Update on diagnostic practice tumors of the nervous system.
* Context.--Changes in the practice of diagnosing brain tumors are
formally reflected in the evolution of the World Health Organization
classification. Beyond this classification, the practice of diagnostic
pathology is also changing with the availability of new tests and the
introduction of new treatment options.
Objective.--Glioblastomas, oligodendrogliomas, glioneuronal tumors, and primitive pediatric tumors are discussed in an exemplary way to illustrate these changes.
Data Sources.--Review of relevant publications through Medline database searches.
Conclusions.--The example of glioblastomas shows how new predictive markers may help identify subgroups of tumors that respond to certain therapy regimens. The development of new treatment strategies also leads to different questions in the assessment of brain tumors, as seen in the example of pseudoprogression or the changes in tumor growth pattern in patients taking bevacizumab. Oligodendrogliomas illustrate how the identification of 1p/19q loss as a cytogenetic aberration aids our understanding of these tumors and changes diagnostic practice but also introduces new challenges in classification. Glioneuronal tumors are an evolving group of lesions. Besides a growing list of usually low-grade entities with well-defined morphologic features, these also include more poorly defined cases in which a component of infiltrating glioma is often associated with focal neuronal elements. The latter is biologically interesting but of uncertain clinical significance. Oligodendrogliomas and glioneuronal tumors both illustrate the importance of effective communication between the pathologist and the treating oncologist in the discussion of these patients. Finally, the discussion of primitive pediatric tumors stresses the clinical importance of the distinction between different entities, like atypical teratoid rhabdoid tumor, "central" (supratentorial) primitive neuroectodermal tumor, "peripheral" primitive neuroectodermal tumor, and medulloblastoma. In medulloblastomas, the recognition of different variants is emerging as a prognostic factor that may in the future also predict therapy responsiveness.
Nervous system tumors
Nervous system tumors (Care and treatment)
Glioblastoma multiforme (Diagnosis)
Glioblastoma multiforme (Care and treatment)
Biological markers (Usage)
Lukas, Rimas V.
|Publication:||Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 College of American Pathologists ISSN: 1543-2165|
|Issue:||Date: July, 2009 Source Volume: 133 Source Issue: 7|
|Topic:||Event Code: 350 Product standards, safety, & recalls; 200 Management dynamics Canadian Subject Form: Nervous system tumours; Nervous system tumours|
|Organization:||Organization: World Health Organization|
The large heterogeneity of central nervous system (CNS) tumors is
reflected in the long list of entities identified in the official World
Health Organization (WHO) classification. (1) A few noteworthy
differences set these tumors apart from most other malignancies. First,
malignancy is not defined by the ability of a CNS tumor to spread to
distant sites, but by its local growth pattern. Hematogenous metastases
are distinctly uncommon; however, some CNS tumors can spread along
cerebrospinal fluid pathways. This type of spread is found in low-grade
tumors, like pilocytic astrocytomas, (2,3) and in high-grade tumors,
like glioblastomas. (4-6) Second, the WHO grade assigned to a tumor is a
description of its biology. Tumors of low grade, including those
classified as WHO grade 1, may still result in significant morbidity and
mortality. Other factors, like tumor location and resectability, are
major predictors of disease outcome.
Some of the challenges in diagnostic practice arise from the evolution in the WHO classification system. The 2007 version of this classification has been reviewed recently in a number of publications. (7-12) The reader is referred to these references as well as the classification system itself (1) for detailed comprehensive discussion of newly described entities and variants. The focus of this article is the more exemplary discussion of established and emerging changes in diagnostic practice. The main sections will discuss glioblastomas, tumors with oligodendroglial differentiation, glioneuronal tumors, and primitive pediatric neoplasms.
The WHO criteria for the definition of glioblastoma multiforme (GBM) are relatively clear: GBMs are anaplastic, astrocytic tumors (Figure 1, A through D). Prominent microvascular/endothelial proliferation and/or necrosis are essential diagnostic features. (1) Glioblastoma multiforme is one of the more common primary brain tumors, and it is regarded as one of the most malignant. Patients most often die of progression of their local disease or of other associated complications, like thrombosis and pulmonary embolism. Systemic metastases are extremely rare, (13) and clinically symptomatic spread along cerebrospinal fluid pathways to other areas of the brain is relatively uncommon. (4,5) Interestingly, there is an emerging body of literature arising from the solid organ transplant experience concerning the potential for hematologic spread of GBM. Some of the immunosuppressed recipients of organ transplants from donors with GBM have been found to develop malignancies in the donated organ that resemble the primary brain tumor. (14) The clinical relevance of this potential for extra-CNS spread in individuals with functioning immune systems is not known. One could speculate that the pattern of tumor dissemination could potentially change with the improvement in patient survival through new therapies.
