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Neuroectodermal Neoplasms of the Head and Neck with Emphasis on Neuroendocrine Carcinomas Stacey E

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Neuroectodermal Neoplasms of the Head and Neck with Emphasis on Neuroendocrine Carcinomas Stacey E Neuroectodermal Neoplasms of the Head and Neck with Emphasis on Neuroendocrine Carcinomas Stacey E. Mills, M.D. Robert E. Fechner Laboratory of Surgical Pathology, University of Virginia Health Sciences Center, Charlottesville, Virginia neck. The focus is on tumors that exclusively involve Tumors exhibiting neuroectodermal differentiation this region or show a strong predilection to occur occur throughout the body, and the diverse tissues here. of the head and neck give rise to a wide assortment of these neoplasms. Neuroectodermal neoplasms KEY WORDS: Head and neck, Malignant melanoma, may be divided into lesions showing primarily epi- Neuroectodermal neoplasms, Neuroendocrine car- thelial differentiation (Group I, neuroendocrine car- cinoma, Nomenclature, Olfactory neuroblastoma, cinomas) and a more diverse group (Group II) of PNET, Sinonasal undifferentiated carcinoma. nonepithelial neoplasms. This article reviews these Mod Pathol 2002;15(3):264–278 neuroectodermal tumors of the head and neck with emphasis on the neuroendocrine carcinomas and Neuroectodermal neoplasms at any anatomic site their nomenclature. The author believes that with can be divided into tumors showing epithelial dif- regard to Group I tumors, the older terminology of ferentiation (Group I) and tumors with predomi- carcinoid, atypical carcinoid, and small cell carci- nantly neural features (Group II). In the head and noma should be replaced by subclassifications of neck (Table 1), Group I lesions such as neuroendo- well-differentiated, moderately differentiated, and crine carcinoma of the larynx typically exhibit cy- poorly differentiated neuroendocrine carcinoma. tokeratin positivity and are often admixed with The latter category should be further subdivided other forms of carcinoma. Group II tumors, such as into small cell and large cell variants. Neuroendo- olfactory neuroblastoma are typically (but not in- crine carcinomas, particularly the moderately dif- variably) cytokeratin negative and are more often ferentiated subtype, are often underdiagnosed in phenotypically “pure” neoplasms. Although, as will the head and neck region. In the larynx, these tu- be discussed, not all tumors fit neatly into this mors are the most common form of nonsquamous classification scheme, the great majority do, mak- carcinoma. Poorly differentiated neuroendocrine ing it a useful overall construct. carcinoma of small cell type is most common in the Early authors describing Group I neuroendocrine salivary glands but can occur elsewhere in the re- neoplasms throughout the body, especially the gion. The large cell subtype of poorly differentiated well-differentiated forms (carcinoid) considered neuroendocrine carcinoma has not been well doc- these unique lesions requiring a well-defined neu- umented in this region. However, the most likely roendocrine precursor cell for their development. candidate for this tumor category is the so-called When such cells were not readily apparent in nor- sinonasal undifferentiated carcinoma. Group II tu- mal tissue counterparts by a variety of techniques, mors discussed include olfactory neuroblastoma, the authors often felt compelled to go to great malignant melanoma, and Ewing’s sarcoma. In ad- lengths to explain the tumor’s origin. We now rec- dition, differential diagnostic problems related to ognize that epithelial cells (or at least their progen- Group I and II tumors are reviewed in detail. This itors) in virtually every organ have the ability to article reviews and updates our understanding of exhibit neuroendocrine differentiation. Moreover, neuroectodermal neoplasms arising in the head and light-microscopically obvious neuroendocrine dif- ferentiation is not uncommonly admixed with squamous or glandular elements, particularly when Copyright © 2002 by The United States and Canadian Academy of Pathology, Inc. dealing with higher grade lesions. Fortunately, VOL. 15, NO. 3, P. 264, 2002 Printed in the U.S.A. Date of acceptance: September 28, 2001. these older, nonproductive discussions regarding Address reprint requests to: Stacey E. Mills, M.D., Department of Pathol- “cell of origin” have given way to more clinically ogy, P.O. Box 800214, University of Virginia Health Sciences Center, Jefferson Park Avenue, Charlottesville, VA 22908; e-mail: sem2r@ relevant studies seeking to understand the clinico- virginia.edu; fax: 434-924-8767. pathologic features of these tumors. 