Mesenchymal, Nonmeningothelial Tumors

Main Text

Preamble

The terminology and pathologic features of benign and malignant mesenchymal, nonmeningothelial neoplasms originating in the CNS correspond to soft tissue or bone tumors found elsewhere in the body.

These unusual neoplasms can be tumors of adipose, fibrous, histiocytic, cartilaginous, or vascular tissues and can also arise from muscle or bone. Both benign and malignant varieties of each type occur, ranging from benign (CNS WHO grade 1) to highly malignant (grade 4) sarcomatous neoplasms.

Nonmeningothelial mesenchymal tumors rarely involve the CNS. When they do, they arise more commonly in the meninges than in the brain parenchyma or choroid plexus. They can occur in patients of any age.

The 2021 5th edition WHO divides these uncommon tumors into three groups: (1) Soft tissue tumors; (2) chondroosseous tumors, and (3) notochordal tumors. This chapter focuses on the most important of these rare neoplasms.

While the 2021 5th edition WHO does not include benign chondroosseous tumors, for the sake of completeness, we close this chapter with a fourth section that focuses briefly on these benign neoplasms.

Soft Tissue Tumors

Preamble

Soft tissue tumors involving the CNS usually originate from the meninges (typically the dura), choroid plexus, or skull base. The cranial meninges contain primitive pluripotential mesenchymal cells that can give rise to a broad spectrum of nonmeningothelial mesenchymal tumors. Most are supratentorial; the falx is the most common site.

Soft tissue tumors included in the 5th edition WHO include solitary fibrous tumor (SFT), hemangiomas, and vascular malformations (such as arteriovenous and cavernous malformations), hemangioblastoma, rhabdomyosarcoma, Ewing sarcoma, and a group of newly recognized but uncommon tumors, such as DICER1-mutant primary sarcoma and CIC-rearranged sarcoma. In this section, we focus on SFTs, hemangiomas, hemangioblastoma, and sarcomas. Vascular malformations are probably not neoplastic and were covered in Chapter 7.

Solitary Fibrous Tumor

Terminology

Solitary fibrous tumor (SFT) represents a continuum of mesenchymal tumors with increasing cellularity. The term “hemangiopericytoma” (HPC) is no longer used.

Although relatively rare, SFT is the most common primary intracranial nonmeningothelial mesenchymal neoplasm. It is a very cellular, highly vascular neoplasm known for its aggressive clinical behavior, high recurrence rates, and distant metastases even after gross total surgical resection.

Etiology

SFTs at all anatomic sites have a genomic inversion at 12q13, which leads to NAB2:: STAT6 gene fusion. Demonstration of this fusion is considered virtually pathognomonic of SFT.

Pathology

Location

Most SFTs are dural based, usually arising from the falx or tentorium. The most common site is the occipital region, where they often straddle the transverse sinus. Intraparenchymal SFTs occur in the cerebrum and spinal cord, often without a discernible dural attachment. The cerebral ventricles are another common site.

Size and Number

SFTs are almost always solitary lesions. They are relatively large tumors, reaching up to 10 cm in diameter. Lesions more than 4-5 cm are not uncommon.

Gross Pathology

SFTs are solid, lobulated, relatively well-demarcated, dura-based neoplasms (28-1)that contain abundant vascular spaces. Myxoid change and intratumoral hemorrhage are common.

Microscopic Features

SFTs are variably cellular tumors composed of spindled to ovoid cells arranged around a branching and hyalinized vasculature. Necrosis is common. Nuclear atypia and mitotic activity vary.

Diagnostic Molecular Pathology

STAT6 nuclear expression can be detected by sequencing techniques or RT-PCR and confirms the diagnosis of SFT. Immunohistochemical detection of strong nuclear STAT6 expression is also a sensitive and specific surrogate for all fusions.

Staging, Grading, and Classification

Three grades of SFT/HPC are recognized in the 2021 WHO. Grading is based on mitotic activity in 10 adjacent high-power fields (HPF). CNS WHO grade 1 tumors have ≤ 5 mitoses/10 HPF. Grade 2 tumors have ≥ 5 mitoses/10 HPF without necrosis. Grade 3 tumors have ≥ 5 mitoses/10 HPF with necrosis.

