3
Pathology of Tumors of the Spinal Cord, Spine, and Paraspinous Soft Tissue

For each tumor, common alternative names, epidemiology/incidence, and location are noted. The gross and microscopic pathologic features, including diagnostic and prognostic details, are discussed. Relevant immunohistochemistry (Table 3-1) is described and illustrated, with attention to differential diagnostic considerations. Tumor genetics are discussed in a different chapter and are noted here only where diagnostically relevant.

Nervous System Tumors

Astrocytomas (Diffuse Astrocytomas, Ordinary Astrocytomas)

For reasons discussed more fully in relation to gangliogliomas and pilocytic astrocytomas, data regarding the frequency of occurrence of diffuse spinal cord astrocytomas are hard to obtain and of questionable validity. Diffuse spinal cord astrocytomas are rare tumors, representing only 6 to 8% of all spinal cord tumors.¹ Several series, however, suggest that they compose 30 to 54% of intramedullary tumors in adults^2–4 and ~60% in children.⁵ The average age of occurrence is ~30 years, and occurrence after 60 years of age is rare.^2,3 When all astrocytomas are considered, their incidence is higher in men than women (M:F ratio 1.3 to 2.2:1). When only diffuse astrocytomas are considered, the ratios vary widely, from about 1:1 to 2.5:1.^1–3 Diffuse astrocytomas usually involve three or fewer spinal cord segments. Most tumors (80 to 85%) occur in the cervical or thoracic spinal cord, often overlapping regions. Thoracolumbar involvement accounts for most of the remainder; isolated lumbar involvement is rare.^1,2

Spinal cord astrocytomas are graded using the same histologic criteria and systems as for their intracranial counterparts. Table 3-2 describes the grading classification of astrocytomas in the World Health Organization (WHO) system. Historically, grade II tumors were officially classified as astrocytomas, without a modifier. Use of this term by itself inevitably causes clinicians to respond: “What grade?” The most recent WHO classification system calls these tumors diffuse astrocytomas, noting that some pathologists prefer the term well-differentiated astrocytomas. The former term is used to describe the entire group of diffusely invasive astrocytomas (rather than more expansive tumors such as pilocytic astrocytomas and pleomorphic xanthoastrocytomas), irrespective of grade, and therefore inspires the same question. Use of the modifier well-differentiated avoids this problem and is preferred. The distribution of tumors according to grade also varies across studies, with 50 to 75% classified as well-differentiated/grade II and the remainder as high grade (grades III to IV). High-grade tumors are more common in adults than children. Most high-grade tumors are anaplastic astrocytomas/grade III; glioblastomas multiforme/grade IV tumors are rare.^1–3,5,6

Well-Differentiated Astrocytomas (Grade II)

Gross and Microscopic Pathologic Features

Externally, spinal cord astrocytomas produce a fusiform enlargement. The cut surfaces vary from soft to firm. The core of cellular tumors is gray, but the tumor may resemble normal parenchyma. The margins are ill defined as the tumor blends imperceptibly into spinal cord parenchyma. Astrocytomas tend to arise eccentrically in contrast to ependymomas, which tend to originate in central locations. Many cases develop a fluid-filled syrinx. Occasionally, penetration of the pia mater results in an exophytic mass in the subarachnoid space.

Like their intracranial counterparts, well-differentiated spinal cord astrocytomas are characterized by a diffuse infiltrate of cells that resembles mildly atypical astrocytes, primarily fibrillary but also gemistocytic and protoplasmic. The tumor cells infiltrate primarily white but also gray matter (Fig. 3-1A). Both in the tumor core and to a greater degree in its infiltrating margins, parenchyma is spared and neurons and axons may be scattered throughout (Fig. 3-1B). The tumor cells can form fascicles or be scattered without obvious pattern. Nuclei are larger than those of normal stromal astrocytes and often exhibit a striking uniformity. They vary from round to oblong and have smooth contours. There may be mild hyperchromasia or irregular clumping of chromatin. They have obvious glial cytoplasm, the distribution of which varies according to astrocytic phenotype. An occasional cell with increased atypia does not warrant classification as anaplastic/grade III. Similarly, whereas mitotic figures are exceptional, a single mitosis in the absence of other high-grade features does not an anaplastic tumor make. Although reported, the presence of Rosenthal fibers, granular bodies, or both prompts a strong consideration of pilocytic astrocytoma or ganglioglioma. Particularly in regard to Rosenthal fibers, caution is urged in interpreting their significance, as they are commonly associated with a syrinx or other reason for chronic gliosis.

FIGURE 3-1 Well-differentiated astrocytoma. (A) Tumor cells resembling fibrillary astrocytes diffusely infiltrate white matter. Edema is present but axons are preserved (hematoxylin and eosin [H&E], ×200). (B) Atypia and hypercellularity are mild. No mitoses are identified. Note the monotonous appearance of the nuclei (H&E, ×400).

Immunohistochemistry

Glial fibrillary acidic protein (GFAP) immunoreactivity may help confirm astrocytoma differentiation in any grade tumor. Reactivity for vimentin is also consistent but is too nonspecific for diagnostic relevance. S-100 positivity is consistent and somewhat more specific but adds little to the classification of the GFAP-positive tumor. p53 protein is identifiable in many well-differentiated cerebral astrocytomas. Although no series has evaluated the presence of p53 in spinal cord tumors, a similar pattern of expression would not be surprising. Concordant with the lack of mitotic activity, Ki-67/MIB-1 labeling indices should be low.

Anaplastic Astrocytomas (Grade III)

Gross and Microscopic Pathologic Features

The macroscopic features of anaplastic astrocytomas may not differ significantly from those of well-differentiated astrocytomas. Compared with grade II astrocytomas, greater cellularity may produce a more pronounced gray or fleshy color in a more obvious tumor core; however, the gradual merging of invading tumor and parenchyma at the periphery is the same in the two grades.

Again, these tumors resemble their cerebral relatives. In contrast to well-differentiated tumors, there is an often much greater degree of hypercellularity and atypia (Fig. 3-2A). In particular, irregularities of nuclear contour, pleomorphism, and abnormalities of chromatin distribution are prominent. In addition, residual neurons and axons may be sparse as tumor cells crowd them out. Mitoses, including atypical forms, are almost always found and are often numerous (Fig. 3-2B). Neither microvascular proliferation nor necrosis is present.

Immunohistochemistry

The immunohistochemical profile of anaplastic astrocytomas should be similar to that of well-differentiated tumors. An exception is the expectation of a high MIB-1 labeling index, which indicates a highly proliferative tumor.

The GBMs are destructive lesions, and little residual parenchyma is identified in the tumor core. Hypercellularity is usually marked. Atypia is pronounced and may manifest as significant irregularities in nuclear contour and chromatin distribution or as bizarre, sometimes multinucleate giant cells. Mitoses are numerous and often atypical (Fig. 3-3A). Microvascular proliferation, tumor necrosis, or both are the sine qua non of GBMs. The former is characterized by small vessels with thick walls formed by multiple layers of cells, presumably hypertrophied endothelial cells and pericyte/smooth muscle cells, and fibrous tissue (Fig. 3-3B). Two patterns of necrosis occur. The most recognizable is pseudopalisading necrosis, in which small irregular foci of necrotic debris are surrounded by a hypercellular, radially oriented band of small anaplastic astrocytes (Fig. 3-3C). Large areas of necrosis without pseudopalisading also occur. Sometimes such foci are accompanied by adjacent vessels with fibrinoid necrosis, prompting their characterization as infarct-type. The diagnostic significance of the two patterns is the same. Penetration of the pia and extension into the subarachnoid space is common in spinal cord astrocytomas (Fig. 3-3D).

Immunohistochemistry

No immunohistochemistry data are specific to spinal cord GBMs. Consequently, these data are derived from cerebral tumors. As with lower-grade astrocytomas, GBMs are reactive for GFAP, S-100, and vimentin, but only the first has diagnostic significance (Fig. 3-3E); however, GFAP expression may be highly variable within a tumor. p53 immunoreactivity is characteristic of secondary GBMs (those that evolve from a well-differentiated astrocytoma) but is rare in primary or de novo GBMs. Primary GBMs are more likely to overexpress epidermal growth factor receptor (EGFR, 60%) or, less commonly, MDM-2 (50%).

Pilocytic Astrocytomas (Juvenile Pilocytic Astrocytomas, Microcystic Astrocytomas)

Whereas pilocytic astrocytomas in the spinal cord are rare, some reports conclude that they are among the most common intramedullary tumors, second only to ependymomas, and are more common than diffuse astrocytomas or gangliogliomas. A combination of two series totaling 133 definitively diagnosed spinal cord astrocytomas found 72 pilocytic and 51 diffuse astrocytomas.^1,2 Again, however, the relative incidence of these tumors is controversial. Thus, the epidemiologic data provided here are meant for reference and cannot be considered definitive.

