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Cancer of the Larynx: Current Concepts in the Treatment of the Neck

Editors

A. Ferlito, Udine, Italy W. Arnold, München, Germany

10 figures, 7 tables, 2000

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S. Karger Medical and Scientific Publishers Basel Freiburg Paris London New York New Delhi Bangkok Singapore Tokyo Sydney

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J..J. N.M. (Maywood. Rinaldo. Fla.. Devaney. A. A. (Krefeld).Y.ch www.karger.. (Munich) 204 The Pathology of Neck Dissection in Cancer of the Larynx Devaney. A.M. W. (Ann Arbor. Stimmer..). (Udine) 217 Surgical Treatment of the Neck in Cancer of the Larynx Ferlito.).). (Udine).com © 2000 S. Angiogenesis and Lymph Node Metastasis Petruzzelli.) 212 Classification and Terminology of Neck Dissections Ferlito. W. (Ann Arbor. (Udine). Mich. Arnold. Ill.D.com/journals/orl/orl_bk. (Maywood. C. Som.Vol. (Udine). (Udine).) 234 Author and Subject Index ABC Fax+ 41 61 306 12 34 E-Mail karger@karger. H. Arnold. Smith. K. Mass. R. (München) 178 The Biology of Tumor Invasion. A. (Udine). G. P.O. R. (Boston.A. Alexiou. C.htm . including tentative ones for forthcoming issues: www. G. (New York. (Gainsville.) 199 Diagnostic Procedures for Detection of Lymph Node Metastases in Cancer of the Larynx Kau. 2000 Contents 177 Preface Ferlito. A.J. Rinaldo. Ferlito.) 186 The New Imaging-Based Classification for Describing the Location of Lymph Nodes in the Neck with Particular Regard to Cervical Lymph Nodes in Relation to Cancer of the Larynx Som. N. P. (Bronx.V. 62. Basel Access to full text and tables of contents. (Bronx. A. (New York.Y.L. Mancuso. H. B.. Mich.Y. S. Emami. N.E.).) 226 Nonsurgical Treatment of Advanced Metastatic Cervical Disease in Cancer of the Larynx Petruzzelli.Y. Karger AG.karger. No. Mondin. Ill. Curtin. Silver. Rinaldo. A. 4. A. N. V.).

Dr. Som. MD ABC Fax + 41 61 306 12 34 E-Mail karger@karger. C. Curtin and A. Rinaldo and V. continuous exchange of opinions and information during the preparation of this special issue. G. Stimmer and W. Petruzzelli discusses the biology of tumor invasion. R.J. H. Rinaldo and R. and lymph node metastasis in laryngeal cancer.E.com © 2000 S. A. The diagnostic procedures for detecting lymph node metastases in cancer of the larynx are presented by Drs.J. Our grateful thanks go to Linda Haas for her continuous help and constant support in organizing the manuscripts. concerns the classification and terminology of neck dissection. Petruzzelli and B.L. Drs. H. Cervical metastasis has been identified in the literature as the most adverse independent prognostic factor in cancer of the larynx and the status of the neck often determines the choice of treatment for the primary lesion. In the last decade. Arnold.J. W. informative and interesting. Devaney. The authors have been selected for their high stature in their respective subspecialist fields. A. It is hoped that this approach will eliminate many often confusing and nondescriptive terms and thereby facilitate better inter-physician and inter-institutional communication.karger. Arnold. written by Drs. A. Ch. Karger AG. as this highly-specialized topic is of growing interest. The editors and authors hope that the reader will find this special issue useful.com/journals/orl . Ferlito. the pattern of spread of laryngeal cancer.62:177 Preface It is a pleasure to present a special issue devoted to ‘Cancer of the larynx: Current concepts in the treatment of the neck’.V. lymph node metastasis. G. A. A. clinical and pathological diagnostic procedures for detecting cervical metastases. Mondin. This is followed by a very interesting article dealing with the new imaging-based classification for describing the location of lymph nodes in the neck. P.ch www.D.karger. Ferlito. Ferlito. The subsequent article. with particular regard to cervical lymph nodes in relation to cancer of the larynx. Emami devote the last article to the nonsurgical treatment of advanced metastatic cervical disease in cancer of the larynx. In the first article.O. Smith. The fourth article.M. many advances have been made in our understanding of the mechanisms of the biology of tumor invasion. The sixth article considers surgical treatment of the neck in cancer of the larynx and is written by Drs. Ferlito. S. Devaney. Basel Accessible online at: www. Som. A. Silver. Kau. Rinaldo and K.ORL 2000. is devoted to the pathology of neck dissection in cancer of the larynx.M. written by Drs. Alexiou. written by Drs. A. P. angiogenesis. Mancuso. and the use of different surgical and nonsurgical modalities for the management of the neck.A. Finally. MD. It has been a pleasure to cooperate with these distinguished authorities and there has been a fruitful.

. It is now well established that the development of cervical metastases.luc. This chapter will begin with an introduction of the important molecular events associated with the transition of the squamous epithelium of the upper aerodigestive tract (UADT) to metastatic squamous cell carcinoma. Finally we will review data from our own and other laboratories which are studying the process of new blood vessel growth (angiogenesis) induced by tumor-derived growth factors.ORL 2000. As we develop a better understanding of the cellular and molecular mechanisms of metastasis in head and neck squamous cell carcinoma. new therapies effective at preventing the development of secondary tumors can be realized ultimately increasing the patient’s survival. in particular those with extranodal extension of tumor. Karger AG. in particular those with extranodal extension of tumor. Karger AG. E-Mail gpetruz@wpo. Copyright © 2000 S. FACS Head and Neck Oncology Program. and Head and Neck Oncology Program. negatively impacts both regional control and survival of patients with laryngeal carcinoma. ABC Fax + 41 61 306 12 34 E-Mail karger@karger. Rm 270 Maywood. MD. PhD. Basel Accessible online at: www. Head and Neck Surgery and General Surgery. USA Key Words Cancer invasion W Angiogenesis W Lymph node metastasis Abstract It is now well established that the development of cervical metastases. Maywood. Cardinal Bernardin Cancer Center. We will then review the critical cellular events identified as the tumor progresses from an in situ to invasive and finally a metastatic HNSCC.62:178–185 The Biology of Tumor Invasion. Angiogenesis and Lymph Node Metastasis Guy J. Bldg 112. Petruzzelli Departments of Otolaryngology.com/journals/orl Guy J. Basel Improved understanding of the patterns of intraorgan spread of laryngeal cancer has led to the increased use of oncologically sound larynx-preserving surgical procedures.it. We will then review the critical cellular events identified as the tumor progresses from an in situ to invasive and finally a metastatic head and neck squamous cell carcinoma. IL 60153 (USA) Tel. continue to fail in the neck and distantly. negatively impacts both regional control and survival of patients with laryngeal carcinoma [1].karger. A better understanding of the cellular and molecular mechanisms of metastasis in head and neck squamous cell carcinoma (HNSCC) may lead to the genesis of new therapies effective at preventing the development of secondary tumors and increasing the patient’s survival. Adjuvant radiation therapy has been shown to reduce the incidence of regional failure and chemoradiation may eventually lead to increased survival by decreasing the development of pulmonary and other distant metastases. First Ave. although controlled at the primary site.edu .com © 2000 S. This chapter will begin with an introduction of the important molecular events associated with the transition of the squamous epithelium of the upper aerodigestive tract to metastatic squamous cell carcinoma. Fax +1 708 327 3248. patients with carcinoma of the larynx. Loyola University Medical Center. Ill. Despite these advances. Petruzzelli. +1 708 327 3315.karger.ch www. Cardinal Bernardin Cancer Center 2160 S.

Recently is has been demonstrated that differential epigenetic mechanisms may account for the development of HNSCC in individuals without traditional exposures to mutagens [4]. a very small percentage (! 0. defects in response to intracellular signals for apoptosis and resistance to cytotoxicity. Not all cells within a given tumor will contain identical cytogenetic abnormalities. Our current understanding of cancer supports the hypothesis that the development of malignant tumors is due to alterations in normal mechanisms of cellular proliferation. or the activation of oncogenes. the local tumor envi- ronment may favor the expansion of more aggressive clones in the formation of metastases. and a failure of programmed cell death (apoptosis). growth factor production loss of tumor suppressor genes. Genetic events associated with the stepwise progression for normal squamous epithelium to an invasive and metastatic HNSCC [adapted from 9]. produc- Lymph Node Metastasis ORL 2000. all of which provide cancer cells a particular growth advantage. invasiveness. Fearon and Vogelstein [6] were the first to present compelling evidence identifying a sequence of reducible cytogenetic events in the development of colorectal tumors and metastases. These genetic alterations may be spontaneous or inherited but are most often due to the actions of viral or chemical mutagens or direct radiation-induced DNA damage [2. Hence the clinical observation that supraglottic tumors will present more frequently with metastasis than comparable stage glottic tumors. is thought to arise after a series of genetic events resulting in accumulation of DNA damage. These genomic changes result in particular phenotypic changes such as defects in terminal differentiation. Many investigators have begun to examine the molecular pathogenesis of HNSCC in terms of alterations in cytogenetic. 1). The Biology of Invasion Essential characteristics of cancer are the ability to invade surrounding tissues and metastasize to regional and distant sites. 3]. 1. a recent comprehensive review by Myers [9] has proposed a hypothesis for HNSCC resembling the multi-step colorectal carcinogenesis model (fig. and these subpopulations will differ with respect to their immunogenicity. which drive cellular proliferation by a variety of mechanisms. this concept of tumor heterogeneity proposes that tumors are composed of subpopulations of cells. growth kinetics.62:178–185 179 . While neoplasms may be heterogeneous.01%) of circulating tumor cells will initiate metastatic colonies. The events attendant to local invasion by an epithelial tumor include loss of adhesion to surrounding tumor cells and basement membrane. Targets of these mutations include inactivation of growth-regulating tumor suppressor genes. proto-oncogene activation. Epithelial tumors represent excellent systems in which to study the stepwise progression resulting in an invasive malignancy. loss of response to normal growth controls. Acquisition of the Malignant Phenotype HNSCC. differentiation. Although the size of the subpopulation of metastasizing cells in any given tumor may be quite large. sensitivity to cytotoxic drugs and ability to metastasize. It is likely that a similar series of cytogenetic alterations exist in the development of HNSCC as well.Fig. and failure of apoptosis [7–9] Although no specific pattern of genetic events in the development of HNSCC has been accepted. First proposed by Fidler and Hart [5]. like all solid tumors.

These studies continue to elucidate the mechanisms of HNSCC local invasion. Our laboratory has investigated alterations in the pattern of integrin expression in tumor cells influenced by endothelial cells and cytokines. Attachment of tumor cells to extracellular matrix. Major components of the basement membrane include type IV collagen. metastasis. Laminin is composed of three long polypeptide chains held together by disulfide bonds in a cross-like configuration. The functional domains of laminin serve as receptors or binding site for other laminin molecules. heparan sulfate proteoglycan. attachment to extracellular membrane molecules. and neovascularization. HNSCC will progress from carcinoma in situ. In 1986. and entactin. Biochemical and structural analysis of the A-9 antigen identified it as an ·6-ß4 integrin [18]. when polymerized. to microinvasive carcinoma. and endothelial cell interactions continue to be investigated. to a deeply invasive tumor with lymphatic metastasis. but not 3 [21]. The presence of increased expression of the A-9 antigen was shown to significantly correlate with early recurrence and reduced diseasefree survival in patients [17]. Both the ·6 and ß4 integrin subunits can function as laminin receptor and bind laminin.tion of enzymes and mediators which facilitate the incursion of malignant cells into the subjacent connective tissue. Incomplete or reduced staining of basement membrane collagen and discontinuous or poor staining for laminin have been correlated with increased nodal metastasis [13–15]. A reasonable interpretation of these studies that increased degradation of basement membrane correlates with increased invasion and metastasis. thus serving as an additional reinforcing bridge within the basal lamina [12].000) kilodalton glycoprotein laminin. Alterations in tumor cell adherence and the expression of these cell surface ligands may facilitate invasion. metastasis. 20]. The distribution of basement membrane collagen has been shown to correlate significantly with the presence of lymph node metastases. Degradation of the Extracellular Matrix In order to breech the basement membrane and invade the connective tissue stroma. to an invasive tumor with stromal invasion. The essential element in the transition from carcinoma in situ or preinvasive to invasive carcinoma is the destruction of the underlying basement membrane. Adherence to the basement membrane and extracellular matrix components is another method by which tumor cells can facilitate local invasion and metastasis. The roles of integrins in the pathology of HNSCC invasion. laminin. neovascularization. entry to and exit from the circulation via attachment to endothelial cell ligands. and the epithelial cell surface. while attempting to isolate a specific HNSCC tumor marker. HNSSC must produce enzymes capable of degrading the extracellular matrix. Entactin is another glycoprotein with two high affinity binding sites. Experimental studies using monoclonal antibodies to the · or ß subunits and laminin receptor analogs have shown inhibition of attachment to laminin in vitro and reduced metastasis formation in vivo [19. Carey’s group [16] identified a membrane associate protein unique to head and neck carcinomas. Although an exhaustive review of basement membrane (basal lamina) biochemistry is beyond the scope of this article. forms a sheet-like network. an understanding of the components within this layer is important to the discussion of tumor-derived mediators of invasion. one for laminin and the other for type IV collagen. Integrins are a class of high-molecule-weight transmembrane glycoproteins composed of two noncovalently bound subunits (· and ß) which attach to extracellular matrix and cytoskeletal components. 11]. On the molecular level type IV collagen is a polypeptide composed of repeating hydroxyproline and hydroxylysine residues which. and the plasminogen activators. 180 ORL 2000. This antigen (A-9) was present in low levels of normal keratinocytes but in much higher levels in HNSCC and seemed to be localized to the basal pole. named for their dependence on Zn2+ as a catalyst. collagen. Soluble factors derived from endothelial cells transiently increase adherence of HNSCC to fibronectin and vitronectin and increase surface expression of the ß integrins 1 and 4. These proteins bind to specific activated MMP and prevent matrix degradation [22–24]. Interspersed within the collage network is the large (850. MMP can be further subdivided based on their respective substrates into (1) interstitial collagenases. (2) stromelysins and (3) gelatinases (table 1). leading to the speculation that it may have a role in cell adhesion.62:178–185 Petruzzelli . and neovascularization (angiogenesis) will be reviewed in more detail with specific regard to molecular mechanisms and the production of growth factors (cytokines) by HNSCC. production of proteolytic enzymes. General classes of these proteolytic molecules include the matrix metalloproteinases (MMP). entactin. and a repeat of this cascade at a distant (metastatic) site [10. Tissue-derived metalloproteinase inhibitors (TIMP-1 and TIMP-2) have also been identified.

The clinical findings of scant vascularity and the absence of metas- Lymph Node Metastasis ORL 2000. Stromelysins 2 and 3 have also been identified in both HNSCC and chemically induced squamous cell carcinoma [31]. -2. 39]. [35] have shown that increased invasion on artificial basement membranes in vitro is correlated with high levels of u-PA production and upregulation of uPA mRNA. The ability to stimulate new blood vessel growth (neovascularization or angiogenesis) is an integral part of organogenesis. obtaining nutrients and exchanging metabolic waste products directly with the host become more efficient and the growth properties of the tumor change. and migration. Folkman first articulated the hypothesis that tumor growth was angiogenesis-dependent. size 11 mm3. Pathologic angiogenesis is not autoregulated and results from alterations in growth control which are part of particular disease processes. 39]. IX Collagens I. Since then. and in this context it is short term and self-limiting. gelatins Laminin and fibronectin Gelatin. 34]. II. Common features of these polypeptides are their relatively low molecular weights and their ability to bind to heparin [36.62:178–185 181 . The plasminogen activators (PA) are another class of proteases which have been studied in HNSCC invasion and metastasis. laminins and other basement membrane components (collagen IV. The genetic mechanisms regulating the expression of these proteins has also been studied. 37]. A specific antibody directed against the uPA catalytic site will prevent invasion of basement membrane-coated filters by HNSCC. their structures sequenced. Clayman et al. V). differentiation. Characteristics of prevascular tumors include a linear growth phase. Overexpression of stromelysin 3 genes. III. In 1972. Plasmin is a fibrinolytic enzyme which also is active in degrading type IV collagen and laminin. and size limited to !1 mm3. Although two forms of PA exist. and their mechanisms of action characterized. Characteristics of tumors in the ‘vascular phase’ are histological demonstration of intratumor capillary networks. studies in several in vivo systems have shown that tumorigenesis begins in a ‘prevascular phase’. psoriasis. collagens IV and V Gelatin. and an exponential growth phase [38. Our current understanding of the biology of angiogenesis in solid tumors is due in greatest extent to the work of Folkman [38. Once tumors become vascularized. HNSCC produce growth factors or cytokines which target other cell types. PA are neutral serine proteases which catalyze the synthesis of plasmin from plasminogen.MMP-1. Recently. enzymes and motility factors. the urokinase type (uPA) has been shown by several investigators to be important in HNSCC invasion and metastasis [33. Many ‘angiogenic cytokines’ have been identified. II. and the synovial inflammatory changes in arthritis are all examples of pathological angiogenesis [36]. genes cloned. collagen IV Proteoglycans. expression of MMP-1 and -9 was variable. reproduction. MMP produced by HNSCC MMP Name Substrate Collagenases MMP-1 Interstitial collagenase MMP-8 Neutrophil collagenase MMP-12 Metalloelastase MMP-13 Collagenase 3 Stromelysins MMP-3 Stromelysin 1 MMP-7 Matrilysin MMP-10 Stromelysin 2 MMP-11 Stromelysin 3 Gelatinases MMP-2 Gelatinase A MMP-9 Gelatinase B Collagens I. Charous et al. III. cytokines usually effect cell-cell communication over short distances. collagen IV. collagen IV. and -9. Cytokines are lowmolecular-weight proteins which effect cell-cell communication and signal cellular proliferation. IX Elastin Collagen III Proteoglycans. V. has been shown in 106 of 111 HNSCC [32]. and wound healing and repair. Table 1. gelatins Fibronectin. activation. III. Tumor angiogenesis as well as the neovascularization of diabetic retinopathy. responsible for the degradation of fibrillar collagen (collagens I. demonstrated by Northern blot analysis. A class of cytokines which has been closely linked to the expansion of the invasive and metastatic phenotypes are the angiogenic factors. absence of intratumoral vessels. In addition to the production of these locally active molecules. Cytokines have most actively been studied in the immune system but their roles in the nervous and vascular system are also being examined. gelatin) have been identified in HNSCC in vitro and in vivo [25– 29]. Unlike the endocrine hormones. II. V. [30] attempted to demonstrate MMP proteins using in situ hybridization. Although expression of MMP-2 and TIMP-1 was consistent in 21 primary HNSCC tested. collagens IV and V Angiogenesis Local tissue invasion and migration into the subjacent connective tissue matrix by HNSCC are dependent of the production of cell surface molecules.

