Small Blue Round Cell Tumor

Nerve Sheath and Neuroectodermal Tumors

Julie C. Fanburg-Smith , in Bone and Soft Tissue Pathology, 2010

Differential Diagnosis

Other small round blue cell tumors, including rhabdomyosarcoma, Ewing sarcoma/primitive neuroectodermal tumor, desmoplastic round cell tumor, and lymphoma, may be considered in the differential diagnosis of neuroblastoma. Neuroblastoma usually occurs in a younger age and has catecholamine secretion, and does not usually express CD99 as does Ewing sarcoma/primitive neuroectodermal tumor or desmoplastic round cell tumor. The true rosettes of neuroblastoma are different from the pseudorosettes of primitive neuroectodermal tumor. Rhabdomyosarcoma can be separated by its morphology and reactivity with myoid (skeletal muscle–specific) markers. Desmoplastic small round cell tumor is generally desmin and keratin positive, and demonstrates stromal desmoplasia. Lymphoma can also be separated by hematopoietic immunostains specific to type. Ganglioneuroma can be separated from schwannoma and neurofibroma by its morphology and presence of ganglion cells.

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Metastatic Tumors Involving the Ovary

Elizabeth Kehr , ... Michelle S. Hirsch , in Diagnostic Gynecologic and Obstetric Pathology (Third Edition), 2018

Metastatic Small Round Blue Cell Tumors

Metastatic small round blue cell tumors in children and young women have been the subject of multiple case reports and small studies. 105,119,123,124 The differential diagnosis includes rhabdomyosarcoma, intra-abdominal desmoplastic small round cell tumor, Ewing sarcoma/primitive neuroectodermal tumor (PNET), and neuroblastoma. Embryonal rhabdomyosarcoma is the more common of the two subtypes of childhood rhabdomyosarcoma to occur as a primary ovarian tumor. 125 In contrast, of 11 cases of rhabdomyosarcoma metastatic to the ovary, more than half were of the alveolar subtype. 119,125 Embryonal rhabdomyosarcoma is composed of small round to spindle-shaped cells associated with discernible rhabdomyoblasts, set in a myxoid matrix. Alveolar rhabdomyosarcoma consists of undifferentiated cells with larger nuclei, rhabdomyoblasts, and wreathlike multinucleated giant cells, associated with fibrous septae. Both subtypes of rhabdomyosarcoma are immunoreactive with desmin and the specific skeletal muscle markers, myogenin (myf-4), and MyoD-1. 126,127 Additionally, a translocation between chromosomes 2 (or 1, less frequently) and 13 is found in most alveolar rhabdomyosarcomas, whereas deletions in chromosome 11 are more characteristic of embryonal rhabdomyosarcomas. 114,128

Metastatic ovarian desmoplastic small round cell tumor and Ewing sarcoma/PNET have been documented in four cases and three cases, respectively. 129 Metastases to the ovary in both tumor types appear similar to their primary counterpart. Desmoplastic small round cell tumors are characterized by nests of small cells with scanty cytoplasm and hyperchromatic nuclei, separated by a prominent desmoplastic stroma. Mitotic figures and necrosis are common. The immunophenotype includes desmin (often with a dotlike staining pattern), keratin, EMA, and WT-1 positivity, whereas specific skeletal muscle markers are negative. 103,123 The presence of the chromosomal translocation t(11;22)(p13:q12) (between the EWS and WT1 genes) is diagnostic of intra-abdominal desmoplastic small round cell tumor. 130

Ewing sarcoma/PNET is also composed of small cells with round to ovoid hyperchromatic nuclei. Rosette-like structures are frequently present, as are mitoses and necrosis. Ewing/PNET is defined as a small round cell malignancy showing pathognomonic molecular findings characterized by recurrent balanced translocations involving the EWSR1 gene and, in most cases, a member of the ETS family of transcription factors. 131 Although it may exclude other malignancies, immunohistochemical staining is not useful for confirming Ewing sarcoma/PNET. However, CD99 (MIC-2) can be helpful if it is diffusely positive (i.e., in all tumor cells) with in a membranous staining pattern.