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Until recently, the utility of chemotherapy in the treatment of glioblastomas was limited, so that surgery and radiation therapy were the main treatment modalities. (15) The introduction of newer chemotherapy agents, including temozolomide, (15) irinotecan (CPT-11), (16-18) bevacizumab (avastin), (18,19) and 13-cz's-retinoic acid, (20) have shown promising responses. Additionally, more biologically targeted therapies are emerging as potential treatment options, which has put new emphasis on the already long-recognized heterogeneity of GBMs. Clinically, primary GBMs that develop de novo have long been distinguished from secondary ones that develop out of progression of lower-grade infiltrating astrocytomas. (21) Additionally, the description of distinct histologic glioblastoma variants, like giant cell glioblastoma (Figure 1, E), and glioasarcoma (Figure 1, F), has also long illustrated this heterogeneity. These earlier reports have found confirmation in more recent years in a number of molecular studies: Primary GBMs, for example, more typically show activation of the epidermal growth factor receptor (EGFR) pathway, whereas secondary GBMs more commonly show p53 mutations together with other acquired molecular alterations. Therefore, the molecular profiling of these tumors confirms this clinical distinction, (21-24) and it also suggests the presence of other potential subgroups. (25,26) Additionally, molecular studies have confirmed the concept of giant cell glioblastoma and gliosarcoma as distinct variants. (27-29) Until now, the identification of these variants was, for the most part, of academic interest and not associated with any significant clinical differences. But this is changing with the introduction of more treatment options, and in particular with more biologically targeted therapies. (23,30) The following discussion will focus on some of these changes and new challenges that are taking place in the diagnostic assessment of glioblastomas.
EGFR and Phosphatase and Tensin Homolog Deleted on Chromosome 10 in Glioblastomas
The EGFR-phosphatidylinositol-3-kinase (EGFR-PI3K) pathway is often indiscriminately activated in glioblastomas through genetic alterations. (31,32) In gliomas this pathway involves the EGFR on the cell surface that activates the serine/threonine kinase AKT (v-akt murine thymoma viral oncogene homolog 1) through PI3K. This in turn inhibits apoptosis, facilitates proliferation, and promotes tumor growth through different pathways, including the activation of the mammalian target of rapamycin. Akt also specifically plays a role in activation of angiogenesis in tumors. (33) As a phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome 10) counteracts the activity of the PI3K. Tyrosine kinase inhibitors, like erlotinib and gefitnib, may offer a therapy option for those tumors in which EGFR signaling is upregulated--especially if this activation of the EGFR signaling pathway goes along with preservation of the natural break on this pathway, PTEN. (31,32) Overall, about 10% to 20% of glioblastomas respond to these drugs clinically. (31) Immunohistochemistry as well as molecular studies have been used to assess the EGFR and PTEN status of glioblastomas (Figure 2). Significant controversy remains regarding the relative importance of wild-type EGFR, the constitutively active mutant EGFRvIII (vlll variant with exon 2-7 deletion), the phosphorylation (activation) status of Akt, and the patients' response to EGFR-specific tyrosine kinase inhibitors. (31,32,34-36) Additional recent preclinical data suggest that combining these kinase inhibitors together with mammalian target of rapamycin inhibition through rapamycin may result in additional benefits, particularly in those patients with PTEN-deficient tumors. (37)
O(6)-Methylguanine DNA Methyltransferase
Alkylating agents, like temozolomide, are thought to have their primary effect by adding methyl groups to the [O.sub.6] position of guanine producing lethal methylguanine adducts in the DNA. O(6)-methylguanine DNA methyl-transferase (MGMT) normally acts to remove these toxic methylguanine adducts. Depletion of normal MGMT sensitizes tumors to these alkylating agents. (38) Different tumors, including some glioblastomas, show loss of MGMT function. The molecular mechanism of this inactivation is usually gene silencing through promoter methylation--not deletions, mutations, or rearrangements. Patients with glioblastomas showing this type of inactivation of MGMT show markedly better response to temozolomide. (39) Unfortunately, immunohistochemical staining for MGMT does not offer a reliable way to stratify glioblastomas, (40) and polymerase chain reaction-based assays are therefore necessary. (30)
The number of chemotherapy agents that are used in glioblastoma patients has increased in recent years to include antiangiogenic agents, like bevacizumab, a humanized monoclonal antibody to vascular endothelial growth factor, as well as alkylating agents, like temozolomide. (15,18,19) The introduction of these new treatment options and patient eligibility for often multiple clinical trials has also introduced new challenges in the therapeutic management of the affected patients and confronts the pathologist with new diagnostic questions.