01). 48]. which was statistically significant at p = 0. Cell-free supernatants were also tested in a nonradioactive proliferation assay using human umbilical vein endothelial cells. When compared to nontumor control tissues. [43] examined the vascular density in 20 intermediate-thickness (0. ovarian and endometrial carcinomas [47. migration and differentiation of endothelial cells in the formation of new blood vessels [41]. We have examined the supernatants of several HNSCC cell lines for the presence of these growth factors and determined their ability to stimulate endothelial cell proliferation. these authors also demonstrated increased endothelial cell migration in response to diffusable HNSCC-derived factors. and vascular endothelial cell growth factor/vascular permeability factor (VEGF/VPF). and that the chick embryo CAM is an effective model for quantifying angiogenesis induced by head and neck tumors [40]. all lines stimulated endothelial cell proliferation in a dosedependent fashion. The current work in our laboratory is directed to defining the specific mechanism(s) and growth factors associated with the angiogenic response induced by HNSCC. Benefield et al.tases associated with in situ and microinvasive HNSCC support these data as well. Factors derived from HNSCC have also been shown to cause enhanced migration of endothelial cells. Our laboratory has been studying the mechanisms of tumor-induced angiogenesis in HNSCC for several years. USA) endothelial cells in media containing supernatants from HNSCC cultures were shown to cover 30–45% of the designated wound space. In 1986. Using a twochamber polycarbonate filter system. Md. Using computerized image analysis (Image-Pro Plus. The addition of PGE2 and TGF-ß but not VEGF/VPF to the endothelial cultures resulted in similar patterns of enhanced migration [41]. non-small cell lung carcinomas [49]. migration and adherence continue to be investigated.001 [42].0 mm of invasion) cutaneous melanomas and demonstrated a more than twofold increase in the vascular area in the 10 metastasizing tumors. All lines produced detectable levels of the cytokines. prostatic carcinoma [50]. using immunocytochemistry for either human factor VIII or the CD34 antigen as an endothelial cell marker. Since this initial study. Initial studies served to demonstrate the angiogenic properties of explants of HNSCC. ade- 182 ORL 2000. Silver Springs. All other histological and clinical parameters were comparable in this study.76–4. The effects of heparin binding on the ability of these supernatants to stimulate endothelial cell proliferation was determined by fractionating the supernatant on a Sephadex heparin-copper biaffinity column.62:178–185 Petruzzelli . compared to only 10% covered by endothelial cells in control media. many other solid tumor systems have been examined. [41] combined two methods to demonstrate that cell-free supernatants derived from two HNSCC lines enhanced the migration of endothelial cells. Additionally. The antiproliferative effects of heparin-copper pretreatment ranged from 31. We concluded that HNSCC can induce an angiogenic response in vivo.. Srivastava et al. The components of HNSCC-induced angiogenesis appear to be differentially regulated by several cytokines. [21] have demonstrated that pretreating endothelial cells with supernatants from HNSCC increased adherence of endothelial cells to fibronectin and laminin.7 to 46. Taitz et al.23% reduction in endothelial cell proliferation. The ability of a tumor to stimulate an angiogenic response should directly determine the capability of a tumor to metastasize and ultimately kill the host. using the chick embryo chorioallantoic membrane (CAM) as a bioassy of angiogenesis. Five HNSCC lines were assayed with an enzyme-linked immunosorbent assay for the production of prostaglandin E2 (PGE2). endothelial cell proliferation is induced by VEGF/VPF and inhibited by TGF-ß while migration is enhanced by TGF-ß and PGE2. A clear correlation between tumor angiogenesis and nodal metastasis (and subsequently outcome) has been demonstrated in early and invasive breast carcinoma [44–46]. transforming growth factor-ß (TGF-ß). The increased adher- ence of these cells corresponds to increased expression of integrins ß1 and ß4 as demonstrated by fluorescence-activated cell-sorting analysis. Current work in our laboratory is being directed at identifying intracellular signal pathways associated with endothelial cell activation and the cytoskeletal reorganization required. Since the embryonic CAM produces little or no inflammatory response we concluded that the proliferation in CAM vessels was a response to the production of an unidentified angiogenic factor. The first assay measured the capacity of endothelial cells to repopulate a wound in their monolayer. basic fibroblast growth factor (FGF-2). in an attempt to correlate microvessel density with nodal metastasis and clinical outcome. We have focused specifically on the relationship between tumor-derived factors and their effects on the proliferation. squamous cell carcinoma xenograft stimulated an augmented angiogenic response (p = 0. In addition to stimulating endothelial cells to proliferate. The effects of HNSCC-derived factors on endothelial cell proliferation. HNSCC also induce structural changes in these cells.

Some studies used biopsy material prior to the initiation of chemoradiotherapy. immune suppression. Additionally there was no standardization of the endothelial antigen (factor VII versus the CD31 or CD34 antigens) used to identify endothelial cell profiles. tumor vascularity is not predictive of the response of a tumor to chemoradiotherapy. in 1993. Conclusions HNSCC arises as a result of a series of genetic transformations of squamous epithelial cells giving rise to the malignant phenotype. evaluated microvessel densities using the CD31 monoclonal antibody in biopsy specimens of 70 patients with advanced head and neck cancer treated with chemoradiotherapy. with initially good correlations between microvessel density and outcome recently being challenged. The accumulated data regarding microvessel density as a predictor of nodal metastasis. the local milieu surrounding the tumor may provide an ample blood supply. Tumors invade local connective tissues by the production of proteinases and the expression of cell surface markers which facilitate attachment to components of the extracellular matrix. in the head and neck. patients with microvessel densities 625 per 200 ! field had a significantly higher (p ! 0. Tumor invasion of capillaries and lymphatics leads to dissemination of tumors and the establishment of histologically identical tumors at secondary sites. Others have reported good correlations between microvessel densities at the leading edge of the tumor and nodal metastases in carcinoma of the tongue [54–56]. and no significant differences in vascularity at the tumor-host interface have been demonstrated between metastatic and nonmetastatic tumors. Acknowledgment This work was supported in part by Grant No. supraglottic larynx [65] and tonsil [66] have been examined independently. and prolonged exposure to tobacco. Factors such as genetic susceptibility of the host. Angiogenesis has been reported to not serve as a predictor of lymph node metastasis by several authors examing tumors from various sites in the head and neck [60. In this study. Conflicting data exist regarding the predictability of lymph node metastasis based on the angiogenic capacity of the primary tumor. 57] and nasopharynx [58. Finally. however tumors circumvent this limitation by recruiting host capillaries to form an intratumor blood supply. despite advances in surgical techniques and more sophisticated radiotherapeutic modalities the development of metastases will result in the death of nearly one-half of the patients with advanced HNSCC. The angiogenic requirements of tumors arising in richly vascularized organs such as the tongue or buccal mucosa may be less than those arising in less well vascularized sites. alcohol and viruses may facilitate these genetic derangements. Tumor size is limited by the diffusion of nutrients from adjacent blood vessels. site of origin may be an important factor in considering angiogenesis data. there was no uniform method for the identification and calculation of microvessel densities in the tumor specimens. and squamous cell carcinoma of the esophagus [52]. 61]. More aggressive clones proliferate and develop into clinically detectable tumors. Principally. Gasparini et al. the tongue [62–64]. and obviate the need for additional angiogenesis. Analysis of these studies reveals possible explanations for the discrepancies in results. Interestingly.nocarcinoma of the colon [51]. Methodological and site-specific differences must be considered in interpreting immunohistochemical data of this type. Lymph Node Metastasis ORL 2000.0046) incidence of local or distant metastases. or response to treatment in HNSCC remains conflicting. 59].62:178–185 183 . floor of mouth [56. survival. 95–74 from the American Cancer Society. Unfortunately. Additionally. while others examined surgical specimens at the time of definitive resection. [53].

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Mount Sinai School of Medicine. Fax +1 212 427 8137 E-Mail peter_som@smtplink. and the spinal accessory nerve.com/journals/orl Peter M.com © 2000 S.karger. the principle landmarks used in cervical nodal classification were clinical and defined either by palpation or found at the operative table. N. middle. and lower jugular subgroups. Basel Abstract For over five decades. Trotter [2]. In the April 1999 issue of the Archives of Otolaryngology – Head Neck Surgery.. These authors mapped the location and drainage of the cervical lymph nodes and referenced the location of these nodes to landmarks assessed by palpation and anatomy seen at surgery. Karger AG..mssm. Gainsville. Such disease can alter planned operative or radiation fields. City University.62:186–198 The New Imaging-Based Classification for Describing the Location of Lymph Nodes in the Neck with Particular Regard to Cervical Lymph Nodes in Relation to Cancer of the Larynx Peter M. NY 10029 (USA) Tel. Basel 0301–1569/00/0624–0186$17. the inferior belly of the omohyoid muscle. USA b Department Key Words Computed tomography W Head and neck neoplasms W Lymph nodes W Lymphatic metastasis sifications. sectional imaging has consistently improved its quality and resolution and it has been shown that imaging can identify deep structures and adenopathy not amenable to palpation. However during the past two decades. of Radiology. New York. Karger AG. Curtin b Anthony A. Shands Hospital. +1 212 241 7420. ABC Fax + 41 61 306 12 34 E-Mail karger@karger. This article describes this imaging-based classification and demonstrates its use with axial diagrams. the common facial vein. These authors noted the importance of the nodal chain surrounding the internal jugular vein and these nodes were divided into upper. Copyright © 2000 S. and c Department of Radiology.50/0 Accessible online at: www. Mass. This classification was developed in consultation with head and neck surgeons so that the nodal levels classified by this imaging-based system would correspond closely with the nodal levels determined by utilizing the most commonly employed clinically-based clas- Introduction and Historical Review In the first four decades of the 20th century. Charpy [1]. New York.karger. Mancuso c a Department of Radiology.edu . and finally Rouvière [3] developed the basis of our present understanding of cervical lymphatic anatomy [1–3]. Som.ORL 2000. University of Florida College of Medicine. Fla. the posterior belly of the digastric muscle. MD Department of Radiology..ch www. Massachusetts Eye and Ear Infirmary. Som a Hugh D. Boston.Y. for the first time an imaging-based classification was published that gave precise anatomic landmarks for use in classifying metastatic cervical adenopathy. Mount Sinai Hospital One Gustave Levy Place. Such surgical landmarks included the carotid bifurcation.

and Robbins [13] in 1998. the subcommittee for neck dissection terminology and classification of the American Academy of Otolaryngology-Head and Neck Surgery [10] in 1991. This advantage of imaging over palpation may be especially relevant when evaluating the retropharyngeal nodes. despite the efforts of these and other radiologists to incorporate imaging-based landmarks into nodal classification. retropharyngeal or superior mediastinal). In 1981. In 1998.62:186–198 187 . nodes not dealt with in the prior clinically-based systems.. When compared to previous papers on the cervical nodes. Thus. Suen and Goepfert [7] in 1987. Shah et al. Cervical Nodal Classification ORL 2000. Some of the key points also noted in these papers included Robbins’ emphasis on the importance of considering the visceral nodes. This work not only suggested a change in terminology.e. In general. As evidence of their benefit. ‘groups’. Reasons to Design an Imaging-Based Nodal Classification After nearly two decades of clinical use. it was felt that an imaging-based classification should specifically address the retropharyngeal nodes. clinical computed tomography (CT) had become widely used to map primary tumors and cervical nodal disease. Mancuso et al. imaging can assess deep infiltration of the primary tumor. as late as 1998 few of these landmarks were accepted by clinicians. today approximately 80% of patients with head and neck cancers have treatment planning CT or MR scans. Curtin et al. the fifth edition of AJCC Cancer Staging Manual [12] in 1997. 16. Lindberg [4] described the distribution of cervical metastases in head and neck cancer. often not appreciated by direct observation and palpation. Following the work of Shah et al. Within these articles there are various definitions of the boundaries of the nodal ‘levels’.e. or ‘regions’. However. [5]. this work was far more pathologically oriented as it related the location of primary head and neck cancers to specific nodal disease. which are inaccessible to palpation and of great prognostic importance in pharyngeal malignancies. have established their usefulness in the assessment of patients with head and neck cancers. [17] suggested that the anatomic landmarks used to separate the jugular nodes into three levels should be the caudal margin of the body of the hyoid bone and the caudal margin of the anterior arch of the cricoid cartilage. almost all of which remained clinically defined. but more importantly related tumor spread to specific nodal levels rather than particular nodal chains as described by Rouvière [3]. Similarly.In 1972. it is only those patients with small. In an attempt to redirect the definitions of the ‘level’ boundaries from those identified by palpation or seen at surgery. the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC) [8] in 1988. Since the introduction of refined CT in the 1980s. Curtin also supported using the dorsal edge of the submandibular gland as the plane of separation between level I and level II nodes. These nodes are usually in locations difficult to palpate (i. it was felt that the mediastinal and visceral nodes described in the fifth edition of the AJCC Cancer Staging Manual should be included in any imaging-based nodal classification.. [5] suggested that the anatomicallybased terminology be replaced with a simpler ‘level’based system. Lindberg started the movement away from pure anatomic studies and into the realm of the pathophysiology of tumor spread. [14] suggested imagingbased landmarks that were easily identified on axial CT scans. and CT and MR imaging can identify clinically silent nodes [14. radiologists have also been attempting to define the cervical nodes. Rather. These various nodal classifications changed the emphasis of classifying nodes from that of pure anatomical localization to providing information that assists the surgeon in choosing the best type of neck dissection for a particular patient [13]. there was no longer any distinction made between the upper internal jugular nodes and the upper spinal accessory nodes. all of these nodes were referred to as their level II. These works included those of Spiro [6] in 1985. superficial tumors that do not receive such pretreatment imaging. Concurrent with the surgical interest in nodal staging. That is. In addition to providing accurate displays of the complex anatomy of the head and neck. Medina [9] in 1989. Som in 1985 [15] and 1987 [16]. In 1983. van den Brekel’s suggestion that the dorsal region of the submandibular nodes is the dorsal margin of the submandibular gland. also reemphasized the preferential use on imaging landmarks as seen on axial CT scans. CT and subsequently MR imaging. a number of clinically-based papers proposed nodal classifications that continued to relate the distribution of nodal metastasis to nodal ‘level’. and his agreement with Lindberg and Robbins to separate the posterior triangle nodes into subgroups. Thus. 18–24]. deep to the sternocleidomastoid muscle or in the tracheoesophageal groove) or they are nodes not amenable to palpation (i. van den Brekel [11] in 1992.

we utilized an oblique line extending from the posterior border of the sternocleidomastoid muscle to the lateral posterior edge of the anterior scalene muscle to separate level IV and V nodes. In fact. the separation between level II and III and level V is the posterior border of the sternocleidomastoid muscle. With MR imaging. in these instances. this boundary works well in the upper and middle neck.Taking into account these potential benefits of CT and MR imaging and assuming that the imaging studies are properly and reproducibly performed. Despite the fact that both the imaging-based and clinically-based classifications are designed as standalone classifications. However. the examination is performed as contiguous 3-mm scans from the skull base to the manubrium or as a spiral study reconstructed as contiguous 2. due to the slope of the shoulders. imaging has the potential to provide both precise anatomic landmarks by which to define a nodal classification and the ability to visualize virtually all potential nodal pathology. If there is a history of thyroid or cervical esophageal cancer. on imaging it may be difficult in some cases to precisely classify some lymph nodes that are located at the junction between levels. to ensure inclusion of the superior mediastinum. the supraclavicular fossa is not as well defined on axial CT and MR imaging as it is to palpation. But. especially when Ho’s triangle is utilized as the defining anatomic plane [12]. imaging may provide knowledge of nodal pathology that is inaccessible to palpation. To solve this potential problem. the best possible evaluation of cervical nodal disease may be obtained by utilizing both clinical palpation and imaging information. In addition. This line consistently places any scalene nodes in level IV. the creation of an imaging-based classification has little practical application if the nodal levels determined are significantly different from those identified by clinically-based classifications. Because these scalene nodes are classically described as being part of the lower internal jugular nodes. The posterior border of the sternocleidomastoid muscle is the anterior border of the posterior triangle and thus should serve well as the imaging border between these nodes. above the axial level of the bottom of the arch of the cricoid cartilage. they should be classified as level IV nodes and not level V nodes. Similarly as mentioned. where such technique includes patient positioning and gantry angulation. At first there did not seem to be any dilemma. on axial images in the lower neck in some patients. However. when imaging landmarks are used. if possible. That is. The scanner gantry is aligned along the inferior orbital meatal (IOM) plane and. With these concepts in mind. a consistent technique must be used. 188 ORL 2000. The axial plane referred to in this classification is obtained with the patient’s head in a comfortable ‘neutral’ position with the hard palate perpendicular to the tabletop and the shoulders down as far as possible. In addition. With CT. The recommended field of view is 16–18 mm. As an example. the scalene nodes should lie anterior rather than posterior to the back of the sternocleidomastoid muscle. the scans should be no thicker than 5 mm (preferably 3–4 mm) with a 1-mm inter-slice gap. Thus. the identifiable posterior border of the sternocleidomastoid muscle is in a plane anterior to the scalene nodes described by Rouvière [3] and Lingeman [25]. This became a particular problem when attempting to define a line of separation between level II. when clinical assessment is added to the imaging classification. it is no longer necessary to resort to surgical definitions of nodal levels. we created an imagingbased nodal classification that first appeared in the April issue of Archives of Otolaryngology – Head Neck Surgery [26]. the examination should be performed with the administration of intravenous contrast to allow the best possible differentiation of nodes from vessels. such problems are easily resolved. the caudal margin of the studies should be extended down to the level of the carina. It was therefore considered imperative that there be agreement between the levels as determined by both the clinically-based and imaging-based classifications.or 3-mm slices. as mentioned in some people it could result in scalene nodes being classified as level V nodes (posterior to the back of the muscle) rather than as level IV nodes and this would be in conflict with the clinically-based classifications. However. if the posterior border of the sternocleidomastoid muscle is used as the division between levels IV and V. However. III and IV nodes and level V nodes. There is no one universal technique that is utilized to perform CT scans of the neck. caudal to the bottom of the cricoid arch. This is especially true for CT.62:186–198 Som /Curtin/Mancuso . How to Scan the Neck It is imperative that any nodal classification based on CT and MR imaging be reproducible no matter what scanner is utilized and no matter where the imaging study is performed. In order to accomplish this. the following technique is used by many head and neck radiologists and slight variations from it do not effectively influence the nodal levels.

medial. If posterior to the vein. these nodes lie lateral to the level IA nodes and anterior to the back of each submandibular gland These nodes extend from the skull base to the level of the bottom of the body of the hyoid bone. they can be easily visually approxi- Cervical Nodal Classification ORL 2000.Table 1. How to Use the Imaging-Based Classification The classification was designed to be easily and readily usable (fig. They are posterior to the back of the submandibular gland and anterior to the back of the sternocleidomastoid muscle These nodes are level II nodes that lie either anterior. They are also above and medial to the ribs These nodes lie within 2 cm of the skull base and they are medial to the internal carotid arteries Level IIA Level IIB Level III Level IV Level V Level VA Level VB Level VI Level VII Supraclavicular nodes Retropharyngeal nodes The parotid nodes and other superficial nodes are referred to by their anatomic names Reproduced and modified with permission of the Archives of Otolaryngology – Head Neck Surgery [26]. Summary of the imaging-based nodal classification Level I Level IA Level IB Level II These nodes lie above the hyoid bone. They are posterior to the back of the sternocleidomastoid muscle Lower level V nodes extend from the level of the bottom of the cricoid arch to the level of the clavicle as seen on each axial scan. They lie anterior to a line connecting the back of the sternocleidomastoid muscle and the posterior-lateral margin of the anterior scalene muscle. below the mylohyoid muscle and anterior to the back of the submandibular gland (previously classified as the submental and submandibular nodes) These nodes lie between the medial margins of the anterior bellies of the digastric muscles above the hyoid bone and below the mylohyoid muscles (previously known as submental nodes) On each side of the neck. They are also lateral to the carotid arteries (previously known as the low jugular nodes) These nodes lie posterior to the back of the sternocleidomastoid muscle from the skull base to the level of the bottom of the cricoid arch. as when one becomes familiar with the classification. They also lie anterior to the anterior edge of the trapezius muscle Upper level V nodes extend from the skull base to the level of the bottom of the cricoid arch. Each side of the neck should be evaluated separately. they lie posterior to a line connecting the back of the sternocleidomastoid muscle and the posterior-lateral margin of the anterior scalene muscle. the ‘lines’ that are used to define the boundaries of the levels should be ‘drawn’ separately for each side of the neck. the nodes are inseparable from the vein (previously classified as upper internal jugular nodes) These are level II nodes that lie posterior to the internal jugular vein with a fat plane separating the nodes and the vein (previously classified as upper spinal accessory nodes) These nodes extend from the level of the bottom of the body of the hyoid bone to the level of the bottom of the cricoid arch. lateral. That is. They lie anterior to the back of the sternocleidomastoid muscle (previously known as the mid-jugular nodes) These nodes extend from the level of the bottom of the cricoid arch to the level of the clavicle. The lines need not actually be drawn. 1–6 illustrate the classification and table 1 summarizes the classification). or posterior to the internal jugular vein.62:186–198 189 . From the level of the bottom of the cricoid arch to the level of the clavicle as seen on each axial scan. They are posterior to a line connecting the back of the sternocleidomastoid muscle and the posterior-lateral margin of the anterior scalene muscle These nodes lie between the carotid arteries from the level of the bottom of the body of the hyoid bone to the level of the top of the manubrium (previously known as the visceral nodes) These nodes lie between the carotid arteries below the level of the top of the manubrium and above the level of the innominate vein (previously known as the superior mediastinal nodes) These nodes lie at or caudal to the level of the clavicle as seen on each axial scan and lateral to the carotid artery on each side of the neck.

