Systemic cancer metastasis in a meningioma: Report of two cases and review of the literature

1. Introduction 

Metastases of systemic cancer to intracranial tumours, albeit rare, have been reported in the literature since 1930, mostly into meningiomas and, less frequently, in acoustic neurinomas, gliomas and pituitary adenomas [1].

Breast and lung are the most common sources of tumour-to-tumour metastasis, while kidney, thyroid, prostate and colon seem to be very rare [2], [3].

Many hypotheses have been postulated to explain this phenomenon: haemodynamic, metabolic, hormonal, and molecular. However, the exact mechanism still remains unknown.

We herein report two patients with breast and renal carcinoma metastases into an intracranial meningioma.

2. Clinical report 

2.1. Case 1 

A 64-year-old woman was admitted to our institution with headache, progressive right hemiparesis and dysphasia. The patient had undergone a right mastectomy and radiotherapy for breast carcinoma 10 years ago. A CT of the brain revealed a hyperdense left fronto-temporal lesion, surrounded by peritumoural edema, which presented marked enhancement. Cranial magnetic resonance imaging (MRI) showed few hypointense areas surrounded by a diffuse hyperintense lesion; contrast-enhanced MRI showed homogeneous enhancement of the whole mass and a few hypointense areas with hyperintense rims in the enhancing mass (Fig. 1). Cerebral angiography showed a late tumoural blush due to some branches originating from the middle meningeal artery.

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Fig. 1. Axial (A), coronal (B) and sagittal (C) gadolinium-enhanced T1-weighted MRI scans showing a large fronto-temporal mass with multiple cystic components and a dural attachment.

The patient underwent a left fronto-temporal craniotomy. A well-circumscribed greyish-white nodular mass was completely removed. The post-surgical course was uneventful. Histopathological findings yielded a diagnosis of metastasis. Postoperative local radiation therapy and chemotherapy were administered. Afterwards, vertebral metastases occurred and the patient died 20 months after diagnosis for the dissemination of the mammary disease.

2.2. Case 2 

A 61-year-old male was admitted to the hospital because of a mass in his right kidney. He underwent a right-sided nephrectomy; pathological examination revealed an invasive renal cell carcinoma (Fuhraman G2-G3; pT2 pN0). In the screening a small (<1cm) asymptomatic pulmonary nodule was detected by CT imaging. Serial CT did not show a progression of the lesion.

Three years later he presented with vertigo, diplopia, headache, nausea and vomiting. On neurological examination abducting nystagmus, dysphagia, dysphonia and left tongue deviation were observed. MRI demonstrated a foramen magnum extra-axial mass extending from the left cerebellopontine angle to premedullary cistern, iso-hyperintense on T1 and hyperintense on T2-weighted images with inhomogeneous contrast enhancement (Fig. 2). Conventional angiography disclosed a dense homogeneous tumour blush supplied by postero-inferior cerebellar artery (PICA) and left ascending pharyngeal artery. External carotid branch was then embolized. To determine the histology and to relieve symptoms the tumour was partially resected. Subsequent workup demonstrated multiple metastases to the lung and left adrenal gland. After the partial tumour removal the patient was treated with local radiotherapy and he is still alive 6 months after the diagnosis.

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Fig. 2. T1-weighted axial (A), coronal (B) and sagittal (C) MRI scans showing an inhomogeneously enhanced extra-axial mass at foramen magnum level, extending from the left cerebellopontine angle to premedullary cistern.

3. Histology 

Surgical specimens were fixed in 10% formalin for light microscopy.

Selected samples from both case specimens were routinely embedded in paraffin. Sections 5μm thick were cut and stained with hematoxylin and eosin (H&E).

Immunohistochemistry (IHC) was performed on paraffin-embedded tissue sections of the lesions by standard avidin–biotin complex method using specific antibodies against vimentin, cytokeratin (KL1), epithelial membrane antigen (EMA), glial fibrillar acidic protein (GFAP), estrogen receptor (ER), progesterone receptor (PgR), epithelial cadherin (E-cadherin) for the breast carcinoma metastasis and CD10, glutathione S-transferase alpha (GST-alpha) and epithelial cell adhesion molecule (EpCAM) for the clear cell renal carcinoma metastasis [4]. In addition, the proliferation index (using ki-67) and two other adhesion molecules (CD44 and NCAM) were studied in both cases.

