Neuroectodermal and Neuroendocrine Tumors Principally Seen in ...

© American Society of Clinical Pathologists 

Pathology Patterns Reviews 

Neuroectodermal and Neuroendocrine Tumors Principally 

Seen in Children 

David M. Parham, MD 

Key Words: Neuroblastoma; Ganglioneuroblastoma; Ganglioneuroma; Ewing sarcoma; Peripheral primitive neuroectodermal tumor; 

Melanotic neuroectodermal tumor; Desmoplastic small cell tumor; Esthesioneuroblastoma; Diagnosis; Biology 

Abstract 

Neuroectodermal tumors comprise a large 

proportion of childhood neoplasms. Neuroblastic 

tumors, including neuroblastoma, 

ganglioneuroblastoma, and ganglioneuroma, are the 

most frequent extracranial solid cancers of childhood, 

occurring primarily in infants and toddlers. Primitive 

neuroectodermal tumors, including Ewing sarcoma and 

peripheral neuroepitheliomas, occur most frequently in 

older children and adolescents, and as pediatric 

sarcomas are second in frequency only to 

rhabdomyosarcomas. Rarer neuroectodermal tumors 

include desmoplastic small cell tumors, 

esthesioneuroblastomas, and melanotic 

neuroectodermal tumors, the first two entities occurring 

as rather site-specific lesions in the abdomen and nose, 

respectively. Diagnosis can be difficult due to the 

undifferentiated nature of many of these cancers, but 

ancillary studies, including electron microscopy, 

immunohistochemistry, cytogenetics, and molecular 

genetics, enhance their recognition. The molecular 

nature of childhood neuroectodermal tumors is as 

diverse as their histology, ranging from the fusion genes 

characterizing the Ewing sarcoma family of tumors to 

the proto-oncogene amplification seen in aggressive 

neuroblastomas. 

Neuroectodermal and neuroendocrine tumors in children 

constitute relatively common entities that appear frequently 

in pediatric populations and intermittently in adult populations. 

The neuroectodermal or neuroendocrine nature of these 

lesions usually is detected easily by standard light microscopy, 

but the wide spectrum of differentiation observed in 

neuroectodermal tissues can create a confusing and seemingly 

contradictory array of phenotypic features that can trap 

the unwary diagnostician. In this review, I discuss most of the 

entities listed in ❚Table 1❚. The term primitive neuroectodermal 

tumor (PNET) is applied commonly to central 

nervous system (CNS) tumors such as medulloblastomas, 

which are beyond the scope of this discussion. However, 

CNS PNETs may metastasize to bone and create an appearance 

similar to peripheral PNETs (PPNETs). Another lesion 

that fits into the general schema of PNET is the retinoblastoma, 

which is more akin to brain tumors such as pineoblastoma 

than to soft tissue lesions. Conversely, PPNETs may 

arise in epidural and subdural tissues and can overlap with 

CNS PNETs in their clinical manifestation. 1 

As a general rule, the origins, phenotypes, and sites of 

childhood neuroectodermal tumors coincide with those of the 

developing peripheral nervous and endocrine systems, being 

analogous to the differentiation and migration of cells in the 

neural crest. This anlage forms as bilateral clusters of embryonic 

cells that abut the dorsal portion of the neural tube. 

Following an amazing meshwork of cell migration, neural 

crest cells differentiate into a wide array of tissues, including 

Schwann cells, dorsal root ganglia, paraganglia, sustentacular 

cells, chromaffin cells, melanocytes, and argyrophilic cells of 

various organs. Of particular note is the ultimate fate of a 

subgroup of neural crest elements in the head and neck, 

which form bone, skeletal muscle, and dentin. This terminal 

Am J Clin Pathol 2001;115 (Suppl 1):S113-S128 S113

Parham / NEUROECTODERMAL AND NEUROENDOCRINE TUMORS PRINCIPALLY SEEN IN CHILDREN 

❚Table 1❚ 

Primitive Neuroectodermal Tumors and Neuroendocrine Tumors Affecting Children 

Neuroblastic tumors, including neuroblastoma, ganglioneuroblastoma, and ganglioneuroma 

The Ewing sarcoma family of tumors, including Ewing sarcoma, Askin tumor, and peripheral primitive neuroectodermal tumor 

Desmoplastic small cell tumor 

Melanotic neuroectodermal tumor 

Esthesioneuroblastoma 

Pancreatic tumors, including pancreatoblastoma and papillary cystic tumor 

Multiple endocrine neoplasia–related neoplasms of the endocrine organs and paraganglia 

Tumors with polyphenotypic differentiation, such as ectomesenchymoma and malignant rhabdoid tumor 

Neuroendocrine carcinoma 

differentiation results from inductive influences in neighboring 

tissues, due to expression of inductive agents such as 

PAX family proteins and transcription factors such as 

NeuroD. These agents intercalate into gene promoter 

sequences and initiate expression of neural differentiation– 

related messenger RNA. In the developing embryo, this 

process constitutes a tightly regulated, carefully orchestrated 

sequence of events critical to the normal endocrine and 

paracrine function of the mature human, but in neoplasms, 

genetic miscues and migrational abnormalities lead to unrestrained 

cell growth coupled with autonomous neuroendocrine 

function and anomalous differentiation. 

In recent years, we have identified many of the genetic 

events that culminate in pediatric neuroectodermal tumors. 

Oncogenes such as MYCN are overexpressed due to gene 

amplification or abnormal promoter signals, leading to unrestrained 

proliferation. Loss of tumor suppression genes such 

as RB1 leads to propensity for the development of neuroectodermal 

neoplasms because of a gatekeeper function that 

normally halts the cell cycle and/or induces apoptosis. Chromosomal 

translocations lead to formation of unique chimeric 

genes such EWS/FLI1, which produce transcription factors 

with aberrant DNA binding, leading to unrestrained cell 

proliferation. These findings afford us new ancillary techniques 

for diagnosis, prognostication, and genetic counseling, 

and they potentially offer novel, less toxic, and more 

efficacious approaches to cancer therapy. 