This tumor is sometimes designated as juvenile pilocytic astrocytoma. In the spinal cord, the average age of diagnosis of pilocytic astrocytomas is ~40 years compared with 30 in diffuse astrocytomas.¹ Most occur in the cervical and/or thoracic spine, whereas ~15% involve the thoracic and lumbar spine together. Almost half involve four or more vertebral segments compared with 30% of diffuse astrocytomas. There is a very slight male predominance.

The microscopic features of pilocytic astrocytomas of the spinal cord are the same as in intracranial tumors. They are composed of variable numbers of well-differentiated bipolar (pilocytes) or stellate astrocytes (Fig. 3-4A,B). The former tend to have abundant prominent fibrinoid processes, whereas the processes of stellate astrocytes tend to be fewer and become finer and less apparent. Areas in which pilocytes predominate tend to have compact fibrillary architecture. Stellate astrocytes are associated with a looser texture, and mucopolysaccharide deposition between processes creates the characteristic microcystic pattern. Degenerative coalition of the microcysts results in the formation of macrocysts. Hypercellularity is mild, as is atypia. Occasional cells may be markedly atypical but have no prognostic significance. Mitotic activity is rare, as is necrosis, which presumably is due to degenerative vascular occlusion. Glomeruloid capillaries are a characteristic feature (Fig. 3-4C); however, they tend to lack the hypercellularity associated with microvascular proliferation in GBMs. Vascular hyalinization is another common feature. Pilocytic astrocytomas are expansive rather than diffusely infiltrative. Consequently, the plane between tumor and parenchyma is usually well defined; however, parenchymal cells can still be entrapped. An occasional typical neuron in an otherwise characteristic pilocytic astrocytoma does not warrant changing the diagnosis to ganglioglioma.

FIGURE 3-4 Pilocytic astrocytoma. (A) Classic pilocytic tumor cells are bipolar astrocytes with thick bundles of fine glial processes. Areas in which these cells predominate tend to be solid. The nuclei are oval-to-oblong with little atypia (H&E, ×200). (B) A second cytologic type, sometimes termed protoplasmic, is variably prominent. The nuclei are round and the cells have radially distributed processes. These areas are associated with microcystic spaces, often with visible blue-gray mucopolysaccharide material (H&E, ×200). (C) Glomeruloid capillary networks are commonly present. The vessels usually have thin walls. The hypercellularity that characterizes microvascular proliferation in glioblastomas multiforme is seldom present (H&E, × 400). (D) Rosenthal fibers, thick reddish-purple filamentous accumulations, may be found diffusely throughout the tumor, especially at the periphery (H&E, ×400).

Rosenthal fibers are nucleus or cell-size, intensely eosinophilic, hyaline structures (Fig. 3-4D). In pilocytic astrocytomas, they are most common in solid areas and at the periphery. Among neoplasms these fibers are most common in pilocytic astrocytomas, but they also may occur in gangliogliomas. They are composed of and are immunoreactive for αB crystallin.

Although surrounded by glial filaments, Rosenthal fibers themselves may be negative for GFAP. Eosinophilic granular bodies are circumscribed clusters of coarse eosinophilic granules. They appear to be membrane bound and distinct from cells; in fact, they are intracellular. They are periodic acid-Schiff (PAS)-positive-diastase resistant. Eosinophilic granular bodies are most common in gangliogliomas and pleomorphic xanthoastrocytomas but occasionally are found in pilocytic astrocytomas.

A heated and sometimes rancorous debate within the neuropathology community surrounds the diagnosis of expansive spinal cord gliomas. One side contends that many of the tumors classified in the past or by others as pilocytic astrocytomas or diffuse astrocytomas in fact are gangliogliomas. For example, among 25 tumors diagnosed by histochemistry as gangliogliomas, 23 were originally identified as astrocytomas.4 Each side provides a respectable champion, convincing arguments, and relatively large series to support its contention.

The differences are highlighted in contradictory series. A study of 174 radically resected intramedullary tumors found 25% to be gangliogliomas, second in frequency only to diffuse astrocytomas at 51%. Ependymomas accounted for 12%, and there were no pilocytic astrocytomas.⁴ Of the 68 definitively diagnosed tumors discussed in the sections on pilocytic and diffuse astrocytomas, pilocytic astrocytomas were the most common, accounting for 63% compared with 37% for diffuse astrocytomas.¹ Although gangliogliomas were not included in this study, the disparity in the diagnosis of pilocytic astrocytomas is obvious. In other studies gangliogliomas have composed ~10% of spinal cord gliomas,⁷ but not a single ganglioglioma was identified in a review of two large series of 460 intramedullary tumors.⁸ In this study, 42% of the pilocytic astrocytomas had eosinophilic granular bodies, a higher incidence than in my experience, in which they have been more suggestive of gangliogliomas. An additional 11 tumors, 14% of the total, could be diagnosed only as astrocytomas but could not be subclassified as pilocytic or diffuse because the sample size was small.

An interesting observation was the disparity in a “proganglioglioma” study of the rate of occurrence of ganglion cell tumors in children compared with adults; however, this disparity does not solve the underlying disagreement. Gangliogliomas composed 31% of 117 pediatric tumors but less than 6% of adult tumors.⁹ The proganglioglioma faction attributes their “success” in identifying gangliogliomas to large resections that provided representative tissue and the use of immunohistochemistry markers for neurons. Their opponents warn of misinterpretation of entrapped neurons and overreliance on immunohistochemistry. With this debate, the incidence data for these tumors are highly variable and of questionable validity.

Gross and Microscopic Pathologic Features

The gross description of spinal cord gangliogliomas closely resembles that of pilocytic astrocytomas. They are characterized by a fusiform expansion of the spinal cord. Cystic degeneration, syrinx formation, or both are common. They appear expansive with a well-defined cleavage plane from the surrounding parenchyma. The fleshy gray cut surfaces are firm in solid areas but soft when associated with cystic degeneration.

Ganglion cell neoplasms are characterized by the presence of irregularly distributed atypical neurons. In addition to pleomorphism and nuclear atypia, bi- or multinucleate ganglion cells can be found. The typical ganglioglioma has an admixture of ganglion cells and well-differentiated fibrillary astrocytes (Fig. 3-5A,B). Sometimes the diagnosis of gangliocytoma is used when the neoplasm is composed primarily or even apparently exclusively of ganglion cells. More commonly astrocytes predominate and ganglion cells may be difficult to identify, a pattern that causes astrocytomas to be misdiagnosed. In addition to large ganglion cells, intermediate-sized neurons and differentiation are present but are particularly difficult to identify without immunohistochemistry.

Eosinophilic granular bodies, collections of coarse membrane-bound granules, are the hallmark of gangliogliomas (Fig. 3-5C). Although a clear association with the cell body is unusual, the granules are intracytoplasmic. Rosenthal fibers may be present but are less common than in pilocytic astrocytomas. Prominent perivascular and interstitial lymphocytic inflammation is a final feature of gangliogliomas that is less common in pure gliomas (Fig. 3-5D).

Immunohistochemistry markers, and just as importantly, their interpretation, play a critical role in the diagnosis of gangliogliomas. The principal players are the astrocytic marker GFAP and the neuronal marker synaptophysin. The glial elements are GFAP positive and synaptophysin negative. At least some of the neoplastic neurons are synaptophysin positive, but many if not most are negative for both markers (Fig. 3-5E). Positivity for neuron-specific enolase (NSE) may be seen in both elements, and thus its presence is not specific for neuronal differentiation.

Ependymomas

Whereas ependymomas account for only 2 to 6% of central nervous system (CNS) tumors,10,11 they account for 40 to 70% of intramedullary spinal cord tumors.⁹ Spinal cord ependymomas, exclusive of myxopapillary ependymomas, account for ~40% of all ependymomas. Their incidence peaks in the fourth decade, and there is a slight male predominance. Ependymomas can occur anywhere in the spinal cord but most often are found in the cervical or high thoracic regions. Myxopapillary ependymomas occur primarily in the cauda equina and lumbosacral spinal cord. Beyond this difference in location, myxopapillary ependymomas are fundamentally different from ordinary spinal ependymomas and are discussed separately. Ependymomas correspond to WHO grade II, whereas anaplastic ependymomas are classified as WHO grade III.

Ependymomas of the spinal cord are thought to arise from residual ependymal cells of the central canal. Consequently, the tumors tend to be located centrally within the spinal cord. Later in their course, however, they may extend in an asymmetric fashion. Occasionally, exophytic tumors extend outside the spinal cord, and intradural-extramedullary examples that lack a connection to the spinal cord have been reported.¹⁰ The ependyma includes both epithelioid cuboidal cells without obvious processes and tanycytes, which have a long unbranched basal process.¹¹ Both cytologic patterns occur in ependymomas, either together or in isolation.

