Grade I meningioma with disseminated bone disease: a rare clinical phenomenon

Abstract

Meningioma, the second most common primary tumour of the central nervous system, is classified into three different grades based on their characteristics. Each tumour grade includes different molecular subtype, growth potential, and thus, different prognosis. Grade I meningioma is the most common subtype with a benign course, in which systemic dissemination rarely occurs. We present the case of a 48-year-old male patient with a history of grade I meningioma who was referred 3 years after the initial diagnosis to our centre due to pelvic pain. Computed tomography (CT) images showed new pelvic bone lesions whose histopathological report was compatible with a grade I meningioma. Neither hormonal therapy concomitant with octreotide nor hydroxiurea treatments were effective. Very little is known about this entity’s prevalence and treatment when disseminated disease occurs. Thus, we think it is important to increase the positive and negative clinical experiences in this setting.

Background

Meningioma is one of the most frequent primary tumours of the central nervous system, representing about one-third of cases.¹ The incidence increases with age and predominates in women, due to the tumour’s dependence on oestrogen.^1–3 WHO classifies this disease in three grades with different prognostic values based on histopathological findings.³ Grade I meningiomas are the most frequent and usually have a benign nature with good response to local treatment, while grade II (atypical meningioma) and grade III (malignant meningioma) are more aggressive with higher relapse rates. The treatment for grade I meningiomas should be individualised to avoid causing unnecessary morbidity and a wait-and-see strategy is an option for many cases, with surgery and radiation being reserved for lesions causing symptoms. Completely resected grade I meningiomas do not receive adjuvant radiation. The long-term local control rate is excellent, having a progression-free-survival (PFS) of 80% at 10 years if complete resection is achieved.⁴ Extracranial metastases of meningiomas are exceptional, with those derived from grade I meningioma being even less common. Given their rarity and poor bibliographic documentation, the prognosis of disseminated disease is unknown and a standard therapeutic option is not available in this situation.³ We report this meningioma case due to the rareness of a grade I intracranial meningioma with multiple bone metastases, without progression of the histological subtype.

Case presentation

A 48-year-old male patient with an active smoking history of 10 pack years, with no known drug allergies and no significant family history, was admitted to the emergency room (ER) because of a syncope event. He was well until 10 days previously, when he began to experience disorientation, and suddenly, presented a syncope with sphincter relaxation and no apparent head or pelvic trauma.

The patient had a history of a cavernous sinus meningioma, treated with a 14 Gy single-dose radiosurgery with gamma-knife, having a rapid tumour recurrence at 2 years of follow-up. An incomplete surgical resection was performed at recurrence, with a histological evaluation revealing a grade I cavernous sinus transitional meningioma. He completed treatment with adjuvant hypofractionated stereotactic radiosurgery with a total dose of 25 Gy divided in five fractions. Since then, he continued prophylactic antiepileptic treatment with levetiracetam.

On admission to the ER, vital signs were within range and physical examination was significant for right pelvic somatic pain with functional disability of the right-lower extremity. No other pathological signs were noted and the neurological examination was normal. An urgent cranial CT showed stability of the intracranial tumour and ruled out acute intracranial pathology. The initial lab work only showed elevation of creatine kinase, the rest was normal. During his hospital stay, a pelvic CT scan was performed which reported a pathological fracture of the right iliac branch due to two infiltrative bone lesions with muscle infiltration, suggestive of metastases. A CT-guided core-needle biopsy (CNB) was performed, whose histological evaluation revealed a ‘carcinoma of unknown origin’, without performing immunohistochemistry (IHQ). He was referred to our centre to complete the diagnosis.

Investigations

On arrival at our medical oncology department, further studies were requested; a pelvic magnetic resonance imaging (MRI) and a thoracoabdominal CT scan (figure 1). Both studies showed multiple areas of bone involvement, but no lesions with radiological characteristics suggestive of a primary bone tumour, so a new bone CNB of the pelvic lesion was performed. After a complete IHQ workup, epithelial membrane antigen (EMA) and progesterone receptors were positive and cytokeratin, protein S100 and melanA were negative. The histopathological morphology and IHQ analysis from the bone tissue were compatible with grade I meningioma (figure 2).

Figure 1.

Pelvic CT shows a fracture of the right iliac branch with increased right iliac and right obturator muscles’ infiltration by the tumour. The image also shows a fracture of the right ischiopubic and iliopubic ramus bones (not shown).

Figure 2.

Bone biopsy. In the low magnification image (top and left), bone trabeculae can be seen alongside a solid cell proliferation. In the large magnification image (above and right), a heterogeneous epithelial cells proliferation with polymorphic nuclei and solid pattern can be seen. Some cells show nuclear pseudoinclusions (arrow). Immunohistochemistry showed positivity for epithelial membrane antigen (EMA; image below and left) and progesterone receptors (image below and right); being negative for cytokeratins 7 and 20, TTF1, GATA3, protein S100 and melanA. The proliferation rate (Ki-67) reached 20%. Morphology and immunohistochemistry were compatible with meningioma.