Equally fascinating has been the epidemiology of pediatric 

neuroectodermal tumors. As a group, peripheral 

neuroectodermal tumors constitute the most common solid 

tumors affecting children, following only acute leukemia, 

CNS tumors, and lymphomas in childhood cancer incidence. 2 

Neuroblastic tumors constitute the most common pediatric 

neuroectodermal lesions and predominantly affect infants and 

young children. They have been the focus of prenatal 

screening in some countries, such as Japan, via ultrasonography. 

3 A large percentage of these congenital lesions 

undergo spontaneous regression, possibly due to maternal 

antibodies. Neuroblastomas do not show a racial or 

geographic predilection. The Ewing sarcoma family of 

tumors (EFTs) constitutes the second most common category 

of pediatric neuroectodermal tumors. Unlike neuroblastomas, 

EFTs usually arise in adolescents and young adults and show 

a striking predilection for whites. A precursor cell or genetic 

predisposition has not been identified for EFTs, precluding 

screening efforts. Thus, despite their morphologic similarities, 

the epidemiologic differences between neuroblastomas 

and Ewing tumors are as distinct as their biologic ones. 

Although a wide array of new tests is available, routine 

histologic examination has retained its primary role in the 

diagnosis of pediatric neuroectodermal tumors. Recognition 

of key structures such as rosettes, ganglionic differentiation, 

neuropil, and Zellballen offers quick diagnosis with histologic 

and cytologic preparations. However, certain caveats 

apply, such as occurrence of rosettes in occasional lymphomas. 

For this reason, it is wise to confirm even histologically 

obvious cases with at least one other modality, particularly 

with tumors occurring outside the sympathetic nervous 

system. Among confirmatory techniques, immunohistochemistry 

is the most widely accessible, and a number of neural 

proteins have been characterized for that purpose. Use of 

electron microscopy has waned in recent years, but ultrastructural 

features of neural differentiation are generally 

easily recognizable and may be more reliable than immunohistochemical 

features. 4 In my opinion, electron microscopy 

of primitive neural tumors is not always necessary if other 

confirmatory techniques are available, but it can be indispensable 

in cases with conflicting features. Last, cytogenetics 

and molecular techniques have acquired much support as 

means of diagnostic confirmation but have their detractors, 5 

so they presently cannot be relied on as “gold standards.” 

Neuroblastoma 

Clinical, Epidemiologic, and Biochemical Features 

Neuroblastomas constitute the most common cause of 

abdominal masses in infants and toddlers. Lesions of adolescents 

and older patients are rare and often confused with 

EFTs. Neuroblastic tumors typically arise as adrenal masses, 

although any part of the sympathetic chain may be affected, 

S114 Am J Clin Pathol 2001;115 (Suppl 1):S113-S128 © American Society of Clinical Pathologists

including ganglia in the mediastinum and pelvis. Abundant 

epidemiologic data are available in Japan as a result of widespread 

prenatal screening, which indicates an incidence of 19 

per million per annum. 3 In the United States, where prenatal 

surveillance is not actively practiced, there is an incidence of 

9.2 per million per annum. 6 Because neuroblastomas secrete 

catecholamines and peptides, a variety of symptoms may 

occur, including hypertension, the Ondine curse, and watery 

diarrhea. Antigenic stimulation occurs with many tumors, 

and the resultant antibodies may produce symptoms such as 

opsoclonus myoclonus. Mass effects may cause lesions such 

as Horner syndrome, and subcutaneous metastases produce 

the sadly disfiguring condition known as “blueberry muffin 

baby.” Tumor catecholamine production leads to excretion of 

vanillylmandelic acid and homovanillic acid in the urine, 

which can be used as a confirmatory diagnostic test and 

tumor marker. Bone marrow and lymph node metastases are 

common, and the presence of malignant cells in the marrow, 

combined with characteristic radiologic findings and urine 

catecholamine excretion, suffices for diagnosis. 7 

Gross Pathologic Features 

Gross examination reveals neuroblastomas as soft, 

purple-tan, encapsulated masses that typically contain flecks 

of calcification visible on abdominal radiographs ❚Image 1❚. 

Many tumors contain areas of necrosis and cystic degeneration. 

As neuroblastic tumors mature, they acquire a firm, 

whorled, light yellow-tan fibrous character reflective of their 

Schwann cell content ❚Image 2❚. Composite lesions, known 

A B 



as composite ganglioneuroblastomas, contain grossly visible 

nodules of dark purple, immature tumor embedded in a 

mature fibrous matrix and cause potential diagnostic confusion 

in small biopsy specimens. Both mature and immature 

tumors acquire a dumbbell configuration with invasion of the 

spinal canal. Lesions may encompass lymph nodes without 

upstaging, but separate, draining lymph node chains must be 

adequately sampled for determination of tumor stage. 

Another key feature in staging is extension beyond the vertebral 

midline. 7 

Microscopic Pathologic Features 

Microscopically, neuroblastic tumors display a range of 

morphologic features consonant with their tendency to 

undergo various degrees of maturation. Undifferentiated 

neuroblastomas are archetypal “small round blue cell 

tumors” with minimal cytoplasm, easily confused with 

EFTs. Fortunately, unlike EFTs, completely undifferentiated 

forms are unusual. Completely differentiated tumors are 

known as ganglioneuromas, benign tumors that may cause 

local symptoms because of pressure or systemic symptoms 

due to hormone secretion. Ganglioneuromas typically consist 

of a dense spindle cell matrix of mature Schwann cells, interspersed 

with clusters of mature ganglion cells and satellite 

cells ❚Image 3❚. Most neuroblastic tumors show some degree 

of partial differentiation, giving rise to the term ganglioneuroblastoma, 

a name of more historic than practical significance. 