1 190 ORL 2000.62:186–198 Som /Curtin/Mancuso .

such a node would be a level IIA node. Level I nodes are caudal to the mylohyoid muscle and extend down to the bottom of the body of the hyoid bone and to the posterior edge of the submandibular gland. They are located below the bottom of the body of the hyoid bone and above the top of the manubrium. Above the level of the bottom of the cricoid cartilage they are posterior to the back edge of the sternocleidomastoid muscle. they are posterior to the oblique plane described above. if a node is medial to the inner aspect of either internal carotid artery. Level IV nodes extend from the inferior margin of the level III nodes to the upper margin of the clavicle as described in the text. that node is classified as a retropharyngeal node.62:186–198 191 . Level III nodes extend from the inferior margin of the level II nodes to the bottom of the cricoid arch. situated between the carotid arteries. Level II nodes extend from the skull base to the bottom of the body of the hyoid bone and from the posterior edge of the submandibular gland to the posterior edge of the sternocleidomastoid muscle. 1. Fig. Diagram of an axial slice of the neck at the level of C2. The region of the level VII nodes is outlined. Nodes posterior to the back of the sternocleidomastoid muscle are level VA nodes (see text). However. 2. These nodes essentially lie at or anterior to the level of the carotid arteries. lateral and behind the internal jugular vein are level IIA nodes. They also extend back to the posterior edge of the sternocleidomastoid muscle. Diagram of the neck in the lateral projection outlining the landmarks of the imaging-based classification. At this level of the neck. Within 2 cm of the skull base.2 Fig. Between the level of the bottom of the cricoid cartilage and the clavicle. Level V nodes extend from the skull base to the clavicles and are anterior to the front edge of the trapezius muscle. Level VI nodes are not indicated on the diagram. Their posterior margin is an oblique plane that extends from the posterior lateral aspect of the anterior scalene muscle (dotted line) to the posterior edge of the sternocleidomastoid muscle. The internal carotid artery (C) and internal jugular vein (J) are identified on each side. there rarely are nodes posterior to (J) and anterior to back edge of the sternocleidomastoid muscle. extending from the top of the manubrium down to the innominate vein. Nodes anterior. This plane is represented by oblique lines in the figure. Cervical Nodal Classification ORL 2000.

Level IA nodes are central to the medial margin of the anterior belly of the each digastric muscle. 3. Level IIB nodes are posterior to the internal jugular vein. C = the internal carotid artery. lateral. the nodes in the lower lateral neck should be classified as being in either level IV or lev- 192 ORL 2000. the side of the line on which the majority of the nodal cross-sectional area lies is the level in which the lymph node should be classi- fied. That is. Level VA nodes are posterior to the back of the sternocleidomastoid muscle. J = the internal jugular vein. and SMG = the submandibular gland. or medial to the internal jugular vein or posterior to this vein but touching it. without touching it. Diagram of an axial slice of the neck at a level just caudal to the body of the mandible. if the scan level is cranial to any portion of the clavicle. mated or a straight-line guide or ruler can be placed on the film or monitor. The supraclavicular fossa is defined on each axial scan whenever any portion of the clavicle is identified on one side of the neck. DG = The anterior belly of the digastric muscle. and anterior to the back of the sternocleidomastoid muscle.62:186–198 Som /Curtin/Mancuso . Level IB nodes are lateral to level IA nodes and anterior to the back edge of the submandibular gland. Whenever a lymph node is transected by one of the ‘lines’ that define the levels.Fig. Level IIA nodes are anterior.

1–3). such nodes are classified as supraclavicular nodes (fig. above the hyoid bone. Level IB represents the nodes which lie below the mylohyoid muscle. Thus. 1. el VB. or IV nodes. 6). and anterior to a transverse line drawn on each axial image tangent to the posterior surface of the submandibular gland on each side of the neck (previously classified as submandibular nodes) (fig. The Imaging-Based Classification Level I includes all of the nodes above the hyoid bone. The clinically important internal jugular nodes described by Rouvière [3] are now classified as level II. but lie anterior to the back of the sternocleidomastoid muscle. below the mylohyoid muscles. Once any portion of the clavicle is seen on the scan. at the lower level of the bony margin of the jugular fossa. Level III nodes are anterior and lateral to the common carotid artery (C) and the internal jugular vein (J). Level IA represents those nodes which lie between the medial margins of the anterior bellies of the digastric muscles. above the hyoid bone and below the mylohyoid muscle (previously classified as submental nodes) (fig. Level II nodes lie anterior to a transverse line drawn on each axial image through the posterior edge of the sternocleidomastoid Cervical Nodal Classification ORL 2000. level I nodes include the previously classified submental and subman- dibular nodes. The silhouette of the thyroid cartilage is seen anteriorly. depending on their location with reference to the axial scan levels of the bottom of the body of the hyoid bone and the bottom of the arch (anterior rim) of the cricoid cartilage.62:186–198 193 . and anterior to a transverse line drawn on each axial image through the posterior edge of the submandibular gland (fig. If nodes are seen below the level of the clavicle and lateral to the ribs. posterior and lateral to the medial edge of the anterior belly of the digastric muscle. 3). to the level of the lower body of the hyoid bone (fig. Level I nodes can be subclassified into levels IA and IB. III. Diagram of an axial slice of the neck just below the level of the bottom of the body of the hyoid bone. they are axillary nodes (fig. 3). 4. 3).Fig. Level VA nodes are posterior to the back of the sternocleidomastoid muscle. Level II extends from the skull base. 7).

Fig. 5. Diagram of an axial slice of the neck just below the level of the bottom of the cricoid arch. The trachea (T) is seen anteriorly in the midline. C = The common carotid artery, J = the internal jugular vein, SCM = the sternocleidomastoid muscle, and AS = the anterior scalene muscle. Level IV nodes are lateral to the medial margin of the

common carotid artery and anteromedial to a line (oblique dotted line) drawn from the lateral aspect of the anterior scalene muscle to the posterior margin of the sternocleidomastoid muscle. Level VB nodes are posterolateral to this line. Level VI nodes are medial to the medial margin (vertical dotted line) of the common carotid arteries.

muscle and lie posterior to a transverse line drawn on each axial scan through the posterior edge of the submandibular gland. If a node situated within 2 cm of the skull base lies anterior, lateral or posterior to the carotid sheath, it is classified as a level II node. If the node lies medial to the internal carotid artery, it is classified as a retropharyngeal node (fig. 2). Caudal to 2 cm below the skull base, level II nodes can lie anterior, lateral, medial and posterior to the internal jugular vein. Level II nodes can be subclassified into levels IIA and IIB. Level IIA nodes are level II nodes that lie posterior to the internal jugular vein and are inseparable from the vein or they are nodes that lie anterior, lateral or medial to the vein (previously classified as upper internal jugular nodes) (fig. 2, 3).

Level IIB nodes are level II nodes that lie posterior to the internal jugular vein and have a fat plane separating the nodes and the vein (previously classified as upper spinal accessary nodes) (fig. 3). Level III nodes lie between the level of the lower body of the hyoid bone and the level of the lower margin of the cricoid cartilage arch (fig. 1, 4). These nodes lie anterior to a transverse line drawn on each axial image through the posterior edge of the sternocleidomastoid muscle. Level III nodes also lie lateral to the medial margin of either the common carotid artery or the internal carotid artery. On each side of the neck, the medial margin of these arteries separates level III nodes (which are lateral) from level VI nodes (which are medial). Level III nodes were previously known as the mid-jugular nodes.

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Fig. 6. Diagram of an axial slice of the neck just below the level of the bottom of the thyroid gland. The trachea (T) is seen anteriorly in the midline. C = The common carotid artery, J = the internal jugular vein, and AS = the anterior scalene muscle. As in figure 5, level IV nodes are seen lateral to the medial margins of the common carotid arteries and anteromedial to an oblique line drawn from the lateral

aspect of the anterior scalene muscle to the posterior margin of the sternocleidomastoid muscle. Level V nodes are posterolateral to these oblique lines. In this figure, both of the ‘level V’ nodes are classified as supraclavicular nodes because portions of the clavicle are seen on each side.

Level IV nodes lie between the level of the lower margin of the cricoid cartilage arch and the level of the clavicle on each side as seen on each axial scan. These nodes lie anterior and medial to an oblique line drawn through the posterior edge of the sternocleidomastoid muscle and the lateral posterior edge of the anterior scalene muscle on each axial image (fig. 1, 5, 6). The medial aspect of the common carotid artery is the landmark which separates level IV nodes (which are lateral) from level VI nodes (which are medial) to this artery (fig. 5, 6). Level IV nodes were previously known as the low jugular nodes. Level V nodes extend from the skull base, at the posterior border of the attachment of the sternocleidomastoid muscle, to the level of the clavicle as seen on each axial

scan (fig. 1–5). Level V nodes all lie anterior to a transverse line drawn on each axial scan through the anterior edge of the trapezius muscle. Between the levels of the skull base and the bottom of the cricoid arch, these nodes are situated posterior to a transverse line drawn on each axial scan through the posterior edge of the sternocleidomastoid muscle (fig. 1, 2–4). Between the axial level of the bottom of the cricoid arch and the level of the clavicle, level V nodes lie posterior and lateral to an oblique line through the posterior edge of the sternocleidomastoid muscle and the lateral posterior edge of the anterior scalene muscle (fig. 5, 6). The level V nodes can be subdivided into VA and VB nodes.

Cervical Nodal Classification

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Fig. 7. Diagram of an axial slice of the neck just below the level of the top of the manubrium which is seen anteriorly in the midline. LBv = the left brachiocephalic vein, RBv = the right brachiocephalic vein, BA = brachial artery, LC = left carotid artery, LS = left subclavian artery, and T = trachea. Level VII nodes are caudal to the top of the manubrium. Axillary nodes are caudal to the clavicle and lateral to the ribs.

Level VA (upper level V) nodes lie between the skull base and the level of the lower margin of the cricoid cartilage arch. They are behind the posterior edge of the sternocleidomastoid muscle (fig. 1–4). Level VB (lower level V) nodes on each side lie between the level of the lower margin of the cricoid cartilage arch and the level of the clavicle as seen on each axial scan. They are behind an oblique line through the posterior

edge of the sternocleidomastoid muscle and the lateral posterior edge of the anterior scalene muscle (fig. 5). Level VI nodes lie inferior to the lower body of the hyoid bone, superior to the top of the manubrium, and between the medial margins of the left and right common carotid arteries or the internal carotid arteries. They are the visceral nodes (fig. 5, 6).

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Head Neck Surg 1987. Henson DE. extending down to the lower internal jugular nodes and the supraclavicular nodes [32]. Ann Otol Rhinol Laryngol 1930. 8 Beahrs OH. Hutter RVP. 5 Shah JP. 100:169–176. etc. vol 2. Thus. level VB are usually not involved. Strong E. parotid. 1909. are post cricoid and upper cervical esophageal cancers which may metastasize to the paratracheal and superior mediastinal nodes [33]. In cases of glottic and subglottic cancers. 30]. 2 Trotter HA: The surgical anatomy of the lymphatics of the head and neck.11: 25–33. Goepfert H: Standardization of neck dissection nomenclature. ed 2.29:1446–1449.39:384–397. That is. level VI and VII nodes are at risk in these cancers. Clin Bull 1981. in Tobias MJ (translator): Anatomy of the Human Lymphatic System. These superior mediastinal nodes extend caudally to the level of the innominate vein. for the line drawings that he created for this paper. Otolaryngol Head Neck Surg 1989. Cervical Nodal Classification ORL 2000. occipital. it is easy to apply the classification when describing lymph node metastases from laryngeal cancer. nodes in levels IV. Bull NY Acad Med 1985. and the other superficial nodes. 9 Medina JE: A rational classification of neck dissections.10:75–77.61:629–637. Ogura [27] found that positive nodes from laryngeal cancers can occur in all triangles of the neck except in the submental triangle. Neck dissection: Current status and future possibilities. In keeping consistency with the prior classifications. References 1 Poirer P. Translating this into the imaging-based nodal classification means that all nodal levels except level IA are at risk [28]. CT and MR imaging form an integral part of the assessment of the majority of cases of head and neck cancer. facial. Edwards Bros. fasc 4. affected. Philadelphia. while level IIB (and rarely level VA nodes) may be affected in supraglottic cancers. however. there is some discrepancy in the literature regarding metastasis of these tumors to the posterior triangle nodes [29. 6 Spiro RH: The management of neck nodes in head and neck cancer: A surgeon’s view. 3 Rouvière H: Lymphatic system of the head and neck. Although submandibular nodes (level IB) may uncommonly be involved in advanced supraglottic cancers. and often virtually inseparable from the larynx. Cancer 1972. The Classification and Laryngeal Cancer Metastasis Conclusions As the imaging-based nodal classification encompasses all of the cervical lymph nodes. Acknowledgement The authors want to thank Bradley Delman. 1988. 4 Lindberg R: Distribution of cervical lymph node metastases from squamous cell carcinoma of the upper respiratory and digestive tracts. VI and the supraclavicular nodes may be involved. 7). the prelaryngeal nodes and occasionally the pretracheal nodes may be Today. it is most commonly to the nodes in the superior portion of this nodal chain [31]. It is also hoped that this classification can add precision and reproducibility to the nodal localization required in the accumulation of data in planned multi-institutional studies involving laryngeal cancer [34]. In general. supraglottic cancers metastasize to levels II and III. the following nodal groups continue to be referred by their anatomic names: supraclavicular. 7 Suen JY. Ann Arbor. This new classification provides added precision and reproducibility to nodal localization and it is hoped that imaging will now become a necessary component of patient classification and staging. retropharyngeal. MD. The imaging findings clearly compliment the physical examination and the imaging-based classification provides the radiologist with clinically acceptable guidelines with which to classify the cervical nodes and communicate these findings to the clinicians in a mutually acceptable way. 1938. III and IV). When the spinal accessory nodes are involved.Level VII nodes lie caudal to the top of the manubrium in the superior mediastinum. Vikram B: Surgical grand rounds. ed 3. postauricular. Charpy A: Traité d’anatomie humaine. Converting this nodal nomenclature into that of the imaging-based classification means that in cases of glottic and subglottic cancers. Related to the larynx. Paris. Lippincott.62:186–198 197 . Meyers MH: Manual for Staging Cancer. between the medial margins of the left and right common carotid arteries (fig. Spiro RH. this appears to occur only in cases with extensive internal jugular chain disease (levels II.

65:867–926. Nojek AM. 26 Som PM. variants of normal.31:639–655. 14 Mancuso AA. 1993. Mancuso AA. Schaefer SD: Computed tomographic evaluation of regional lymph node involvement in cancer of the oral cavity and oropharynx. Rinaldo A: Level I dissection for laryngeal and hypopharyngeal cancer: Is it indicated? J Laryngol Otol 1998. The Department of Veterans Affairs Laryngeal Cancer Study Group: Regional metastases in patients with advanced laryngeal cancer. vol. Ishwaran H.158:961–969. Krause CJ. 1972. University of California. Herter FP. 24 Som PM: Detection of metastasis in cervical lymph nodes: CT and MR criteria and differential diagnosis. 136:381–385. Mafee M.148:715–723. 22 Close LG.62:186–198 Som /Curtin/Mancuso . Yarbro JW (eds): Manual for Staging of Cancer. Saunders. 1985. van der Waal I. 21 Stevens MH. Radiology 1987. Radiology 1998. Meyer CJ. Johnson LP. Hutter RVP. Hart AAM. Arch Otolaryngol Head Neck Surg 1999. 12 American Joint Committee on Cancer: Fleming ID. Caudry J. 13 Robbins KT: Classification of neck dissection: Current concepts and future considerations. Hanafee WN: CT of cervical lymph node cancer. O’Sullivan B. ed 5. Arch Otolaryngol Head Neck Surg 1984. Castelijns JA. Weinberg LA (eds): The lymphatics in cancer. 32 Berman JM: Surgical anatomy of the larynx. American Academy of Otolaryngology-Head and Neck Surgery Foundation. Head Neck 1989. Valk J. Hilgers FJM. 1997. University of Amsterdam. Radiology 1983. Henson DE. Fisher SG. Laryngoscope 1978. in Margulis AF. Davis RK. Mosby-Year Book. 25 Lingeman RE: Surgical anatomy. Stevens MH: Computed tomography of cervical and retropharyngeal lymph nodes: Normal anatomy. Kennedy BJ.177:379–384. Philadelphia. Cooper JS. Alexandria. pp 59–230. Otolaryngol Clin North Am 1998. 28 Ferlito A. 198 ORL 2000. pp 1–31. 30 Moe K. pp 1–152. and application in staging head and neck cancer. Arch Otolaryngol Head Neck Surg 1987. 27 Ogura JH: Surgical pathology of cancer of the larynx. Mancuso AA.112:438–440. Hong WK. Harnsberger R.165:593–600. Gooding CA (eds): Diagnostic Radiology. Balm AJM. Utrecht. 23 Feinmesser R. Schuller DE (eds): Otolaryngology – Head and Neck Surgery. Philadelphia. Birt BD: Metastatic neck disease: A clinical/radiographic/pathologic correlative study. Arch Otolaryngol Head Neck Surg 1985. Part II. St Louis. Stel HV. Philadelphia. 20 Friedman M. Freeman JL. Head Neck 1997. Harker LA. AJR 1981. Merkel M. Grybauskar V. Vuitch MF.122:644– 648. 11 Van den Brekel MWM: Assessment of Lymph Node Metastases in the Neck: A Radiological and Histopathological Study. 33 Feind CR: The head and neck. 1992. 29 Gregor RT. Muraki AS. Murphy GP.19:650–658.207:123–130.105:845–850. 34 Weymuller EA: Clinical staging and operative reporting for multi-institutional trials in head and neck squamous cell carcinoma. AJR 1992. 19 van den Brekel MWM. Curtin HD. Saunders. Harnsberger HR. Rice D. Laryngoscope 1955. Sobin LH. Wolf GT. Fredrickson JM.111: 735–739. Arch Otolaryngol Head Neck Surg 1996.113:1307– 1310. Oei SS. in Bailey BJ. in Haagensen CD. Mancuso AA: An imaging-based classification for the cervical nodes designed as an adjunct to recent clinically based nodal classifications. 18 Mancuso AA. Krause CJ: Spinal accessory lymph nodes: A prospective study of metastatic involvement. Parkin JL: Computed tomography of cervical lymph nodes: Staging and management of head and neck cancer. Maceri D. Ann Otol Rhinol Laryngol 1996. Biller HF (eds): Surgery of the Larynx. 1985.10 Robbins KT: Pocket Guide to Neck Dissection and TNM Staging of Head and Neck Cancer. 16 Som PM: Lymph nodes of the neck. 88:439–449. Lippincott-Raven. Reisch J. Snow GB: Cervical lymph node metastasis: Assessment of radiologic criteria. 1991. 31 Schuller DE.110: 443–447. Slanetz CA Jr. Keus RB: Management of cervical metastases in supraglottic cancer. in Cummings CW. Radiology 1990. Bellity P. McNeil BJ: Comparison of CT and MR imaging in staging of neck metastases. Platz CE. Feind CR. 17 Curtin HD. 2.11:309–317. Daryl J. 15 Som PM: An approach to tumors of the head and neck: The role of computed tomography in the staging and follow-up of patients. Dalley RW.125:388–396. Shelton VK. Skolnik E: Metastatic neck disease: Evaluation by computed tomography. Nauta JJP. San Francisco.