Clinical Issues

Epidemiology

SFTs are rare, accounting for < 1% of all primary intracranial neoplasms and 2-4% of all meningeal tumors.

Demographics

Meningeal SFTs generally occur at a slightly younger age than meningiomas. Mean age at diagnosis is 43 years. There is a slight male predominance.

Natural History

Even with complete resection, local recurrence is the rule. The majority of meningeal SFTs eventually metastasize extracranially to bone, lung, and liver. There is no significant difference in survival between grade 2 and grade 3 SFTs.

Treatment Options

Surgical resection with radiation therapy or radiosurgery is the treatment of choice.

Imaging

CT Findings

SFTs are hyperdense extraaxial masses (28-5A)that invade and destroy bone. Extracalvarial extension under the scalp is common. Calcification and reactive hyperostosis are absent. Strong but heterogeneous enhancement is typical.

MR Findings

Low-grade intracranial SFTs are circumscribed masses that are usually dura based and resemble meningioma. Lesions are isointense with gray matter on T1WI (28-3A)and have variable signal intensity on T2WI (28-3B). A mixed hyper- and hypointense pattern is common. Collagen-rich areas can be very hypointense (28-5C). Avid enhancement following contrast administration is typical (28-5E).

Most SFTs demonstrate mixed signal intensity on all sequences (28-5). They tend to be predominantly isointense to gray matter on T1 scans and iso- to hyperintense on T2 scans (28-3B). Prominent “flow voids” are almost always present. Contrast enhancement is marked but heterogeneous. Nonenhancing necrotic foci are common. A dural tail sign is absent.

Angiography

SFTs may invade and occlude dural sinuses, so CTV or MRV are helpful noninvasive techniques for delineating patency.

DSA shows most SFTs as hypervascular masses with prominent vascularity, “early draining” veins, and intense prolonged tumor “staining.” SFTs usually recruit blood supply from both dural and pial vessels.

Differential Diagnosis

The major differential diagnosis of grade 1 SFT is CNS WHO grade 1meningioma. Grades 2 and 3 SFTs may resemble higher grade (2, 3) meningiomas. Unlike meningiomas, SFTs rarely calcify or cause hyperostosis, and a dural tail sign is typically absent.

Dural metastases with skull invasion can be indistinguishable from SFTs. Rare neoplasms that can resemble SFTs include other sarcomas.

Hemangioma

Terminology

Hemangiomas are true benign mesenchymal nonmeningothelial tumors. They closely resemble normal vessels and are found in all organs of the body (28-6). Hemangiomas are completely different from—and should not be confused with—cavernous or capillary malformations and arteriovenous malformations, which are all vascular malformations rather than true neoplasms. Vascular malformations were discussed in Chapter 7.

Etiology

Hemangiomas probably arise by endothelial hyperplasia and hamartomatous-like proliferation.

Pathology

Location

Hemangiomas arise preferentially in the spine. Intracranial hemangiomas can be located in different cranial compartments but are almost always extraaxial. They are found in the calvarium (28-7), dural venous sinuses, and dura.

Size and Number

Hemangiomas vary in size from microscopic to massive. Transspatial extension across different anatomic compartments (e.g., scalp and skull, soft tissues, orbit, and cavernous sinus) is common. Multicentric lesions are uncommon in the CNS.

Gross Pathology

Hemangiomas are nonencapsulated, vascular-appearing, soft reddish-brown lesions. When they involve the calvaria, radiating spicules of lamellar bone are interspersed with vascular channels of varying sizes (28-7). Hemangiomas of the venous sinuses and dura do not contain bone but otherwise resemble calvarial hemangiomas, consisting of large vascular channels in a soft, compressible mass.

Microscopic Features

Most intracranial hemangiomas consist of tightly packed, capillary-sized, and cavernous vessels with large, endothelium-lined spaces separated by fibrous septa.

Staging, Grading, and Classification

Hemangiomas are CNS WHO grade 1 neoplasms.