Partial differentiation is manifested by Homer Wright 

rosettes ❚Image 4❚, neuropil, and maturing neuroblasts 

❚Image 1❚ A, Gross specimen of adrenal neuroblastoma. The encapsulated mass has a fleshy, yellow, focally hemorrhagic tan 

cut surface punctuated by flecks of calcification. B, Abdominal computed tomography (CT) scan of child with adrenal 

neuroblastoma. A large, heterogeneous mass is situated anterior to the right kidney and contains multiple small radiopacities 

representing flecks of calcification. CT scan courtesy of Charles James, MD, Arkansas Children’s Hospital, Little Rock. 



❚Image 2❚ Bivalved ganglioneuroma, with pale gray, 

glistening, fibrous cut surface. 

containing increased cytoplasm, more prominent nucleoli, 

and sparse Nissl substance ❚Image 5❚. A variety of unusual 

morphologic features occur, including rhabdoid cells, 

anaplasia, and melanocytic differentiation, but they have no 

proven significance. Neuroblastic tumors often exhibit 

rosettes or ganglionic cells on cytologic preparations ❚Image 

6❚, so that cytologic diagnosis is usually feasible if confirmatory 

means are available. Neuroblastic tumors frequently 

contain aggregates of mature lymphocytes that cytologically 

can be mistaken for neuroblasts, but CD45 staining offers a 

straightforward means of confirming this phenomenon. 

❚Image 4❚ Neuroblastoma. The tumor cells form Homer 

Wright rosettes, composed of wreaths of nuclei encircling a 

pale-staining neurofibrillary core. 

❚Image 3❚ Ganglioneuroma. Clusters of mature ganglion cells 

are embedded in a spindly, stroma-rich Schwann cell matrix. 

When examining bone marrow smears, it is important to 

look at the edges carefully, as tumor clumps often are 

deposited there by the smearing procedure. 

Grading of neuroblastoma is accomplished using the 

Shimada classification, a scheme now accepted with minimal 

alterations as the International Classification 8 ❚Table 2❚. This 

classification is an amalgamation of age, differentiation, 

Schwann cell content, and the mitotic-karyorrhectic index 

(MKI). To determine the MKI, one examines 5,000 tumor 

cells and notes the number of mitotic figures and karyorrhectic 

nuclei. This process presents a challenge to one’s 

❚Image 5❚ Differentiating neuroblastoma, containing maturing 

neuroblasts with enlarged nuclei, prominent nucleoli, 

increased cytoplasm, and Nissl substance. 


❚Image 6❚ Fine-needle aspirate sample of neuroblastoma 

containing clusters of small round tumor cells and central 

rosette with neurofibrillary core. 

time, energy, and eyesight if performed in a precise manner; 

however, a simplified, semiquantitative method works 

equally well. 10 To perform the semiquantitative MKI evaluation, 

one estimates the total number of tumor cells based on 

the cellularity of several standard high-power fields. This 

number is surprisingly high in a densely cellular tumor such 

as neuroblastoma. Then, the number of mitoses and karyorrhectic 

nuclei are counted. One continues to sum the total 

number of cells based on the semiquantitative estimates until 

roughly 5,000 are counted, and the total sum of mitoses and 

karyorrhectic nuclei in these fields equals the MKI. 

Factoring in the age of the patient and amount of differentiation, 

the MKI then stratifies tumors into prognostically favorable 

or unfavorable categories. Tumors composed primarily 

of large amounts of mature Schwann cells (stroma-rich 

tumors) always belong to the favorable category. Nodular 

ganglioneuroblastomas have been placed automatically into 

the unfavorable group, although recent data indicate that this 

is an oversimplification. 9 The Shimada classification is 

highly reproducible, relatively simple to perform, and predictive 

of outcome in multivariate analyses. 8 One caveat is that 

it can be applied only to material obtained before 

chemotherapy. Also, cytologic material, although often diagnostic, 

often contains insufficient numbers of cells for 

grading purposes. 

Electron Microscopic Features 

Even in the most histologically undifferentiated neuroblastomas, 

electron microscopy usually reveals easily recognized 

features of neural differentiation. These features 

mainly consist of dendritic elongations or processes that 



❚Table 2❚ 

The International Neuroblastoma Pathology Classification 

(the Shimada System) 8 

Prognosis Tumor Characteristics 

Good Stroma-rich tumors * 

Stroma-poor tumors with 

Age


are common in undifferentiated tumor cells. Thus, it is wise 

to exercise careful judgment with granules occurring with 

perinuclear cytoplasm, particularly if they are associated 

with Golgi apparatuses. Various means of ultrastructural 

confirmation of neurosecretory granules, such as the 

uranaffin reaction or immunoelectron microscopy, have been 

devised, but routine immunohistochemical examination 

usually suffices. 

Immunohistochemical Studies 

The surfeit of neural proteins produced during 

ganglionic differentiation has led to the discovery of many 

markers applicable to immunohistochemical diagnosis of 

primitive neural tumors11 ❚Table 3❚. These markers vary 

widely in their specificity. So-called neuron-specific enolase 

(NSE) ❚Image 8❚ is now often referred to as nonspecific 

enolase. A similarly nonspecific protein originally touted as 

a neural marker is CD57, recognized by the monoclonal antibody, 

Leu-7, and originally described as a marker of natural 

killer cells. A related nonspecific neural marker, CD56, 

belongs to the neural cell adhesion molecule superfamily, a 

group of membranous proteins expressed by a variety of 

primitive cancerous cells. 12 Proteins such as chromogranin 

and synaptophysin, which are contained within neurosecretory 

granules, have retained their specificity for neural cells, 

but unfortunately they are somewhat less sensitive than NSE. 