As many as 25% of patients with adrenal neuroblastoma have ovarian involvement at autopsy. 132 Rarely an ovarian metastasis is discovered along with the primary tumor. 119,133,134 Neuroblastomas are composed of small round cells with hyperchromatic nuclei, arranged in an ill-defined lobular or nested pattern with thin fibrovascular septae and variable amounts of pale fibrillary material between the tumor cells. Rosettes with fibrillary material in their center are also sometimes present. These findings, along with immunostaining (i.e., neuron-specific enolase (NSE) positive, desmin negative), help to distinguish neuroblastomas from other metastatic small round blue cell tumors.

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Immunohistology of Endocrine Tumors

Ronald A. DeLellis , ... Diana O. Treaba , in Diagnostic Immunohistochemistry (Third Edition), 2011

NEUROBLASTOMA

Neuroblastomas are small, round, blue cell tumors that may arise in the adrenal gland and a variety of extra-adrenal sites. The differential diagnosis is wide and includes rhabdomyosarcoma, Ewing's sarcoma-primitive neuroectodermal tumor (ES-PNET), medulloblastoma, small cell osteosarcoma, lymphoblastic lymphoma, blastematous Wilms' tumor, and small cell desmoplastic tumor. Numerous markers have been used for the diagnosis of neuroblastomas including NE markers, cytoskeletal proteins, catecholamine-synthesizing enzymes, and neuroblastoma-‟specific" antibodies (Fig. 10.32). 279-285 Many of these markers lack specificity or sensitivity, or both, as individual reagents and must be used as panels.

NSE is present in 85% to 100% of cases of neuroblastoma, and a similarly high level of positivity has been reported for PGP9.5 (Fig. 10.33). 283 However, both of these markers may also be present in other small, round, blue cell tumors. Wirnsberger and colleagues 283 reported that among antibodies directed against chromogranins and related proteins, HISL-19 was present in 100% of neuroblastomas, followed by chromogranin A (52%) and chromogranin A and B (45%) (Fig. 10.34A). Neurofilament protein was present in 80% and was localized primarily in cell processes or nerve fibers, whereas synaptophysin was present in 75% of cases. Dopamine β-hydroxylase was present in 75% of cases. In general, reactivity for these markers was greater in well-differentiated than in poorly differentiated neuroblastomas. 283 Among peptide hormones, VIP was present in 30% and neuropeptide Y was present in 10%. CD57 was not found in any neuroblastoma but was demonstrable in seven of seven ganglioneuromas. 283 Microtubule associated protein-1 (MAP1) and MAP2 and beta-tubulin are present in 100% of cases, but the number of cases studied to date has been small. 284,285 S-100 protein is restricted in its distribution to the sustentacular (stromal) cells (see Fig. 10.34B).

CD99 is a useful marker for the distinction of neuroblastomas from other small, round, blue cell tumors. 286-290 More than 100 cases of neuroblastoma have now been studied for CD99, and all have been negative. In contrast, nearly 100% of cases of Ewing's sarcoma-primitive neuroectodermal tumor (ES-PNET) are CD99-positive. Anti-β2-microglobulin is another marker that is negative in neuroblastoma but positive in approximately 75% of ES-PNET. 291