Clinical Issues

Demographics

Hemangiomas represent only about 1% of all bone tumors. Most are found in the spine; the diploic space of the calvaria is the most common intracranial site. Dural and venous sinus hemangiomas are rare.

Hemangiomas can occur at any age, although the peak presentation is between the fourth and fifth decades. The M:F ratio is 1:2-4.

Presentation

Most calvarial hemangiomas are asymptomatic, limited to the diploic space, and do not extend beyond the inner and outer tables of the skull (28-10). Large lesions may present as painless firm masses. Scalp hemangiomas presenting with Kasabach-Merritt syndrome (consumptive coagulopathy due to sequestration and destruction of clotting factors within the lesion) have been reported.

Cavernous sinus hemangiomas can be asymptomatic but often present with headache, diplopia, or other cranial neuropathies, such as anisocoria.

Intracranial hemangiomas occasionally occur as part of POEMS syndrome, a rare, multisystem disease with typical features of polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma-proliferative disorders, and skin changes.

Natural History

Hemangiomas typically grow very slowly and do not undergo malignant degeneration. Pregnancy or hormone administration may trigger enlargement.

Capillary hemangiomas of infancy (usually in the skin, scalp, orbit, or oral mucosa and only rarely involving the brain) appear within a few months of birth, grow rapidly, plateau, and then involute.

Treatment Options

Calvarial hemangiomas are typically left alone unless tumor growth is demonstrated. The treatment of venous sinus hemangiomas is much more problematic. These highly vascular lesions bleed easily, and surgical mortality is high. Radiation (gamma knife surgery) has been used with some success in a few reported cases and may become the primary treatment choice for hemangiomas in critical locations, such as the cavernous sinus.

Imaging

CT Findings

A calvarial hemangioma is seen as a sharply marginated, expansile diploic mass on NECT. Some lesions isolated to the scalp may have no underlying bony involvement.

Bone CT shows that the inner and outer tables are thinned but usually intact (28-10A). A thin sclerotic margin may surround the lesion. “Spoke-wheel” or reticulated hyperdensities caused by fewer but thicker trabeculae are present within the hemangioma, giving it a honeycomb or jail bars appearance (28-8A).

On CECT, foci of intense enhancement interspersed with focal hypodensities caused by the residual thickened trabeculae are typical.

MR Findings

Mixed hypo- to isointensity is the dominant pattern on T1WI. Scattered hyperintensities usually are caused by fat—not hemorrhage—within the lesion. Most hemangiomas are markedly hyperintense on T2WI (28-10C) (28-12B).

Contrast-enhanced scans show diffuse intense enhancement (28-8B). Dynamic scans show slow centripetal “filling in” of the lesion (28-12C).

Angiography

Dural and venous sinus hemangiomas can closely resemble meningiomas with slow, persistent contrast accumulation in the capillary and venous phases of the angiogram.

Differential Diagnosis

The differential diagnosis of calvarial hemangioma includes “holes in the skull” caused by venous lakes and arachnoid granulations, burr holes, dermoids, eosinophilic granuloma, and metastasis.

The major differential diagnosis for dural/venous sinus hemangioma is meningioma. Except for the microcystic variant, meningiomas do not display the marked hyperintensity on T2WI seen in most hemangiomas. Hemangiomas also exhibit the classic “filling in” from the periphery to the center of the lesion on rapid-sequence, dynamic contrast-enhanced T1WIs.

Hemangioblastoma

Terminology

Hemangioblastoma (HGBL) is a benign, slow-growing, relatively indolent vascular neoplasm. HGBL occurs in both sporadic (70%) and multiple (30%) familial forms.

Multiple HGBLs are almost always associated with the autosomal-dominant inherited cancer syndrome von Hippel-Lindau disease (VHL). A rare non-VHL form of multiple disseminated HGBLs is termed leptomeningeal hemangioblastomatosis.

Etiology

Allelic losses or mutations of the VHL gene at 3p25-26 are found in both sporadic HGBL and VHL. VHL gene mutations (losses or inactivations) are present in up to 80% of sporadic HGBLs. Multiple key angiogenic pathways, including VEGF-related angiogenesis, are massively activated in HGBL and contribute synergistically to the tumor’s abundant vascularization.