An even less sensitive marker is neurofilament protein, an 

intermediate filamentous substance consisting of components 

with 3 molecular weights: high (200 kd), intermediate 

(150 kd), and low (68 kd). The high-molecular-weight 

component is expressed by terminally differentiated cells, 

causing its sensitivity as a marker to suffer greatly. Neurofilaments 

are most heavily expressed at the axon hillock 

region, requiring careful evaluation of immunohistochemical 

stains, and staining is not improved by antigen retrieval. 11 

Cytogenetics and Molecular Biologic Studies 

Cytogenetic evaluation reveals a number of structural and 

numeric alterations in neuroblastomas, particularly random 

losses and gains of whole chromosomes. Variable deletions of 

the short arm of chromosome 1 are the most common karyotypic 

alterations, and loss of heterozygosity for this region 

occurs even more frequently. 13 Analyses of areas of common 

overlap within the deleted regions have formed the basis of 

numerous searches for a neuroblastoma tumor suppressor 

gene, still without definitive success. Chromosome 1p deletions 

and alterations occur frequently in a variety of solid 

tumors, so that the finding lacks specificity as a diagnostic 

marker. However, they have been applied to prognostic stratification 

of neuroblastoma, with some degree of controversy. 

14,15 Nevertheless, in the setting of localized neuroblastoma, 

1p deletions seem to portend a worse outcome. 16 

❚Table 3❚ 

Immunohistochemical Markers for Childhood 

Neuroectodermal Tumors 

Neuron-specific enolase (limited specificity) 

CD57 (Leu-7) (limited specificity) 

CD56 (neural cell adhesion molecule) (limited specificity) 

Synaptophysin 

CD99 (to exclude neuroblastoma) 

PGP 9.5 

Neurofilament protein 

Chromogranin (weak in poorly differentiated neuroblastoma; 

generally negative in peripheral primitive neuroectodermal tumor) 

Neuropeptides and related endocrine markers (for 

neuroendocrine carcinoma) 

Other frequent cytogenetic findings in neuroblastomas 

include double minute chromosomes (dms) and homogeneous 

staining regions (HSRs). Dms appear on mitotic 

spreads as numerous small doublets that create an illusion of 

karyotypic “dirt.” HSRs consist of chromosomal elongations, 

often striking in length and having a smooth, light gray, 

nonbanded quality. Neuroblastomas that possess these cytogenetic 

features can be easily propagated in vitro and are 

associated with aggressive clinical behavior. Dms and HSRs 

consist of amplified segments of MYCN, a proto-oncogene 

that encodes a helix-loop-helix transcription factor inducing 

cell proliferation. Amplification of MYCN can best be 

demonstrated by fluorescence in situ hybridization, which 

highlights both dms and HSRs ❚Image 9❚. Paradoxically, 

hyperdiploidy, a frequent predictor of aggressive clinical 

outcome in adult cancers, portends good behavior in neuroblastoma. 

13 A variety of other biologic modulators of neuroblastoma 

growth also have been identified, including the 

❚Image 8❚ Neuron-specific enolase immunostain of 

neuroblastoma with strong cytoplasmic positivity in the 

neurofibrillary cores of rosettes. 


A B 

TRK gene family, which encodes nerve growth factor receptors, 

17 and telomerase, which immortalizes tumor cells. 18 

Prognosis and Outcome 

Prognosis and outcome of neuroblastic tumors have 

been linked to a number of factors, 7 including stage, age, 

Shimada classification, and a host of genetic lesions 

including MYCN amplification, ploidy, chromosome 1p deletions, 

and TRK and telomerase expression. The simplest 

prognostic grouping using genetic factors is that of Brodeur 

et al, 13 who separated neuroblastomas into 3 tumor types 

❚Table 4❚. Of note in staging neuroblastomas is stage 4S, 

comprising infantile lesions with localized primary tumors 

and dissemination limited to skin, liver, and/or bone marrow 

(


and medullary cavity, with massive extension into the adjacent 

soft tissues and formation of a soft tissue mass. An 

inflammatory reaction often ensues, creating clinical confusion 

with osteomyelitis. Radiographs have a moth-eaten, 

permeative appearance ❚Image 10❚, and periosteal reaction 

may create a sunburst appearance. EFTs arising in soft tissue 

form similarly rapid-growing, destructive lesions, and those 

affecting the kidneys usually aggressively invade pericapsular 

tissues and renal veins. 

Microscopic Features 

Like the embryonic neuroectoderm, EFTs display a 

wide and sometimes surprising array of phenotypic features. 

Nevertheless, the most common microscopic appearance is 

that of the archetypal small round blue cell tumor that 

exhibits no evidence of differentiation on routine stains 

❚Image 11❚. Glycogen usually accumulates within the cytoplasm 

of these undifferentiated lesions, so that periodic 

acid–Schiff stains show strong positivity that is digested by 

diastase. Unfortunately for diagnosticians, this finding 

frequently occurs in a wide array of primitive neoplasms, 

including rhabdomyosarcoma and germinoma, and glycogen 

may be dissolved in aqueous fixatives. Reticulin stains show 

a dearth of reticulin fibers in the pericellular milieu of EFTs, 

in contradistinction to the wealth of fibers often seen in other 

primitive sarcomas and some lymphomas. 

