferation and is classified as grade IV, the highest grade according to the World Health Organization (WHO) classification of brain tumors [1]. Patients diagnosed with these tumors have a poor prognosis, even with appropriate treatment like total resection followed by whole brain radiotherapy and adjuvant chemotherapy [2]. Due to an aggressive clinical course, extracranial metastases are very rare and are only reported in 2% of all patients with glioblastoma [3]. We report an extremely rare case of extracranial metastasis of supra-tentorial glioblastoma involving the skin, subcutaneous and muscular layers, periauricular region and parotid gland and review the literature. A total of 13 glioblastoma parotid gland metastases cases have been hitherto described.

Main text

A 42-year-old male patient presented to our outpatient clinic with headache, syncope and tinnitus. Magnetic resonance imaging (MRI) scan revealed a mass lesion approximately 5*4 cm in size, with central hypointensity and peripheral contrast involvement located in the right temporal lobe causing a midline shift. The patient underwent subtotal resection of the tumor via temporal craniotomy as intense vascularization made a total removal impossible and was discharged without any neurological deficits a week later (Fig. 1). Pathological biopsy was reported as glioblastoma grade IV-NOS (not otherwise specified) (Fig. 2). The patient received 60 Gy/30 fractions radiotherapy (RT) with concurrent temozolomide at 75 mg/m² one month after surgery.

Fig. 1

Primary glioblastoma. A, B Preoperative axial and coronal cranial MRI scan. C, D Postoperative axial and coronal cranial MRI scan

Fig. 2

Cellular tumor with palisading necrosis and vascular endothelial proliferation. A Haematoxylin and eosin (H&E*100). B GFAP positivity (IHC*100)

Seven months later, while continuing his chemotherapy, the patient developed left hemiparesis with muscle strength of 2/5. MRI demonstrated a recurrence approximately 6*5 cm in size, with a midline shift in the right temporal region. Emergency total removal of the tumor was made within temporal lobectomy (Fig. 3). Again, the biopsy was reported as glioblastoma (WHO Grade IV-NOS) (Fig. 4). The patient was discharged with left hemiparesis with muscle strength 3/5 and transferred to the physical rehabilitation unit. After the second surgery, chemotherapy was continued with bevacizumab irinotecan.

Fig. 3

Recurrence of the glioblastoma. A, B Preoperative axial and coronal cranial MRI scan. C, D Postoperative axial and coronal cranial MRI scan

Fig. 4

Gemistocytic cells, areas of necrosis and vascular endothelial proliferation. A H&E*100. B GFAP positivity (IHC*100)

Fifteen months later, the patient complained of swelling in the right neck region. On ultrasonography (USG), a lesion with a heterogeneous internal structure with lobulated contours was observed in the right preauricular region. Intense vascularization was noted in the Doppler USG examination in which the superficial temporal artery passed through the lesion. On MRI, a heterogeneous internal mass lesion with lobulated contours infiltrating toward the superficial lobe of the parotid gland was observed. The mass extended to the upper part of the previous craniotomy border. Also, multiple pathological lymphadenopathies were detected in the right submandibular area (Fig. 5). Fine needle aspiration biopsy and tru-cut biopsy revealed a high-grade malignant tumor (Fig. 6). In the immunohistochemical (IHC) study; glial fibrillary acidic protein (GFAP) (Leica/ GA5) was positive in a small number of cells and Pan-cytokeratin (BioGenex/ AE1-AE3) was negative. The findings were evaluated with the diagnosis of glioblastoma in the patient’s anamnesis and radiological features, and they were considered to be compatible with glioblastoma.

Fig. 5

Neck MRI scan (A axial- B coronal sections)

Fig. 6

Subcutaneous soft tissue biopsy. A Tumor cells in liquid-based cytology cell block (H&E*100). B. GFAP positivity in tumor cells in liquid-based cytology cell block (IHC*400). C Subcutaneous soft tissue tru-cut biopsy: pleomorphic tumoral infiltration with hyperchromatic nuclei within the fibrous stroma (H&E*100). D. Subcutaneous soft tissue tru-cut biopsy: GFAP circulating positivity (IHC*400)

Despite salvage chemotherapy and adjuvant RT, on the 6 months follow-up, the neck swelling increased and the patient developed subcutaneous nodules in his scalp of the prior craniotomy scar. Cranial MRI revealed cortico-subcortical cystic encephalomalacia in the right temporal lobe, multiple new distinct lesions and recurrent intracranial tumor growth (Fig. 7). The patient declined any further treatment and continues his life 39 months after the primary diagnosis of intracranial glioblastoma.