Worthy of note is an immunohistochemical marker, NB84, that is a monoclonal antibody raised to neuroblastoma cells. 291 Miettinen and coworkers 292 studied 22 cases of undifferentiated neuroblastomas and 83 cases of differentiated neuroblastomas (total of 105 cases) and found that 95.5% of the former and 100% of the latter were positive for NB84. In addition, 4 of 5 (80%) of ES-PNETs and 3 of 3 (100%) of desmoplastic small, round cell tumors also showed positive staining. In contrast, 7 of 39 (17.9%) of ES and 1 of 14 (7.1%) cases of blastomatous Wilms' tumors were NB84-positive. Alveolar and embryonal rhabdomyosarcomas, lymphoblastic lymphomas, and pulmonary small cell carcinomas were negative. 292 However, Folpe and coworkers 293 reported NB84 immunoreactivity in 3 of 13 rhabdomyosarcomas, 10 of 11 medulloblastomas, 1 of 9 esthesioneuroblastomas, and 2 of 3 small cell osteosarcomas. A panel of antibodies including NB84, CD99, cytokeratins, lymphoid, and muscle-specific markers should be used in rendering a diagnosis of neuroblastoma.

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Adrenal Gland

Sylvia L. Asa , Sandra E. Fischer , in Differential Diagnosis in Surgical Pathology (Second Edition), 2010

Histopathology

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Cellular, small round blue cell tumor with vague lobular architecture

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Nodular aggregates of tumor cells separated by delicate fibrovascular septa

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Prominent Homer-Wright pseudorosettes (round spaces surrounded by palisading peripheral nuclei and filled with a faintly eosinophilic fibrillary matrix) may be seen

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Fibrillar matrix representing neuritic cell processes; resembles neuropil of the central nervous system

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Cells are medium sized and round to oval with high nuclear-to-cytoplasmic ratio and scant cytoplasm; hyperchromatic nuclei have stippled chromatin and inconspicuous nucleoli

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Hemorrhage and microcalcifications are common findings

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Variable mitotic activity

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Microscopic grading criteria (International Neuroblastoma Pathology Committee [INPC]): the criteria divide tumors into subtypes

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Neuroblastoma, undifferentiated: small, medium, or large round neuroblasts showing lack of differentiation or neuropil by routine light microscopy

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Neuroblastoma, undifferentiated, pleomorphic subtype: neuroblasts are large, with pleomorphic nuclei, prominent nucleoli, and moderate to abundant cytoplasm (some cells may have rhabdoid features); no neuropil

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Neuroblastoma, poorly differentiated: less than 5% neuroblasts show synchronous differentiation toward ganglion cells

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Neuroblastoma, differentiating: more than 5% neuroblasts show synchronous differentiation toward ganglion cells

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Mitosis karyorrhexis index (MKI) is based on percentage seen in 10 high-power fields (total of 5000 cells): less than 2% (low), 2% to 4% (intermediate), and more than 4% (high)

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Assessment of the MKI is crucial because it is used to determine prognostic categories (unfavorable versus favorable histology) in combination with the tumor differentiation and age of the patient (Table 9-1)

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Neuroendocrine Neoplasms of the Lung

Alain C. Borczuk MD , in Practical Pulmonary Pathology: A Diagnostic Approach (Third Edition), 2018

Primitive Neuroectodermal Tumor

Definitions and Synonyms

PNET is a small, round, blue cell tumor of bone and soft tissue in children and young adults that is histologically and molecularly similar to Ewing sarcoma and belongs in the same family. It occurs in the chest wall but less commonly in lung, and is therefore a rare tumor. 323 Its original description was by Arthur Purdy Stout as PNET 324 and James Ewing as Ewing sarcoma. 325 The description of this tumor in the thorax is attributed to Frederic Askin in 1979. 326

Incidence and Demographics

PNET of the thorax is a rare tumor and is very rare as a lung tumor. 327–330 It is seen in children and young adults with an overall average age of 29, with an equal male-to-female ratio. 331 Because SCLC incidence begins around age 40, most, but not all, PNET cases will not be confused with SCLC.

Clinical Manifestations

A common presentation of PNET is chest pain. However, patients can also present with dyspnea and pleural effusion.

Radiologic Features

CT scans show chest wall infiltration with rib destruction. FDG PET is typically positive in PNET. 332

Gross Pathology

Although pulmonary involvement is possible, this is usually a tumor of the chest wall requiring chest wall excision. This is not a tumor of large airways. Pulmonary cases in peripheral lung have been described, albeit rarely. 328 They are soft, fleshy tumors, with hemorrhage and necrosis.