Cytologic and histologic features traditionally have 

been used to separate the commonly occurring variants of 

EFTs. Cytologically, the typical Ewing sarcoma cell contains 

monomorphous round nuclei, smooth chromatin, 

❚Image 10❚ Plain radiograph of Ewing sarcoma arising in the 

humeral diaphysis. The lesion permeates the cortex and 

marrow, with an overlying periosteal reaction. Courtesy of 

Charles James, MD, Arkansas Children’s Hospital, Little Rock. 

inconspicuous nucleoli, and modest amounts of lightly 

amphophilic or vacuolated cytoplasm. Usually “light cells,” 

having the aforementioned features, coexist with “dark 

cells,” which contain darkly staining nuclei and more 

basophilic cytoplasm ❚Image 12❚. Mitotic figures are paradoxically 

rare, although areas of geographic necrosis are not 

unusual. EFT cells are often effete, fragile structures, so that 

rough handling easily converts them into a sea of smeared, 

basophilic smudge cells, a situation that may require 

repeated biopsy. Cytologic preparations are often helpful, 

particularly during intraoperative consultations, as 

frozen section findings may be confused with chronic 

inflammation. 

Atypical Ewing sarcomas comprise common variants of 

EFTs. Compared with the typical Ewing sarcomas already 

described, the cells composing these neoplasms exhibit 

greater size and more pleomorphic nuclei with increased 

nucleolar prominence and chromatin heterogeneity ❚Image 

13❚. Mitotic figures occur with greater frequency. Atypical 

Ewing sarcomas more commonly exhibit subtle features of 

neural differentiation with electron microscopy or immunohistochemistry. 

Although it is important to recognize atypical 

Ewing sarcomas, this morphologic distinction bears no clinical 

relevance. 

At the most common differentiated end of the EFT 

morphologic spectrum lie PPNETs. Homer Wright rosettes 

❚Image 14❚, formed by wreaths of columnar cells encircling 

lightly eosinophilic neurofibrillary cores, are the standard 

diagnostic feature of these tumors with routine stains. 

Flexner-type rosettes with central lumens not uncommonly 

❚Image 11❚ Ewing sarcoma. The lesion consists of sheets of 

uniform, undifferentiated small cells with round nuclei and 

bubbly cytoplasm. Note the paucity of mitotic figures. 


❚Image 12❚ Ewing sarcoma. Clusters of cells with dark, 

smudged chromatin are interspersed among a background of 

cells with light cytoplasm and evenly stained nuclei. 

occur ❚Image 15❚, and rare cases contain differentiated 

ganglion cells. 22 EFTs containing epithelioid and rhabdoid 

foci, consisting of cell clusters with increased cytoplasmic 

content, eosinophilia, and hyaline inclusions, belie a potential 

for epithelial differentiation. Spindle cell foci may 

suggest Schwann cell differentiation ❚Image 16❚. As with 

embryonic neuroectoderm, the potential for myogenic differentiation 

exists, creating the rare lesions known as primitive 

ectomesenchymomas that contain both neural and rhabdomyomatous 

components. 23 

❚Image 14❚ Peripheral primitive neuroectodermal tumor. In 

this renal tumor, cells form prominent Homer Wright rosettes 

with central fibrillary cores. 



❚Image 13❚ Atypical Ewing sarcoma. The tumor cells exhibit 

moderate variation in size and shape, and some contain 

enlarged nuclei. 

Electron Microscopic Features 

Electron microscopy may be used to diagnose EFTs. 

Glycogen accumulation in primitive tumors creates large 

cytoplasmic pools that often contain irregular electron lucencies 

owing to partial dissolution in aqueous fixation. Scattered 

primitive intercellular junctions differentiate EFTs 

from lymphomas and cause the cohesiveness noted on cytologic 

examination. Primitive EFTs otherwise contain few 

cytoplasm organelles other than free ribosomes, polyribosomes, 

and rare ergastoplasm. Atypical Ewing sarcomas 

❚Image 15❚ Peripheral primitive neuroectodermal tumor 

containing Flexner-type rosettes with central lumens. 



❚Image 16❚ Peripheral primitive neuroectodermal tumor with 

spindle cell component. 

contain an increased content of organelles and decreased 

glycogen. Occasional neurosecretory granules are identified, 

linking these tumors to PPNETs. In fully developed, rosetteforming 

PPNETs, neural differentiation is more conspicuous, 

with dendritic processes and arrays of microtubules ❚Image 

17❚, albeit less so than in neuroblastomas. 4 Electron 

microscopy also has been used to confirm the appearance of 

unexpected differentiation, and it remains a valuable tool in 

discrepant cases. 

❚Image 17❚ Electron micrograph of peripheral primitive 

neuroectodermal tumor. Cytoplasmic processes contain 

pleomorphic neurosecretory granules. 

Immunohistochemical Studies 

The immunohistochemical era brought new tools to 

characterize EFTs, bringing them from the abyss of “diagnosis 

by exclusion.” Initial attempts to characterize EFTs 

with immunohistochemical studies yielded positivity only 

with nonspecific markers such as vimentin. However, 

immunohistochemists soon recognized frequent positivity in 

Ewing sarcomas for neural markers such as NSE, CD57 

(Leu-7), and synaptophysin. A smaller subset of EFTs 

(roughly 20%) displays expression of epithelial markers 

such as cytokeratin ❚Image 18❚. 24 A major epiphany has 

been the development of CD99 (also known as HBA71 or 

MIC2), a marker that characterizes EFTs and appears in 

more than 90% of them regardless of morphologic features. 

CD99 staining is typically strong and membranous ❚Image 

19❚, but, unfortunately, similar staining may be seen in other 

round cell tumors such as synovial sarcoma and 

lymphoblastic lymphoma. 25 Nevertheless, CD99 provides 

diagnosticians with a marker of identity for Ewing tumors, 

best used with a panel of other markers or diagnostic techniques. 