First, these drugs change the imaging characteristics that are traditionally used to follow the patients and assess treatment response: With radiation therapy alone, a small percentage of patients is found to exhibit magnetic resonance imaging findings that mimic tumor progression. (41) Typically, these are new areas of enhancement on follow-up magnetic resonance imaging scans that pathologically are found to correspond to reactive radiation-induced changes. This type of pseudoprogression is more commonly found now that patients are treated with radiation therapy in combination with drugs like temozolomide, which is typically administered concomitantly with radiation and then followed by adjuvant cycles of temozolomide. (42-44) The distinction between true tumor progression and pseudoprogression is critical in determining whether a patient's therapy needs to be adjusted or whether it should be continued. (42) In some cases, surgery and pathologic examination of the tissue in question are helpful in resolving this problem. (44) It is therefore important for the pathologist to be aware of these questions. The evaluation of these specimens can be challenging. Based on the basic biology, one expects to find individual infiltrating tumor cells within the brain parenchyma surrounding the tumor bed. But the main objective of examining these specimens is the determination of the pathologic changes that explain the radiologic findings--the distinction between viable, usually solid or bulky areas of recurrent tumor and reactive therapy-induced changes. In some cases, immunohistochemical staining with the marker MIB-1 can be helpful in assessing the proliferative activity of areas suspicious for tumor growth (Figure 3). Evaluation of this stain can be difficult, but it is useful if the proliferating cells can be identified as morphologically consistent with tumor cells, not reactive inflammatory cells.
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Second, bevacizumab is associated with marked reduction of the contrast enhancement that is observed in glioblastomas as well as metastatic CNS lesions on magnetic resonance imaging. (45,46) This reduction is likely related to its effect on vascular permeability. The target of this monoclonal antibody, vascular endothelial growth factor, is an extremely potent facilitator of vascular permeability and was initially named vascular permeability factor.47 This effect is also illustrated by the fact that bevacizumab has actually been shown to reduce radiation necrosis by decreasing capillary leakage and edema. (48) Tumor recurrences in patients treated with bevacizumab may exhibit different growth patterns and imaging features than traditionally observed, with a higher burden of diffusely infiltrating nonenhancing tumor (Figure 4). (19,46) This observation may in part be a reflection of the general tendency of recurrent high-grade astrocytomas to shift their phenotype toward one characterized by the expression of a more mesenchymal gene set. (26)
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The examples of EGFR/PTEN status as well as the MGMT methylation status of GBMs illustrate how the pathologic analysis of these tumors is changing and adapting to the available treatment options. Currently, testing for these biologic variants is not yet part of the routine diagnostic work-up. But on a clinical trial basis and in collaboration with the treating neuro-oncologist, the utilization of these additional biomarkers is expected to increase. (30,49) The confirmation of pseudoprogression and the changes in tumor growth pattern with bevacizumab illustrate how the questions to pathologists are changing with the evolution of patient management.
DISTINCTION BETWEEN PILOCYTIC ASTROCYTOMAS AND INFILTRATING GLIOMAS
Pilocytic astrocytoma has been long recognized as a distinct entity, and it is classified in the WHO system as a grade 1 tumor. Clinically, pilocytic astrocytomas are distinctly different from infiltrating astrocytomas, and in most cases pathologic classification is possible even on small biopsy specimens. Molecular studies have provided additional information to support the fact that pilocytic astrocytomas are not a lower-grade precursor lesion for infiltrating astrocytomas, but are biologically different from infiltrating astrocytomas. (50-52) They typically do not progress to higher tumor grades, as the WHO grade 2 infiltrating astrocytomas do. In some clinical studies, this distinction is not adequately reflected. Sometimes, inaccurate terms like "low-grade astrocytoma" or "brainstem glioma" are used that obscure this distinction. (53-56) In this context, the pathologists have an important role for introducing clarity and consistency of terminology.