Snyderman et al. Accurate determination of lymph node involvement is therefore a prerequisite for individualized therapy in patients with squamous cell carcinoma of the larynx.7%) and ultrasound (72.ORL 2000. staging was based completely on clinical examination results. Lymphatic Drainage of the Larynx According to the pioneering work of Pressman et al. the accuracy of computed tomography scanning (84. Lutherplatz 40 D–47805 Krefeld (Germany) Tel. has been documented in a series of studies.com/journals/orl Prof. The inaccuracy of clinical examination. [1] retrospectively reviewed the data on a group of patients with squamous cell carcinoma of the supraglottic larynx. computed tomography. Clinical palpation of the neck is not very accurate and the role of imaging techniques such as ultrasound.5%). According to our investigations and review of the literature. The rapid advances in imaging technology introduced in the past decade appear to have affected the physician’s ability to identify metastatic disease in the head and neck. Karger AG.karger. Germany Key Words Laryngeal cancer W Lymph node metastases W Ultrasound W Computed tomography W Magnetic resonance imaging W Positron emission tomography Introduction Abstract Squamous cell carcinoma is the most common malignant neoplasm of the larynx. 17% of patients judged clinically to have a single cervical metastasis !3 cm in diameter and 7% of patients judged to have cervical metastases staged N2 or N3.com © 2000 S. Copyright © 2000 S. +49 2151 322501. Technical University of Munich. One of the most important influences on prognosis is the presence of metastases to the cervical lymph nodes. Klinikum Krefeld. Fax +49 2151 322011 . Basel Cervical lymph node staging in patients with laryngeal cancer remains a major concern for all head and neck cancer surgeons. Conversely. had no evidence of histologic metastases.62:199–203 Diagnostic Procedures for Detection of Lymph Node Metastases in Cancer of the Larynx Reinhardt J. magnetic resonance imaging and positron emission tomography is being applied in order to improve upon the results of clinical investigation alone. b Department of Otorhinolaryngology-Head and Neck Surgery and c Department of Radiology. In the past.50/0 Accessible online at: www. Klinikum rechts der Isar.ch www. Forty-one percent (20 out of 49 patients) with no palpable adenopathy were found to have metastatic disease on histologic evaluation of neck-dissection specimens. Dr. [2] who injected dyes and radioactive isotopes into different sites within the larynx to demonstrate submucosal ABC Fax + 41 61 306 12 34 E-Mail karger@karger. Reinhardt J. Basel 0301–1569/00/0624–0199$17.9%) and magnetic resonance imaging (85%) was superior to palpation (69. ultrasound-guided fine needle aspiration cytology. Ultrasound-guided fine needle aspiration cytology showed an accuracy of 89% and was in the same range with positron emission tomography (90. color Doppler ultrasound. Munich. however. Kau Direktor der Hals-Nasen-Ohren Klinik Klinikum Krefeld.karger. Karger AG.7%). Kau a Christoph Alexiou b Herbert Stimmer c Wolfgang Arnold b a Department of Otorhinolaryngology-Head and Neck Surgery.

none 1 6 cm in greatest dimension. Thus. glottic carcinomas are much less likely to metastasize than are supraglottic lesions [3]. Clinical Palpation Diagnosis of Lymph Node Metastases For an appropriate. although the majori- 200 ORL 2000. 1 3 cm but not 1 6 cm in greatest dimension Metastasis in multiple ipsilateral lymph nodes. laryngeal cartilage invasion or carotid encasement by tumor represent some of the indications for using CT imaging as a preoperative staging tool. X3 cm in greatest dimension Metastasis in a single ipsilateral lymph node. CT revealed an accuracy of 84. Som et al. or in bilateral or contralateral lymph nodes. base of skull invasion. CT is clearly more useful than US for defining the extent of primary cancers of the upper aerodigestive tract. 13 cm but not 1 6 cm in greatest dimension. The ability to detect bony erosion of the mandible. The site of the primary tumor within the larynx is an important factor affecting the frequency and the pattern of lymph node metastases to the neck. Micrometastases are difficult to evaluate and their reported incidence depends on the skill and commitment of the pathologist and of the techniques involved (conventional pathologic methods. none 1 6 cm in greatest dimension Metastasis in bilateral or contralateral lymph nodes. an improvement in both sensitivity (so that patients who require treatment to the neck are selected to receive it) and specificity (so that patients who do not require treatment to the neck are spared the unnecessary treatment and morbidity) are desirable. Drainage into the cervical lymph nodes is essentially ipsilateral. ryngology. [5] integrated anatomical imaging criteria with the two most commonly used nodal classifications: those of the American Academy of Otola- CT (B contrast medium) is generally considered superior to palpation [11. it is of utmost importance to determine the status of the regional lymph nodes in the neck. none 1 6 cm in greatest dimension Metastasis in a lymph node 1 6 cm in greatest dimension Palpation of the neck lymph nodes has the advantage of being both easy and inexpensive. it is generally accepted that this is not very accurate. if the efferent flow to the ipsilateral side is obstructed (as it could be by metastatic involvement). 12]. CT is superior to US in detecting involved retropharyngeal nodes. Computed Tomography Note: Midline nodes are considered ipsilateral nodes. semiserial sections.62:199–203 Kau/Alexiou/Stimmer/Arnold . but it is inaccurate and of low sensitivity. Furthermore. Although clinical palpation of the head and neck is still widely used for staging of the neck.compartments of the larynx and their lymphatic drainage.7%) [13]. there appear to be two lymphatic drainage systems: (1) one superficial intramucosal system forming an interconnecting web spreading over the entire mucosal surface without limitation to the side and (2) a deep submucosal system forming an independent network with no communications between the right and left sides. size 11 cm. computed tomography (CT).7%) and US alone (72. Head and Neck Surgery [6] and those of the American Joint Committee on Cancer (AJCC) [7]. then contralateral flow may occur [2. none 1 6 cm in greatest dimension Metastasis in a single ipsilateral lymph node. Because the majority of patients with head and neck malignancies presently undergo sectional imaging prior to treatment planning. immunohistochemistry. More recently. a necrotic center. magnetic resonance imaging (MRI). 3]. color Doppler ultrasound (CDUS) and positron emission tomography (PET) have also been used to improve the results of clinical staging. rim enhancement with contrast or grouping of three or more lymph nodes in an area of high-risk nodal drainage.9% in terms of screening the N0 neck compared with palpation (69. In a collective of 25 patients and 33 performed neck dissections. However. definitive treatment to be planned for any laryngeal tumor. Typical criteria for considering a lymph node suspicious for metastatic disease included a round shape. molecular biology) [8– 10]. or in multiple ipsilateral lymph nodes. ultrasound (US) and ultrasound-guided fine needle aspiration cytology (US-guided FNAC). The International Union Against Cancer (UICC) TNM classification defines the regional lymph node (N) categories as follows [4]: Nx N0 N1 N2 N2a N2b N2c N3 Regional lymph nodes cannot be assessed No regional lymph nodes Metastasis in a single ipsilateral lymph node. Since treatment modalities and prognostic information are also based on staging of the presence of neck nodes.

Extracapsular spread is correlated with a poorly defined nodal border that may or may not enhance and is typically associated with obliteration of fat planes. = thyroid gland. Combined with US-guided FNAC the accuracy was 89%.7 mm (metastasis of a laryngeal cancer). Magnetic Resonance Imaging MRI (B contrast medium) has a better soft tissue contrast resolution than CT. who suffered from a HNSCC that US alone never exceeded the accuracy of 70% [17]. irradiation or infection can also cause similar findings [16]. like radiation and dental artifacts. In another study. Central necrosis and extracapsular spread also have characteristics on CT and MRI that can be mimicked by other pathological processes. which can show the benign or malignant nature of such lymph node preoperatively. specificity 67%). Nodes were interpreted as malignant on MRI if central necrosis was depicted. RF = A hypoechogenic mass with a diameter of 18. On these patients. GL. Ultrasound and Ultrasound-Guided Fine Needle Aspiration Cytology Although US is able to detect lymph node metastases (fig.ty of tumors with specific drainage to this area would usually require a CT for staging of the primary tumor. US image of the neck (right side). MSCL = sternocleidomastoid muscle. Lymph nodes near the mandible are sometimes difficult to visualize on US due to the ‘shadow’ cast by the mandible. [14] investigated retrospectively the sensitivity and specificity of MRI vs. 1). These characteristics usually indicate metastatic disease. bleeding. Van den Brekel et al. ACC = carotid artery (common). which revealed a sensitivity of 65% and a specificity of 47% [15]. They examined 100 patients with head and neck cancer. compared with CT scans. The accuracy of USguided FNAC was significantly better than of any other technique used in this investigation [18]. who underwent surgery. Fig. in a majority of patients the accuracy of this technique is low. palpation in detection of cervical lymph node metastases. can be avoided by MRI.THY. MRI was also superior to CT in lymph node detection on head and neck squamous cell carcinomas (HNSCC) in a study group investigated at our university hospital. [17] found in a study with 107 patients.5 ! 15. 132 patients with HNSCC were examined radiologically before undergoing a total of 180 neck dissections as part of their treatment. 136 neck dissections were performed (64 patients had unilateral. 8 or 9 mm for all other levels) is seen in the lymph node drainage region of the tumor.) during this invasive investigation. van den Brekel et al. 36 patients bilateral neck dissections). In a large study group. minimal axial diameter exceeds 11 mm in the subdigastric level (II) or 10 mm in other lymph node levels (I. VJI = internal jugular vein.62:199–203 201 . IV. Contrast-enhanced MRI showed a sensitivity of 81% and specificity of 88% and was superior to palpation (sensitivity 68%. who had neck dissection (34 ipsilateral.e. but it should kept in mind that especially false benign cytologic findings are possible and that there is a risk of injury (i. Beside these results it should be noted that US is a dynamic investigation. III. 36 bilateral). 1. Central necrosis usually appears as a central area of low attenuation with a surrounding irregular wall but can be simulated by abscesses or cysts and spontaneous lymph node necrosis. Lymph Node Metastases ORL 2000. CT. V) and the presence of grouping of three or more borderline nodes (minimal axial diameter 9 or 10 mm for level II. MRI had a sensitivity of 88% and specificity of 40%. US-guided FNAC is the only method among the techniques described above. but prior surgery. Nodes in this location can also be difficult to evaluate on CT due to the effects of dental amalgams. MRI and/or CT scan were previously performed on 70 patients with HNSCC. US and MRI proved to be significantly more accurate than palpation for cervical lymph node staging. nerve palsy etc. Peripheral enhancement of contrast medium is often seen in lymph node metastases and some problems of CT. highly operator-dependent and a learning curve exists for even experienced ultrasonographer.

cervical spine or brachial plexus. respectively [15]. However. In a prospective study. Despite the high accuracy of the invasive US-guided FNAC. whereas nodal metastases had mainly peripherally located flow [19]. which is suitable for routine clinical use. showing color signals in the center as well as in the nodal periphery [19]. They are also valuable tools in defining the relation of metastases to critical structures such as carotid artery. there remains an uncertainty of false results (110%). It has been proven that head and neck carcinomas have high glycolytic activity and increased FDG uptake (fig. however. upper mediastinal and paratracheal lymph nodes. 202 ORL 2000. 2) [21]. Fluorine-18 fluorodeoxyglucose (18F-FDG) is a At present. Differentiation between reactive enlargement of lymph nodes and tumor-infiltrated nodes may be difficult on the basis of radiological criteria [16]. the use in a routine clinical setting is at present not practicable. imaging procedures like CT and MRI do have clearer roles in evaluating lymph nodes that are not easily accessible to clinical and US examinations such as the retropharyngeal. B sagittal. We could demonstrate in a nonselected patient group that a short PET protocol. Nonattenuation corrected PET images of a patient with metastatic lymph nodes on the left side (A transversal. is superior to morphologic procedures (CT or MRI) for lymph node staging of HNSCCs [15]. since this investigation is expensive and limited to certain locations. Color Doppler Ultrasound Color flow imaging allows simultaneous two-dimensional imaging and evaluation of blood flow. Perfusional patterns may provide therefore useful additional information in the differential diagnosis of cervical lymphadenopathy. Furthermore.Fig. PET demonstrated one previously unknown metastatic lymph node contralateral (C) which has not been reported as suspicious on MRI. based upon the increased glycolysis that is associated with malignancy as compared with normal tissues. Reactively enlarged lymph nodes showed characteristically intense hilar perfusion. Nevertheless. CDUS is a sensitive noninvasive imaging technique capable of detecting vessels as small as those found in lymph nodes. we are unable to establish lymph node involvement accurately using current available noninvasive methods. regional lymph node involvement and their relationship to adjacent anatomical structures. PET investigation revealed a higher sensitivity (87%) and specificity (94%) compared with CT values of 65 and 47% and MRI values of 88 and 40%. PET has also a high accuracy in detecting malignant lymph nodes. C coronal). The primary tumor has not been found by morphologic procedures or by PET. in experimental studies the value of US contrast medium is ongoing investigated to improve the accuracy of US and to give additional information about tumor patterns [20].62:199–203 Kau/Alexiou/Stimmer/Arnold . Lymph nodes invaded by malignant lymphoma were highly perfused. marker of tumor viability. 63 untreated patients with palpable cervical lymph node enlargement underwent examination with CDUS. 2. Conclusions Positron Emission Tomography Imaging procedures as described above are used for the detection and localization of the primary tumor.

Croll GJ. Weisberger EC. 16 Van den Brekel MWM. Lymph Node Metastases ORL 2000. Choi Y. Monell C: Anatomical studies related to the dissemination of cancer of the larynx. Ultrasound Med Biol 1999. Myers EN. 12 Lenz M. Stel HV. Radpour S: Comparison of ultrasound-fine needle aspiration and computed tomography in patients undergoing elective neck dissection. 1997.12:109– 113. Snow GB: Cervical lymph node metastasis: Assessment of radiological criteria. Snow GB: Magnetic resonance imaging vs. Bailet J. 17 Van den Brekel MWM. Silver CE. Wittekind Ch (eds): TNM Classification of Malignant Tumours. 20 Brown JM.162:362– 366. Arnold W: Lymph node detection of head and neck squamous cell carcinomas by positron emission tomography with 18 F-fluorodeoxyglucose in a routine clinical setting. Cooper JS.125:388–396. Snow GB: Modern imaging techniques and ultrasound-guided aspiration cytology for the assessment of neck node metastases: A prospective comparative study. for supporting this study. Arch Otolaryngol Head Neck Surg 1999. Simon MD.120:344–349.25: 1213–1219. it must be considered that in these times of cost containment the routine use of imaging studies may not be justified in all laryngeal cancer patients. Golding RP. 2 Pressman JJ. Kersting-Sommerhoff B. Laubenbacher C. Am J Surg 1991. 21 Jabour BA. van der Waal. Meyer CJL. Castelijns JA. Chaiken L.117:663–673. Persky MS.19:604– 610. 3 Welsh LW. 9 Ferlito A. Schramm VL Jr. Arch Otolaryngol Head Neck Surg 1991. Kenzel P. Sessions RB.64:628–638. van der Waal I. Felix R: Differential diagnosis of lymph node lesions: A semiquantitative approach with colour Doppler ultrasound.250: 11–17. Arch Otolaryngol Head Neck Surg 1991. Henson DE. WileyLiss. Radiology 1990. 4 International Union Against Cancer: Sobin LH. Valk J. Stel HV. Mancuso AA: An imaging-based classification for the cervical nodes designed as an adjunct to recent clinically based nodal classifications. 1997. Meyer CJ. Trans Am Acad Ophthalmol Otolaryngol 1960. Arch Otolaryngol Head Neck Surg 1999. 13 Righi PD. Thiel T. Nauta JJ. Caldemeyer KS. Gross M: Diagnosis and treatment of the N0 neck in carcinomas of the upper aerodigestive tract: Current status of diagnostic procedures. Sobin LH. Acta Otolaryngol (Stockh) 2000. Maddahi J. Kennedy BJ. Mueffelmann M. Rege SD. Böck JC. Meyer CJLM. Schwaiger M. 8 Ferlito A.62:199–203 203 . Yarbro JW (eds): Manual for Staging of Cancer ed 5.With this in mind. Philadelphia. 6 Robbins KT. Soong JC. Cancer 1985. Head Neck 1997. Radiology 1993.71:828–833. Rizzo TA: Internal anatomy of the larynx and the spread of cancer.108:1185–1189. Lippincott-Raven. Murphy GP. Devaney KO: Pathologic detection of occult metastases in regional lymph nodes in patients with head and neck cancer. Alderman J. Castelijns JA. 5 Som PM.117:601–605.250:432–438. References 1 Snyderman NL. Golding RP. ORL J Otorhinolaryngol Relat Spec 2000. Wolfe GT. 10 Devaney SL.186:27–35. Thearle P: Extracapsular spread of carcinoma in cervical lymph nodes. O’Sullivan B. New-York. Castelijns JA. Eur Arch Otorhinolaryngol 1993. Ferlito A. Stel HV. ed 5. Hoh CK. Greener Y: Contrastenhanced ultrasound for guidance of local tumor ablation. Lufkin RB. Alexiou Ch. The examination of patients with laryngeal cancer should be performed ‘stepwise’ and in an individualized manner. Devaney SL. Heller KS: Computed tomography of the clinically negative neck. Valk J. Ball VA. 7 American Joint Committee on Cancer: Fleming ID. Carbone A: Micrometastases: Have they an impact on prognosis? Ann Otol Rhinol Laryngol 1999. 18 Van den Brekel MWM. Munich. 19 Steinkamp HJ.177:379–384. Impact upon survival in patients with carcinoma of the supraglottic larynx. Kopecky KK. Devaney KO. Rinaldo A. Castelijns JA. 14 Van den Brekel MWM.125:1322–1328. Werner M. 15 Kau RJ. 11 Stern WBR. Rinaldo A: False negative conventional histology of lymph nodes in patients with head and neck cancer. Bedetti CD. Chaloupka J. Levine PA. Head Neck 1990. Rinaldo A. Hutter RPV.98:228–234. Taylor KJ. Curtin HD. Zeifer BA. palpation of cervical lymph node metastasis.56:1597–1599. et al: Extracranial head and neck: PET imaging with 2-[18 F] fluoro-2deoxy-D-glucose and MR imaging correlation. Stel HV. Ann Otol Rhinol Laryngol 1989. Medina JE. Acknowledgement We thank the Margarete Ammon Foundation. Croll GA. Eur Arch Otorhinolaryngol 1993. Br J Radiol 1998. Welsh JJ. Johnson JT. Snow GB: Lymph node staging in patients with clinically negative neck examinations by ultrasound and ultrasound-guided aspiration cytology.62:112–114. Pruet CW: Standardizing neck dissection terminolgy: Official report of the Academy’s Committee for Head and Neck Surgery and Oncology. Hanafee WN. QuedensCase C.