Fli-1 protein promises to be an equally effective 

diagnostic immunohistochemical marker of EFTs, although 

as with CD99, lymphoblastic lymphomas are positive. 26 

One must also beware the unexpected, rare reactivity of 

EFTs with reagents such as desmin or glial fibrillary acidic 

protein. 

Cytogenetics and Molecular Biologic Studies 

Along with electron microscopy, use of cytogenetic 

techniques provided the first evidence that Ewing sarcomas 

❚Image 18❚ Immunohistochemical stain for cytokeratin in 

renal primitive neuroectodermal tumor. Scattered cells exhibit 

cytoplasmic positivity. 


and PPNETs constituted a single biologic entity. These 

observations followed the discovery of a characteristic karyotypic 

anomaly found in Ewing sarcoma, PPNETs, and 

Askin tumors, a reciprocal translocation between the long 

arms of chromosomes 11 and 22 ❚Image 20❚. This anomaly, 

the t(11;22)(q24;q12), results in fusion of 2 unrelated genes, 

FLI1 and EWS. FLI1, a member of the ETS family of genes, 

encodes a transcription factor that binds to DNA promoter 

regions, whereas EWS encodes a protein that contains both 

RNA and DNA binding regions. 27 The resultant fusion gene, 

EWS/FLI1, encodes a protein that causes cell transformation 

in vitro and unrestrained proliferative capability in vivo. 

Although EWS/FLI1 constitutes more than 90% of EFT 

fusions, other ETS genes such as ERG, ETV1, EIA-F, and 

FEV can bind to EWS and produce EFTs, but without 

apparent clinical significance. 27 EWS/FLI1 encodes variably 

sized proteins, categorized by size into fusion types. Types 1 

and 2 are most common ❚Image 21❚. Fusion type has 

emerged as an important biologic predictor of prognosis, as 

EFTs with type 2 fusions are less aggressive clinically. 28 

EFTs may contain a variety of other chromosomal anomalies 

besides the t(11;22), such as chromosome 1 deletions or 

translocations and trisomy 8. These anomalies represent 

tumor progression factors rather than initiators. 29 The recognition 

of a primary genetic lesion in EFTs has led to a 

plethora of studies related to EWS/FLI1 in recent years, indicating 

the existence of many downstream and upstream 

modulators. 

❚Image 19❚ Immunohistochemical stain for CD99 in renal 

primitive neuroectodermal tumor. The tumor cells exhibit 

diffuse membranous positivity. 



Prognosis and Outcome 

Besides fusion status, prognosis and outcome in EFTs 

relate to a variety of factors, including stage, size, location, 

chemotherapy, and histologic response to therapy. 30,31 Neural 

differentiation has been used as a predictor of EFT behavior, 

but with recent advances in therapy, it seems to have little 

practical usefulness. 32 

Differential Diagnosis 

Diagnostic considerations for EFTs are listed in ❚Table 

5❚. Neoplasms in the differential diagnosis of EFTs include a 

large list of small cell lesions, 33 but several deserve special 

consideration. Neuroblastomas may manifest as primitive, 

undifferentiated lesions with rosettes similar to PPNET, but 

they should be CD99 negative. 33 EWS/FLI1 fusions also 

serve to distinguish EFTs from neuroblastomas, but a 

report34 suggests that this is not absolute. Rhabdomyosarcomas, 

particularly solid alveolar variants, may closely 

mimic EFTs and even contain MYCN amplifications, 

creating potential confusion with neuroblastoma. 35 Positivity 

of PPNETs with desmin immunostaining rarely may lead to 

confusion, but negative immunostains for MyoD and 

myogenin should exclude rhabdomyosarcoma. 33 Ectomesenchymomas 

exhibit immunophenotypic and ultrastructural 

features of both lesions. The reciprocal t(2;13) translocation 

and its attendant gene fusion, PAX3/FRHR, characterize 

alveolar rhabdomyosarcomas, and fusion gene studies using 

reverse transcriptase–polymerase chain reaction (RT-PCR) or 

1 

6 

13 

2 3 4 5 

7 8 9 10 11 12 

14 15 16 17 18 

19 20 21 22 

mm 

❚Image 20❚ Karyotype of tumor in the Ewing family. A 

reciprocal translocation is present between the long arms of 

chromosomes 11 and 22. Numeric abnormalities also are 

present. 

? 



1 2 3 4 5 6 7 8 9 

❚Image 21❚ Chromatograph of reverse transcriptase– 

polymerase chain reaction for EWS/FLI1 fusion products. 

Note the positive results in lanes 2, 4, and 6. Lanes 2 and 6 

contain type 1 fusions and lane 4 a type 2 fusion, as 

evidenced by the differing molecular weights (compare with 

standards in lanes 1 and 9). Courtesy of Julia Bridge, MD, 

University of Nebraska, Omaha. 

fluorescence in situ hybridization can be of great diagnostic 

value. However, some studies disclaim the absolute specificity 

of fusion studies, 5 so that microscopic diagnosis has 

not yet been superseded by genetic analysis. Lymphoma, 

particularly the lymphoblastic type, is a particularly treacherous 

entity, for its undifferentiated nature, occasional origin 

in soft tissue and bone, and CD99 positivity may easily lead 

to diagnostic confusion and therapeutic misadventure. 36 For 

this reason, I recommend the use of cytologic preparations 

that allow recognition of noncohesive cells with nuclear 

folding. In this setting, an entire panel of lymphoma 

❚Table 5❚ 

Differential Diagnosis for the Ewing Sarcoma Family of 

Tumors 

Neuroblastoma 

Rhabdomyosarcoma 

Lymphoma 

Leukemia (lymphoblastic and myeloid) 