Pathology

Location

HGBLs can occur in any part of the CNS, although the vast majority (90-95%) of intracranial HGBLs are located in the posterior fossa (28-15). The cerebellum is, by far, the most common site (80%) followed by the vermis (15%). Approximately 5% occur in the brainstem, usually the medulla. The nodule of an HGBL is superficially located and typically abuts a pial surface (28-13).

Supratentorial tumors are rare, accounting for 5-10% of all HGBLs. Most are clustered around the optic pathways and occur in the setting of VHL.

Size and Number

HGBLs vary in size from tiny to large, especially when associated with a cyst. Unless they are syndromic, HGBLs are solitary lesions. If > one HGBL is present, the patient, by definition, has VHL. A positive family history or presence of other VHL markers (such as visceral cysts, retinal angioma, renal cell carcinoma) should prompt genetic screening.

Gross Pathology

The common appearance is that of a beefy red, vascular-appearing nodule that abuts a pial surface (28-14). A variably sized cyst is present in 50-60% of cases (28-15B). Cyst fluid is typically yellowish, and the cyst wall is usually smooth. Approximately 40% of HGBLs are solid tumors.

Microscopic Features

HGBLs contain two different cell types, stromal and vascular cells. Generally, it is the stromal (not the vascular) cells that are the neoplastic element of an HGBL.

The cyst wall of most HGBLs is nonneoplastic, composed of compressed brain with fibrillary neuroglia devoid of tumor cells. The intratumoral cyst fluid shares a proteomic fingerprint with normal serum and has no proteins in common with HGBL tumor tissue. Cyst formation in HGBLs is therefore a result of vascular leakage from tumor vessels, not tumor liquefaction or active secretion.

Mitoses in HGBLs are few or absent, so proliferation rates are low, too (usually MIB-1 < 1). HGBL is a CNS WHO grade 1 neoplasm. There is no recognized atypical or anaplastic variant.

Clinical Issues

Epidemiology

HGBL accounts for 1.0-2.5% of primary CNS neoplasms and approximately 7% of all primary posterior fossa tumors in adults. It is the second most common infratentorial parenchymal mass in adults (after metastasis).

Between 25-40% of HGBLs are associated with VHL.

Demographics

HGBL is generally a tumor of adults between the ages of 30 and 65 years. Pediatric HGBLs are rare. VHL-associated HGBLs tend to present at a significantly younger age but are still relatively rare in children under the age of 15. There is a slight male predominance.

Presentation

Most symptoms in patients with the cystic form of HGBL are caused by the cyst, not the neoplastic nodule. Headache is the presenting symptom in 85% of cases. HGBLs produce erythropoietin, which causes secondary polycythemia in approximately 5% of patients.

Natural History and Treatment Options

Because HGBLs exhibit a stuttering growth pattern, they are frequently stable lesions that can remain asymptomatic for long intervals. Imaging progression alone is not an indication for treatment, although tumor/cyst growth rates can be used to predict symptom formation and future need for treatment.

Although HGBLs show no intrinsic tendency to metastasize, there are sporadic reports of intraspinal dissemination. Complete en bloc resection is the procedure of choice. Total resection eliminates tumor recurrence, although new HGBLs may develop in the setting of VHL.

Imaging

General Features

HGBLs have four basic imaging patterns: (1) Solid HGBLs without associated cysts, (2) HGBLs with intratumoral cysts, (3) HGBLs with peritumoral cysts (nonneoplastic cyst with solid tumor nodule), and (4) HGBLs associated with both peri- and intratumoral cysts (nonneoplastic cyst with cysts in the tumor nodule). A nonneoplastic peritumoral cyst with solid nodule is the most common pattern, seen in 50-65% of cases. The second most common pattern is the solid form, seen in about 40% of cases.

CT Findings

The most common appearance is a well-delineated iso- to slightly hyperdense nodule associated with a hypodense cyst. Calcification and gross hemorrhage are absent. The nodule enhances strongly and uniformly following contrast administration.

MR Findings

An isointense nodule with prominent “flow voids” is seen on T1WI. If an associated peritumoral cyst is present, it is typically hypointense to parenchyma on T1WI but hyperintense compared with CSF (28-17).