Fig. 7

Cranial MRI scan. A, B axial sections. C, D coronal sections

Discussion

Glioblastoma are highly malignant primary brain tumors with a median survival of 15 months despite standard treatment which consists of debulking surgery, followed by RT and chemotherapy in selected patients [4]. Extracranial metastases are extremely rare with incidences between 0.2 and 2.7% due to the poor prognosis not allowing sufficient time to spread [5,6,7]. The implantation of tumor cells into extracranial blood vessels and lymphatics during the surgery is postulated as its main mechanism of spread [8]. In addition, postoperative neovascularization of the surgical field; especially the dura is estimated to lead to dissemination of these tumor cells [5]. Subependymal seeding or drop metastases via the cerebrospinal fluid are also considered as a possible cause [5, 7]. With all these pathophysiological theories, the physical disruption of the blood–brain barrier; scalp metastasis adjacent to the craniotomy, leptomeningeal spread to the spine, metastases to lymph nodes, to the abdomen via ventriculoperitoneal shunt or seeding along the biopsy tract has been documented. Also, there are reports presenting extracranial metastases of glioblastoma to the lungs, heart, pleura, liver and bone marrow [9, 10]. The parotid gland is the largest of the salivary glands in the head and neck. Its major function is to secrete saliva to participate in lubrication, digestion and immunity in the human body. It contains lymph nodes draining the lymph of the forehead, nasal root, upper lip, cheek, temple and external ear [11]. The majority of metastases in the parotid gland arise from primary tumors of the head and neck which mostly develop by lymphomatous spread and rarely by hematogenously [12]. However, the exact mechanisms for metastases of glioblastoma to the parotid gland remain unknown. Despite some authors considering tumor seeding being a logical consequence to neighboring tissues near the surgical site, Nguyen et al. reported subgaleal metastasis on the contralateral side which can be an indication for possibly local vascular invasion of tumor cells [13]. In addition to this, Willis postulated that the thin-walled and poorly supported dura mater; central nervous system venules may permit metastatic spread [14]. But this theory does not explain how metastases to more distant organs work. We believe that the leptomeningeal dissemination and invasion of the superficial temporal artery by dural extension through the craniotomy defect are the most likely way of seeding in our patient. By reviewing the literature, the number of parotid gland metastases of glioblastoma is 13 together with our case (Table 1) [6, 15,16,17,18,19,20,21,22,23,24,25]. Age distribution ranged from 25 to 66 years, with an average of 46.15 years. Nine cases were men and four were women. In all cases, the location of the primary tumor was supra-tentorial; temporal in six cases, frontal in four and frontoparietal, temporoparietal and occipital in one case. The time between the diagnosis of the glioblastoma and spread to the parotid gland ranged from 3 months to 2 years with an average of 9.2 months which is almost identical to extracranial metastases to other organs. The onset of the symptoms ranged from immediately postoperatively to 14 months [26].

Table 1 Metastasis of glioblastoma to the parotid gland reported in the literature

Cervical lymph nodes were noted as the area of concomitant metastasis which supports our pathophysiological theory. For the diagnosis of parotid gland metastases; authors have used different methods: cervical lymph node biopsy, parotid biopsy, fine needle aspiration cytology or parotidectomy. Likewise, it was seen that there was no consensus on the treatment. Only surgery, RT and/or chemotherapy in addition to surgery were among the options for palliative purposes. No standard treatment protocol is currently available for glioblastoma spreading to the parotid gland, whereas no significant difference in clinical efficacy has been observed between these treatment modalities [27].

Overall survival times in glioblastoma that develop extracranial metastases are not different from the expected survival in patients without metastatic disease; are which is roughly estimated as 12 months. It has been reported that the average life expectancy of patients with local intracranial tumor recurrence is 7.5 months [2, 3, 27]. Furthermore, according to data with parotid gland metastases, the median survival time from the time of extracranial disease diagnosis was found between 2 months and 2.5 years with an average of 9 months. Our patient was the patient who was found to have survived the longest.

Conclusions

Due to the recurrence rate of the intracranial glioblastoma and its malignant nature; close imaging follow-up is highly crucial. The increase in reported cases of extracranial metastases is generally due to the modern diagnostic tools and prolonged survival attributed to the improvement in treatment modalities, where now radical surgery with adjuvant RT and chemotherapy is the standard protocol. Patients with glioblastoma who experience enlargement of cervical lymph nodes developing mass lesions in the neck area should undergo further investigation to rule out parotid gland metastasis.