TUMORS WITH OLIGODENDROGLIAL DIFFERENTIATION
Traditionally, oligodendrogliomas are identified by tumor cells that mimic oligodendroglial differentiation. (57) It is unclear, though, whether this histologic appearance is truly reflective of a derivation from oligodendroglial cells. Alternatively, these cells may be derived from more primitive tumor stem cells that can differentiate along a line of oligodendroglial differentiation. (58) An imperfect adherence to such a developmental differentiation program may explain reports of oligodendrogliomas with neuronal differentiation. (59) The prototypical oligodendroglioma is an infiltrating glioma that grows into the cerebral cortex and shows cells with regular round to ovoid nuclei with even chromatin staining and perinuclear halos (Figure 5, A and B). These halos that result in the typical "fried egg" appearance are an artifact of slow fixation. At least in the more solid areas of the tumor the typical chicken wire-type vasculature may be present. Some cases show prominent microcyst formation or microcalcifications. Features like "minigemistocytes" and "gliofibrillary oligodendrocytes" mimic astrocytic differentiation. The distinction between infiltrating astrocytoma and oligodendroglioma is difficult on frozen section samples because halos are not seen and artifactual change distorts the nuclear morphology--fortunately, a diagnosis of infiltrating glioma is usually sufficient at the time of frozen section. (60) Different studies vary in the reported proportion of oligodendrogliomas in sets of glioma patients, ranging between 4% and 7% of gliomas (61) and 25% and 30% of gliomas. (62,63) These differences are at least in part explained by the stringency with which the above-mentioned criteria of oligodendroglial differentiation are applied.
The current WHO classification grades oligodendrogliomas into 2 different categories as WHO grade 2 and anaplastic WHO grade 3. (1) Prominent mitotic activity and microvascular/endothelial proliferation are the 2 features that define anaplastic tumors. The use of immunohistochemical staining for Ki-67 to establish a MIB-1 labeling index is not part of the official grading system, but this test is commonly used as an additional helpful way to assess the proliferative activity of a tumor. (64-66) This in turn may guide therapeutic management. Other histologic features, including necrosis, pleomorphism, nuclear hyperchromasia, and nuclear to cytoplasmic ratio, are discussed in the literature as morphologic features associated with anaplastic tumors, and some older classification systems distinguished more than 2 grades of oligodendrogliomas. (67-69) Some authors have advocated the use of a third category, "WHO grade 4" oligodendrogliomas, for those that show pseudopalisading necrosis. (64) In general, areas of necrosis may not be of prognostic significance in pure anaplastic oligodendrogliomas. (70,71) Beyond infiltrating astrocytomas, a number of other entities may be considered in the differential diagnosis, including central neurocytomas, clear cell ependymomas, dysembryoplastic neuroepithelial tumors (DNETs), small cell glioblastoma (Figure 1, D), and pilocytic astrocytomas with oligodendroglioma-like areas. Central neurocytoma is typically but not exclusively a periventricular lesion that is composed of small regular neuronal cells that can mimic oligodendrocytes histomorphologically (Figure 5, C through F). Clear cell ependymoma is a variant of ependymoma that can resemble oligodendroglial differentiation because of the cytoplasmic clearing that is found around the neoplastic cells that may lack ependymal architectural features (Figure 6, A and B). The lack of individual tumor cell infiltration into adjacent neuropil at the margin of the tumor and the presence of at least focal ependymal perivascular pseudorosettes are helpful diagnostic features. The small round cells of the glioneuronal tumor DNET can also sometimes resemble oligodendroglial cells (Figure 6, C and D). Immunohistochemical studies, molecular testing, electron microscopy, and clinical correlation usually resolve these questions.