Copyright © 2000 S. A robust surgical literature discusses the relative merits and demerits of a host of techniques for cervical node dissection – particularly in the patient with either low stage disease or a clinically negative neck [11–22]. it appears as though neither clinical examination (including even intraoperative ABC Fax + 41 61 306 12 34 E-Mail karger@karger. At present. University of Udine. rather than after the fact. USA. Basel 0301–1569/00/0624–0204$17. Karger AG. Basel Abstract Cancer of the larynx is a common problem in a head and neck oncological surgical practice. patients are best served when these Introduction Surgical therapy is an essential element in the comprehensive treatment of many patients with laryngeal cancer [1. Ann Arbor.ch www.62:204–211 The Pathology of Neck Dissection in Cancer of the Larynx Stephanie L. Issues to be settled among pathologists and surgeons include – How precise an anatomic dissection of the specimen is called for? What histological features of the specimen will be of most use to the clinicians who are devising a course of postoperative therapy for the patient? What sorts of methods are needed to identify the maximum number of micrometastases which may be lurking within the lymph nodes of the specimen? Is there a role for routine application of special techniques – such as immunohistochemistry or molecular biology – in the analysis of these specimens? While the answers to these questions are likely to vary somewhat from one center to another. Devaney Department of Pathology.50/0 Accessible online at: www. Devaney a a Department b Department of Pathology.com/journals/orl Stephanie L. Mich. Fax +1 517 780 7295. MI 48109-0054 (USA) Tel. as such. the routine practice of cervical lymph node dissection as an adjunct to treatment of the primary tumor has likewise assumed an essential role in the care of many of these patients [3–10]. E-Mail devaney@umich. Devaney a Alfio Ferlito b Alessandra Rinaldo b Kenneth O. University of Michigan 1500 E Medical Center Drive Ann Arbor.ORL 2000. Italy Key Words Cervical node metastases W Pathology W Specimen processing questions are discussed amongst the respective physicians before surgical procedures are undertaken.com © 2000 S. and of Otolaryngology-Head and Neck Surgery. Karger AG.karger. At the same time. 2]. University of Michigan.karger. pathology departments supporting such surgical practices will examine cervical lymph node dissection specimens with some frequency. the radiological literature is filled with studies of the efficacy of imaging methods at detecting occult cervical node disease [23–29].. As understanding of the modes of spread of primary laryngeal cancer has crystallized.edu . +1 734 997 0853.

it may be necessary for the surgeon and the pathologist to collaborate on the dissection of the specimen. from inferior mandible to the clavicle. Before turning to a consideration of the specific techniques which might be applied to the laboratory study of a neck dissection specimen. 37–44]. As it is not routine to obtain large numbers of random sections of surgical margin in a large neck dissection specimen. as a range – from largest to smallest. The first meeting of the pathologist and node dissection specimen usually comes after the specimen has undergone some period of formalin fixation – a process which typically alters the color and the configuration of that specimen from its appearance in the fresh state. and from lateral to the sternohyoid to the anterior trapezius. As a consequence. While some investigators have attempted to develop methods for more readily identifying individual nodes in a dissection specimen (as. the surgeon with a particular concern about a particular margin would be well advised both to mark the area of interest and to bring this to the attention of the pathologist. it can only be viewed as prudent for the various participants to discuss the issues raised by this review and adapt them to the particular needs of their own clinical settings. The Initial Processing of a Cervical Node Dissection Specimen in the Surgical Pathology Suite – Gross Examination In most instances. To this end.62:204–211 205 . clearing of fat by solvent application). this finding too should be recorded in the formal gross examination report. as should the associated soft tissue (with an eye toward documenting the presence of gross tumor). the internal jugular vein should be opened along its length. and/or the SCM are preserved). for example). a sampling of all cervical node groups one side of the neck. It is fair to confess at this point that many surgical pathologists are not likely to appreciate the precise distinctions between a radical neck dissection (the standard by which the other variants are judged. the margins of excision as a whole should be assessed for the presence of grossly identifiable tumor. for example. It is customary for pathology protocols to suggest that pathologists dissect a radical neck specimen with a high degree of precision. This is of great import. insofar as it relates to the ability of the pathologist to expertly dissect the specimen. being careful to segregate and identify nodes from each of a great many different anatomical regions [14. for foreknowledge of the primary tumor’s appearances may be a great aid in interpreting a confusing picture on frozen section examination at the time of definitive surgery. the specimen includes the spinal accessory nerve internal jugular vein and SCM). the tail of the parotid. in a search for either tumor or thrombus in its lumen. Finally. in turn. the sizes (usually recorded as the greatest single dimension) of the grossly identified nodes (both grossly positive and grossly negative) can be recorded as well (often. The salivary glands and SCM should be briefly described. and the number of grossly positive lymph nodes. Irrespective of the details of the planned dissection of the neck specimen. the pathologic study of the cervical node dissection occupies a particularly critical role in the planning of a laryngeal cancer patient’s subsequent therapy. This is not a trivial matter. their relative anatomic locations.examination) nor radiographic study will suffice to unerringly segregate out all of those patients who have developed metastatic disease involving their regional lymph nodes [30]. This. In addition. the number of lymph nodes identified on gross examination. the surgical pathologist should already be familiar with the microscopic appearances of the patient’s primary laryngeal cancer. the submandibular gland. As some or all of these landmark structures may be absent in a particular specimen (as a function of the surgical procedure performed). a modified radical neck dissection (where one or more nonlymphatic structures such as the spinal accessory nerve. Should it appear on naked eye examination as though metastatic tumor has penetrated the node capsule and grown into the adjacent soft tissue. or through preoperative review of the histologic sections of the biopsy specimen which were obtained from another facility [31–35]. relates to the degree of anatomical detail in the final pathology report which will be required by the patient’s surgeons and oncologists. Matted groups of confluent nodes (presumably replaced by metastatic tumor) should be noted as well. it should be possible at the conclusion of this gross examination for the pathologist to record the side of the neck the specimen came from. internal jugular vein. As such. pathologic practice in most centers does not rely on any such ancillary techniques and the pathologist’s dissection is carried out on the routinely fixed specimen [36]. either by virtue of having handled that initial diagnostic specimen him or herself. of course. it bears noting that practice is likely to diverge widely from one center to another – both amongst the pathologists and surgeons. the internal jugular vein. valuable landmarks for orientation purposes include the sternocleidomastoid muscle (SCM). a selective neck dissection (where some lymphatic levels The Pathology of Neck Dissection ORL 2000.

deep to the SCM (superior jugular nodes). 5. 43]. ultimately. the cervical node dissection specimen may first be divided from to bottom into two equal portions – an upper half and a lower half. deep to the inferior 1/3 of the SCM (these three groups comprising the jugular nodes). upper. It is here – in the interpretation of frozen section material – that the pathologist will be particularly aided by having reviewed in advance the diagnostic biopsy material. of course’ – taking into account the time and expense involved in preparing and then examining a great many more microscopic sections than is customary. the answer would be a resounding ‘one. the number of nodes reported out by the pathologist can only serve as a very crude proxy for the adequacy of either surgical or pathologic efforts. At the outset. As such. deep to the middle 1/3 of the SCM. lower. can some simple factor such as the number of lymph nodes identified in the final pathology report serve to gauge the probable success of the surgical procedure? The cervical region has been estimated to hold some 300 or so lymph nodes [45]. serial sectioning of the putatively negative nodes revealed an additional two nodes which harbored small deposits of metastatic tumor which were missed by the initial sectioning. Microscopic examination of selected histologic sections of the neck dissection specimen relies. As a rough generalization. upper. adequate? In other words. In one. and lower. anterior to the SCM (inferior anterior cervical triangle nodes). deep to the SCM (inferior jugular nodes). neck dissections from patients with head and neck cancer contain on average 20–30 nodes – although the range in individual patients varies quite widely indeed [46]. These authors found metastatic deposits in 40 of 802 cervical lymph nodes studied microscopically by examination of a single histologic section from each tissue block. five nodal regions are recognized – anterior to the SCM (including the submental and submandibular nodes). How many individual slides from each paraffin-embedded tissue block should the pathologist routinely examine? Typically. what might otherwise seem a simple matter may pose unexpected questions – for example. one pertinent consideration comes into play – and that is the role of frozen section diagnosis in the intraoperative management of patients with laryngeal cancer [30]. and. Once the individual lymph nodes have been identified. of course. At least two anatomical methods of grouping cervical nodes are used in modern practice. each cross section of a node on a glass slide corresponds to a single node identified on gross dissection (unless.which would have been removed in a standard radical neck dissection are instead preserved). 206 ORL 2000. and so is not likely to be entirely useful for this purpose. At this preliminary stage. finally. there has been at least one study which has examined this question critically [54]. deep to the superior 1/3 of the SCM. One perfectly reasonable question for the surgeon to pose might be – Was the cervical node excision. and an extended radical neck dissection (in which lymphatic and/or nonlymphatic structures – in addition to those removed in a standard radical neck dissection – are excised as well) [3. As a consequence. lower. so as to fix in his or her mind the appearance of the tumor which is being sought on the frozen section slide. while others do not. it is customary to take a single cross section through the longest axis of each node and submit that section for microscopic examination. as a function of their relation to the anterior and posterior borders of the SCM. in which case it may be subdivided into a pair of cassettes). Microscopic Study of the Cervical Node Dissection Specimen Cervical metastases are currently regarded as the single most important prognostic factor in patients with cancers of the head and neck [47–53]. In this way. including supraclavicular nodes) [37– 41].62:204–211 Devaney/Ferlito/Rinaldo/Devaney . anterior to the SCM (superior anterior cervical triangle nodes – including submental and submandibular nodes). Each of these halves is then divided from dorsal to ventral (or anterior to posterior) into thirds. Alternatively. on routine light microscopy and hematoxylin and eosin stained slides cut from paraffin-embedded blocks of tissue trimmed from the specimen. 7. 19. including spinal accessory nodes). in most instances. This. yields six nodal regions – upper. or the subsequent analysis of that specimen by the pathologist. posterior to the SCM (posterior cervical triangle. Some surgeons employ routine intraoperative frozen section as an adjunct to intraoperative staging. posterior to the SCM (posterior cervical triangle. the individual node is too large to fit into a single tissue cassette. the pathologic examination of the cervical node dissection specimen supplies information which is an irreplaceable element of the approach to the laryngeal cancer patient. posterior to the SCM (posterior triangle nodes). While this remains current practice in virtually all hospitals.

Once the threshold matter of how many slides from each block to examine has been settled. The alternative – creating thousands upon thousands of slides from a single large surgical specimen which has been totally embedded in paraffin – is simply not practicable with current techniques. the added data yielded by undertaking such a heroic effort does not appear to warrant doing this routinely [54]. In deciding whether or not to routinely employ such an ancillary modality of testing. we do not routinely stain all negative lymph nodes for cytokeratin. nodes measuring !1 cm or so in greatest dimension are.and with micrometastases. as their presence in an otherwise negative neck dissection may have an impact on prognosis – although this is a controversial area [18. immunohistochemical staining for cytokeratin has been shown to be particularly effective in pinpointing tiny metastases which might have otherwise escaped notice [63. As a general rule. correlation with the anatomic dissection performed at the time of gross examination is usually carried out. it has been suggested that between 5 and 10% of nodes negative by routine light microscopy may prove to be positive by immunohistochemical staining for cytokeratin [63. some pathologists will also report separately the number of positive nodes with macro. ultimately a process of sampling. while we do not do this in our practice. nonetheless. presence or absence of invasion of tumor beyond the lymph node capsule. In both instances. 64]. It is a matter to be settled between pathologists and clinicians whether the report should separately designate occult metastases (micrometastases) as a distinct category. this usually translates into a measure of size – cervical nodes 11 cm or so in greatest dimension are clinically suspicious and usually detectable by surgeons and radiologists (macrometastases). While it is usually no great challenge to recognize the many centimeter diameter lymph node which has been wholly replaced by metastatic cancer. In primary oral and pharyngeal cancers. and compared with the gross impression of the number of positive nodes by naked eye examination. less readily detected prior to microscopic study and thus regarded as occult metastases or micrometastases [25]. As it happens. so that the number of metastatic deposits in whichever anatomic regions were segregated by the pathologist can be reported. by contrast. In particular. Micrometastases should be aggressively sought by the surgical pathologist. and usually will show neither extension of tumor beyond the node capsule or central necrosis [25]. and the possibility that any additional information thus produced will add measurably to the patient’s care). looking for larger. the pathologist next turns to a microscopic examination of each lymph node sampled. and the possibility that any additional information yielded by this procedure will add nothing to the care of the patient) against the advantages (greater incidence of identification of micrometastases in cervical lymph nodes. In tallying up the number of positive nodes. Such factors include: differentiation of the metastatic deposit. All experienced microscopists have at one time or another been impressed by the ability of tiny deposits of metastatic tumor lurking in a lymph node (on the order of a scant few cells) to escape detection by the pathologist making a routine scan of the lymph node landscape. more readily detected metastases. In our practice. others may find this information to be valuable and so request that it be routinely recorded. the pathologist can expect that these clinically occult positive cervical nodes will measure !10 mm in greatest dimension. there are ancillary techniques (immunohistochemistry and molecular biology) available to increase the pathologist’s ability to detect lymph node micrometastases [59–62]. ‘micrometastases’. Once the presence or absence of metastatic deposits within individual lymph nodes has been noted and recorded.At present. a macrometastasis is usually thought of as a nodal deposit which can be identified either by the surgeon on physical examination or by the radiologist via imaging studies. host response to tumor invasion beyond the lymph node capsule. the presence or absence of extracapsular extension of tumor has traditionally been regarded by The Pathology of Neck Dissection ORL 2000. it can be more difficult to recognize the presence of small tumor deposits – that is. of necessity. and the presence or absence of vascular space invasion by tumor [68]. In clinical practice. 30. but it should be borne in mind that this is still a sorting process – sections from one area will be studied. Usually the number of patients with micrometastases is underestimated [65–67]. while sections from elsewhere will not. 64]. this emphasizes one truth threaded throughout all of surgical pathology practice – selection of sections for microscopic study is. The number of positive lymph nodes should be tallied. it is then possible for the microscopist to assess discrete microscopic changes within individual positive lymph nodes.62:204–211 207 . Pathologists should be expected to carry out that sampling which is calculated to yield valuable information. this calculus should be applied: balance disadvantages (the cost – both technical and professional – of preparing and studying these additional immunohistochemical slides. separate from macrometastases. 55–58]. Of these. It is customary to report the maximum dimension of the largest positive node.

in some instances. The pathologist should at this point recall those outstanding abnormalities noted on gross examination (a suspicion of tumor in the jugular vein. soft tissues. taken together. rather. explaining that the clinically enlarged node contained in reality a benign lymphoid hyperplasia) would be prudent. An explanation in the pathology report of the reason for this discordance (a note. or an impression of a grossly positive margin of resection) and attempt to confirm them on microscopic study of sections from those same areas. represents a response of that tumor mass to the radiation therapy. Radiation therapy can result in a slight decrease in the number of both positive and nega- tive nodes. they can occur – which provides all the more reason to note unexpected findings (sizable portions of nerve. salivary glands. It is not difficult to imagine the application of similar techniques to the metastases in an attempt at extracting yet more information from those specimens. Future Prospects The scheme outlined above captures the procedures followed in the majority of hospitals at the present time. pathologic methods have never been static. 68–70]. the needs of individual groups will result in the adaptation of such a stylized model as this one for use in each discrete practice setting. there remain some clinically suspicious lymph nodes which. However. When the tumor is confined to the lymph node or shows a microscopic invasion beyond the capsule. and the cell adhesion molecule E-cadherin in the primary tumor as a means of predicting the presence of nodal metastases [78]. molecular studies) Any other unexpected gross findings (including status of margins. should provide clinicians with the maximum information needed to continue the patient’s care. MIB-1. and jugular vein) Microscopic report Number of negative nodes (with maximum dimension or largest node) Number of positive nodes by anatomic region (with maximum dimension or largest node) Number of positive nodes by anatomic region with apparent invasion of tumor beyond the node capsule Microscopic features of metastatic tumor (differentiation. however. While the historical data provided by the surgeon will vary tremendously from one practitioner to another. on microscopic study. The risk of recurrence and death are higher when there is a macroscopic extracapsular extension. For the present. Neck dissection – the surgical pathology report Gross report Side of neck. for example) when they are encountered [74–77]. 48. soft tissues. This. for example. Researchers have already attempted to exploit the presence or absence of proliferating cell nuclear antigen (PCNA). While serious complications of cervical nodes dissection are not particularly common. prove unexpectedly to harbor changes other than metastatic cancer – changes such as malignant lymphoma. It is not expected that each hospital will employ this scheme precisely – rather. it might be subject to misinterpretation if the pathologist has not been informed of the prior course of irradiation. but no recognizable neoplastic cells [72]. we continue to report the presence or absence of the extracapsular spread. Table 1 summarizes these elements which. type of surgical procedure Number of negative nodes by anatomic region (with maximum dimension or largest node) Number of positive nodes by anatomic region (with maximum dimension or largest node) Number of positive nodes by anatomic region with apparent invasion of tumor beyond the node capsule Any other unexpected gross findings (including status of margins. presumably. perhaps. host response. some question this. there are no statistically significant differences in risk rates [71]. and jugular vein) most – but not all – observers as the most critical factor. SCM. 47. there is one piece of information which really should always be noted – and that is the presence or absence of preoperative radiation therapy. however [10. It has been suggested that the next frontier in the pathologic analysis of cervical node dissection specimens might be the routine application of molecular biologic techniques.Table 1. radiologists and gross pathologists.62:204–211 Devaney/Ferlito/Rinaldo/Devaney . One final caveat – despite the best efforts of surgeons. it can convert an obvious metastatic deposit of squamous carcinoma into a ‘keratin granuloma’– a featureless mass of keratin material. they are subject to (sometimes radical) revision as new information about disease accumulates. De Carvalho [71] believes that the macroscopic extracapsular spread of cervical lymph node disease is the most significant adverse prognostic factor. or mycobacterial or fungal infection [73]. salivary glands. 208 ORL 2000. vascular space invasion) Results of any ancillary testing (immunohistochemistry. SCM. in terms of its impact on prognosis.