Compared with brain parenchyma, the tumor nodule of an HGBL is moderately hyperintense on T2WI and FLAIR. Intratumoral cysts and prominent “flow voids” are common. The cyst fluid is very hyperintense on both T2WI and FLAIR (28-17).

Occasionally, an HGBL hemorrhages. If present, blood products “bloom” on T2*.

Intense enhancement of the nodule—but not the cyst itself—is typical (28-16C). Cyst wall enhancement should raise the possibility of tumor involvement, as compressed, nonneoplastic brain does not enhance.

Noncystic HGBLs enhance strongly but often heterogeneously (28-18). Multiple HGBLs are seen in VHL and vary from tiny punctate to large solid tumors (see Chapter 43).

Supratentorial HGBLs are rare. Most occur around the optic nerves or chiasm. HGBL also sometimes occurs as a hemispheric mass with a cyst + nodule appearance.

Angiography

The most common appearance is that of an intensely vascular tumor nodule that shows a prolonged vascular “blush”(28-21). “Early draining” veins are common. If a tumor-associated cyst is present, vessels appear displaced and “draped” around an avascular mass.

Differential Diagnosis

The differential diagnosis of HGBL varies with age. In a middle-aged or older adult, the statistically most common cause of an enhancing posterior fossa intraaxial (parenchymal) mass is metastasis, not HGBL! DWI and DSC-PWI are helpful in the characterization and differentiation of HGBL from brain metastases. HGBL has higher minimum ADC values and relative ADC ratios compared with metastases.

A cerebellar mass with “cyst + nodule” in a child or young adult is most likely a pilocytic astrocytoma, not HGBL or metastasis. Occasionally, a cavernous malformation can mimic an HGBL with hemorrhage.

Tumors of Uncertain Differentiation

The 2021 WHO groups a number of rare sarcomas together as “tumors of uncertain differentiation.” These include intracranial mesenchymal tumor, FET:: CREB fusion-positive, CIC–rearranged sarcoma, primary intracranial sarcoma DICER1–mutant, and Ewing sarcoma. Most of these appear as relatively circumscribed extraaxial tumors attached to the dura. Mixed solid and cystic components, variable edema, and avid enhancement are typical features on imaging studies. Many have an enhancing dural “tail” and mimic meningioma (28-23).

Chondroosseous Tumors

Preamble

Chondroosseous tumors include mesenchymal chondrosarcoma and chondrosarcoma. Approximately 1% of all chondrosarcomas are intracranial.

Chondrosarcoma

Terminology

Chondrosarcomas are a family of malignant mesenchymal tumors with cartilaginous differentiation.

Etiology

Chondrosarcomas arise from remnants of embryonal cartilage, endochondral bone, or from primitive mesenchymal cells in the meninges. The majority of skull base chondrosarcomas harbor an IDH1 or IDH2 mutation.

Most chondrosarcomas are sporadic, but individuals with enchondromatosis (Ollier disease, Maffucci syndrome) have an increased risk of developing a chondrosarcoma.

Pathology

Location

Most intracranial chondrosarcomas are located in the skull base, typically off-midline and centered on the petrooccipital fissure.

Gross Pathology

A smooth, lobulated, grayish-white mass arising from the petrooccipital fissure is the typical appearance.

Microscopic Features

Moderate hypercellularity with cartilaginous differentiation in a myxoid or hyaline matrix is typical. Chondrosarcomas are distinguished from chordoma by the absence of cohesive nests of cells. The neoplastic chondrocytes are negative for cytokeratin.

Staging, Grading, and Classification

CNS sarcomas are designated CNS WHO grade 1, 2, or 3 based on the degree of cellularity, cytologic atypia, and mitotic activity. Most skull base chondrosarcomas are grade 1 neoplasms.

Clinical Issues

Most patients are middle aged with headache and sometimes cranial nerve palsies.

Imaging

CT shows an expansile mass at the petrooccipital fissure with erosive/destructive bone changes in the adjacent clivus and petrous apex (28-25A). Approximately 50% of cases have a classic chondroid matrix with “rings and arcs” calcification.