In parallel, appropriate positive and negative controls were set up.

3.1. Case 1 

Microscopically, two types of cells were observed: spindle-shaped cells with a scanty cytoplasm which tended to form syncytial aggregates were infiltrated by wide foci of polygonal cells, which were intensively ER positive and E-cadherin positive (Fig. 3). GFAP and NCAM were negative and PgR proved to be intensively positive in both the metastatic and the meningothelial components. A focal CD44 positivity was observed in the meningioma, whereas the metastatic breast carcinoma was negative. Ki-67 value was >25% in the metastases and <3% in the meningioma.

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Fig. 3. Case 1: breast carcinoma metastasis in meningioma. At H&E, the surgical specimen was composed of two distinct cellular sub-population (A and B: 20× and 40×, respectively). One component was constituted by smaller cells, focally arranged in whirls and was intensively vimentin positive at IHC (C, 20×) and was diagnosed as meningioma. The other cellular population was formed by larger cells with nuclear atypias, arranged in nests, vimentin-negative and diffusely positive at IHC for ER (D, 20×). This second component was the metastasis of breast ductal carcinoma, and displayed a wide E-cadherin positivity on the cell membrane. The meningioma also was focally E-cadherin positive, with a granular cytoplasmic pattern (E and F: 40× and 60×, respectively).

3.2. Case 2 

At histology, in the metastatic clear cell renal carcinoma microscopic examination disclosed two distinct cell types: a meningothelial meningioma with small cells somewhere arranged in whirls strictly intermingled with large clear cells partly arranged in acinar structures, which were keratin positive and strongly CD10 positive, whereas the surrounding meningothelial cells were negative for both antibodies (Fig. 4). Vimentin, EMA and CD44 were coexpressed in both the metastatic and the hosting meningothelial lesion. Finally, E-cadherin and EpCAM were negative within the whole specimen and NCAM proved to be positive in the metastatic cells from renal carcinoma, as well as GST-alpha. Ki-67 value was >15% in the metastases and <4% in the meningioma.

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Fig. 4. Case 2: clear cell renal carcinoma metastasis in meningioma. The excised tissue was composed of two distinct cell types, strictly intermingled (A and B: 20×; C: 40×). The meningiomatous population was of smaller cells, partly elongated, keratin negative and displaying a low proliferative index (D, left side of the picture). The other component was of larger cells, with a clear cytoplasm, which displayed an intense positivity at IHC using KL1 (E, 20×; F, 40×) and CD10 (G, 40×) antibodies. These cells were the highly proliferating (Ki-67>15%, D, right side of the picture: 20×) metastatic counterpart of the lesion and derived from the primary renal carcinoma. In this case, IHC for vimentin and EMA was not useful in distinguishing the two populations since both were positive. Finally, E-cadherin staining was absent in both components of the lesion (H, 40×).

4. Discussion 

It is not uncommon that different histopathological types of tumour arise in the same patient, but metastases of one tumour to another is a rare pathological entity [5], [6].

Meningiomas are the most common primary intracranial tumour to harbour metastases [2], [3], [7]. They are generally slow-growing benign neoplasms (WHO I) arising from leptomeninges; atypical meningiomas (WHO II) and anaplastic meningiomas (WHO III), which are characterized by increased cellularity and mitotic activity, account respectively for 8% and 2% of this tumour type.

The first description of a systemic carcinoma metastasizing to a cranial meningioma was credited to Fried in 1930 [8]. Subsequently few cases of metastasis into a cerebral tumour have been reported: a recent review collected 63 published cases, the majority of which arise from breast (50%) or lung (30%) carcinomas: together they account for 80% of all reported cases [3]. Although the overall percentage of cranial metastases from breast and lung appears to be similar (70%) [9], their relative ratio is reversed since lung accounts for 50% and breast for 20%, as the most common origins of brain metastasis. Therefore breast seems to be overrepresented among metastases to meningiomas, probably for the presence of specific receptors.

In very few cases the metastasis in meningioma was the first clinical manifestation of the occult primitive carcinoma.