Gross and Microscopic Pathologic Features

Ependymomas tend to be solid but may have cystic or hemorrhagic areas. Because they are expansive rather than diffusely infiltrative, they tend to be circumscribed with a cleavage plane that makes them amenable to complete resection. However, reactive gliosis makes them variably adherent to the surrounding parenchyma. The cut surfaces are gray-to-reddish-tan. The tumor tissue is slightly soft; myxoid stroma is rare in nonmyxopapillary tumors. Exophytic and extramedullary tumors appear encapsulated with smooth glistening surfaces.

Microscopic examination confirms the gross impression of an expansive, noninfiltrating neoplasm. Reactive astrocytes are present in variable numbers between the tumor and the adjacent spinal cord. Occasionally, Rosenthal fibers may be seen. The microscopic hallmark of ependymomas is the perivascular pseudorosette. Glial tumor cell processes appear to radiate from nuclei that surround small blood vessels, creating anucleate fibrillary rings around the vessels (Fig. 3-6A). Pseudorosettes should be distinguished from true ependymal rosettes or tubules, where the processes surround a membrane-delineated lumen. The latter are uncommon in spinal ependymomas. As mentioned, the ependyma includes both cuboidal epithelioid cells without obvious processes and tanycytes, with obvious processes and often a spindle-cell appearance.

Whereas tanycytic ependymomas are rare in the ventricles, the tanycytic phenotype predominates in spinal cord tumors. Although typical cellular ependymomas occur, spinal ependymomas tend to be less cellular than their ventricular counterparts, with a richer glial fibrillary stroma. The prominence of the cell processes and relative paucity of nuclei may confound recognition of perivascular pseudorosettes. Instead, clusters of nuclei and fibrillary anucleate zones without obvious vascular orientations may be seen (Fig. 3-6B,C), presumably representing a plane of section artifact. Vascular hyalinization, presumably reflecting plasma leakage of protein, may be present but not as often as in ventricular ependymomas.

Typically, spinal cord ependymomas are indolent low-grade tumors classified as WHO grade II. They demonstrate little atypia. Their round to spindle-shaped nuclei have smooth contours, and the distribution of chromatin is uniform. There is little pleomorphism. Mitotic figures are absent or rare. Microvascular proliferation is not seen. Rarely, infarct-type necrosis may be observed. The histologic grading of ependymomas is less predictive than for astrocytomas. In the rare anaplastic ependymoma, mitotic figures are numerous, and microvascular proliferation with pseudopalisading tumor necrosis is common. Of these features, a high mitotic rate is the most important; however, a threshold mitotic count for classifying a tumor as anaplastic has not been determined. In the WHO system, mitotic activity is characterized only as “high” or “brisk.”¹²

Immunohistochemistry

Consistent with their glial origin, ependymomas are immunoreactive for S-100, vimentin, and particularly in fibrillary areas, GFAP. Focal immunoreactivity to epithelial membrane antigen (EMA) and keratin may be seen. Almost all spinal cord ependymomas have low MIB-1 labeling indices. A series of 35 grade II tumors had a mean labeling index LI) of 1.25.¹³ Other smaller series have found similar results.^9,14 In a series of 61 spinal and intracranial ependymomas, an LI ≥ 4.0 was more likely to be found in aggressive tumors.⁹ However, no predictive threshold has been determined.

Myxopapillary ependymomas are a special variant of ependymomas almost always found in the conus medullaris or cauda equina. Like ordinary ependymomas, myxopapillary ependymomas presumably arise from residual ependymal cells. These indolent, rarely invasive tumors are less aggressive than ordinary ependymomas and are classified as WHO grade I. They are usually amenable to complete resection. In the largest series the recurrence rate was less than 20%, and only five of 77 patients died from their tumor. Although the best outcomes were associated with gross total resection, patients with subtotal resections also had good outcomes.15 Myxopapillary ependymomas compose ~13% of all ependymomas. In the spinal cord, they account for a higher percentage of cases than when brain and spinal cord ependymomas are considered, and they are the most common ependymoma of the distal spinal cord. They occur from childhood to old age, with a peak incidence in the fourth decade. A 2:1 male predominance is reported.¹⁶

Gross and Microscopic Pathologic Features

The tumors often appear encapsulated and are irregularly lobulated. The cut surfaces are soft and gray-to-pink. Abundant myxoid/mucoid stroma is the norm and may create a grossly papillary texture.

As their gross appearance suggests, these tumors are not truly papillary. Instead, clusters of tumor cells around blood vessels are separated by the abundant mucopolysaccharide stroma (Fig. 3-7A). A microcystic appearance is typical. Foci resembling ordinary ependymoma are found in most tumors (Fig. 3-7B). In fact, the separation of individual perivascular pseudorosettes by the myxoid stroma gives the tumor its characteristic architecture; however, the extensive stroma also distorts the perivascular pseudorosettes and may make their recognition difficult. Only a single layer of tumor cells may surround a vessel, and their processes can be hard to distinguish in the stroma. Reactive hyalinization of vessel walls also distorts the pseudorosettes and obscures radial cell processes. The tumor cells usually have the cuboidal or unipolar appearance characteristic of ependymomas, but the nuclei may appear flattened and spindle-shaped. There is little or no atypia. Mitotic figures are unusual. Rarely, infarct-type necrosis may be associated with vascular injury.

FIGURE 3-7 Myxopapillary ependymoma. (A) A pseudopapillary pattern is created by fragmentation of the tumor. The tumor cells adhere to the blood vessels, whereas the abundant myxoid/mucopolysaccharide stroma provides little structural support. The perivascular pseudorosettes may have only a single layer of tumor cells (×H&E, 200). (B) Areas resembling more typical ependymoma may be present (×H&E, ×200).

Immunohistochemistry

The neoplastic cells are immunoreactive for GFAP, S-100, and vimentin and are usually negative for keratin. This pattern distinguishes myxopapillary ependymomas from chordomas, chondrosarcomas, and papillary adenocarcinomas, the principal differential diagnostic considerations. In 14 cases, the median MIB-1 LI was 0.9 and the LI was not predictive of recurrence.17

Subependymomas

Subependymomas are benign tumors that primarily arise in the ventricles and rarely arise in the spinal cord. A literature review identified fewer than 40 spinal cord subependymomas.¹⁸ Their cell of origin is uncertain, but it has been speculated that they are derived from the subependymal cell plate. They also have been proposed to originate from the subependymal astrocyte, in the manner of tanycytic ependymomas.^19,20 Their relationship to ependymomas is uncertain; however, unlike ordinary ependymomas, which often demonstrate genetic abnormalities, particularly loss of chromosome 22, the rare cytogenetic studies of subependymomas have identified no such abnormalities.^21,22 Coincidentally, or perhaps not, tanycytic ependymomas also lack cytogenetic changes.

Almost 90% of spinal cord tumors occur in men, primarily between the ages of 30 to 60 years.²³ The typical tumor involves three to four spinal levels. Almost all are in the cervical or cervicothoracic spinal cord; the lumbar spinal cord is rarely affected.^19,20

Gross and Microscopic Pathologic Features

Subependymomas are soft, well-circumscribed tumors. They are primarily intramedullary but may have an exophytic component. Their cut surfaces are tan-to-pink. They are rarely associated with a syrinx. Unlike ependymomas, they tend to develop in an eccentric location within the spinal cord.

The microscopic features of subependymoma are generally characteristic (Fig. 3-8). Overall, these tumors are poorly cellular, with small clusters of round nuclei in a dense glial fibrillary stroma. The nuclei and cell processes have no obvious association with blood vessels. In some tumors, however, foci with perivascular pseudorosettes are indistinguishable from those of ependymomas. There is little atypia. Nuclei are bland, but scattered large atypical nuclei may be present occasionally. Most tumors contain microcysts filled with mucopolysaccharide material. About half display hemosiderin-laden macrophages, indicative of previous hemorrhage. Vascular fibrosis is also present in about half. Microcalcifications are another common feature. The interface with the surrounding spinal cord is expansive. The latter demonstrates gliosis and, occasionally, Rosenthal fibers.

FIGURE 3-8 Subependymoma. (A) Small clusters of oval-to-oblong nuclei are scattered in a fibrillary stroma. Microcystic degeneration with myxoid stroma is common. (B) There is minimal atypia. No mitoses are seen. Perivascular pseudorosettes may be present.

No mitotic figures are present, and neither microvascular proliferation nor necrosis is a feature of this tumor. Two series analyzed proliferative activity and found mean MIB-1 LIs of 0.3 and 3.4.20,24 The first is low and indicates a negligibly proliferative neoplasm. Despite the apparently significant proliferative activity identified in the second study, the authors describe the LI as similar. The difference is likely related to methodology. Our own experience is consistent with the lower levels.

The neoplastic cells are immunoreactive for GFAP and S-100; however, immunohistochemistry plays little role in diagnosis.