Microscopic Pathology

The histology of PNET is only vaguely organoid (Fig. 14.20A), with larger sheets of cells with occasional rosette-like structures and little associated stroma (eSlide 14.5). The cells are uniform and round and have little cytoplasm. Often the chromatin is very fine and often described as powdery (Fig. 14.20B); however, like in all neuroendocrine tumors, the characteristic nuclear features will not be present in all cells of the tumor. These are usually mitotically active tumors, but a strict cutoff is not established as it is for other neuroendocrine tumors.

Cytologic assessment of PNET tumors in effusions shows cells with loose cohesive clusters with round to ovoid nuclei and nuclear molding resembling small cell carcinoma. 333

Special Studies

The cytoplasmic clearing in PNET is periodic acid–Schiff positive and is diastase sensitive representing glycogen. IHC is of utility in the diagnosis of PNET. Although not entirely specific for this tumor, CD99 with strong membranous staining is typical (Fig. 14.20C). IHC for Fli-1 protooncogene, ETS transcription factor (FLI1) is also of utility, although the specificity of this marker depends on technical issues and specifics of the differential diagnosis (e.g., endothelial tumors). Chromogranin is usually negative in this tumor, but synaptophysin is positive in about one-third of cases. Although cytokeratin is expected to be negative in this tumor, the experience is that at least focal staining can be seen in one-quarter of cases, and in some instances this will be multifocal. Importantly, WT1 should be negative, distinguishing this tumor from a DSRCT and mesothelioma (small cell variant); in addition, desmin should be negative, also in contrast to DSRCT. Calretinin is positive in about 15% of cases, and EMA also can be positive in a few cases. TTF1 is negative in PNET. The combination of positive cytokeratin and TTF1 would be in support of a SCLC. Overall, a panel approach can strongly support the diagnosis, leading to relevant molecular testing confirmation.

Differential Diagnosis

The main histologic differential diagnostic categories of PNET include other tumors that manifest highly cellular proliferations with scant cytoplasm ("small blue cell tumors"). Lymphoma can be mistaken for PNET, but the architecture of PNET and rosette formation should help avoid this confusion, as will IHC, if needed. DSRCT is also in the differential diagnosis, and the desmoplastic stroma and IHC pattern of DSRCT should be helpful in this analysis. Some synovial sarcomas can have a monotonous round cell appearance, but this can also be resolved by a combination of IHC and if needed, cytogenetics or fluorescence in situ hybridization (FISH) testing. SCLC is often not in the differential diagnosis because of younger patient age, but the combination of cytokeratin and TTF1 should be able to resolve difficult cases.

Genetics

PNET tumors have a characteristic chromosomal translocation t[11;22][q24;q12] involving the Ewing Sarcoma Breakpoint Region 1 (EWSR1) gene resulting in an EWS-FLI1 fusion gene. Although this can be detected by classical cytogenetics, 334 the need for fresh cells and the presence of small rearrangements leading to translocations below the resolution of classical cytogenetics leads to the use of other techniques. Break-apart probe FISH testing in the EWS gene is effective at detection in about 90% of PNETs, but this approach does not identify the fusion partner or the specific site of the translocation. 335,336 Fusion partners include FLI1, which is the most common, as well as V-Ets Avian Erythroblastosis Virus E26 Oncogene Homolog (ERG), ETS variant (ETV), E1AF, and FEV, ETS Transcription Factor (FEV). Although identification of the fusion partner may become more relevant in the future as suggested by some series showing effect on biology, 337,338 from the diagnostic point of view, break-apart testing is sufficient. However, EWS break-apart testing will not detect the subset of cases with other translocations (e.g., FUS-ERG fusion). 339

Also important is that the family of tumors harboring EWS translocation is growing and includes desmoplastic small round cell tumors, which may be in the differential of PNET. The combination of morphology and IHC should resolve these cases, with some requiring specific fusion detection to resolve the diagnosis.