23 Van den Brekel MW. Millar HS: Lymph node dissection for head and neck cancer. Leemans CR. The Pathology of Neck Dissection ORL 2000. Aust NZ J Surg 1987. it is likely that the use of a protocol such as the one discussed here – or some variation on this theme – will serve the twin aims of making the pathologist’s efforts more efficient while at the same time maximizing the valuable information which will be available to the clinicians caring for the patient. 15 Shah JP.9:547– 558. Lufkin RB: Imaging of nodal metastases in the head and neck.31: 657–669. nonetheless. other tech- niques for studying these nodes are also being explored. pp 435–438. Suen JY: Management of the N0 neck. Brunberg JA. Curr Opin Oncol 1996.19:604– 610. Feinmesser M.45:352– 368. and cell adhesion molecules (Ecadherin) detection as an adjunct to routine hematoxylin and eosin analysis of histologic sections [41]. 24 Tschammler A. Wolfe GT. Marti JR: Cervical lymph node metastasis. time-consuming process. 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Snow GB: The size of lymph nodes in the neck on sonograms as a radiologic criterion for metastasis: How reliable is it? Am J Neuroradiol 1998. Crit Rev Oncol Hematol 1996. Franco EL. 21 Breau RL. Castelijns JA. by routine light microscopy) for the presence of p53 mutations might reveal the presence of additional unsuspected metastatic deposits which otherwise would have escaped detection [61]. All of these approaches are presently in the investigative stage. Phillips DE. Ann Surg Oncol 1994. 10 Sizeland AM. Schwager K. Am J Surg 1996.62:204–211 209 . Shaha AR. Johnson JT. Kopecky KK. Andersen PE. Radiology 1998. 79–81]. 6 Shah JP: Editorial: dissection: Which and when? Aust NZ J Surg 1994. CA Cancer J Clin 1995. the needle aspiration process seems unlikely to be able to reliably sample small occult metastases. 22 Van den Brekel MW. Clin Otolaryngol 1995. James TH. for the foreseeable future. SeelbachGoebel B.7:9–13. 17 Shah JP. Head Neck 1992. 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Prior to the Second World War. City University of New York.karger. It is hoped that this approach will eliminate many of the often confusing and nondescriptive terms and there by facilitate better inter-physician and inter-institutional communication. Ogura and Bello [4] and Barbosa [5].uniud.e. MD. Basel Since the 19th century. Copyright © 2000 S. USA Key Words Neck dissection W Head and neck cancer W Classification Historical Perspective Abstract With the proliferation of operations designed to treat cervical metastatic nodal disease. However.Y. Som b Alessandra Rinaldo a Vanni Mondin a a Department b Department of Otolaryngology-Head and Neck Surgery. the relevant nonlymphatic structures removed. and of Radiology.karger. [3]. Suarez and Ballantyne each developed the technique of conservative neck dissection [6]. I–33100 Udine (Italy) Tel.ch www. internal jugular vein. For the first time only the lymph nodes between the aponeurotic compartments of the neck were removed.com/journals/orl Alfio Ferlito. George Crile [2] published a report that is now considered the first surgical method of ‘en-bloc’ resection of the cervical lymph nodes. it has become ever apparent for the need to more clearly and precisely communicate the location of the metastatic cervical nodes and the specific surgery performed. Policlinico Città di Udine Viale Venezia 410.com © 2000 S. ABC Fax + 41 61 306 12 34 E-Mail karger@karger. and those structures that are preserved. It is also suggested that the new imaging-based nodal classification be used to standardize the definition of the nodal levels. Karger AG. sternocleidomastoid muscle) were spared [7]. E-Mail clorl@dsc. It was only after the 1950s that this surgical procedure received significant support thanks to the studies of Martin et al. while the nonlymphatic structures (i.50/0 Accessible online at: www. Suarez’s technique was then popularized by Italian otolaryngologists [8–11] and this type of neck dissection was called a functional neck dissection [7]. surgeons were aware of the fact that cancers of the upper aero-digestive tract tended to metastasize to the cervical lymph nodes. Professor and Chairman Department of Otolaryngology-Head and Neck Surgery University of Udine. spinal accessory nerve. Karger AG. +39 0432 239302. To this end. the surgical treatment of the neck was woefully inadequate and often resulted in progressive and rapid dissemination of the malignant tumor [1]. Fax +39 0432 532179. Mount Sinai School of Medicine. In 1906..62:212–216 Classification and Terminology of Neck Dissections Alfio Ferlito a Peter M. N. During the 1960s. Italy.ORL 2000. University of Udine.it . the radical neck dissection technique of Crile underwent only modest technical improvements and there was little clarification of the indications for this procedure. It is suggested that a simplified technology be used that specifically describes the nodal levels dissected. Basel 0301–1569/00/0624–0212$17. this paper reviews the variety of operations and the resultant confusing terminology that has emerged over the past five decades.

in type II. and the sternocleidomastoid muscle. the anterior border of the trapezius muscle posteriorly. the incidence of neck recurrences observed with these neck dissections is the same as that obtained with radical or modified radical neck dissections [6. The inferior boundary of this dissection is the omohyoid muscle. only the nodes in levels I and II are removed. hyoid bone. The inferior boundary of this surgical procedure is represented by the carotid bifurcation. In properly selected patients. which was simplified 2 years later by Medina [16]. developed a classification system based on the following concepts: (1) the radical neck dissection is the fundamental procedure with which every other neck dissection has to be compared. Suen and Goepfert [15] were the first to suggest a classification of neck dissections. Both the radical and modified radical neck dissections can be grouped in the same category (‘comprehensive’ neck dissection) as the lymphatic structures removed are the same. but it is not easy to avoid the current confusion on this subject. The Academy’s classification of the neck dissections [from 17] Comprehensive neck dissection Radical neck dissection Modified radical neck dissection Type I Type II Type III Selective neck dissection Supraomohyoid neck dissection Posterolateral neck dissection Lateral neck dissection Anterior neck dissection Extended neck dissection Neck Dissection Terminology and Classification As the various modified neck dissection techniques have appeared in the literature. In the extended supraomohyoid neck dissection. in conjunction with the Education Committee of the American Society for Head and Neck Surgery [17]. The radical neck dissection includes complete removal of all the lymph node levels I–V and sacrifices the spinal accessory nerve. In 1991 the Committee for Head and Neck Surgery and Oncology created by the American Academy of Otolaryngology-Head and Neck Surgery. the nodes in levels II–V and the suboccipital and retroauricular nodes are removed. all of the nodes in levels I–IV are removed extending from the inferior border of the mandible to the clavicle. and (4) the extended neck dissection denotes removal of more lymphatic and/or nonlymphatic structures. depending on the site of the primary cancer and its expected lymphatic spread. The basic idea behind both proposed classifications was to identify three broad categories of neck dissections: (1) the standard radical neck dissection. The two surgical techniques differ only with respect to the nonlymphatic structures spared. The boundaries of the dissection are the same as those of the radical neck dissection. and contralateral anterior belly of the digastric muscle anteriorly. only the upper. internal jugular vein and sternocleidomastoid muscle) are preserved. Classification of Neck Dissections ORL 2000. where one or more selected groups of nodes considered at risk are removed.Today there are a variety of different types of neck dissection that are considered oncologically. the nodes in level III are also removed. there has resulted a nomenclature that is both nonuniform and often confusing. and (3) the selective neck dissection. only the spinal accessory nerve is preserved. in type III.e. These less radical surgical procedures are often performed bilaterally and may be followed by postoperative radiotherapy.62:212–216 213 . the internal jugular vein. The boundaries of this kind of neck dissection are the lower border of the mandible superiorly. both the spinal accessory nerve and the internal jugular vein are spared. In the posterolateral neck dissection. (2) the modified radical neck dissection denotes preservation of one or more nonlymphatic structures. all the three nonlymphatic structures (i. (2) the comprehensive modified radical neck dissection. functionally and cosmetically effective in the therapeutic or prophylactic treatment of the neck in patients with head and neck cancers. The need to use a common nomenclature for these different neck dissections appears obvious. (3) the selective neck dissection denotes sparing of one or more lymph node levels. In the suprahyoid neck dissection. spinal accessory nerve. 12–14]. the clavicle inferiorly. and the lateral border of the sternohyoid muscle. In the supraomohyoid neck dissection. Table 1. In the lateral neck dissection. In type I. The selective neck dissection refers to any type of lymphadenectomy that spares one or more lymphatic levels. In 1987. The following classification has been therefore recommended and table 1 summarizes these different types of neck dissections [17]. The modified radical neck dissection preserves one or more nonlymphatic structures.

and the sternocleidomastoid muscle are preserved in the majority of these types of dissections. the carotid artery. They defined a neck dissection as radical when four or five lymph node levels are excised (this includes patients who have an otherwise classical neck dissection for supraglottic or hypopharyngeal cancer sparing level I nodes). IV. SCM SAN. V. III. middle and lower jugular nodes (levels II. IV VI II. IJV. III. SCM SAN. II I. IV. the hypoglossal nerve. III. III I. IJV. IJV. except for the anterior dissection. IJV. III and IV) are removed. Table 2 summarizes the different types of neck dissections and shows the lymph node levels removed and the structures preserved [18]. SCM SAN. [17] does not cover all possible operations and suggested a new classification. II. it is necessary to modify the actual classification of selective neck dissections. VI I. 20]. IV. IJV SAN. V I. In 1994. Table 3 summarizes their proposed neck dissection classification [21]. IV. suboccipital and retroauricolar nodes II. IJV. specifying the specific nonlymphatic structures removed. III. In the anterior neck dissection. the internal jugular vein. the lymph nodes (level VI) surrounding the visceral structures of the anterior compartment of the neck are removed (this procedure may be extended to include level VII nodes). Terminology of current classification of the neck dissection [modified from 18] Type of neck dissection Comprehensive Radical Modified radical Type 1 Type 2 Type 3 Selective Suprahyoid Supraomohyoid Extended supraomohyoid Posterolateral Lateral Anterior Anterolateral Extended neck dissection Lymph node levels removed Structures preserved I. V and one or more additional lymph node groups (such as the paratracheal nodes or anterior compartment lymph nodes) SAN. III. III. the vagus nerve) are removed SAN = Spinal accessory nerve. there is no reason why at least one of these three nonlymphatic structures cannot be sacrified [14]. It is important to emphasize the fact that the posterior border of dissection in all these selective procedures. the anterolateral neck dissection groups these two previous surgical procedures together so that levels II. II. The extended neck dissection is the most aggressive of these surgical techniques because additional lymph node groups and/or nonlymphatic structures not encompassed by the radical neck dissection are removed. III and IV) nodes.Table 2. IJV. Another aspect to be taken into consideration is the fact that although the spinal accessory nerve. SCM I. otherwise the risk of neck recurrences can be high [19. IV and VI are removed. V I. In such cases. SCM SAN. Finally. III. [21] from the Memorial SloanKettering Cancer Center. V None SAN SAN. IV II. II and III). III. II.62:212–216 Ferlito/Som/Rinaldo/Mondin . IJV = internal jugular vein. II. Examples are the lymph nodes of the anterior compartment of the neck. IV. IV. SCM None and structures that are not routinely removed by radical neck dissection (such as the carotid artery. IJV. pointed out that the classification of neck dissections according to Robbins et al. II. is the cutaneous branches of the cervical plexus [18]. IV. V I. III. Spiro et al. A limited neck dissection is any lymphadenectomy that removes no more than two nodal levels. IJV. II. SCM SAN. SCM SAN. A selective neck dissection was defined as any lymphadenectomy that encompassed no more than three nodal levels. and the hypoglossal or vagus nerve. III. SCM = sternocleidomastoid muscle. New York. or jugular (levels II. 214 ORL 2000. usually the supraomohyoid (levels I. II.

but do not specify the extent of dissection. The terms ‘therapeutic’ and ‘elective’ refer to the indication for neck dissection. complete functional neck dissection. In addition. we must first adopt a common nomenclature for the lymph node groups of the neck and the classification recently proposed by Som et al. Delphian) Superior mediastinal nodes Other Terminology The term ‘comprehensive’ neck dissection includes radical neck dissection and the three types of modified radical neck dissections which remove the nodes in levels I–V. The ‘therapeutic’ neck dissection is performed for preoperative diagnosis. whereas selective neck dissection is often performed in ‘elective’ situations [6]. nerve/muscle-sparing radical neck dissection. supraclavicular group) Anterior (central) compartment lymph nodes (paratracheal. lower neck dissection. paratracheal node dissection. That is. upper-lateral node dissection. [25] Classification of Neck Dissections ORL 2000. retropharyngeal and parapharyngeal node dissection. The term ‘functional’ neck dissection is less precise than the ‘type III modified neck dissection’. submental triangle dissection. submandibular triangle dissection. nerve/muscle/vein-sparing radical neck dissection. but has been used so extensively in the literature that these two names may be considered synonymous. ‘Conservative’ neck dissection usually refers to the same procedure [23]. upper neck dissection. jugular neck dissection. many authors prefer the term functional neck dissection. terms such as functional. suboccipital node dissection. Lymph node groups corresponding to levels I–VII and the various subzones [modified from 26] 1 Radical (4 or 5 node levels resected) a Conventional radical neck dissection b Modified radical neck dissection c Extended radical neck dissection d Modified and extended radical neck dissection 2 Selective (3 node levels resected) a Supraomohyoid neck dissection b Jugular neck dissection c Any other 3 node level dissection levels specified 3 Limited (no more than 2 node levels resected) a Paratracheal node dissection b Mediastinal node dissection c Any other 1 or 2 level dissection levels specified Level Ia Ib IIa IIb III IVa IVb Va Vb VI VII Lymph node group Submental nodes Submandibular nodes Upper jugular. lower-lateral neck dissection. The terms ‘classical’. ‘elective’ or ‘prophylactic’ neck dissection were proposed by Conley and Von Frankel [22] to distinguish the radical (classical) procedure from the modified (functional procedure). nerve-sparing radical neck dissection. is usually performed for a ‘therapeutic’ indication. perithyroidal. posterior to IX (submuscular recess) Middle jugular nodes Lower jugular nodes (behind sternal head of sternocleidomastoid muscle) Lower jugular nodes (behind clavicular head of sternocleidomastoid muscle) Posterior triangle nodes (spinal accessory group) Posterior triangle nodes (transverse cervical artery group. infrahyoid neck dissection. Other terms include conservation neck dissection. Proposal To classify neck dissections. minor neck dissection. radical posterolateral neck dissection. extended selective neck dissection. fascial neck dissection. modified neck dissection. interjugular node dissection.62:212–216 215 . anterior to IX Upper jugular. These operations can be simply distinguished from their counterparts in which the level I nodes are removed by designating them as subtype A (I–V lymph node groups) and subtype B (II–V lymph node groups) respectively. posterior neck dissection. etc. anterior/posterior neck dissection. mediastinal node dissection. conservative and limited neck dissection are not precise and are primarily nondescriptive [16]. Neck dissection classification [from 21] Table 4.Table 3. The prophylactic or preferably the ‘elective’ neck dissection is employed for the management of potential subclinical disease in the neck. In current surgical practice. regional node dissection. usually of palpable cervical metastasis. Suarez neck dissection. but the term should be avoided because of its lack of precision. the term ‘limited’ neck dissection proposed by Turkula and Woods [24] is not precise. ‘complete neck dissection’ either modified or radical. Similarly. precautional neck dissection. Bocca neck dissection. Medina [16] recognizes a subcategory of radical or modified radical neck dissections in which the level I is not removed. however. total neck dissection. anterior compartment dissection.

Medina JE. 23 Skolnik EM. Bello JA: Laryngectomy and radical neck dissection for carcinoma of the larynx. Mancuso AA: An imaging-based classification for the cervical nodes designed as an adjunct to recent clinically based nodal classifications. Everts EC: Selective neck dissection and the management of the node-positive neck. Andersen PE.62:212–216 Ferlito/Som/Rinaldo/Mondin . Ann Otol Rhinol Laryngol 1991. as well as those that are preserved. Laryngoscope 1984.47:1780–1786. Del Valle B. Von Frankel PH: Historical aspects of head and neck surgery. [17]. 27 Shah JP.31:639–655. Deutsch EC: Conservative neck dissection.168:415–418.65: 643–655. 5 Barbosa JF: Radical laryngectomy with bilateral neck dissection in continuity.is simple and clear. 22 Conley JJ. Arch Otolaryngol 1965. It has been proposed that this imaging-based nodal classification be utilized to help standardize the terminology of nodal classification. Am J Surg 1993. 14 Pellitteri PK. 216 ORL 2000. Rinaldo A: Selective lateral neck dissection for laryngeal cancer in the clinically negative neck: Is it justified? J Laryngol Otol 1998. Shah JP: Selective jugular node dissection in patients with squamous carcinoma of the larynx or pharynx.172:654–657. Arch Otolaryngol Head Neck Surg 1991. 16 Medina JE Editorial: A rational classification of neck dissections. Saunders. Philadelphia. The lymph node groups that correspond to the neck levels and subgroups are outlined in table 4 [26]. 12 Houck JR. Vikram B: Neck dissection: Current status and future possibilities. Spiro RH. 8 Bocca E. To avoid confusion. Many other terms are often confusing and nondescriptive and do not facilitate interinstitutional communication.125:388–396. The current classification defines in a more precise manner the anatomical zones or levels of the neck which were previously classified by Shah et al. Ann Otol Rhinol Laryngol 1983. surgical technique. Cappa C: Functional neck dissection: An evaluation and review of 843 cases. Surg Clin North Am 1977. Wolfe GT. Ann Otol 1956.10:75–77. 15 Suen JY. in Silver CE. Levine PA.124: 348–352. Current concepts and future considerations.62:1–52. 7 Suarez O: El problema de las metastasis linfati´ cas y alejadas del cancer de laringe e hipofa´ ringe. Pignataro O: A conservation technique in radical neck dissection. 21 Spiro RH. 19 Spiro RH.166:399–402. Pignataro O. pp 299–324. 20 Clayman GL. Rev Otorrinolaringol 1963.100:169–176. Ferlito A (eds): Surgery for Cancer of the Larynx and Related Structures.63:372–383. Am J Surg 1996. J Laryngol Otol 1983. [27] and by Robbins et al. clinical observations. 24 Turkula LD. Silver CE: Neck dissection. Pruet CW: Standardizing neck dissection terminology. Otolaryngol Head Neck Surg 1989. 9 Calearo CV. Neuman T: Expanded application of selective neck dissection with regard to nodal status. Strong EW. Oldini C.100:261–267. Gary J. Sessions RB. Shah JP: Classification of neck dissection: Variations on a new theme. Ann Otol 1967.57:663–700.11: 228–239.94: 942–945.112:921–924. Arch Otolaryngol Head Neck Surg 1999. Cancer 1951. Am J Surg 1984.92:215–222. References 1 Beahrs OH: Surgical anatomy and technique of radical neck dissection. Curtin HD. Ehrlich H. Teatini G: Functional neck dissection. 3 Martin H. 1996. Cohen JI. Robbins KT. Head Neck Surg 1987. 11 Bocca E: Surgical management of supraglottic cancer and its lymph node metastases in a conservative perspective. Otolaryngol Clin North Am 1998. 19:260–265. Cahan WB: Neck dissection. Woods JE: Limited or selective nodal dissection for malignant melanoma of the head and the neck. This classification includes seven levels and proposes precise imaging-based anatomic landmarks for use in classifying metastatic cervical adenopathy. 25 Som PM. 10 Bocca E. 18 Ferlito A.23:83–99. Head Neck 1997. 2 Crile G: Excision of cancer of the head and neck with special reference to the plan of dissection based upon one hundred thirty-two operations.4:441–499. Clin Bull 1981. Semin Surg Oncol 1995. 4 Ogura JH.11:25–33.148: 446–448. Gallo O. Am J Surg 1994. Strong E. Goepfert H Editorial: Standardization of neck dissection nomenclature. Official report of the Academy’s Committee for head and neck surgery and oncology. Laryngoscope 1952. 6 Ferlito A.117:601–605. 17 Robbins KT. Frank DK: Selective neck dissection of anatomically appropriate levels is as efficacious as modified radical neck dissection for elective treatment of the clinically negative neck in patients with squamous cell carcinoma of the upper respiratory and digestive tracts.8(suppl):105– 107. 26 Robbins KT: Classification of neck dissection. Medina JE: Management of cervical lymph nodes in squamous carcinomas of the head and neck. JAMA 1906. Arch Otolaryngol Head Neck Surg 1998. 13 Traynor SJ.76:975–987. any neck dissection should be described specifying the levels dissected and the relevant nonlymphatic structures removed. Anatomical grounds. redundancy and misinterpretation among head and neck oncologists.