Meningiomas

Meningiomas are tumors of arachnoid (meningothelial) cells. They compose 25% of intradural spinal tumors, which makes them the second most common. The ratio of intracranial-to-intraspinal tumors is ~5:1.^25,26 Occasionally, they occur in children, but spinal meningiomas are tumors of adults: Their mean age of diagnosis is ~50 years.^26,27 Most (80 to 90%) spinal meningiomas occur in women, compared with 60% of intracranial tumors.

A review of 571 cases found that 80% involved the thoracic region, 17% the cervical region, and only 3% the lumbar region.²⁵ Curiously, the male-to-female ratio in cases involving the cervical cord was 1:1.²⁶ About 75% are located anteriorly or laterally, adjacent to the nerve root exit zone.^25,27–29 They tend to arise near but not directly involving the nerve root itself. Most tumors are purely intradural extramedullary. From 3.5 to 16% involve the extradural space, and about half of these are purely extradural.^{25–27,29,30} In contrast to intracranial tumors, extradural spinal tumors rarely involve adjacent bone. Intramedullary tumors are rare.

Most meningiomas are slow-growing benign tumors; however, higher-grade tumors with more aggressive behavior compose as many as 10% of all meningiomas. The recurrence rate of benign spinal meningiomas is 1 to 7%, compared with as high as 20% for intracranial tumors.^26,27,30,31 Factors predisposing to recurrence include incomplete resection, anterior location, and extensive tumor calcification.³¹

Most intraspinal meningiomas are sporadic. Even in sporadic tumors, mutations of the NF2 gene occur in more than half the meningiomas.^32–35 Such mutations are most common in fibrous meningiomas, which are relatively unusual in spinal tumors. Consequently, the rate of NF2 mutations is lowered in spinal tumors. Neurofibromatosis type 2 (NF2) per se often is associated with multiple spinal tumors, the presence of which is almost diagnostic of NF2. There are six reported cases of spinal meningiomas diagnosed during pregnancy.³⁶ The association of pregnancy with intracranial meningiomas is well known, although the basis—hormonal, immunosuppression, or water–salt imbalances—remains unclear.

Gross and Microscopic Pathologic Features

Intraspinal meningiomas are smooth ovoid tumors measuring from 1 cm to several centimeters. They have a variably extensive dural attachment. Their texture depends on the histologic subtype. Most, including the most common subtype, meningothelial, are soft. Consistent with their name, fibrous meningiomas are firm. Depending on the presence of extensive calcifications, psammomatous meningiomas can be gritty or hard. The cut surfaces similarly vary from gray-pink to tan. The tumors have an expansive interface with the spinal cord, which may show remarkable compression deformity due to the slow growth of the tumors. Invasion of the spinal cord is exceptional. Extradural tumors rarely invade bone or even deform it.

The wide variety of histologic subtypes that occurs in intracranial tumors is replicated in spinal meningiomas, but with different relative frequencies (Table 3-3). Meningothelial and transitional are the most common, but psammomatous tumors are also frequent. The fibrous subtype is less common intraspinally than intracranially. Only these relatively common types are discussed in detail, as the other patterns are relatively rare.

Nests and lobules of epithelioid cells with round-to-oval nuclei and abundant cytoplasm with indistinct cell borders characterize meningothelial or syncytial meningiomas (Fig. 3-9A). Occasional whorls and psammoma bodies (lamellar microcalcifications) may be seen. Central nuclear clearing (pseudoinclusions) may be prominent. Fibrous meningiomas are composed of intersecting fascicles of spindle cells that resemble fibroblasts (Fig. 3-9B). In pure forms, only occasional small whorls and psammoma bodies are seen. Collagen is often abundant and may be spread diffusely among the tumor cells or as bundles or columns surrounded by tumor cells. Transitional meningiomas have both meningothelial and fibrous features (hence the name) (Fig. 3-9C). They also frequently have numerous whorls and psammoma bodies. As their name suggests, psammomatous meningiomas are tumors in which psammoma bodies are numerous enough to predominate over tumor cells (WHO Grade).

Typical benign meningiomas (WHO grade I) demonstrate only mild cytologic atypia, although occasional scattered atypical cells may be present. Mitoses are usually absent or rare and never present more than 3 mitoses/10 high-power fields (HPFs). Rare spontaneous necrosis may be associated with vascular thrombosis. Tumors with a mitotic rate of ≥ 4 mitoses/10 HPFs are classified as atypical (WHO grade II). In the absence of a high mitotic rate, at least three abnormal cytologic or histologic features (i.e., marked hypercellularity, diffuse or sheet-like growth, necrosis, high nuclear-cytoplasmic ratio, prominent nucleoli) must be present to label a tumor as atypical. Anaplastic meningiomas (WHO grade III) are defined as having a mitotic rate of ≥ 20 mitoses/10 HPFs or obviously malignant histologic features (typically sarcomatous).

Immunohistochemistry

Almost all meningiomas demonstrate at least some staining for EMA (Fig. 3-9E). S-100 reactivity is inconsistent and rarely strong. Cytokeratins are usually negative except in the glandular foci of secretory meningiomas. Many meningiomas have significant immunoreactivity for progesterone receptor (PR) and less commonly for estrogen receptor (ER). Although PR-positive tumors are unresponsive to hormonal therapy, they are associated with better outcomes than PR-negative tumors. Consistent with the role of mitotic activity determining tumor grade, a high MIB-1 LI (5 to 10%) is associated with a higher recurrence rate than a low MIB-1 LI.

Solitary Fibrous Tumors (Localized Fibrous Tumor)

Solitary fibrous tumors were originally described in the pleura and were thought to originate from the mesothelium. Recently, solitary fibrous tumors have been identified at a variety of sites, including the meninges. Their lineage is now thought to be fibroblastic. Meningeal tumors are rare, and most are intracranial, with fewer than 10 reports of intraspinal tumors.^37–40 A very rare intramedullary case has been reported.⁴¹ Overall, extrathoracic solitary fibrous tumors do not demonstrate gender predominance.⁴² Most occur in patients older than 40 years.^39,42 Solitary fibrous tumors tend to be indolent and are classified as WHO grade I.

Gross and Microscopic Pathologic Features

These tumors tend to be well circumscribed with a smooth fibrous pseudocapsule. They are often lobulated. They arise from the dura to which they are attached loosely. The interface with surrounding structures tends to be expansive; however, they may invade bone or CNS parenchyma. Their cut surfaces are gray or tan, often with obvious whorls. Most tumors are solid and have a firm, rubbery texture. Areas of cystic degeneration or hemorrhage are present in a few tumors.

The tumors are composed of spindle cells in a collagenous stroma, with the cellularity inversely proportional to the density of the stroma. Short, often curving fascicles are arranged haphazardly or in a vaguely storiform pattern. The cells are uniform, without significant pleomorphism, and have indistinct cytoplasmic borders (Fig. 3-10A). The fusiform nuclei are smooth, without significant atypia. They are vesicular or have evenly distributed chromatin. Nucleoli are not seen. Mitotic figures are present but not numerous. Counts range from 0 to 7 mitoses/10 HPFs.^39,42 Dilated, thin-walled blood vessels are prominent and may suggest the staghorn pattern seen in hemangiopericytomas.

FIGURE 3-9 Meningioma. (A) Meningothelial meningioma. Epithelioid cells with round nuclei and moderate amounts of eosinophilic cytoplasm with indistinct cell borders are arranged in sheets, lobules, and small whorls. Nuclear pseudoinclusions—central clear areas within the nucleus—are common (H&E, ×200). (B) Fibrous meningioma. Spindle cells with bipolar fibrillary eosinophilic processes are arranged in irregular fascicles and whorls (H&E, ×200). (C) Transitional meningiomas have features of both meningothelial and fibrous meningiomas. Here there are sheets, lobules, and whorls of meningothelial cells, and fascicles and cords of spindle cells (H&E, ×200). (D) Psammoma bodies may form from degeneration of small whorls with sclerosis and subsequent lamellar calcification. Psammomatous meningiomas are characterized by a preponderance of psammoma bodies to the exclusion of viable tumor cells (H&E, ×200). (E) Like normal arachnoid cells, meningiomas almost always show reactivity to epithelial membrane antigen (EMA-DAB and hematoxylin, ×).

The principal differential diagnostic considerations for solitary fibrous tumors are fibrous meningiomas, hemangiopericytomas, and schwannomas. Immunohistochemistry allows definitive distinction based primarily on the cell determinant (CD)34 reactivity of solitary fibrous tumors (Table 3-4). Hemangiopericytomas have dilated vessels that can resemble those of solitary fibrous tumors, and their mitotic activity may be similar. However, hemangiopericytomas have a more diffuse architecture with less prominent fibrous stroma and nuclei that are more angular and atypical. Schwannomas have a better developed fascicular growth pattern and lack collagenous stromal bands. Hyaline fibrosis of blood vessels and Verocay bodies are common in schwannomas but are not found in solitary fibrous tumors. Fibrous meningiomas are the most problematic. Although not as prominent, the stroma is fibrous, often with bands of collagen. Fascicles are usually better developed, and whorls and psammoma bodies are often present.