Unfortunately, there is a significant gray zone between cases of prototypical oligodendroglioma and infiltrating astrocytomas. This gray zone has found official recognition in the WHO category of mixed oligoastrocytoma.1 These cases with overlap features make the diagnoses of oligodendroglioma, mixed oligoastrocytoma, and infiltrating astrocytoma some of the most poorly reproducible distinctions in the diagnostic practice of typing brain tumors. (63,64,72) In some instances the grade of a glioma as WHO grade 2, 3, or 4 can depend on whether it is classified as astrocytic, oligodendroglial, or mixed because necrosis alone puts tumors with astrocytic component into the WHO grade 4 category. Therefore, these are distinctions that affect treatment decisions. Patients with mixed tumors are often treated according to the presumably more aggressive astrocytic component.
Typical oligodendrogliomas show loss of chromosomal arms 1p and 19q as characteristic cytogenetic aberrations. Some recent studies suggest that the combined loss of 1p/ 19q may follow a (1;19)(q10;p10) translocation, with subsequent loss of the derivative chromosome der(1;19)(q10; p10). (73,74) The determination of these chromosomal rearrangements by fluorescence in situ hybridization, polymerase chain reaction, or comparative genomic hybridization has become commonplace in diagnostic practice. (30) No defining molecular alteration has been identified yet in the form of a specific fusion product or specific lost tumor suppressor gene, despite the suggestion of several possible candidates. (75-77) Identification of 1p/19q loss correlates with better prognosis and response to chemotherapy. (72,78,79) The identification of these chromosomal alterations now redefines the above-mentioned gray zone between oligodendrogliomas and astrocytomas as the spectrum of tumors that falls between (1) histomorphologically typical oligodendrogliomas with the 1p/19q loss and (2) histomorphologically typical astrocytomas lacking these same chromosomal changes. Many of the details of tumors in this gray zone still require further studies, and the true importance of mixed oligoastroctyic differentiation will therefore continue to be debated. (80) It has been suggested that isolated loss of 1p or 19q may still be a predictor of better survival in subsets of tumors histologically classified as oligodendroglioma or oligoastrocytoma. (81,82) At least in anaplastic oligodendrogliomas and oligoastrocytomas, codeletion of 1p/19q may be associated with prolonged survival, whereas the histologic distinction between these 2 entities may not be an independent prognostic factor. (83,84)
Initial studies suggested that astrocytomas show poor response to chemotherapy regimens, whereas oligodendrogliomas are sensitive to PCV chemotherapy that consists of procarbazine, lomustine (CCNU), and vincristine. (62,78,79,85) A correct diagnosis of oligodendroglioma was therefore important in predicting therapy responsiveness. More recently, temozolomide has been used instead of PCV chemotherapy because of better tolerability. The response to temozolomide is similarly predicted by the cytogenetic changes, with a significantly better response in those tumors with combined 1p/19q loss or isolated 1p loss. (86-88) Astrocytic tumors, however, also respond to temozolomide. (15,89) In anaplastic tumors the distinction between oligodendroglioma and astrocytoma may therefore now be a less important predictive factor in predicting responsiveness of a tumor to therapy.
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Traditionally, it is believed that the diagnosis of an oligodendroglioma with 1p/19q loss was not only of predictive but also of prognostic importance. A recent study of WHO grade 2 tumors treated solely with surgery and watchful waiting, however, suggests that 1p/19q loss may be mostly a predictive marker. (90) It may not only be predictive of response to chemotherapy, but also of response to radiation therapy. (83,84)
Molecular testing to assess the 1p/19q deletion status is helpful in these tumors to confirm and reinforce the morphologic assessment of oligodendroglial differentiation and to provide prognostic and predictive information about the tumor. Additionally, the assessment of these chromosomal rearrangements is helpful in the diagnostic distinction between oligodendroglioma and some of its mimics, like small cell glioblastoma, central neurocytoma, and DNET.
The example of oligodendrogliomas illustrates how clear communication with local treating clinical colleagues is important in a situation in which some of the diagnostic tests and their interpretation are still in evolution. This type of interdisciplinary interaction will establish a better understanding of the issues involved in the management of these patients on both sides. The decision of when to order 1p/19q testing is also best made in collaboration with the treating neuro-oncologist.