Given this finding of bone invasion by grade I meningioma, the histology of the initial surgical resection was reviewed as well as the bone CNB performed, confirming the surprising diagnosis (figures 2 and 3). Due to the disease’s aggressiveness, telomerase reverse transcriptase (TERT) mutation was attempted at the meningeal surgical resection sample, but the quality of the DNA obtained was suboptimal for analysis. Unfortunately, we could not evaluate the presence of TERT mutation in the bone sample due to the damage the DNA suffers during the processing of such biopsies. Alterations of the DNA repair genes were analysed and resulted to be negative. An OctreoScan was performed, showing uptake at the level of all bone lesions. During hospitalisation, a brain MRI was performed which showed an extra-axial tumour at the centre of the petrosal portion of the right temporal lobe compressing the trunk, stable compared with previous CT studies (figure 4).

Figure 3.

Review of brain biopsy of previous recurrence (December 2017). At low magnification (above and left), meninges are seen accompanied by a solid atypical cell proliferation with signs of bleeding and cauterisation artefacts. At large increase (above and right), a proliferation of heterogeneous nuclei with the presence of nuclear pseudoinclusions (arrow) can be seen. Immunohistochemistry shows positivity for epithelial membrane antigen (EMA; image below and left) and progesterone receptors (image below and right); being negative for cytokeratins 7 and 20, TTF1, GATA3, protein S100 and melanA. The proliferation rate (Ki-67) also reached 20%.

Figure 4.

Brain MRI shows an extra-axial tumour at the centre of the petrosal portion on the right temporal lobe with involvement of the skull base and compressing the trunk, apparently stable with respect to size compared with previous CT studies. It associates postsurgical changes in the temporal area from the previous partial resection.

After reviewing the previous and new biopsies, together with the imaging studies, the final diagnosis was multiple bone metastasis from a grade I transitional cavernous sinus meningioma.

Treatment

We decided to start treatment with tamoxifen, octreotide long-acting release(LAR) and zoledronic acid. This was due to the positive uptake of octreoscan and the presence of positive hormonal receptors at histological examination. Likewise, it was decided to perform radiotherapy with 8 Gy single dose on the left shoulder and 20 Gy in four fractions on the right pelvis. He was discharged to a rehabilitation centre to begin physical rehabilitation.

Outcome and follow-up

Three months after discharge, intracranial and extracranial disease progression was documented, with the appearance of new bone metastasis at the spinal column and new hepatic lesions. A following line of treatment with hydroxyurea was started with poor tolerance, requiring dose reduction. Best supportive care was decided after 2 months of hydroxiurea due to deteriorating clinical status. He died peacefully 9 months after the diagnosis.

Discussion

Metastatic dissemination of meningioma is an uncommon event, making the dissemination of a grade I meningioma especially exceptional. This makes the diagnosis extremely difficult. The incidence of distant metastases in grades II and III is 5% and 30%, respectively.⁵ The main route for distant metastases includes the venous system through the internal jugular vein or paraspinal plexus and the lymphatic system.⁵ Despite these data reported in the literature, cases of pulmonary and hepatic metastasis of a grade I meningioma have been described, none of which reported bone metastasis.^{6 7} Enomoto et al described a case of metastatic grade I meningioma, 26 years after resection of the primary tumour. They also report a 27% of pathological upgrade, confirmed at the time distant metastasis occur from initial surgery.⁵ Our patient had a metastatic recurrence 2 years after the primary surgery, without an increased histopathological grade.

Despite the limited experience and reported data, systemic treatment was proposed based on the characteristics found in this neoplasm and reported in the literature. The presence of progesterone, androgen and oestrogen receptors in up to two-thirds of meningiomas makes them a likely therapeutic target. Furthermore, up to 90% of meningiomas express somatostatin receptors,³ evidenced in the OctreoScan from our patient.

A good response to immune checkpoint inhibitors has also been reported in patients with meningioma and the presence of mismatch repair (MMR) deficiency, which represent 7% of cases.⁸ Unfortunately, our patient did not present MMR deficiency and could not benefit from immunotherapy.

On top of this, the presence of TERT mutations have been related to worse survival and greater tumour aggressiveness.⁹ It was for this reason that we requested this alteration in our patient, taking into account the atypical characteristics of our case.

Hydroxyurea was prescribed after progression to hormonal and somatostatin analogue combined treatment, justified by the positive results in objective response rate (ORR) and PFS reported in several case series. No randomised clinical trials are available in the literature to date.^10–13 Agents against specific molecular targets and immune response modulators are in an exploratory phase.

In conclusion, despite the benign nature of this tumour, metastatic meningioma must be considered as a possible cause of systemic disease in the setting of an unknown primary cancer. Future prospective trials will be necessary to help define a new possible diagnostic approach and optimal therapeutic sequence for metastatic meningioma.

Patient’s perspective.

I will try my best to stay healthy, not only for me but also for my family. They told me it was a benign tumour, but it spread suddenly to my bones. I trust my doctors and hope this new therapy can stop the disease.

Learning points.

• Metastatic meningioma is rare but can occur even in patients with a non-aggressive (grade I) subtype.

• Meningioma’s tumours express oestrogen, progesterone and testosterone receptors as well as somatostatin receptors. These findings can guide systemic therapy.

• TERT mutations confer a worse survival, without a specific targeted treatment.

• Future prospective trials will be necessary to help define a new diagnostic approach and further investigations must be done in order to evaluate optimal therapeutic sequence since there is not a standard treatment yet.