FIGURE 3-10 Solitary fibrous tumor. (A) Small fascicles of bland spindle cells are haphazardly arranged in a fibrous stroma (H&E, ×200). (B) The neoplastic cells demonstrate strong immunoreactivity for CD34 (CD34-DAB and hematoxylin, ×200).

Immunohistochemistry

Immunoreactivity for CD34 is the diagnostic hallmark of solitary fibrous tumors (Fig. 3-10B). Almost all tumors are diffusely and strongly reactive.^37–44 Consistent reactivity for vimentin, factor XIIIa, bcl-2, and Leu-7 has been reported.^38,42 They stain weakly for S-100, keratin, and p53 protein. They are consistently negative for EMA, GFAP, and muscle actins [muscle-specific antigen, muscle-specific action (MSA); smooth muscle actin (SMA)]. MIB-1 LI is generally low, consistent with the mitotic activity.

Hemangiopericytomas (Angioblastic Meningiomas, Archaic)

The architecture of meningeal hemangiopericytomas resembles that of many atypical meningiomas—like a meningioma but not quite. This similarity led to their incorrect classification as angioblastic meningiomas. Histologically, they are identical to systemic hemangiopericytomas and have the same low-to-intermediate grade malignant potential.

As their name suggests, hemangiopericytomas are thought to be derived from pericytes. They occur most commonly in the thigh, pelvis, and retroperitoneum.⁴⁵ Meningeal hemangiopericytomas are rare, accounting for 1 to 7% of meningeal tumors. Most are intracranial; spinal meninges account for only 15% of the tumors, ~80% of which are in the cervical spine.^46,47 Even more rare are primary intravertebral tumors.⁴⁵

The epidemiology of meningeal hemangiopericytomas and hemangiopericytomas as a whole is similar.^46–48 They occur equally in both sexes. Age at diagnosis ranges from childhood to old age, but they tend to be tumors of middle age. The mean or median ages have ranged from 30 to 46 years in several studies. For all meningeal hemangiopericytomas, recurrence and metastasis rates are reported as 61% and 23%, respectively.⁴⁹ The rates for intracranial meningeal tumors are somewhat higher.⁵⁰ The limited data for intraspinal tumors suggest a recurrence rate of ~50%, with a 10-year survival rate of 70%.47

Gross and Microscopic Pathologic Features

Hemangiopericytomas are soft, lobulated tumors that may have well-circumscribed or poorly defined margins. Both patterns can occur in the same tumor. A reddish-brown color corresponds to high vascularity. The cut surfaces may have gray-white areas. The tumors occupy the extradural space and adhere to the dura. They often invade the adjacent vertebra, particularly the posterior elements.

Highly vascular tumors, hemangiopericytomas, are characterized by marked proliferation of cells that surround poorly formed or slitlike capillaries (Fig. 3-11A,B). Clusters of dilated branching blood vessels in a “staghorn” pattern are almost pathognomonic (Fig. 3-11C). In some tumors, trabecular or alveolar architecture is present. Rarely, mucopolysaccharide deposition is prominent. The tumor cells are pleomorphic with profiles that range from oval to angular to polygonal (Fig. 3-11D). They have variably atypical, hyperchromatic oval-to-angular nuclei. Scattered giant cells are seen in many tumors. Almost half have foci of tumor necrosis, but they are not associated with prognosis. Mitoses are found in almost all cases and are often numerous (Fig. 3-11D). For nonmeningeal tumors, a mitotic count of more than 3 mitoses/10 HPFs is associated with aggressive behavior and poor clinical outcomes.⁵¹ Similar analyses of intracranial tumors are conflicting. The largest series of 94 cases found a similar correlation between proliferation and outcome.⁴⁹ However, studies of 62 and 44 cases have shown only a nonsignificant trend toward good outcomes.^46,52

Special stains for basal lamina, such as reticulum (Fig. 3-11E) or collagen IV, show a prominent network that surrounds individual cells or small clusters of tumor cells. This feature is helpful in distinguishing hemangiopericytomas from meningiomas.

Immunohistochemistry

Immunohistochemistry allows definitive distinction between hemangiopericytomas and meningiomas. Whereas hemangiopericytomas are immunoreactive for CD34 (Fig. 3-11E) and negative for EMA, meningiomas exhibit the opposite pattern. Hemangiopericytomas are also immunoreactive for Leu 7, factor XIIIa, and vimentin. S-100 reactivity is inconsistent. Despite the presence of actin-like filaments on ultrastructural examination, actin immunoreactivity is rarely seen. The tumors are consistently negative for cytokeratins and CD31.^46,48 Most tumors demonstrate few or no cells positive for p53 protein.⁵⁰ As mentioned, collagen IV labeling of basal lamina produces a characteristic network surrounding individual cells and small clusters of cells.

Melanocytomas

Meningeal melanocytomas are extremely rare neoplasms. Only ~30 cases have been reported, some of which are controversial.^53–55 They are benign tumors of meningeal melanocytes. Melanocytes are diffusely distributed throughout the meninges, perhaps with the highest frequency in the upper spine.⁵³ Melanocytomas almost always arise in the spinal meninges or posterior fossa. Based on limited data, there appears to be a 2:1 female predominance. The intraspinal tumors are limited to the cervical and uppermost thoracic spine. They have occurred at any age from adolescence onward. They are slow-growing benign tumors but have a tendency to recur.^53,54

Melanocytomas were once classified as pigmented meningiomas and are still misdiagnosed as such or as pigmented schwannomas or malignant melanomas. The latter are closely related, and rare reports suggest that melanocytomas may transform into malignant melanomas.

Gross and Microscopic Pathologic Features

Melanocytomas are soft, well-demarcated tumors. They may be attached to the dura but remain distinct from the spinal cord and nerve roots. They do not penetrate the dura to involve the spine. The external surface may be gray or strikingly black. The cut surfaces also may be reddish, the result of high vascularity.

The tumors are highly cellular. The neoplastic cells have vaguely granular acidophilic or amphophilic cytoplasm and indistinct cell borders. With hematoxylin and eosin (H&E) staining, melanin is seldom apparent. At best, most cells show a fine dusty brown pigment. Stromal macrophages, however, may contain abundant melanin (Fig. 3-12A). A Fontana stain may be used to demonstrate the melanin in all cells. The nuclei range from round to fusiform. They tend to be monotonous with little atypia and may have a nucleolus (Fig. 3-12B). The cells are arranged in lobules, fascicles, and whorls. Occasional mitoses may be present. Tumor necrosis is not seen. The stroma is highly vascular.

Malignant melanomas are distinguished by significant atypia and mitotic activity, as well as by the presence of necrosis. In difficult cases, electron microscopy may help distinguish schwannomas from meningiomas. On ultra-structural examination, melanocytomas demonstrate both mature melanosomes and premelanosomes, which also are found in the other tumors; however, unlike schwannomas, individual tumor cells are not surrounded by a basal lamina. Interdigitating cell processes with numerous desmosomes are not found at the interface between cells, a pattern characteristic of meningiomas.

Consistent with their elastic nature, neoplastic cells are immunoreactive for S-100 (Fig. 3-12C) and HMB-45. They are also reactive for vimentin. They are not reactive for EMA or Leu-7, other features that differentiate them from meningiomas and schwannomas, respectively.

Schwannomas (Neurilemmomas, Neurinomas, Neuromas)

As their name suggests, these tumors are presumed to derive from neoplastic Schwann cells. Schwannomas are benign peripheral nerve sheath tumors, classified as WHO grade I. Malignant transformation of schwannomas is exceptional. In fact, the tumor sometimes designated malignant schwannoma is thought to be derived from or related to neurofibromas. Consequently, they are preferably called malignant peripheral nerve sheath tumors (MPNSTs). Multiple schwannomas are characteristic of NF2.

