Neuroectodermal and Neuroendocrine Tumors Principally Seen in ...

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.

© American Society of Clinical Pathologists

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

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❚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 S114

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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, © 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

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

B

❚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.



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❚Image 2❚ Bivalved ganglioneuroma, with pale gray, glistening, fibrous cut surface.

❚Image 3❚ Ganglioneuroma. Clusters of mature ganglion cells are embedded in a spindly, stroma-rich Schwann cell matrix.

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.

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 Classification8 ❚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 4❚ Neuroblastoma. The tumor cells form Homer Wright rosettes, composed of wreaths of nuclei encircling a pale-staining neurofibrillary core.

❚Image 5❚ Differentiating neuroblastoma, containing maturing neuroblasts with enlarged nuclei, prominent nucleoli, increased cytoplasm, and Nissl substance.

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❚Table 2❚ The International Neuroblastoma Pathology Classification (the Shimada System)8 Prognosis

Tumor Characteristics

Good

Stroma-rich tumors* Stroma-poor tumors with Age