Small cell osteosarcoma 

Metastatic medulloblastoma 

Wilms tumor 

Germinoma 

Mesenchymal chondrosarcoma 

Small cell carcinoma 

Neuroendocrine carcinoma 

Melanoma 

Rhabdoid tumor 

Clear cell sarcoma of the kidney 

Malignant peripheral nerve sheath tumor 

Synovial sarcoma 

immunostains that includes markers such as CD3, CD43, 

and terminal deoxynucleotidyl transferase, as well as CD45, 

is appropriate. Poorly differentiated monophasic synovial 

sarcoma may contain areas with small cell morphologic 

features, particularly on small biopsy specimens. CD99 positivity 

does not exclude this diagnosis, nor does cytokeratin 

staining exclude PPNET. Electron microscopy or genetic 

studies that include the synovial sarcoma translocation, 

t(X;18), or gene fusion, SSX/SYT, should resolve this difficulty. 

A final neoplasm to consider in differential diagnosis 

is the desmoplastic small cell tumor, which overlaps with 

EFTs in age range and clinical manifestation. This neoplasm 

cannot always be distinguished from PPNET without genetic 

studies, 37 although WT1 staining may be helpful. 38 

Desmoplastic Small Cell Tumor 

Desmoplastic small cell tumor (DSCT) is a relatively 

new entity, first described in detail by Gerald et al in 1991. 39 

Previous examples of this neoplasm may have been 

described as adult Wilms tumor, PPNET, Ewing sarcoma, 

alveolar rhabdomyosarcoma, extrarenal rhabdoid tumor, or 

small cell mesothelioma. However, 2 major discoveries 

provided fuel for the recognition of DSCT as a discrete 

pathologic entity: its amazing tendency to exhibit polyphenotypic 

differentiation on immunohistochemical evaluation and 

its unique reciprocal translocation, the t(11;22)(p13;q12). 40 

These features, combined with the typical clinical manifestations 

of DSCT, create a distinctive pathologic entity whose 

boundaries seem to segue into EFTs. 

Like EFTs, DSCT primarily affects young adults and 

adolescents, who seek care because of increased abdominal 

girth or obstructive symptoms related to tumor spread. 

Because of the extension of the peritoneum into the 

processus vaginalis, DSCT sometimes occurs as an 

intrascrotal mass. Other unusual locations include the thorax, 

central nervous system, and extremities. Otherwise DSCT 

arises within diverse intra-abdominal and intrapelvic locations, 

including pancreas, prostate, and ovaries. 39,41 

Gross examination reveals DSCTs as sclerotic lesions 

that infiltrate adjacent tissues, creating intra-abdominal adhesions 

and omental nodules. Microscopic examination reveals 

an intense desmoplastic reaction enveloping nests of tumor 

cells within a dense, fibrous stroma ❚Image 22❚. The malignant 

portion usually forms nondescript aggregates of primitive 

cells with high nuclear/cytoplasmic ratios. The tumor cells 

may exhibit epithelioid or rhabdoid features or even form 

rosettes. 41 Although DSCTs typically display desmin positivity, 

frank myogenous differentiation has not been described. 

Immunohistochemical examination has a major role in 

the diagnosis of DSCT, as noted. Typically, there is reactivity 


❚Image 22❚ Desmoplastic small cell tumor. Nests of 

epithelioid tumor cells are surrounded by a dense 

collagenous stroma. 

to a wide panoply of proteins, including mesenchymal 

markers such as desmin and vimentin, neural markers such 

as NSE and synaptophysin, and epithelial markers such as 

cytokeratin and epithelial membrane antigen. 39,42 On occasion, 

cytokeratin stains are negative. 43 Unfortunately, some 

lesions show positivity with CD99, excluding its use as a 

definitive marker to rule out EFTs. 42 However, results for 

myogenin or MyoD should be negative, excluding rhabdomyosarcoma 

despite the positive desmin staining. 42 

Recent reports indicate that WT1 can be used as an immunomarker 

for diagnosis of DSCT, possibly because it is overexpressed 

as a result of gene fusion. 38,44 WT1 also is expressed 

highly in mesothelium, suggesting a reason for the similarities 

between DSCT and mesothelioma. 45 

The t(11;22)(p13;q12) found in DSCT reveals that it 

results in fusion of the WT1 gene at 11p13 and the EWS gene 

on 22q12. 40 DSCT thus joins the list of non-EFT neoplasms 

with EWS fusions, including extraskeletal myxoid chondrosarcoma 

and clear cell sarcoma of soft tissues. Some have 

advocated the use of RT-PCR as a diagnostic tool for the 

detection of EWS/WT1. 46,47 As in EFTs, EWS may combine 

at different sites or with alternative fusion partners other than 

WT1 to produce DSCT. 48,49 Use of fusion gene technology 

suggests that DSCT may have a wider range of appearances 

and phenotypes than indicated by the initial morphologic 

descriptions. 40 Conversely, occasional tumors possess phenotypic 

and clinical features of DSCT but contain the 

EWS/FLI1 of typical EFTs. 37,50 Regardless of semantic 

issues, DSCTs are usually high-stage, aggressive neoplasms 

with a poor prognosis, although they respond to multimodal 

therapy. 51 


Esthesioneuroblastoma 


Esthesioneuroblastomas (also known as olfactory neuroblastomas) 

are primitive neuroepithelial tumors unique in their 

clinical manifestation as aggressive, rapidly growing masses 

arising in the anterior superior nasal cavity. Among neuroectodermal 

tumors of children, they are relatively rare entities. 

Because of their location, they have an unfortunate propensity 

to invade the chambers of the CNS via the lamina cribrosa. 