Treatment and Prognosis

The optimal treatment of PNET of the thorax is resection followed by radiotherapy and chemotherapy. 331 In resectable disease, the survival rate at 10 years is 57% to 84%, but this decreases significantly in unresectable disease. In initially resected cases, recurrent unresectable disease is a cause of mortality. Nodal involvement is not typical. Younger patients have a better prognosis overall. 340

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Bones and Joints Cancer: Pathology and Genetics

Pancras C.W. Hogendoorn , Carlos E. de Andrea , in Encyclopedia of Cancer (Third Edition), 2019

Ewing Sarcoma

Ewing sarcoma is a small round blue cell tumor characterized by the pathognomonic EWSR1 gene fusion to a member of the ETS family of transcription factors, creating a novel fusion oncogene crucial to its pathogenesis. Ewing sarcoma is the second most frequent bone sarcoma in children and young adults, about 80% of patients are younger than 20   years of age. It predominantly affects the diaphysis or the metaphyseal–diaphyseal portion of long bones but can also affect other bones or occur in soft tissue (10%–20%). Radiographically, Ewing sarcoma is an ill-defined, most often osteolytic lesion. Permeative bone destruction, periosteal reaction, and soft tissue extension are often seen. Histologically, undifferentiated uniform small round cells with round nuclei and fine chromatin are seen (Fig. 15A ). Although not specific, immunohistochemistry typically shows diffuse membranous CD99 staining in Ewing sarcoma (Fig. 15B). Approximately 85% of Ewing sarcomas harbor the t(11;22)(q24;q12) translocation, fusing EWSR1 to FLI1.

Fig. 15

Fig. 15. Ewing sarcoma. (A) Undifferentiated uniform small round blue cells with round nuclei with fine chromatin. (B) Diffuse membrane staining for CD99.

Recently a number of new rare translocations involving ETS family members have been described. Also, small blue round cell tumors harboring non-ETS translocations have been identified. The condensing opinion in literature is that the non-ETS translocation round cell tumors might best be considered a separate group of tumors as the clinical behaviour including reaction to chemotherapy may differ from that seen in classic Ewing sarcoma.

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Markers for bone sarcomas

Gonzague de Pinieux , ... Corinne Bouvier , in Bone Cancer (Second Edition), 2015

Differential diagnosis between ESFT and mesenchymal chondrosarcoma

Mesenchymal chondrosarcoma is a small blue round cell tumor consisting of the juxtaposition of a proliferation of small round cells and islands of hyaline cartilage in varying proportions. Wehrli and coworkers 64 and more recently Fanburg-Smith and coworkers 65 have shown that the small round cell component of mesenchymal chondrosarcoma expressed transcription factor Sox9 (Figure 24.2), which plays a major role in the early stages of chondrocytic differentiation. Expression of this marker may be helpful in differentiating mesenchymal chondrosarcoma from other small blue cell tumors such as ESFT and small cell osteosarcoma, particularly when the cartilaginous hyaline component of the tumor has not been sampled by the biopsy.

Figure 24.2. (a) Small round cell component of a mesenchymal chondrosarcoma exhibiting a hemangiopericytic vascular pattern. (b) Strong nuclear positivity of tumor cells for Sox9.

Mesenchymal chondrosarcoma can be also separated from small cell osteosarcoma, using osteocalcin, a marker for the osteoblastic phenotype, and which is not expressed by the small round cells in mesenchymal chondrosarcoma.

A tumor-specific fusion gene, HEY1-NCOA2 fusion, was recently identified in a large subset of mesenchymal chondrosarcomas and will be a valuable diagnostic marker for this entity. FISH analysis was highly sensitive in detecting this HEY1-NCOA2 fusion in adequately prepared tumor samples 66 . A t(1;5)(q42;q32) leading to fusion between the IRF2BP2 gene and the transcription factor CDX1 gene was also described in one case, suggesting that genetic heterogeneity exists in mesenchymal chondrosarcomas 67 .