Both breast cancer and meningioma are relatively common isolated tumours. Epidemiological studies have shown that the tumours occur simultaneously with a higher frequency than expected individually. Breast cancer and meningioma share several features that might account for their apparent association. Both tumours occur commonly in individuals in the fifth and sixth decades and have a tendency to flare up during pregnancy. These features give support to the hypothesis of a possible hormonal relationship [6], [10]. The presence of receptors for sex hormones in a large proportion of meningiomas is well established. Progesterone, estrogen and androgen receptor expression seems to be inversely related to tumour grade (they are more frequent in grade I than in atypical/anaplastic histotype) and to mitotic index (patients with progesterone receptor-positive meningiomas show better progression-free survival rates) [11], [12]. Steroid hormones regulate target tissues via locally increased sensitivity to growth factors (e.g. EGF, IGF-1 and TGF-alpha) [11], [13]. Sex hormones have relevance in the development, growth and recurrence of both meningioma and breast cancer. The high positivity of PgR observed in case 1 might support the hypothesis that sex hormones could play a role in tumour-to-tumour phenomenon.

Chambers proposed criteria which could be used to assess a true tumour-to-tumour metastasis and to exclude the occurrence of two isolated tumours that successively fuse (collision tumours) [14]. They are as follows: the metastatic nidus must at least be partially enclosed by a rim of histologically distinct tumour tissue; the existence of the metastasizing primary tumour must be proven and be compatible with the metastasis. Both the here reported cases met the Chambers’ criteria.

Metastases from tumours of the kidney are exceedingly rare: beyond the present case, only two reports fulfilling the Chambers’ criteria exist in the literature (Table 1) [15], [16]. In fact the case reported by Osterberg is doubtful because the presumed extracranial primary tumour was never established either surgically or by post-mortem examination [17]. Likewise in the case reported by Breadmore et al. the renal primary tumour was detected by an abdominal CT scan, but the lesion was neither resected nor biopsied [18]. In cases described here, the metastatic clear cell renal carcinoma was fully immuno-characterized using a panel of specific antibodies (such as CD10, GST-alpha, EpCAM).

Table 1. Review of renal metastatic tumours to a meningioma

	References	Sex/age	Other metastases	Cranial surgery	Autopsy	Extracranial surgery or biopsy	Primary tumour histology
	Stortebecker [15]	F/45	Yes	Yes	No	Yes	Hypernephroma
	Osterberg [17]	M/51	No	Yes	No	No	No
	Breadmore et al. [18]	F/82	No	Yes	No	No	No
	Han et al. [16]	F/67	Yes	Yes	No	Yes	Clear cell carcinoma
	Present case	M/61	Yes	Yes	No	Yes	Clear cell carcinoma

The exact mechanisms responsible for the development of metastases within meningiomas are not known. The rarity of this situation could suggest that it represents a casual occurrence, even more rare both in the cranial (atypical, anaplastic and fibroblastic histological variants) and in the spinal sites, according to their overall low frequency of occurrence among meningiomas [2]. However, several theories have been put forward concerning the genesis of this event (Fig. 5).

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Fig. 5. Hypothetical mechanisms responsible for the development of metastases within meningiomas.

First, it has been suggested that the indolent growth of meningiomas provides a prolonged exposure to the primary tumour and the low metabolic rate may act as a non-competitive metabolic environment leading to the growth of metastatic tumours [19].

Second, the high collagen and lipid content of meningiomas has been postulated to provide a “fertile soil” for the seeding of malignant cells [20].

Third, the enhanced vascularisation of a meningioma may increase the chances of the tumour to “catch” circulating cancer cells and to form a metastasis. The vascular network may filter metastatic emboli from the bloodstream [21]. However, the rarity of metastases in a glioblastoma, a highly vascularized tumour, suggests that other factors are involved in the mechanism.