Esthesioneuroblastomas more commonly affect older children, 

adolescents, and young adults, with a slight preponderance 

of males. As with EFTs, most patients are white. Signs 

and symptoms include nasal obstruction, epistaxis, excessive 

lacrimation, and cerebrospinal fluid rhinorrhea, followed in 

advanced cases by frontal headaches, anosmia, diplopia, and a 

malar mass. Symptoms are typically present for long periods 

before they come to medical attention. 

Esthesioneuroblastomas arise from the neuroepithelium 

of the olfactory placode, giving them unique clinical and 

histologic features among pediatric neuroectodermal tumors. 

Like other pediatric neuroepithelial tumors, these are primitive 

lesions with few features of differentiation ❚Image 23❚. Their 

neuroepithelial nature may be expressed histologically as both 

neural and epithelial morphologies. The neural elements may 

differentiate into Homer Wright and Flexner rosettes, and the 

epithelial elements may form primitive glandular structures 

with central lumina. 52,53 Esthesioneuroblastomas also 

frequently show paragangliomatous differentiation. 52 

Electron microscopic and immunohistochemical 

features of esthesioneuroblastomas recapitulate those of 

olfactory epithelium, sensory neurons, and sustentacular 

❚Image 23❚ Esthesioneuroblastoma. This tumor arose from 

the superior nasal cavity and consists of primitive small 

round cells in a wispy, fibrillary stroma. 



cells. The neuronal cells contain processes with neurosecretory 

granules, and the sustentacular cells contain elongate 

cell processes, cytoplasmic microfilaments, and paramembranous 

basal lamina. 53 Immunohistochemically, they stain 

with cytokeratin, NSE, neurofilament proteins, chromogranin 

A, S-100, and synaptophysin. Adjacent preserved 

olfactory neuroepithelium will exhibit similar staining 

features. CD99 immunostains, however, are negative, serving 

as a possible means of distinction from EFTs. 54 

Some authors have described the presence of either a 

t(11;22) or an EWS/FLI1 fusion in esthesioneuroblastomas, 55 

but these findings have been disputed by others. 56,57 Because 

of the potential for EFTs to arise in the parameningeal 

regions of the CNS, 1 it is possible that the former results 

were obtained from basal PPNETs rather than esthesioneuroblastomas. 

Esthesioneuroblastomas may exhibit mild overexpression 

of TP53, although mutations have not been 

demonstrated. 54,58 

If one assumes that esthesioneuroblastomas do not 

contain an EWS/FLI1 fusion, it thus becomes possible to 

distinguish esthesioneuroblastoma from EFTs by absence of 

the fusion and negative CD99 staining. Neuroblastomas pose 

another potential diagnostic dilemma, but they lack the 

cytokeratin staining and unique clinical manifestations of 

esthesioneuroblastoma. Nasal glioma also should be considered 

in the diagnosis of pediatric nasal masses, but these 

tumors have distinct astrocytic qualities. Finally, small cell 

neuroendocrine carcinoma of the nasal cavity should be 

considered, but these lesions exhibit features more akin to 

oat cell carcinoma of the lung and lack S-100 and neurofilament 

positivity. 59 

Esthesioneuroblastomas generally require treatment by a 

combined approach of surgery and radiation, possibly with 

chemotherapy. At present, survival rates are about 80% at 5 

years. Preliminary data suggest that survival rates coincide 

with S-100 reactivity and proliferative index. 52 

Melanotic Neuroectodermal Tumor 

Melanotic neuroectodermal tumors typically arise in 

neonates and young infants, often as congenital neoplasms. 

Although they have been reported in diverse sites, such as 

genitourinary tract and extremities, they most often occur as 

facial masses, usually involving the maxilla or mandible. 

They are known by a variety of names, such as melanotic 

progonoma, retinal anlage tumor, and pigmented neuroectodermal 

tumor. 

As their name implies, melanotic neuroectodermal 

tumors comprise a mixture of melanin-producing cells and 

primitive neural cells embedded in a fibrous stroma ❚Image 

24❚. The melanocytes form cohesive nests and contain a granular, 

brown pigment accentuated by the Fontana stain. They 

❚Image 24❚ Melanotic neuroectodermal tumor. Nests of 

tumor are embedded in a fibrous stroma and contain a 

mixture of small undifferentiated cells and polygonal cells 

with a dusting of brown pigment. 

intermingle with primitive neural cells that contain hyperchromatic 

nuclei and modest cytoplasm and often form rosettes. 

Ultrastructurally, the latter cells contain dendritic processes 

and neurosecretory granules, and the former ones contain 

melanosomes. 60 Immunohistochemical staining yields the 

expected positivity for neural markers in the small cell component, 

but anti–S-100 fails to stain the melanocytic component, 

which is otherwise positive for melanoma-associated antigens 

such as HMB-45. 61 Muscle differentiation markers such as 

desmin and actin may be expressed in occasional cases, 

creating possible confusion with rhabdomyosarcoma. 61 

Molecular genetic study of melanotic neuroectodermal 

tumors indicates no evidence of MYCN amplification, 1p 

deletion, or EWS/ETS fusions, indicating no biologic relatedness 

to either EFTs or neuroblastomas. 62 

Despite their ominous microscopic appearance, melanotic 

neuroectodermal tumors are usually cured by simple 

excision. They recur in about 15% of cases, and fewer than 

5% metastasize. 63,64 

From the Department of Pathology, University of Arkansas for 

Medical Sciences, and Arkansas Children’s Hospital, Little Rock. 

Address reprint requests to Dr Parham: Slot 820, Arkansas 

Children’s Hospital, 800 Marshall St, Little Rock, AR 72202. 

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