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Chemotherapy of Central Nervous System Primitive Neuroectodermal Tumors

Miriam Bornhorst , Eugene I. Hwang , in Handbook of Brain Tumor Chemotherapy, Molecular Therapeutics, and Immunotherapy (Second Edition), 2018

WHO Classification

PNETs are highly malignant small round blue cell tumors that are of neuroectodermal origin. PNET includes tumors in the CNS (CNS PNETs), periphery (pPNET such as Ewing's sarcoma), and tumors that arise from the autonomic nervous system (Neuroblastoma). Although nearly identical on histology, these tumor groups have been treated as separate entities, owing to their vast differences in location and clinical presentation. Supratentorial PNETs were first described as a diagnostic entity in 1973 by Hart and Earle [5]. At that time, sPNETs were defined as tumors composed of undifferentiated cells that resemble germinal or matrix cells, with focal areas of glial and/or neuronal differentiation. Although histologically similar to medulloblastoma, sPNET were found outside the posterior fossa and had a different age of presentation and different response to therapy with poorer overall outcomes.

In the original WHO classification guidelines, published in 1979, CNS PNETs were not yet recognized as a distinct tumor type, but were instead included under "poorly differentiated and embryonal tumors" as medulloblastoma (with desmoplastic and medullomyoblastoma variants), medulloepithelioma, and primitive polar spongioblastoma [6].

In 1983, a publication by Rorke suggested that the term PNET should be applied to all embryonal tumors, including medulloblastoma, ependymoblastoma, epndymoblastoma, neuroblastoma, and pineoblastoma, on the assumption that they all shared a common progenitor cell population [7]. This suggestion, along with Hart and Earle's previous description of supratentorial PNETs in 1973, led to a new classification schema in the 2nd edition of the WHO guidelines, published in 1993, that introduced PNET as a generic term for tumors that are indistinguishable from medulloblastoma (aside from pineoblastoma, which was still in its own category) but located in other sites throughout the CNS [5,8].

By 2000, when the 3rd edition of the WHO guidelines was published, the concept that all PNETs share a common progenitor cell was questioned. New evidence indicated that medulloblastoma and sPNETs not only seemed to have different progenitor cells, but alterations involved in the evolution of medulloblastoma (such as PTCH and APC mutations) were also not found in the sPNETs [9–11]. Thus, medulloblastoma and sPNETs were no longer combined into one category, but were considered separate diagnoses [12]. In 2000, ATRT were also separated from other supratentorial embryonal tumors based on specific genetic driver identification. These tumors, which were previously either diagnosed as medulloblastoma or PNET, can now be easily identified by the loss of either INI1 (SMARCB1) or BRG1 (SMARCA4) in the tumor, allowing for the evolution of ATRT-specific treatment protocols that will be discussed in a separate chapter [13–18]. The 2007 WHO guidelines continued to build on the 2000 version, with CNS PNET as one of the embryonal tumor categories that included CNS neuroblastoma, CNS ganglioneuroblastoma, medulloepithelioma, and ependymoblastoma as subcategories [19].

In the most recent 2016 WHO guidelines, PNET is no longer included as a diagnostic category, and ependymoblastoma and embryonal tumor with abundant neutrophil and true rosettes (ETANTR) have been essentially replaced with embryonal tumor with multilayered rosettes (ETMR) [2]. This was driven in large part by the discovery of molecular changes that help to classify these tumors further, including C19MC amplification on chromosome 19 (19q13.42) [20]. Under these new guidelines, tumors that were previously called CNS PNETs would now include medulloepithelioma, CNS neuroblastoma, CNS ganglioneuroblastoma, ETMR with or without C19MC-amplification, and CNS embryonal tumor, not otherwise specified.