Schwannomas account for 30% of all extraosseous spinal tumors.⁵⁶ They are almost always extramedullary and may be extradural as well as intradural, or both. Among the latter are classic dumbbell tumors that extend through the neural foramina. About two thirds are purely extradural.^57,58 They may arise in any level of the spinal cord. Overall, tumors involving the lumbar region, sacrum, and cauda equina are more common than those involving cervical or thoracic sites. In contrast, dumbbell tumors usually occur in the cervical or thoracic cord. NF2-associated tumors also tend to occur proximally, whereas sporadic tumors are more common distally. Sporadic schwannomas are almost always solitary; the presence of multiple tumors is indicative of NF2. Sensory nerve roots are affected more often than motor roots.⁵⁸

In the spine, the male-to-female ratio favors males (1.25 to 1.5:1).^59–61 In contrast, intracranial and peripheral sites are associated with a 1.5:1 and 1.6:1 ratio of female predominance, respectively.⁵⁹ The peak incidence is in the sixth decade, with most tumors diagnosed between the ages of 20 and 70 years. Intracranial and peripheral tumors occur at similar ages.59>

Intramedullary schwannomas are very rare, with ~44 sporadic cases reported in the literature. They account for 0.3 to 1.5% of spinal tumors. Like their more common counterparts, they are usually solitary.⁵⁶ Endophytic growth of extramedullary tumors or exophytic growth of intramedullary tumor may confuse the site of origin. Males and females are affected with equal frequency. The reported age at diagnosis ranges from 12 to 75 years, with a mean of 43 years. The distribution differs significantly from that of extramedullary schwannomas. Cervical tumors are most common, accounting for 62% followed by 20% thoracic and 18% lumbar. The tumors typically involve two to six spinal levels.^62–64 The origin of intramedullary schwannomas and the source of Schwann cells are uncertain, but several possibilities have been proposed: peripheral nerve axons displaced within the spinal cord, ectopic or residual developmental Schwann cells rests, axons accompanying the anterior spinal artery, or metaplastic pial cells.^65–67

Gross and Microscopic Pathologic Features

Typically, schwannomas are circumscribed, ovoid masses at the periphery of intra- or extraspinal segments of peripheral nerves. Dumbbell-shaped tumors with both intra- and extraspinal components connected through the spinal foramina are common. Whereas the tumor surface is smooth, the cut surfaces are highly varied. Intact tumor tissue is gray-tan and glistening. Yellow areas, reflecting lipid in macrophages, are characteristic. Foci of recent or old hemorrhage may be seen. Degenerative cysts may develop, and the term cystic schwannoma is applied when this pattern predominates.

Schwannomas are composed of cells that, like the Schwann cells from which they are derived, are spindle-shaped with slender, tapering nuclei (Fig. 3-13A). They have abundant cytoplasm with ill-defined cellular borders. In cellular areas, this creates a seamless, featureless stroma that contrasts with the bundles or columns of dense collagen wrapped by tumor cells in meningiomas or with the short wavy bundles of loosely textured collagen filaments that course through neurofibromas. Small intersecting fascicles are the most consistent morphologic feature of schwannomas. This pattern of compact tumor cells is termed Antoni A. Antoni B areas are loosely textured, with individual tumor cells separated by edematous fluid or lipid-rich macrophages (Fig. 3-13B). Verocay bodies, a distinctive feature of some schwannomas, are composed of rows of parallel nuclei separated by cytoplasmic processes (Fig. 3-13C). The blood vessels of schwannomas lack tight junctions. The leaky nature of the vessels allows contrast enhancement on imaging studies and produces characteristic histologic features (Fig. 3-13D). The extravasation of plasma proteins results in thick, hyalinized walls.

A distinctive feature that may be worrisome to the unaware is the presence of scattered tumor cells with highly atypical, often bizarre, nuclei. They have no prognostic significance and the basis for their development is unknown. To account for the absence of a negative prognostic influence, as is usually associated with atypia, their presence has been termed a “degenerative” phenomenon. The tumors in which they are common are sometimes called “ancient schwannomas” (Fig. 3-13E). Schwannomas tend to grow slowly. Consequently, mitoses, if present at all, are usually rare. Necrosis is also uncommon and results from vascular lesions rather than tumor overgrowth when present.

The interface between a schwannoma and its parent nerve reflects the ability to respect the tumor without compromising the nerve. In neurofibromas, tumor cells diffusely invade between individual axons of the nerve. This growth pattern precludes tumor resection without sacrificing or significantly damaging the nerve. In contrast, at gross and even low-power microscopic levels, a schwannoma and its associated nerve appear spatially distinct (Fig. 3-13F); however, despite their sharp circumscription, schwannomas are not truly encapsulated. Like many soft tissue tumors, compressed layers of tumor cells at the surface intermix with reactive fibroblasts to form a pseudocapsule. Consequently, examination under high power of the most superficial aspect of the tumor where it contacts the nerve reveals a few axons intermingled with the tumor cells. Inevitably, complete tumor resection requires the sacrifice of at least a few axons.

Neurofibromas, fibrous meningiomas, and solitary fibrous tumors are considerations in the differential diagnosis. The last two are distinguished by their immunohistochemical patterns (meningiomas are EMA positive, S-100 negative; solitary fibrous tumors are CD34 positive, S-100 negative). However, neurofibromas and schwannomas share both nerve sheath origin and S-100 positivity. The most important difference is that neurofibromas are not limited to the peripheral nerve sheath; tumor cells permeate the nerve itself, and axons may be found between tumor cells. The spindle-shaped nuclei are often wavy. The background is composed of well-defined wavy bundles of collagen. The organization is more haphazard than that of a schwannoma. The tumor cells in fibrous meningiomas have elongate nuclei and slender processes; however, they do not blend into as seamless a background as a schwannoma. The tumor cells surround thick, brightly eosinophilic bundles of collagen. Solitary fibrous tumors are composed of spindle cells in a prominent collagenous stroma. Short, curving bundles of cells are common, but the fascicular architecture is not well developed. Dilated, thin-walled blood vessels are prominent but hyalinized vessels are not seen.

Immunohistochemistry

Although rarely necessary, immunohistochemistry may be used to confirm the diagnosis of schwannoma. Like Schwann cells, schwannomas are diffusely and strongly immunoreactive for S-100 protein. Leu-7, transforming growth factor (TGF)-β,68 and vimentin immunoreactivity is typical but has no diagnostic significance. Unlike meningiomas, schwannomas are negative for EMA. A significant feature of schwannomas is the loss of merlin/schwannomin protein expression.^69,70 As noted, multiple schwannomas are a hallmark of NF2. The specific associated genetic abnormality, loss of the tumor suppressor gene NF2 on chromosome 22p, is also a feature of most sporadic schwannomas.^69,71–73 This gene codes for merlin, a widely expressed cytoplasmic protein. Loss of merlin expression is considered essential to schwannoma tumorigenesis in both neurofibromatosis and sporadic cases. NF2 mutations resulting in inactive merlin are found in the germline in NF2 or limited to tumor cells (somatic) in sporadic cases.⁷¹ Studies of immunohistochemical evaluation of proliferative activity using the Ki-67/MIB-1 antibody are limited, but they typically report LIs of less than 2%, consistent with our experience.^74,75 The studies suggest that higher LIs are associated with more rapid interval growth on magnetic resonance imaging (MRI); however, the clinical usefulness of this observation is uncertain.

Neurofibromas

Neurofibromas are benign tumors (WHO grade I) of peripheral nerves and are composed of Schwann cells, fibroblasts, and perineurial-like cells. They account for ~25% of all intraspinal neoplasms.⁷⁶ In the spine, they occur primarily in association with the spinal nerve roots; intramedullary examples are rare. Among sporadic tumors, most are intradural. About 25% have an extradural component, about half of which are purely extradural and half of which are intradural-extradural. The latter include the classic “hourglass” configuration with an extension through the foramen. Neurofibromas are distributed relatively evenly throughout spinal cord, including the cauda equina. Paraspinous nerve segments are often involved. There is no sex predilection. They occur at any age, from childhood to old age; the average age at diagnosis is ~45 years.^76,77

Spinal neurofibromas are usually solitary and, except for cauda equina tumors, are indicative of von Recklinghausen’s neurofibromatosis (neurofibromatosis type 1, NF1) when multiple.^61,76 Multiple neurofibromas at any site are a hallmark of NF1 but single tumors also occur. NF1 is a relatively common genetic disease with a prevalence of 1/3000. About half the cases are familial, and the rest are from sporadic mutations of the NF1 gene. Symptomatic spinal involvement occurs in less than 2% of cases.⁷⁸ In contrast to sporadic tumors, extradural and intraforaminal tumors are the most common.⁷⁹

Whereas neurofibromas are benign, they may undergo progression to MPNSTs, particularly in patients with NF1.⁸⁰ Presumably, the progression is the result of secondary mutations of tumor suppressor genes. Malignant progression and histologic features differentiating benign from malignant tumors are discussed in the section devoted to MPNSTs (see later).

Gross and Microscopic Pathologic Features

The gross appearance of neurofibromas varies according to the tumor’s relationship to the parent nerve. Symmetric, fusiform enlargement of the nerve is one manifestation sometimes referred to as a localized intraneural neurofibroma. Eccentric involvement can also cause a lateral globoid mass. Finally, a globoid neoplasm without obvious nerve involvement can occur. Spinal tumors also can involve the foramen, creating the classic dumbbell or hourglass shape. The intertwining involvement of multiple nerve trunks is designated plexiform neurofibroma and is diagnostic of NF1. Typical neurofibromas have a fibrous pseudocapsule, but they may invade soft tissue and have indistinct margins. They vary from soft to firm, depending on the relative proportions of collagen and myxoid stroma. The cut surfaces, ranging from gray to tan, may glisten depending on the nature of the stroma. Intraspinal tumors often expand the foramen or reshape bone by the pressure they exert. The mutation is not seen.