is the procedure of choice for elective treatment. regional disease in the neck repre- ABC Fax + 41 61 306 12 34 E-Mail karger@karger.62:217–225 Surgical Treatment of the Neck in Cancer of the Larynx Alfio Ferlito a Carl E.com/journals/orl Alfio Ferlito. More advanced disease has been treated in this manner often in association with adjuvant chemotherapy and/or irradiation. as levels I and V are almost never involved. Occult disease in the neck not detected by physical and radiographic examination may also be difficult to identify on routine histologic examination. The selective lateral neck dissection (levels II. I–33100 Udine (Italy) Tel. Italy. Elective neck dissection provides important information for prognostic purposes and therapeutic decisions. The neck may be treated electively by either surgery or irradiation. Copyright © 2000 S. by establishing the presence. but irradiation is best reserved for cases where that modality is employed for the primary tumor. Policlinico Città di Udine Viale Venezia 410. The selective neck dissection can be extended to include structures at risk. and glottic or subglottic tumors staged T3 or higher. unilateral or bilateral. III and IV).karger. location and nature of occult lymph node metastases. number. particularly for N1 or occasionally N2 nodal involvement.50/0 Accessible online at: www. University of Udine. Sentinel lymph node biopsy may fail to detect tumor on frozen section examination or may not reveal ‘skip’ metastases.com © 2000 S. Departments of and c Otolaryngology. Basel Treatment of the Neck in Laryngeal Cancer While management of both early and advanced primary laryngeal cancer has undergone revolutionary change during the past decade. The surgeon should be aware of the relatively high incidence of micrometastases in patients with laryngeal cancer to establish optimal treatment approaches. USA Key Words Larynx W Lymph nodes W Metastasis W Neck dissection Abstract Current concepts in management of the clinically negative and clinically positive neck in laryngeal cancer are reviewed.it .ch www.uniud. Montefiore Medical Center. Albert Einstein College of Medicine. Immunohistochemistry or molecular analysis may detect metastatic involvement not apparent by light microscopy. Karger AG. Bronx. Fax +39 0432 532179. Silver b Alessandra Rinaldo a Richard V. MD. Paratra- cheal nodes (level VI) should be dissected in cases of advanced glottic and subglottic cancer. The clinically involved neck is usually treated by complete radical or functional neck dissection of levels I through V. Complete radical or functional neck dissections are excessive in extent. Elective treatment of the neck is recommended for supraglottic tumors staged T2 or higher. Selective neck dissection has been employed successfully in selected cases. Karger AG. Basel 0301–1569/00/0624–0217$17.karger. Professor and Chairman Department of Otolaryngology-Head and Neck Surgery University of Udine. N. Smith c a Department b Surgery of Otolaryngology-Head and Neck Surgery.. While the benefit of adjuvant treatment is difficult to assess.Y. a factor associated with the worst prognosis.ORL 2000. +39 0432 239302. E-Mail clorl@dsc. it appears most useful in cases with extranodal spread of disease.

radioimmunoscintigraphy. Clinical and pathologic assessment of lymphatic metastases may also be difficult to assess. radiologically or pathologically negative. The choice of surgery or irradiation for elective treatment of the clinically negative neck often depends on the treatment chosen for the primary cancer: neck dissection if surgery has been used to treat the primary cancer. Elective Treatment of the Neck Staging the Clinically Negative Neck Detection and staging of cervical lymph node disease. or irradiation if that modality has been employed for the primary tumor. semiserial sections and/or histochemistry for cytokeratins and molecular analysis) [7. The N0 neck may be either clinically. Elective neck dissection or elective neck irradiation. Decisions regarding management of the neck in laryngeal cancer must be considered for the patient with no clinical evidence of neck disease (elective treatment of the neck). Options for elective treatment include neck dissection. Therapeutic decisions regarding the neck must also be undertaken in context with the size. with development of an armamentarium of surgical procedures of various extent as well as the use of irradiation for definitive or adjuvant therapy. in a recent editorial published in Cancer. This may be due to disease located at another level in the lymph node or. and variations in type and extent of surgical dissection have evolved. It is disconcerting to note that approximately 20–30% of nodal metastases may be unrecognized by pathologists on routine final histological examination [8]. Our concepts of appropriate management of the neck in laryngeal and other head and neck cancers have also evolved extensively during the same period. or consistency [5]. phenotype and treatment plan for the primary cancer. particularly when not clinically evident. Reintgen and Shivers [9]. The reported incidence of micrometastases may vary according to the method used for detection (e. molecular analysis). observation with subsequent salvage neck dissection if clinical evidence of metastases emerges (the ‘waitand-see’ policy). but also previous treatment such as surgery or radiotherapy. and radionuclide scanning) may be unable to reveal micrometastases preoperatively [2–4]. the clinical impact of such information is unclear. 11–13]. The reported false negative rate in assessing the presence or absence of cervical lymph node metastasis by palpation is 20–51% [1]. lymphangiography. and these treatments may reduce the risk of distant metastases. Factors affecting this large variance include not only the experience of the examiner and the patient’s body habitus. hematoxylin and eosin). However.62:217–225 Ferlito/Silver/Rinaldo/Smith . irradiation. The surgeon often cannot distinguish whether a node is positive for cancer by palpating and closely examining it intraoperatively. using a dose of 5. or intraoperative examination of the sentinel lymph node (sentinel lymphadenectomy) with im- 218 ORL 2000. In fact. as the staging systems and treatment reports have previously been based upon standard hematoxylin and eosin staining. rarely. to having been overlooked by the microscopist [7]. immunohistochemistry). although even neck nodes reported as pathologically disease-free following light microscopic study may not truly be free of occult metastases. magnetic resonance imaging. are indicated in reducing the incidence of recurrence in the clinically negative neck. continues to present a major challenge to the head and neck oncologist. important for its prognostic and therapeutic implications. The role of elective treatment of the neck in laryngeal cancer continues to be controversial.000 rad. ultrasoundguided fine needle aspiration biopsy. The status of the cervical lymph nodes. site.sents a source of potential failure that exceeds the risk of failure at the primary site. The pathologically negative neck may further be defined by conventional histological examination (pN0. or molecular analysis (pN0. a neck that is N0 on conventional pathologic evaluation may be positive by either immunohistochemical or molecular analysis. showing no change in size. Treatment of the Clinically Negative Neck The surgeon should be aware of the relatively high incidence of micrometastases in patients with laryngeal cancer to establish optimal treatment approaches.g. immunohistochemistry (pN0. single photon emission computed tomography. While such reporting obviously has staging implications. Evidence of metastatic infiltration in neck nodes may be minimal. the classification of N0 necks suggested by Ferlito and Rinaldo [10] may be more useful. is difficult to evaluate in the absence of palpable or radiologically obvious metastases. There is extensive evidence that even the most sensitive and technologically advanced procedures (computed tomography. emphasize the fact that such examination may fail to detect low volume micrometastatic disease. ultrasound. positron emission tomography. Frozen section biopsy is a valuable tool for intraoperative evaluation of suspect nodes [6]. It has become conventional to describe any neck that appears clinically negative as N0. as well as for the patient with clinically evident cervical metastases (therapeutic treatment of the neck). macroscopic morphology.

Ninety-five percent of N0 patients never developed cervical metastasis. only 1 of 7 patients with clinically negative necks had a histologically positive neck specimen. Another disadvantage of irradiation is that surgical treatment retains the ability to employ subsequent radiotherapy for second primary tumors. [45] found metastases in the ipsilateral paratracheal nodes in 9% of the 22 positive necks and contralateral metastases in 4. as the supraglottis is a midline structure. One third of patients presenting with N2a nodes had contralateral metastases. Moe et al. selective neck dissection (3 node levels resected). Johnson [19] recommends an ipsilateral neck dissection including levels II–IV and VI. or adjunct. which are located within level VI Surgical Treatment of the Neck ORL 2000. [18] advocated a policy of watchful waiting also for T3 and T4 N0 glottic cancer. after supraglottic laryngectomy.mediate lymph node dissection in the case of identification of metastasis. Lutz et al. Although no morbidity was observed from dissecting the contralateral side. Conversely. Primary irradiation for elective treatment of the neck has been considered as effective as surgery in preventing neck recurrence since the report of Fletcher [26] in 1972. or limited neck dissection (no more than 2 node levels resected) [14]. if the first specimen is negative. location and nature of occult lymph node metastases. for either staging or treatment purposes. Yuen et al. 37–40]. Bilateral metastases are common [36]. number. The nodes at high risk for T3 and T4 glottic cancers include level II–IV and VI [19]. by establishing the presence. This is a generic term used for any type of neck dissection. [27] found no difference in the rate of neck recurrence. makes it impossible to establish whether there were metastases in the treated lymph nodes [29]. and none developed distant metastases. and tumors of the supraglottic region metastasize in 25–75% of cases when all stages are considered [35]. Lymphatic spread from glottic or subglottic tumors is also highly predictable. 30–33]. Subglottic cancers spread initially to the paratracheal and recurrent lymph nodes. the value of such irradiation may be questioned. however. For example. The Role of Irradiation in Elective Treatment of the Neck The role of radiation therapy as an alternative. and if frozen sections confirm the presence of metastasis. and improvement in survival and local-regional control when patients were treated with bilateral neck dissection [28. [46] found that no patients with advanced glottic cancers had level I and V involvement. and those whose necks were observed. [43] have recommended that the ipsilateral neck dissection be performed routinely in the clinically N0 neck. Several authors have noted a high incidence of recurrence on the contralateral side of the neck in patients treated by unilateral neck dissection. Elective neck dissection provides important information for prognostic purposes and therapeutic decisions. in patients who had unilateral neck dissection. [42] reviewed 89 patients treated from 1979 to 1988. 22–24] and in patients with recurrent supraglottic and advanced glottic cancers treated by radiotherapy and salvaged by laryngectomy [25]. while 100% of patients with N2b nodes had contralateral metastases. Gregor et al. to surgery for neck disease remains controversial. Not all authors agree that elective bilateral neck dissection is necessary in all cases. DeSanto et al. and therefore makes it difficult to compare the efficacy of elective neck dissection versus elective neck irradiation. Elective (prophylactic) neck dissection has been recommended for the N0 neck in patients with T2– T4 supraglottic cancers [15–17]. Choice of Surgical Procedure for Elective Treatment of the Neck The location of cervical lymph node metastases is closely linked with the site of the primary lesion. such as conventional radical neck dissection. the ‘second’ side of the neck should be dissected. most often within the first 5 years after treatment [34].5% of advanced glottic cancers. Goffinet et al. Weber et al. modified radical neck dissection. Elective Neck Dissection Elective neck dissection refers to the dissection of cervical lymphatics in the absence of metastatic disease. which develop in 11–19% of patients with cancer of the larynx [19. [28] found radiation therapy ineffective for preventing metastasis in the contralateral neck. T3–T4 glottic cancers [17–22]. The use of primary irradiation to treat these patients. T3–T4 subglottic cancers [17. The authors felt that their data did not support routine bilateral neck dissections in patients with clinically negative necks. with an observed decrease in neck recurrence from 20 to 9%. [41] demonstrated the efficacy of bilateral neck dissection in the management of the cervical lymphatics in patients with supraglottic cancer. Shenoy et al. The supraglottic area is richly supplied with lymphatics. Nevertheless. Güney and Yigitbasi [44] do not recˇ ommend an elective treatment of the second side in patients with T1–T2 unilateral supraglottic cancer. between patients who received radiation therapy.62:217–225 219 .

[14] defined as a limited neck dissection any lymphadenectomy that involved removal of no more that two nodal levels. as this has virtually no effect on the morbidity or duration of the procedure and it provides additional valuable information. Anderson Cancer Center who suggested removing only those lymph node groups that. is low [24]. These results confirm the efficacy of lateral neck dissection in elective treatment of the neck in patients with laryngeal cancer. All patients (100%) with pathologically positive nodes had level II involvement [62]. and complications were similar in the two treatment groups of patients [98]. in particular the ‘type III’ (or functional neck dissection) [15. At present. however. This finding represents a significant departure from previously reported series [22. and the axilla can become the major lymphatic drainage site from the anterior and lateral neck [58]. are at highest risk of containing metastases [86]. 22. This probably depends on accuracy in definition of levels I and II. III. however. several institutions have adopted selective neck dissection as the standard treatment for patients with clinically negative necks in order to reduce regional recurrence rates [14. clearing only levels II and III. Thus selective lateral neck dissection is a valid option in laryngeal cancer as this procedure preserves levels I and V. The extent of neck dissection for laryngeal cancers has been debated for many years. Selective lateral neck dissection (called also jugular neck dissection) includes the dissection of levels II–IV. [47]. This concept was introduced by surgeons at M. for cancer of the larynx. where laryngeal tumors rarely metastasize. Glottic. was usually modified neck dissection.and VII of the recent classification of cervical lymph nodes proposed by Som et al. remains to be adequately studied. 63–75]. while avoiding the prohibitive morbidity of bilateral standard radical neck dissection.D. which removes lymph node levels I. Bocca [37] popularized this method and reported an overall 5-year cure rate of 78% for supraglottic cancer treated by supraglottic laryngectomy with bilateral functional neck dissections. the spinal accessory nerve and the submandibular gland. [89] mentioned that Steiner advocates performing limited neck dissection. 220 ORL 2000. conventional radical neck dissection is not indicated for elective neck dissection unless the surgeon rejects the modified neck dissection procedure or lacks experience in its performance. until recently. called upper neck (level II) dissection for N0 supraglottic cancer. 76–82]. the rates of 5-year overall survival.62:217–225 Ferlito/Silver/Rinaldo/Smith . complete functional neck dissection has been considered an unnecessarily extensive procedure for treatment of the clinically negative neck as levels I and V are rarely involved. [84] suggest that the postero-superior jugular lymph nodes (the ‘submuscular recess’) may not need to be dissected in the clinically N0 neck. and Talmi et al. 50. supraglottic. which are only present after the involvement of the paratracheal nodes. laryngeal cancer has metastasized to the axillary lymph nodes [56–58]. Tu [88] suggests a limited neck dissection. Ferlito and Rinaldo [90] suggest including level IV. This concept. The morbidity of this surgical procedure is minimal in experienced hands. 49– 55]. In a recent multi-institutional prospective study designed to compare type III modified radical neck dissection with lateral neck dissection in the management of clinically negative neck findings in patients with supraglottic and transglottic squamous cell carcinoma. 89–98]. of the 17 patients who had clinically N0 necks but pathologically positive nodes. particularly in the absence of clinically or radiologically apparent neck metastases [85]. 46. considering such type of resection of upper neck nodes a diagnostic as well as a therapeutic modality. IV and V and preserves the sternocleidomastoid muscle. transglottic and subglottic cancers may metastasize to precricoid or prelaryngeal lymph node or Delphian node and to sub-Delphian nodes in the anterior tracheal compartment of level VI [23. Spiro et al. However. the internal jugular vein. 67. Ambrosch et al. provided that strict adherence to surgical boundaries is maintained [87]. Suarez [61] developed the concept of ‘functional’ neck dissection to permit removal of disease-bearing lymphatic tissue. Rarely. 61. II. Hicks et al. Surprisingly. 49. does not guarantee normal shoulder function [83]. 60]. More recently. middle (level III) and lower jugular (level IV) node metastases. axillary node metastasis remains an uncommon occurrence in squamous carcinoma of the upper aerodigestive tract [59. based on the location of the primary cancer. Preservation of the spinal accessory nerve. [62] recommend bilateral neck dissection of levels I through IV to adequately address those regions at highest risk of occult disease. In the surgical management of the clinically N0 neck in supraglottic cancer. 14 (82%) had involvement of the submandibular triangle. At present. neck recurrence. 42. The procedure of choice for elective surgery. thereby limiting injury to spinal accessory nerve without compromising the removal of lymph nodes at risk for involvement with cancer. The jugular chain of lymph nodes should be considered as a secondary site of lymphatic spread for subglottic cancers [48]. The number of lymph nodes removed in selective lateral neck dissection should be comparable to that of the corresponding levels in radical neck dissection. The incidence of supraclavicular (level V).

Thus a small metastatic lymph node. 106–108]. nearly 3 cm in diameter. [103]. the occurrence of ‘skip’ metastases. however. and point to the importance of immunohistochemistry and molecular biology in the staging of these tumors [101]. although some authors have employed selective neck dissection for metastatic disease staged as N2a [8. often only in patients with N2 or N3 neck disease. the N1 category may include lesions that differ considerably in size and extent. Davidson et al. Such factors. has been well documented in patients with head and neck cancers. [104] demonstrated no metastatic involvement of the posterior triangle lymphatic system in either the therapeutic or elective neck dissection groups for cancer of the larynx. level V nodes were never involved. but represent entirely different pathological and clinical situations.Sentinel node biopsy has also been considered in the management of the lymphatic spread of cancer. There is little evidence to support the routine dissection of levels I and V in N1 laryngeal cancer because involvement of the lymph nodes at these levels is virtually nonexistent [74. Dissection of nodes in level VI is an important feature of neck dissection for treatment of primary tumor that may metastasize to this region. must be assessed by the clinician to determine which type of neck dissection is most appropriate [108]. with low morbidity. which bypass the first draining lymph node. 104. Dissec- tion of the anterior aspect of level I. as introduced by Crile [102] in 1906 and popularized by Martin et al. Traynor et al. while it includes level I and V lymph nodes which are seldom involved in laryngeal cancer. which may be metastatic in subglottic and advanced glottic cancers. Level I may occasionally be involved (1 or 2% or less of the cases) [42. Treatment of the Clinically Positive Neck Therapeutic Neck Dissection Treatment of the clinically positive neck must be based on the extent and location of lymph node involvement. The technique is minimally invasive. conservative modifications of the therapeutic radical neck dissection may be indicated [105]. where the individual nodes are not fixed. Radical neck dissection. as nodal involvement occurs only in the submandibular triangle. or by immunohistochemical or molecular biology assays. Surgical Treatment of the Neck ORL 2000. the floor of the mouth [100]. selective neck dissection has also been advocated for more advanced stages of neck metastases. 91]. particularly if there is extensive involvement along the jugular chain. Recently. 65. is not indicated. Some groups have employed selective lateral neck dissection for laryngeal cancer with metastatic disease staged as N1 [8. 86] or even N2b [8]. On the other hand. not in the submental triangle. In addition. This concept has been rapidly adopted by the surgical community for assessment of lymph nodes status in patients with primary cutaneous malignant melanoma and breast cancer. for staging purposes. and larynx [69. 98]. and one that is fixed. Despite its name. 75]. the submental triangle. [110] extend the indications for this operation also for N2c. 3 cm or less in greatest dimension’ [109].62:217–225 221 . 74. radical neck dissection. There is ample evidence that the presence of micrometastases has clinical and prognostic implications [101]. in predicting the lymph node status of head and neck cancer patients. may both be classified N1. fails to dissect pretracheal and paratracheal lymph nodes (level VI). with no capsular invasion. Skolnik et al. Intraoperative examination by frozen section analysis and routine pathological assessment of the sentinel lymph node may fail to detect metastases later revealed by serial sections. The fifth edition of the TNM appearing in 1997 (International Union Against Cancer) defines N1 as ‘Metastasis in a single ipsilateral lymph node. 75]. While radical or modified radical neck dissection (with inclusion of level VI as indicated) is generally employed for treatment of the clinically involved neck. rather than simple staging classification. Biopsy of the ‘first level’ node may be less effective. Metastases have been found in level V in 1% or less of the cases [72. These findings argue in favor of using selective lateral neck dissection for cancer of the larynx. Nicolai et al. This type of neck dissection has generally not been advocated for the management of more advanced nodal status. particularly in patients with tumors of the tongue [99]. [106] noted that patients who developed ipsilateral regional recurrences did so within previously dissected neck zones which suggests that earlier dissection of additional ipsilateral zones would not have been beneficial. [75] observed that in a series of 402 consecutive patients treated for supraglottic squamous cell carcinoma. modified radical neck dissection and selective lateral neck dissection may be employed depending on the extent and location of metastatic disease. and has macroscopic infiltration of the capsule. As the goal of neck dissection is to remove all clinically evident metastatic nodal disease and the nodal groups at greatest risk. The value of postoperative irradiation and/or chemotherapy must be considered.