Fourth, the interactions between cell adhesion molecules expressed by both tumours could explain the affinity of several metastases towards some subtypes of meningioma [22]. In this regard, various papers have shown the possible role of the E-cadherin, a member of the cadherin family [2], [23]. E-cadherin is a cell-surface glycoprotein that plays an important role in calcium-dependent cell–cell adhesion. Its expression has been observed in most types of normal epithelia and systemic cancers and its dysfunction is related to carcinogenesis, tumour invasion and metastasis, especially in epithelial tumours. Although our series is very limited, only the case 1 IHC showed a E-cadherin positivity both in meningioma and in breast cancer metastasis confirming other reports in the literature [2], [23]. Otherwise E-cadherin was negative in the case 2, both in clear cell renal carcinoma metastasis and in meningioma; in addition, the other adhesion-related molecules tested (CD44 and NCAM) displayed an heterogeneous staining in the metastatic component of the two cases. Interestingly, despite the different E-cadherin pattern, both our cases displayed a similar strict intermingling among the two neoplastic populations. Such evidence suggests that various other factors, possibly including additional molecules interfering with cell adhesion, i.e. integrins, may participate in the crosstalk between these cellular subsets and modulate their modality of interfacing. Altogether these results suggest that the role of cell adhesion molecules needs further extensive investigation.

Immunological factors may also influence the risk that an intracranial tumour will receive metastases from other extracranial primary tumours: the lack of an immune response might support the growth of a metastasis within a brain tumour [3]. A depressed systemic cellular immune response in patients with meningiomas has been described [24], [25]. Anyway the exact role of immunological factors remains still debated.

The preoperative diagnosis of metastasis to meningioma is very difficult. Hypodense areas within a hyperdense, well-demarcated and enhancing mass on CT has been described in some patients with meningioma containing metastatic breast carcinoma [26], [27]. This appearance is however non-specific and could be due to areas of calcification, necrotic foci, cystic degeneration or haemorrhage. MRI features of metastasis in tumour have been reported only in a few cases in the literature [3], [28]. No particular MRI features were observed in these cases. Lee et al. [28] reported areas of marked enhancement in a background of moderate enhancement in MRI of breast carcinoma metastatic to meningioma. Elmaci et al. [26] described marked enhancement surrounded by a moderately enhancing halo compared with homogeneous enhancement of meningioma.

It is likely that the radiological diagnosis of metastasis to other tumours will become easier by using physiology-based neuroimaging methods, in fact it may be possible to differentiate each tumour type by its distinct biological properties. Perfusion-MRI (p-MRI) relies on haemodynamic differences in microvasculature to discriminate between unique tissue types [29]: meningiomas are highly vascular tumours with densely packed capillaries, whereas breast carcinoma metastases have more diffusely spaced capillaries because of interposed pools of mucin. This difference in capillary attenuation is consistent with p-MRI finding of Jun et al. [29], who showed a greater T2 maximal signal intensity drop, and therefore a greater relative cerebral blood volume (rCBV), for the meningioma than the metastasis. However, hypervascular lesions, such as kidney carcinoma or melanoma metastases present an elevated rCBV which may be indistinguishable from that of meningiomas [30]. So, more rigorous and systematic validation is necessary by correlating p-MRI data with histopathology and outcome.

MRI spectroscopy (s-MRI) has been reported as a useful diagnostic method for determining the proliferative or malignant potential of meningiomas according to the choline/creatine ratio, statistically correlated with MIB-1 staining index, and to the lactate/lipide peak, correlated with intratumoural necrosis [31]. Watanabe et al. [23] reported a patient with a breast cancer metastasis into a frontal parasagittal meningioma. The preoperative s-MRI showed increased choline/creatine ratio and high lactate/lipid peak, suggesting a possible malignant nature of the tumour. Nevertheless, the correct diagnosis was achieved only by histology, for the difficulty to differentiate an intratumoural metastasis of the systemic cancer from a malignant transformation of the meningioma.

A correct preoperative diagnosis showing that a meningioma contains a metastasis does not change the indication to surgical removal of the lesion, if technically feasible, as the first choice of treatment. In contrast, the possibility of a metastatic infiltration in the meningioma to be treated could suggest a different technical approach, namely an en bloc removal of the lesion, if possible, to avoid any intraoperative seeding of metastatic cells.

5. Conclusion 

Systemic cancer metastasizing into an intracranial meningioma is still a rare phenomenon.

The mechanism of such tumour-to-tumour metastasis is not completely understood and the preoperative diagnosis remains challenging. CT and/or MRI atypical features of meningiomas may suggest the possible occurrence of an intratumoural metastasis in patients affected by a systemic cancer.