CNS PNETs have historically been difficult to classify based on histopathology, and new methods that allow for the biological identification of these tumors are being developed. For example, a recent study has shown that, despite their histological homogeneity, CNS PNETs have highly heterogeneous DNA methylation patterns, and tumors previously diagnosed as CNS PNET are better classified as something else, such as high-grade gliomas [21]. Moving forward, the appropriate biological identification of CNS PNETs will be important to incorporate in clinical trials for treatment, as this information can be used to help predict response to chemotherapy, and/or allow for a more personalized approach to treatment in this patient population [22].

With each new edition of the WHO classification of tumors of the central nervous system, the diagnostic criteria for CNS PNETs has changed to allow for better segregation of tumors based on their histologic and molecular characteristics (Fig. 49.1). Although "CNS PNET" is no longer included in the WHO guidance, we will continue to use this term throughout the chapter to reference the nonmedulloblastoma, non-ATRT, nonpineoblastomas that were previously called CNS PNETs (or supratentorial PNETs).

Fig. 49.1

Fig. 49.1. Timeline and summary of the WHO guideline recommendations for CNS PNETs. ⁎Subgroups for Medulloblastoma are not included in this figure.

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Neuroblastoma☆

L.M. Kopp , E. Katsanis , in Reference Module in Biomedical Sciences, 2015

Histology

Neuroblastoma is one of the small round blue cell tumors of childhood that can be differentiated from the others in this classification based on immunohistochemical staining of neuronal markers. Dr. Shimada developed a histopathologic classification system in 1984 that is predictive of the tumor's behavior clinically (Shimada et al., 1984). A modification of this system was developed in 1999, the International Neuroblastoma Pathology Classification System, which continues to be used. Tumors are classified as favorable or unfavorable based on neuroblast differentiation, Schwannian stroma content, mitosis-karyorrhexis index, and age at diagnosis (Cohn, 2010; Maris et al., 2007; Shimada et al., 1999).

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Neuroblastoma

Katherine K. Matthay MD , ... Suzanne L. Wolden MD , in Leibel and Phillips Textbook of Radiation Oncology (Third Edition), 2010

Pathologic Conditions

Neuroblastoma is a classic "small round blue cell" tumor. Others include Ewing sarcoma, non-Hodgkin lymphoma, primitive neuroectodermal tumors, and rhabdomyosarcoma. Histologic subtypes, including neuroblastoma, ganglioneuroblastoma, and ganglioneuroma, represent different points along the maturation pathway in order of increasing differentiation. The typical neuroblastoma is composed of small, uniform cells containing dense, hyperchromatic nuclei and scant cytoplasm. The presence of neuritic processes (neuropil) is pathognomonic. Homer-Wright pseudorosettes, neuroblasts surrounding areas of eosinophilic neuropil, are seen in 15% to 50% of cases. Ganglioneuromas are composed primarily of mature ganglion cells, neuropil, and Schwann cells, and behave in a benign fashion. Ganglioneuroblastomas have histopathologic characteristics of both neuroblastomas and ganglioneuromas. Because histopathologic features may vary within any single tumor, multiple sections must be examined. 32 , 33 Distinguishing neuroblastomas from other small round blue cell tumors requires special techniques including immunohistochemistry and electron microscopy. Neuroblastoma stains with monoclonal antibodies that recognize neuron-specific enolase, synaptophysin, and neurofilament. Electron microscopy reveals neurosecretory granules that contain catecholamines, microfilaments, and parallel arrays of microtubules within the neuropil. 34

Although many different classification systems have been used to help define the prognosis for neuroblastoma, the International Neuroblastoma Pathology Commmittee (INPC) defined and tested a modification of the Shimada system, now widely accepted and validated. 32 It is divided into favorable and unfavorable prognostic groups based on histologic category, age, amount of Schwann cell stroma, degree of differentiation; and the mitosis-karyorrhexis index. Each of these features are also independently prognostic. 35 In addition, nodular versus diffuse histologic pattern is noting macro nodules, which tend to be associated with a poor prognosis compared with intermixed nodules. Characteristics of the INPC system are listed in Table 56-2 .

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