264 TABLE 1. Neuroectodermal Neoplasms of the Head and should be distinguished by being the sole neo- Neck: Nomenclature plasms to carry the “carcinoid” designation. The Group 1 Well-differentiated neuroendocrine carcinoma (carcinoid tumor) argument against this approach emphasizes the Moderately differentiated neuroendocrine carcinoma (atypical need for uniform terminology and the fact that carcinoid tumor) carcinoid tumors, even the typical type, can Poorly differentiated neuroendocrine carcinoma, small cell type Poorly differentiated neuroendocrine carcinoma, large cell type metastasize. Pituitary adenoma/carcinoma Some authors have suggested for the lung that Group 2 the term atypical carcinoid should be retained for a Granular cell tumor Heterotopic glial tissue narrowed set of lesions showing most of the fea- Malignant peripheral nerve sheath tumor tures of typical carcinoid but with increased mitotic Malignant melanoma Neurofibroma activity, greater nuclear pleomorphism, and focal Olfactory neuroblastoma necrosis (2, 3). Some lesions considered to be atyp- Paraganglioma ical carcinoids in earlier studies have been rele- PNET/Ewing’s sarcoma Schwannoma gated to the more recently described diagnostic PNET, peripheral neuroectodermal tumor. category of large cell neuroendocrine carcinoma (4). In the head and neck, lesions in both categories are rare, and their biologic behavior is correspond- ingly poorly understood. It has not been convinc- NOMENCLATURE ingly proven, for example, that atypical carcinoids, The terminology surrounding Group I neuroen- stage for stage in the head and neck, are any differ- docrine neoplasia at any anatomic site remains in ent in their biologic behavior from higher grade a state of considerable flux. In 1993, the World neuroendocrine carcinomas. Health Organization (WHO) divided laryngeal I believe that the term atypical carcinoid should neuroendocrine neoplasms into carcinoid, atypi- be abandoned, even when used to designate a re- cal carcinoid, and small cell carcinoma (1). I be- stricted group of lesions with some features of car- lieve that there are several problems with this cinoid tumor. There is simply too much confusion approach, particularly with regard to the term among clinicians with regard to the meaning of this atypical carcinoid tumor. Most important, this term. The terminology that I favor for neuroendo- term requires clinician understanding that in crine neoplasia is outlined in Table 1. Under this fact, an atypical carcinoid is an overtly malignant, system, typical carcinoid tumors are designated as often high-grade neoplasm, meriting an aggres- well-differentiated neuroendocrine carcinomas, fol- sive clinical approach. This is counterintuitive to lowed in print, at least for now, by (carcinoid tu- a name that seems more closely allied to the mor) to make certain that the clinician understands indolent typical carcinoid tumor. the meaning of this designation. So-called atypical Although much is written about the morpho- carcinoid tumors are designated as moderately dif- logic spectrum of neuroendocrine tumors, it is ferentiated neuroendocrine carcinomas, a term that not entirely clear whether typical carcinoid tumor more accurately reflects their biologic potential. is a member of a blurred spectrum of neoplasms This system also recognizes poorly differentiated or an entity distinct from higher grades of neu- neuroendocrine carcinomas of both small cell and roendocrine neoplasia. Typical carcinoid tumor large cell subtypes. of the larynx (or lung) appears to be unrelated to The World Health Organization (WHO) classifica- smoking, whereas all other forms of neuroendo- tion of ear, nose, and throat (ENT) tumors included crine neoplasia in the larynx (or lung) show a no category for large-cell neuroendocrine carcino- striking association. Most so-called atypical car- mas, a relatively recently recognized entity in the lung cinoid tumors are obvious, often highly ma- lignant-appearing neoplasms. In contrast, typical and some other sites. In the former location, such carcinoid tumors are almost never associated tumors appear to fall into two categories: large with areas of significant cytologic atypia. Finally, cell, light-microscopically undifferentiated carci- so-called atypical carcinoids and small cell carci- nomas with occult neuroendocrine differentia- nomas will often show divergent differentiation tion detectable only at the immunohistochemical with foci of squamous or glandular cells. Such or ultrastructural level and high-grade carcino- features are extremely rare in typical carcinoid mas composed of larger cells, with some neu- tumors. In other words, typical carcinoid tumor roendocrine features at the light-microscopic may be a morphologically and clinically distinct level. The former tumors have not been charac- lesion having little or no overlap with other, terized in the ENT region. The latter appear to higher grade neuroendocrine proliferations. merge with the high-grade end of the moderately Therefore, it may be argued that such tumors differentiated category described below. Neuroectodermal Neoplasms
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