One of the fastest-growing lists of entities in the WHO classification has been that of the glioneuronal tumors. (1) These are tumors with an admixture of glial and neuronal components. Both cell types are thought to be part of the same neoplastic process. Entrapment of preexisting neurons by an infiltrating glioma (Figures 1, B and 5, B) therefore has to be distinguished from glioneuronal tumors. More well-established examples of glioneuronal tumors include DNETs (Figure 6, C and D), (91) ganglioglioma (Figure 6, E and F), (92,93) and desmoplastic infantile ganglioglioma. (94) More recently recognized entities95 partly included in the latest version of the WHO classification include the rosette-forming tumor of the fourth ventricle, (96) the papillary glioneuronal tumor, (97) and rosetted glioneuronal tumor/glioneuronal tumor with neuropil-like islands. (11,98,99) The glial component in these tumors varies but often resembles either a pilocytic astrocytoma or an infiltrating glioma with astrocytic or oligodendroglial features. In the papillary glioneuronal tumor of the fourth ventricle, the glial component has unique features forming distinct papillary structures. The neuronal component can be composed of mature large ganglion cells, small but mature neuronal cells, or immature neuronal tissue. In most of these mixed tumors, the glial component appears to be the main determinant of clinical outcome. This is illustrated by the following scenarios: (1) Glioneuronal tumors like gangliogliomas or DNETs only rarely show aggressive clinical behavior. Sometimes, such an aggressive transformation is described after radiation therapy. In these tumors it is typically the glial component that progresses. (100-104) Only in rare cases is there also evidence of dedifferentiation of the neuronal component (105-107); (2) In the case of desmoplastic infantile ganglioglioma, even the presence of an immature neuronal component does not necessarily indicate a poor outcome, (1,108,109) even though exceptions to this rule are described. (110)
In diagnostic practice one still encounters glioneuronal tumors that cannot be placed into any of the well-defined WHO categories despite the growing list of entities. From a pragmatic standpoint, the most important clinical distinction is between those glioneuronal tumors that behave as low-grade lesions potentially cured by surgery and those tumors that show a similar behavior to that observed in infiltrating gliomas without a neuronal component. Examples of the former include those lesions that are typically classified as WHO grade 1 and may be hamartomatous rather than neoplastic, including gangliogliomas, papillary glioneuronal tumor, DNET, or the rosette-forming tumor of the fourth ventricle. Examples of the latter include tumors like the rosetted glioneuronal tumor. In some of the latter cases, the true significance of focal neuronal differentiation may be debated. Some cases of infiltrating astrocytoma, oligodendroglioma, ependymoma, or pleomorphic xanthoastrocytoma show evidence of neuronal differentiation. (59,95,111-115) Secondary glioblastomas can have primitive neuronal areas mimicking a primitive neuroectodermal tumor (PNET). (116,117) These findings may raise interesting questions about the biology of these tumors and a possible origin from a primitive multipotent (tumor) stem cell. In the case of PNET-like areas in glioblastomas, this morphologic finding suggests an increased risk for cerebrospinal fluid spread and possible response to platinum-based chemotherapy regimens. (116) But, in general, the true clinical significance of these findings remains to be determined. This fact has to be clearly communicated to the clinicians. The pathologist should be careful to not distract from the problem of a high-grade infiltrating tumor by a long, elaborate discussion of focal neuronal elements. (95)
PRIMITIVE NEURAL TUMORS OF CHILDHOOD
A number of primitive, small round blue cell tumors are found in the CNS. (118,119) These are typically pediatric tumors and include medulloblastoma, supratentorial "central" PNET, medulloepithelioma, ependymoblastoma, and atypical teratoid rhabdoid tumor (AT/RT). Molecular studies support the fact that these tumors differ in their biology. (120,121) Despite variations in their prototypical morphologic features, these tumors are often indistinguishable based solely on histomorphology. Medulloblastomas and pineoblastomas are partly defined by their anatomic location. Other malignant tumors, like glioblastomas, may also have to be considered in the differential diagnosis of these tumors. (122,123) The following important diagnostic distinctions have emerged in recent years:
1. Medulloblastomas are best viewed as a heterogeneous group of different variants with important clinical and biologic differences, in contrast to some of the other small blue cell tumors that form well-defined diagnostic entities. (119) Heterogeneity within the group of tumors designated medulloblastoma has long been suggested by morphologic studies and the association between medulloblastomas and different familial syndromes, including LiFraumeni, Gorlin, and Turcot syndromes. (119) More recently, molecular studies have confirmed this heterogeneity. (119) With current combined treatment regimens that include surgery, craniospinal radiation, and chemotherapy, a large proportion of these young patients are cured of their primary disease. (124) These therapies, unfortunately, are associated with significant long-term morbidity, including decrease in body height, hypopituitarism with endocrinopathies, neurocognitive sequelae with drop in IQ scores, radiation vasculopathy, and secondary therapy-induced tumors. (124,125) Better stratification of medulloblastomas according to their risk is therefore important in deciding which patients may in the future achieve cure with modified, less aggressive therapy. Recent studies have confirmed that beyond molecular variants, simple morphologic features are powerful predictors of clinical behavior (Figures 7 and 8). (126-129) Extensively nodular tumors often behave in an indolent fashion, whereas those tumors that show significant anaplasia or large cell morphology are characterized by a much more aggressive course. (128) Anaplasia is defined by abundant mitotic figures, abundant apoptotic cells, enlarged nuclei, and pavement-like wrapping of nuclei. (128) These results suggest that risk stratification of medulloblastoma patients based on tumor morphology as well as additional biologic markers will help in deciding on the most appropriate treatment regimen. (124) Additionally, expression of specific biologic markers may in the future identify those tumors that can be expected to respond to targeted biologic therapies.