Neurofibromas are composed of Schwann cells, fibroblasts, and perineurial-like cells. The latter are distinguishable from Schwann cells only on ultrastructural examination. They are all spindle-shaped with inapparent processes. The nuclei are more slender than those of schwannomas and tend to have curved or wavy contours (Fig. 3-14A). Most demonstrate little atypia, but scattered individual atypical nuclei are common and have no prognostic significance (Fig. 3-14B). The stroma may be densely fibrous but more often is loose and myxoid, with short thick bundles of curved or wavy collagen (Fig. 3-14C). The tumors are often poorly cellular, typically less than normal nerves or schwannomas; however, confluent hypercellularity may be present throughout or in a portion of the tumor. The architecture may be fascicular or the tumor cells may be diffusely distributed. Where the parent nerve has been invaded significantly, the tumor cells tend to course parallel to the axons. In many tumors, no residual nerve is present, or at most, individual axons are dispersed widely and demonstrable only with stains for myelin and axons, such as luxol fast blue and PGP 9.5. Numerous mast cells are scattered throughout the tumor. Perivascular lymphocytes are common. Bloodv vessels may be prominent but lack the hyalinization that characterizes schwannomas.

FIGURE 3-14 Neurofibroma. (A) “Wavy” is an apt word for describing neurofibromas—wavy nuclei and wavy collagen bundles. Scattered mast cells are numerous; however, most are degranulated and appear as round lymphocytelike cells with scant cytoplasm (H&E, ×200). (B) Generally, cytologic atypia is mild; however, occasional atypical cells without clinical significance may be seen. Mitotic activity should be absent or rare (H&E, ×200). (C) Neurofibromas are spindle cell tumors with a fibrous stroma. The bundles of collagen often appear discrete and separate from tumor nuclei (H&E, ×200).

With the exception of scattered typical cells, neurofibromas lack linking features. Mitotic figures are rare. The MIB-1 LI is correspondingly low, averaging 4.7 in one series, compared with 18.5 in MPNSTs. Tumor necrosis is not seen.

Immunohistochemistry

Many but not all of the tumor cells are immunoreactive for S-100. About half of the tumors demonstrate Leu-7 reactivity. Despite ultrastructural evidence for perineurial cell differentiation, EMA immunoreactivity is not seen. As mentioned, individual axons can be demonstrated by PGP 9.5.

Malignant Peripheral Nerve Sheath Tumors (Malignant Schwannomas, Neurofibrosarcomas)

Malignant peripheral nerve sheath tumor (MPNST) is an awkward but accurate name for a horrific tumor. Whereas MPNSTs are malignant Schwann cells tumors, the term malignant schwannoma is inaccurate because the tumors only exceptionally are derived from schwannomas. MPNSTs are related to neurofibromas and can be considered their malignant counterparts; however, the term neurofibrosarcoma, although intended to indicate a malignant neurofibroma, that is, a neurofibroma-sarcoma, sounds too much like a fibrosarcoma variant. In fact, the architecture of many tumors is reminiscent of fibrosarcomas (e.g., a herringbone fascicular pattern).

Overall, MPNSTs compose ~5% of all soft tissue sarcomas.81 It has been suggested that the diagnosis of MPNST be limited to histologically appropriate tumors that meet at least one of three criteria: demonstrable origin from a nerve, contiguity with a benign neurofibroma, or present in a patient with NF1. MPNSTs are associated with NF1 in 50 to 60% of the cases. The incidence of MPNSTs in NF1 patients is 2 to 4.6%, compared with 0.001% in the general population.^82–85 Malignant progression is presumed to result from additional mutations involving tumor-suppressor genes, such as p53 (see later). Only two subtypes of neurofibromas, plexiform and intraneural, are commonly associated with progression to MPNST.85 Very rarely, MPNSTs arise in benign schwannomas or ganglioneuromas.^81,82,86,87 For all tumors, ~10% are assumed to arise after radiation therapy. For paraspinous tumors, however, this percentage increases to 20%. Radiation-induced tumors have an average latency of ~17 years. They show no clear-cut association with neurofibromatosis or a preexisting neurofibroma. The remaining tumors are sporadic.^81,82,87

There is a slight male predominance; men compose 52 to 67% of the cases in several large series. This pattern is true for both sporadic and NF1-associated tumors.^81,82,84,87 MPNSTs are tumors of adults; only ~10% occur in children. The average age at diagnosis is 34 to 37 years. NF1-associated tumors arise earlier, with an average age at diagnosis of ~29 years compared with 40+ years for sporadic cases. The proximal spinal nerves are often involved. Only the sciatic nerve and brachial plexus are more common sites. Distal sites are more common than proximal sites. Lumbar and sacral tumors are ~2.5 times more common than thoracic tumors, and tumors arising in the trunk are three times more common than those of the head and neck.^82,87 About 50% of paraspinous tumors encroach the spine, and 10% have foraminal or intradural involvement.⁸⁷ Paraspinous tumors have a worse prognosis than tumors in other sites, possibly because complete resection is rare.

Gross and Microscopic Pathologic Features

The macroscopic appearance of MPNSTs depends on the presence of identifiable nerve involvement, which was present in 32% of the cases in one series.⁸⁴ Where the parent nerve is identified, fusiform enlargement, similar to but larger than that seen in benign neurofibromas, is often found. Eccentric involvement creates a more globoid lesion. A globoid or lobulated mass is characteristic of tumors without identifiable nerve involvement. The size of the tumors range from 2 to 40 cm. Most are larger than 5 cm, an important threshold because it is associated with a poor prognosis. They often appear well circumscribed, with a fibrous pseudocapsule caused by compression of the surrounding soft tissue. They tend to be firm to rubbery. The cut surfaces are fleshy and tan-white to gray. Softer red or yellow areas correspond to foci of hemorrhage, necrosis, or both. Both are common, with necrosis seen in 60% of tumors.⁸⁸

MPNSTs are spindle cell tumors. Cellularity often varies within tumors, but they are usually highly cellular. The tumor, cells are arranged in fascicles that may demonstrate a herringbone pattern in the manner of fibrosarcomas (Fig. 3-15A) or a storiform pattern as occurs in malignant fibrous histiocytomas. Within the tumor, the cells may be densely packed or more loosely distributed with myxoid stroma. The nuclei can be hyperchromatic. They may be wavy as in benign neurofibromas. Mitoses are present and often numerous (Fig. 3-15B). Necrosis is common (Fig. 3-15C). Where the involved nerve is identified, tumor invasion tends to course parallel to the axons. PGP 9.5 and modified Bielschowsky stains may help identify axons.

MPNSTs are graded by a two- or four-tiered system. Neither is highly predictive possibly because most MPNSTs are high grade (or grades III and IV).^82,84,85,87 All are considered high grade in the WHO system, and the tumor-specific grade is only relevant as to whether the tumor is WHO grade III or IV. Grading is based on cellularity, pleomorphism/atypia, mitotic activity, and necrosis. Compared with low-grade tumors, high-grade MPNSTs have greater hypercellularity and atypia and consistently have necrotic foci. Mitotic activity is also greater. Thresholds of 4 and 6 mitoses/10 HPFs have been reported.^82,84,87 The presence of necrosis is a significant prognostic factor by itself.⁸⁴

Immunohistochemistry

Fifty percent to 80% of MPNSTs demonstrate S-100 immunoreactivity (Fig. 3-15D).^86,87,89 Although these percentages are significantly lower than for schwannomas or neurofibromas, S-100 is useful marker for distinguishing MPNSTs from other soft tissue sarcomas. A recent report identified CD99 positivity in 86% of MPNSTs.⁸⁹ Overexpression of p53 proteins occurs in 50 to 87% of cases.^86,90–93 In contrast, significant p53 immunoreactivity is rare in benign neurofibromas.^91,93 This finding suggests that this pathway plays a significant role in the development of malignant progression in MPNSTs. Immunoreactivity for MDM-2 and p21 occurs in about two thirds of cases but does not appear to have a significant association with prognosis. However, an MIB-1 LI > 25% is associated with shorter survival times.⁹²

MPNSTs with Divergent Differentiation (Triton Tumor-MPNSTs with Rhabdomyosarcoma Differentiation, Epithelioid MPNSTs, Glandular MPNSTs)

From 16 to 27% of MPNSTs also contain areas of divergent malignant differentiation.^81,82,84,87 This feature is most common in NF1-associated tumors. The most common patterns, in descending order of frequency, are rhabdomyosarcomas, chondrosarcomas, osteosarcomas, epithelioids (including glandular), and angiosarcomas (Table 3-4). MPNSTs with rhabdomyosarcomas are sometimes called triton tumors (Fig. 3-15E,F). The other patterns of metaplasia have only descriptive names.