Chondrosarcomas are low to intermediate signal intensity on T1WI and usually hyperintense on T2WI (28-25B). Heterogeneous enhancement on T1 C+ is typical (28-25C).

Differential Diagnosis

The major differential diagnosis for chondrosarcoma is chordoma. Chordomas are more often midline, centered in the clivus. Metastases to the skull base are often multiple, hypointense on T2WI, and exhibit moderately strong enhancement. DWI and dynamic contrast-enhanced pMR can be helpful in differentiating these three common skull base tumors.

Notochordal Tumors

Preamble

There is only one notochordal neoplasm in the 2021 5th edition WHO classification of CNS tumors: Chordoma.

Chordoma

Terminology

Chordomas are rare, locally aggressive primary malignant bone neoplasms with a phenotype that demonstrates notochordal differentiation.

Etiology

Skull base (clival) chordomas probably arise from the cranial end of primitive notochordal remnants. Subpopulations of cancer stem-like cells have been identified in some chordomas.

Signal transducer and activation of transcription (STAT) proteins regulate key cellular fates, including proliferation and apoptosis. STAT3 is activated in chordoma.

Pathology

Chordomas almost always arise within the axial skeleton, anywhere along the primitive notochord. The sacrum is the most common site (50% of all chordomas) followed by the sphenooccipital (clival) region (35%) (28-26)and spine (15%).

Most sphenooccipital chordomas are midline lesions. Occasionally, a chordoma is predominantly extraosseous and arises off-midline, usually in the nasopharynx or cavernous sinus.

Four major histologic forms of chordoma are recognized: Conventional (“classic”), chondroid, differentiated, and poorly differentiated SMARCB1-deficient types. Conventional chordoma is the most common type and consists of physaliphorous cells that contain mucin and glycogen vacuoles, giving this tumor a characteristic bubbly appearance to its cytoplasm.

Chondroid chordomas have stromal elements that resemble hyaline cartilage with neoplastic cells nestled within lacunae (28-27). Dedifferentiated chordoma represents < 5% of chordomas and typically occurs in the sacrococcygeal region, not the clivus.

Both conventional and chondroid chordomas are strongly immunopositive for the epithelial markers cytokeratin (especially CK8) and epithelial membrane antigen (EMA). Dedifferentiated chordomas exhibit SMARCB1/INI1 loss and are associated with dismal prognosis.

Clinical Issues

Chordomas account for 2-5% of all primary bone tumors but cause almost 40% of sacral tumors. Although chordomas may occur at any age, peak prevalence is between the fourth and sixth decades. SMARCB1-deficient chordomas are childhood tumors, presenting at a median age of seven years. There is a moderate male predominance.

Clival chordomas typically present with headaches and diplopia secondary to CNVI compression. Large chordomas may cause multiple cranial neuropathies, including visual loss and facial pain.

Although they grow slowly, chordomas are eventually lethal unless treated with aggressive resection and proton beam irradiation. Chondroid chordomas exhibit the most favorable outcomes, whereas dedifferentiated and poorly differentiated tumors are associated with the most rapid progression and worst overall survival.

Imaging

NECT shows a relatively well-circumscribed, moderately hyperdense midline or paramedian clival mass with permeative lytic bony changes (28-28A) (28-29A). Intratumoral calcifications generally represent sequestrations from destroyed bone.

Chordomas exhibit substantial heterogeneity on MR. Most conventional chordomas are typically intermediate to low signal intensity on T1WI. On sagittal images, a “thumb” of tumor tissue is often seen extending posteriorly through the cortex of the clivus and indenting the pons (28-28B).

Conventional chordomas are very hyperintense on T2WI, reflecting high fluid content within the physaliphorous cells (28-28C) (28-29B). Intratumoral calcifications and hemorrhage may cause foci of decreased signal within the overall hyperintense mass.

Enhancement is quite variable. Some cases demonstrate moderate heterogeneous enhancement, although many clival chordomas demonstrate minimal or no enhancement.

CHORDOMA

Etiology

• Arises from cranial end of primitive notochordal remnants

• STAT3 activation

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