2. Atypical teratoid rhabdoid tumors are small blue cell tumors that often arise in the posterior fossa, where they can mimic medulloblastoma. Atypical teratoid rhabdoid tumors are characterized by a distinct immunohistochemical staining pattern and molecular alterations. (130-134) The rhabdoid morphology that gives these tumors part of their name is often conspicuously absent (Figure 9, A), and appropriate special studies are therefore necessary to correctly classify these tumors. Atypical teratoid rhabdoid tumors are characterized by the often focal variable expression of many different markers, including epithelial membrane antigen, smooth muscle antigen, cytokeratins, glial fibrillary acidic protein, and sometimes also synatophysin (Figure 9, B through F). Most characteristic is the loss of expression of INI-1 (also known as BAF-47, SMARCB1, or hSNF5; Figure 9, F) and the associated cytogenetic change, monosomy 22. (134,135) Medulloblastomas, in contrast, are typically positive for markers of neuronal differentiation, including Neu-N (Figure 7, B), synaptophysin (Figure 7, C), or CD56 (Figure 8, B). Sometimes, they show focal expression of glial fibrillary acidic protein. Epithelial membrane antigen (Figure 7, D), keratins, and desmin are absent in medulloblastomas, and INI-1 staining is preserved. Clinically, the distinction between atypical teratoid rhabdoid tumor and medulloblastoma is important because of the more aggressive nature of the former and the partially differing chemotherapy regimens. (136) Atypical teratoid rhabdoid tumors tend to occur at a younger age. Based solely on age, atypical teratoid rhabdoid tumor should be considered for small blue cell tumors in very young (younger than 2 years) patients.
3. So-called peripheral PNETs that are characterized by the translocation t(11;22), the EWS/FLI-1 fusion product, and expression of markers like FLI-1 and CD99 have to be distinguished from the typical supratentorial "central" PNETs that lack these molecular alterations and typically lack the expression of FLI-1. (118,137-139) Presentation of peripheral PNETs as tumors arising in the CNS is rare. Some of the reported cases are dural-based superficial tumors.138 Clinically, this may be an important distinction because prognosis and treatment protocols for central and peripheral PNETs may differ. (137,139)
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This discussion illustrates that the collaboration between the oncologist and the pathologist has a critical role in appropriately classifying these primitive pediatric brain tumors to (1) identify prognostically important medulloblastoma variants, (2) separate atypical teratoid rhabdoid tumors from other small blue cell tumors, and (3) distinguish between central and peripheral PNETs when appropriate. In the future, subclassification of medulloblastomas according to a profile of biologic markers may become important, analogous to the emerging development in therapy of glioblastomas.
In summary, there are continuous changes in the questions asked of practicing pathologists who diagnose brain tumors. In addition to those changes that are related to the revision of the WHO classification, other challenges are introduced by the evolution of the treatment modalities.
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Accepted for publication October 15, 2008.
From the Departments of Pathology (Dr Pytel) and Neurology (Dr Lukas), University of Chicago Medical Center, Chicago, Illinois.
The authors have no relevant financial interest in the products or companies described in this article.
Reprints: Peter Pytel, MD, Department of Pathology, University of Chicago Medical Center, MC6101, Room E-607-C, 5841 S Maryland Ave, Chicago, IL 60637 (e-mail: email@example.com).
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