Paragangliomas

Paragangliomas are tumors of the autonomic nervous system and occur most often in the adrenal gland as pheochromocytomas. They are derived from neural crest cells. Most extraadrenal paragangliomas arise in specialized autonomic receptors, with 80 to 90% occurring in the carotid body or glomus jugulare.94 They also arise in autonomic ganglia, and sympathetic chain tumors are found from the skull base to the pelvic floor in a paravertebral/periaortic distribution. In these tumors, the source of neoplastic cells is obvious; however, paragangliomas also occur as intradural-extramedullary spinal tumors. These very rare tumors are almost always associated with the cauda equina but rarely occur in proximal locations or in the filum terminale. The origin of cauda equina tumors is uncertain. It has been suggested that these tumors may arise from sympathetic neurons in the lateral horns whose processes run through the rami communicantes.⁹⁴

Paragangliomas are benign, slow-growing tumors that are classified as WHO grade I. In contrast to adrenal tumors where 10% of pheochromocytomas are malignant, only one malignant spinal cord tumor has been reported. The clinical course of the benign extraadrenal tumors also depends on location. Only ~4% of intraspinal paragangliomas recur after gross total resection, and the prognosis for glomus jugulare and carotid body tumors is similar. In contrast, as many as 42% of paravertebral tumors recur.^95,96 There is a 1.4 to 2:1 male predominance.⁹⁷ In a large series, ages have ranged from 13 to 71 years. They occur most commonly in the fourth to sixth decades, with a median age at diagnosis of 47 years. They are very rare in children.

Gross and Microscopic Pathologic Features

Most paragangliomas are from 1 to 3 cm in size and are globoid or sausage shaped. They have a thin fibrous capsule and are well demarcated from adjacent nerve roots. They have no dural attachment. They are soft with red-gray cut surfaces, consistent with their highly vascular nature.

The tumors are composed of lobular nests (zellballen) or ribbons of chief cells (Fig. 3-16A,B). In some tumors, the nests of cells are closely packed, whereas others are only modestly cellular with the lobules of cells separated by edema and fibrous tissue. The polygonal cells demonstrate only mild atypia. The round-oval nuclei have a granular chromatin that characterizes neuroendocrine cells and lack large nucleoli (Fig. 3-16C). The cytoplasm is eosinophilic or clear with fine granularity that corresponds to neurosecretory granules. Their nature can be demonstrated using a Grimelius or other argentaffin stain, or one of several neural immunohistochemistry markers as described later. Mitotic figures are rare. In cauda equina tumors, ~50% also have large ganglion cells and transition forms. They have typical cytologic features with a large round vesicular nucleus and a large nucleolus. The cytoplasm is abundant and may have obvious Nissl substance. Where ganglion cells are numerous, a background of Schwann cells may be seen.

A fine capillary network and a layer of sustentacular cells surround the lobules or ribbons. The sustentacular cells have small oval nuclei and delicate elongate processes.

Immunohistochemistry

The neoplastic chief cells are immunoreactive for the neuronal markers chromogranin, synaptophysin, and NSE, and the first two are specific enough to be diagnostically useful (Fig. 3-16D,E).^61,97–100 The chromogranin staining corresponds to the granules seen on a Grimelius stain. The tumor cells also may be reactive for other neuropeptides including serotonin, somatostatin, and metenkephalin.^61,97 Cauda equina tumors are often reactive for cytokeratins.^64,101 The sustentacular cells are reactive for S-100 and GFAP.^61,102

Neuroblastic Tumors

A better understanding of the histogenesis and the clinical behavior of ganglioneuromas, ganglioneuroblastomas, and neuroblastomas has made it clear that these tumors, which range from indolent and benign to aggressive and highly malignant, designate three patterns of maturation of a single neoplastic process. Consequently, they are now grouped under the more general heading neuroblastic tumors.

Peripheral neuroblastic tumors are tumors of the sympathetic nervous system. The neoplastic cells are derived from the neural crest. In the normal development of the sympathetic nervous system, neural crest cells migrate to form the chain of ganglia that parallel the spine and into the developing adrenal gland. Neural crest cells differentiate into ganglion cells and Schwann cells to form the sympathetic nervous system and into pheochromocytes (among others) that become the adrenal medulla. This pattern of distribution and differentiation explains both the location of tumors and their histologic features. About 60% of neuroblastic tumors arise in sympathetic ganglia, and their cervical-to-sacral distribution is about proportional to the number of ganglia in each region. The adrenal gland accounts for the other 40% and is the single most common site. Neuroblastic tumors are primarily a pediatric problem. They account for 15% of solid tumors in patients younger than 4 years. About 90% of all neuroblastic tumors occur before age 5. Ganglioneuromas are the exception, typically occurring in young adults.103 The involvement of the paraspinal nervous system and the frequent bony invasion associated with immature tumors bring these lesions to the attention of spine surgeons.

FIGURE 3-16 Paraganglioma. (A) Paragangliomas are often organized in small lobules with fine fibrovascular septa, a pattern referred to as zellballen (balls of cells) (H&E, ×40). (B) The reticulum stain highlights the lobular architecture. The pattern resembles normal pituitary gland (reticulum, X40×0). (C) The cells have eccentric, round-to-oval nuclei and a moderate amount of granular cytoplasm. There is usually little atypia (H&E, ×400). (D) Paragangliomas are immunoreactive for synaptophysin (seen here) and other neuronal/neuroendocrine markers (synaptophysin-DAB and hematoxylin, ×200). (E) Immunoreactivity for chromogranin, a marker of neurosecretory granules, is seen (chromogranin-DAB and hematoxylin, ×200).

In 1984 Shimada and colleagues^104,105 described a classification system for neuroblastic tumors that linked gross and histologic features with age. With minor refinements, the International Neuroblastoma Pathology Committee adopted the renamed International Neuroblastoma Pathology Classification system in 1999.^106–109 Since then further refinement to the classification of the intermediate-grade ganglioneuroblastoma has been suggested and is included in this discussion (Table 3-5).¹¹⁰

Conceptually, all neuroblastic tumors begin as neuroblastomas composed of primitive neuroectodermal cells. Over time, the tumor cells mature into intermediate forms, mature ganglion cells, and Schwann cells. The rate of this maturation predicts the tumor’s behavior; a faster rate of maturation corresponds to a more favorable prognosis. The microscopic features of a tumor provide a “snapshot” of its development at a given time. In astrocytomas (and in most tumors), a high grade and a poorly differentiated pattern are associated with a grim prognosis, irrespective of age. Neuroblastic tumors are unique in that only a correlation of the “snapshot” with a patient’s age is predictive of tumor behavior. Thus, in a patient 5 years of age or older, a differentiating neuroblastoma has an unfavorable prognosis, whereas the same histology has a favorable prognosis in a younger patient. Presumably, the latter tumor would have continued to mature into a ganglioneuroblastoma or ganglioneuroma by the time the patient had reached the older patient’s age. Nodular ganglioneuroblastomas are viewed as the result of local development or persistence of aggressive clones. Consequently, the neuroblastic foci are genetically distinct from the ganglioneuromatous regions.

As a group, neuroblastic tumors have a wide range of possible histologic patterns. The prevalence of mature or immature neurons and Schwannian stroma forms the bases for differentiating neuroblastic tumors into the three major subtypes and for further subdividing the neuroblastoma group. The mitosis-karyorrhexis index (MKI), defined as the sum of mitotic and karyorrhectic figures/5000 cells, is also used to subclassify neuroblastomas. Tumor cellularity ranges from 100 to 900 mitoses/HPF ((400). Table 3-6 defines specific terms used in classification.

Neuroblastomas—schwannian stroma-poor: The neoplastic neuroblasts have small-to-intermediate sized, round-to-angular nuclei and minimal cytoplasm (Fig. 3-17A). The chromatin ranges from dense to coarsely stippled. In undifferentiated tumors, no neuropil—a fine eosinophilic meshwork of neuritic processes—is present. The poorly differentiated subtype is characterized by the presence of stromal neuropil; otherwise, similar cells, Homer-Wright rosettes, may be present (Fig. 3-17B). As many as 5% of cells demonstrate features of ganglion cell maturation, primarily in the form of differentiating neuroblasts. The differentiation and cytologic features of these cells are intermediate. Compared with undifferentiated cells, differentiating neuroblasts have a larger, clearer nucleus and often a nucleolus. The nucleus is placed eccentrically in eosinophilic or amphophilic cytoplasm. Although this description is similar to that of mature ganglion cells, the nuclei are not as large, nor are the cytoplasms as abundant. Mature ganglion cells have large round vesicular nuclei and a prominent nucleolus. The abundant eosinophilic cytoplasm often contains peripheral coarse basophilic granules (Nissl substance). In differentiating neuroblastomas, the percentage of cells with ganglion cell maturation is greater than 5% and often includes mature ganglion cells. Typically, a Schwann cell stroma is present and may compose as much as 50% of the tumor.

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