72% of patients without extracapsular spread of disease survived 2 years. and by stage.Selective lateral neck dissection may be extended to include the spinal accessory nerve. 67. Macroscopic extracapsular spread of cervical lymph node disease is the most significant. 91. leading the authors to recommend postoperative irradiation with chemotherapy for patients who are found to have extracapsular spread of their cervical lymph node disease. often combined with appropriate adjuvant therapy. 89. Robbins et al. extent of the dissection (Steiner – cf. anterolateral and lateral neck dissections [106]. The efficacy of adjuvant chemotherapy and irradiation remains under investigation. regardless of the type of neck dissection employed. Postoperative irradiation may perhaps best be employed selectively in patients with extranodal spread of disease. The value of adjuvant radiation postoperatively for patients with pathologically positive necks is controversial. Traditional radical neck dissection is clearly indicated for patients with massive adenopathy. with no apparent influence of postoperative radiotherapy on recurrence in the dissected neck. compared with only 46% of patients with nodal metastasis. Suarez et al. Adjuvant Treatment Adjuvant treatment may improve results in treatment of patients with advanced stage neck disease. particularly when extracapsular spread of tumor is present. and patients with extracapsular spread in their neck specimens have the highest incidence of regional recurrence. Overall survival of the whole series. but these modalities would appear indicated for the most advanced cases. the selective lateral neck dissection. Of this latter group. Additionally. as well as distant metastases. independent adverse prognostic factor [113]. in comparison with only 31% of patients with extracapsular spread. This use of multimodality treatment in association with limited surgery may best represent current thinking in the management of advanced head and neck cancer. 94. Management of the clinically positive neck may also be modified according to the stage and location of neck involvement.62:217–225 Ferlito/Silver/Rinaldo/Smith . was not statistically altered by combined therapy. compared to surgery alone. laryngeal and hypopharyngeal cancers). The structure most frequently sacrificed is the internal jugular vein [94]. the internal jugular vein and the sternocleidomastoid muscle [111]. as well as the characteristics of the primary tumor.9% of patients. 95] because of differences in patient selection (N0 and N1. and the use of postoperative radiotherapy. Nine of 14 patients who had recurrence in the neck had extracapsular spread at initial surgery. some studies report results that include both lateral and supraomohyoid neck dissections [94] and supraomohyoid. 92. further complicating the issue. [114] believe that targeted chemoradiation with the use of intra-arterial supradose cisplatin and concomitant radiation therapy followed by planned selective neck dissection for patients with cancer of the upper aerodigestive tract with N2 to N3 neck nodes is highly effective for controlling regional disease. The information obtained by evaluation of specimens from selective neck dissection renders this modality more useful than elective irradiation of the neck as primary treatment. Adjuvant therapy may be employed in association with selective or extended selective neck dissection to increase its effectiveness while limiting surgical morbidity. adequate evaluation of this approach has been limited to date. Myers and Alvi [40] reported minimum 2 year results of treatment in 103 patients with cancer of the supraglottis treated between 1987 and 1992. It is difficult to compare the results achieved with selective lateral neck dissection at various institutions [22. [89] – advocates clearing only levels II and III). Approximately half the patients received postoperative radiation therapy. with macroscopic extracapsular spread and infiltration of the fascial compartments of the neck. [112] ´ reviewed 193 patients with primary supraglottic cancer who received a total of 284 elective or therapeutic neck dissections. Conclusions Management of the neck in laryngeal cancer has evolved from more radical historical techniques to limited dissections. While complete conventional or modified radical neck dissections constitute appropriate treatment for many patients. 222 ORL 2000. sternocleidomastoid muscle or internal jugular vein. Ambrosch et al. may offer a more efficient and effective treatment tailored to the requirements of the particular situation. Eighty-four percent of patients without nodal metastasis survived at least 2 years. extended as necessary to include resection of accessory nerve. Selective lateral neck dissection has become the procedure of choice for elective treatment of the clinically negative neck. Nevertheless. Neck recurrence was observed in 12.

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Bldg 112. Maywood. patients with advanced cervical adenopathy remain at the highest risk for the development of local recurrences and distant metastases.50/0 Accessible online at: www.ch www. Cardinal Bernardin Cancer Center. FACS Head and Neck Oncology Program. First Ave. Karger AG. Karger AG.luc. Petruzzelli a Bahman Emami b a Departments of Otolaryngology-Head and Neck Surgery and General Surgery.karger. IL 60153 (USA) Tel. Copyright © 2000 S. MD. patients in this category have between a 20 and 30% chance of surviving their disease at 5 years from treatment [1]. Maywood.com © 2000 S.62:226–233 Nonsurgical Treatment of Advanced Metastatic Cervical Disease in Cancer of the Larynx Guy J.. Cardinal Bernardin Cancer Center 2160 S. Petruzzelli.edu . Ill. Cardinal Bernardin Cancer Center. discuss the evolution of combined chemoradiation therapy for these patients. including resection and reconstruction of the carotid artery. USA Key Words Chemotherapy W Radiotherapy W Advanced cervical metastases Abstract Historically. Ill. Rm 270 Maywood. Fax +1 708 327 3248. Despite attempts at more aggressive surgical resection. This chapter will review the current limitations of surgical resectability for advanced neck disease. This chapter will review the current limitations of surgical resectability for advanced neck disease. E-Mail gpetruz@wpo. Historically. and finally present promising recent technological advances in radiation oncology which will have significant impact on the treatment of these patients. Loyola University Medical Center. Basel The development of advanced metastatic cervical adenopathy (N2 or N3) remains a prognostic indictor connoting the poorest outcome in patients with squamous cell carcinomas of the head and neck.it.com/journals/orl Guy J. ABC Fax + 41 61 306 12 34 E-Mail karger@karger. Despite attempts at more aggressive surgical resection. +1 708 327 3315.ORL 2000. and finally present promising recent technological advances in radiation oncology which will have significant impact on the treatment of these patients. Basel 0301–1569/00/0624–0226$17. discuss the evolution of combined chemoradiation therapy for these patients. patients with advanced cervical adenopathy (N2 or N3) have between a 20 and 30% chance of surviving their disease at 5 years from treatment.. and b Department of Radiation Oncology. Loyola University Medical Center. and Head and Neck Oncology Program. PhD.karger. including resection and reconstruction of the carotid artery. patients with advanced cervical adenopathy remain at the highest risk for the development of local recurrences and distant metastases.

It remains an accepted principle that for neck dissection to be effective in controlling cervical metastases. improved local/regional control and successful palliation are reasonable therapeutic goals. 277 patients were stratified based on primary site and T and N status.e. Locoregional control in the surgery-RT group was superior to that in the RT-surgery group (65 vs. measurement of carotid stump pressures. Increased sophistication in the nonsurgical and intraoperative care of these patients has led however to significant reductions in operative mortality from the originally reported 8% to less than 1% [1]. Attempts at evaluating the safety of carotid resection include both anatomic and functional assessments of collateral circulation by combinations of carotid arteriography. XII. ‘fixed node’).Limitations of Surgical Resectability The surgical treatment of advanced neck disease in patients with head and neck squamous cell carcinoma has not changed dramatically since 1906 when Crile [2] published his first series of patients treated with radical neck dissection. Many authors have reported case series detailing the technical considerations and neurological sequelae in patients with elective carotid resection with and without reconstruction [8]. Advanced Metastatic Disease ORL 2000. somatosensory-evoked potential testing. The utility of extended radical neck dissection in controlling head and neck cancer remains extremely controversial. in patients presenting with advanced cervical adenopathy the utility of the CT scan may be reduced. and to date no studies have demonstrated increases in survival.62:226–233 227 . Involvement and resection of cranial nerves VII. Their results indicated the overall accuracy for CT scan in this setting is poor with sensitivity and specificity at 50 and 61% respectively. no study can clearly predict outcome for a given patient [7]. Evolution of Combined Modality Treatment Induction Chemotherapy Beginning in the 1970s it became clear that patients with locally advanced head and neck squamous cell carcinoma treated with combined surgery and radiation therapy experienced improved local and region control of their disease when compared to those treated with either single modality [10. The report of RTOG 73-03 in 1987 illustrated the clear superiority of postoperative radiation over preoperative radiation therapy in patients with head and neck squamous cell carcinoma. to 48% respectively). Although potentially useful in risk stratification. Patients were randomly assigned to receive 50 Gy of preoperative radiotherapy (RT) followed by surgical resection or surgical resection followed by 60 Gy. Although significantly reducing local recurrence. xenon blood flow CT imaging. involvement of the cervical spine. the carotid artery. However. Computed tomography (CT) has been used extensively in the staging of patients with head and neck carcinoma and has a high negative predictive value [5]. In 1973 the Radiation Therapy Oncology Group (RTOG) initiated a clinical trial to determine the optimal sequencing of radiation therapy and surgery for the treatment of advanced head and neck squamous cell carcinoma. However. temporary balloon occlusion. Resection of the carotid artery in patients with advanced cervical metastases remains controversial. or extension of disease into the mediastinum constitutes an extended radical neck dissection [4]. and serial neurological examinations. singlephoton emission tomography. Extracapsular extension into the sternocleidomastoid muscle. Contraindications to neck dissection include. Meta-analysis estimates the rate of major neurologic complications at approximately 17%. deaths due to distant metastases were identical in all treatment groups [12]. extracapsular extension into the deep layer of the deep cervical fascia (i. Righi et al. [6] reported their experience with 29 patients in whom the preoperative CT scan was interpreted by the neuroradiologists as either ‘suspicious’ (12) or ‘nonsuspicious’ (17) for invasion of the prevertebral muscles by tumor. The authors advocate neck exploration in patients with potentially resectable tumors to determine fixation to prevertebral fascia (hence not surgically resectability). In that trial. Reconstruction of the carotid artery may be considered in selected patients with advanced head and neck cancer. jugular vein. paraspinal muscles. X. carotid resection has not been associated with an increase in disease-free survival in patients with advanced head and neck carcinoma [9]. and the presence of metastatic disease. An additional treatment arm of definitive RT to between 65 and 70 Gy was included for patients with oral cavity and oropharyngeal tumors. every attempt must be made to remove disease from the allnode-bearing tissue [3]. or clavicle. or cranial nerve XI mandates resection of these structures as well and constitutes the traditional radical or comprehensive neck dissection. Resection and reconstruction of the carotid artery remain valuable additions to the surgical armamentarium in treating patients with advanced head and neck cancer. 11].

Fifty-nine (36%) patients in the chemotherapy arm required salvage total laryngectomy. what the study did show was the reduction in the frequency of distant metastases and the increased time to first distant failure in patients receiving maintenance chemotherapy compared to either the control or the induction groups [19]. the incidence of distant metastases was significantly lower in the group which received systemic chemotherapy prior to the initiation of radiation therapy [20]. Kish et al. addition of bleomycin or methotrexate. Significant differences were again observed in that patients receiving chemotherapy had an increased incidence of local failure but fewer distant metastases. Larynx preservation without compromise of survival was achieved in 64% of patients in the induction chemotherapy arm [21]. prospective multi-institutional study was undertaken to determine the role of neoadjuvant (induction) chemotherapy in the treatment of stage III and IV head and neck squamous cell cancer. Through the 1970s. Clinical response rates of 50–70% with 20–30% complete and up to 15% pathological responses were reported [13]. Two large and noteworthy trials have examined the role of induction chemotherapy in organ preservation strategies of the larynx (Veterans Administration – VA Larynx Trial) and the hypopharynx (European Organization for the Research and Treatment of Cancer – EROTC). patients received primary surgery followed by either standard radiation therapy or interval chemotherapy consisting of three cycles of cisplatin and 5-fluorouracil followed by radiation therapy. Close examination of the literature reveals that the majority of studies reporting a favorable response of head and neck squamous cell carcinoma to chemotherapy can be criticized due to small sample size. improved disease-free survival. or (3) induction chemotherapy and standard therapy followed by six cycles of monthly cisplatin (maintenance chemotherapy). The EROTC trial consisted of 194 randomized patients who received either conventional surgery (total laryngectomy-partial pharyngectomy) with postoperative radiation therapy or three cycles of cisplatin and 5-fluo- 228 ORL 2000. In the patients treated with primary surgery. neck dissection and radiation therapy. like the Head and Neck Contracts Program. single institution.The development of distant metastases in the absence of locoregional failure and the overall poor prognosis for advanced disease heightened interest in developing new treatment strategies involving systemic chemotherapy. However. In this multi-institutional trial. Interestingly. or excessively heterogeneous patient populations. survival or disease-free survival were observed. In 1978. under the direction of the National Institutes of Health. Overall survival at 4 years was 44 and 48% respectively for the surgery 1 RT and surgery 1 chemotherapy 1 RT groups. In addition to prolonged survival and reductions in the development of distant metastases. As in the Head and Neck Contracts Program. no significant differences in time to local recurrence. and biomodulation of 5-fluorouracil with interferon-·-2B [15– 17]. An 86% response rate with 31% complete response was reported following two cycles of chemotherapy. Similar results were reported by the Head and Neck Intergroup Study 0034 in 1992. Results from this study did not demonstrate any differences in improved survival. leucovorin rescue. [14] reported that using a combination of cisplatin and 5-fluorouracil yielded response rates between 80 and 90% with 40% clinical and 30% pathological responses. multiple drugs used as either single agent or in combinations were used to treat head and neck cancer in a variety of clinical situations. The dose of radiation in both groups was dependent on risk stratification defined by the pathological status of the lymph nodes and the surgical margins.62:226–233 Petruzzelli/Emami . In 1982. a randomized. Overall survival was the same in both treatment groups. The Head and Neck Contracts Program randomly assigned 462 patients to receive one of three treatments: (1) surgery followed by radiation therapy (standard therapy). (2) induction chemotherapy consisting of a single course of bleomycin and cisplatin followed by standard therapy. the VA Larynx Trial randomized 332 patients with stage II or IV cancer of the larynx to either standard therapy (total laryngectomy and postoperative radiation therapy) or neoadjuvant chemotherapy consisting of three courses of cisplatin and 5-fluorouracil followed by definitive radiation therapy (66–70 Gy). Other investigators have attempted to enhance the response to chemotherapy by dose escalation. Begun in 1985. organ preservation has continued to be a goal in head and neck cancer treatment. metastatic adenopathy in three or more nodes and positive nodes in the posterior triangle (zone 5) were independent predictors of distant failure and ultimate reduced survival [22]. There is however conclusive data regarding the lack of survival advantage provided by induction chemotherapy. These studies have been replicated by many investigators and the combination of cisplatin and 5-fluorouracil is now the most widely used chemotherapeutic regimen in chemotherapy of naive head and neck squamous cell carcinoma [18]. or alterations in relapse patterns between any of the three treatment groups. retrospective nature.

Potential concerns regarding the use of neoadjuvant chemotherapy remain: (1) reduction in the efficacy of local therapies (surgery and radiation) due to proliferation of chemotherapy-resistant clones during induction cycles. The activity of cisplatin-based regimens in the treatment of advanced head and neck cancer has been demonstrated by both randomized and nonrandomized trials. 5-fluorouracil concurrently with identical RT). The four mechanisms underlying this synergistic response were articulated by Steel and Peckham [26] in 1979: (1) spatial cooperation: simultaneously treating the tumor at both locoregional and presumed micometastatic sites. (3) protection of normal tissues: potential selective cytoprotective mechanisms of certain agents. carboplatin. 46 of the 166 patients receiving chemoradiation had N2 or N3 disease at the time treatment began. In this study. although they may be additive (i. It is beyond the scope of this review to detail the results of these multiple studies.e. In patients demonstrating less than a complete response in the neck. chemoradiotherapy has been delivered in one of several schedules: (1) sequential RT following induction (neoadjuvant) chemotherapy (see previous section). and recently paclitaxel have all demonstrated in vivo radiosensitization [24. which revealed no viable tumor. Fifty-three patients had advanced (N2/N3) cervical disease. an interval endoscopy and biopsy was performed after the second cycle of chemotherapy and nonresponders were then offered conventional treatment. Of the 97 patients receiving induction chemotherapy.e. Neck dissection following chemoradiation did not affect outcome as indicated by the 20– 30% survival demonstrated following neck dissection in partial responders [34]. Concurrent Chemoradiotherapy The ability of certain drugs to enhance the toxicity of ionizing radiation has been known for many years. In 47 early-stage patients (N0/N1) there were 43 complete responders. The rate of both locoregional and distant failure can be reduced by the addition of chemotherapy. (2) toxicity independence: toxicities of the two modalities are different (i. In their study. a complete response was observed in 54% at the primary site and 51% (31 of 61 patients) with cervical metastases. Six neck dissections were performed in these patients. As in the VA Larynx Study. A fifth method has been described to enhance the local responses which involves concurrent chemoradiation using high-dose selective intra-arterial chemotherapy with systemic neutralization [33]. (2) failure to comply with consolidation therapy (surgery and/or radiation) in patients who initially respond to chemotherapy thus resulting in tumor repopulation and a ‘missed opportunity for cure’.e. however. We shall therefore focus our attention on the question of the ability of chemoradiation to control advanced cervical metastases (N2 or N3). hydroxyurea. a survival advantage has yet to be shown. There were significantly fewer distant failures in the induction chemotherapy arm than the surgery arm (25 vs. 28].rouracil followed by definitive radiation therapy to 70 Gy. 100 patients were treated in a phase III randomized trial and received either definitive radiotherapy (68–72 Gy) or chemoradiation (cisplatin. overall death rate was increased and the survival time was decreased. split-course radiation therapy) [30–32]. local effects of radiation versus myelosuppression of chemotherapy). Patients who were less than complete responders to chemoradiation underwent a salvage neck dissection. Mitomycin. there were no recurrences in these 6 patients. 35 of which under- Advanced Metastatic Disease ORL 2000. increased severity of mucositis). In general. The VA Larynx Study has been previously cited as an example of one organ preservation strategy utilizing induction chemotherapy followed by definitive RT. This data is derived from trials in which patients received primary chemoradiation and underwent either planned or salvage neck dissection as part of their treatment. (2) standard dose radiation with single-agent chemotherapy used as a radiosensitizer [27. both enhancement of the locoregional radiotherapeutic effect and the elimination of micometastatic distant disease can be expected. p = 0. 5-fluorouracil. Three of the remaining 41 patients had progression of disease and 4 of the final 38 patients developed recurrences at the original primary site. 25].62:226–233 229 . cisplatin. 36%. By concurrently administering a radiosensitizing drug with ionizing radiation. and (4) concurrent full-dose chemoradiotherapy with planned treatment breaks in the radiation (i. (3) rapidly alternating cycles of chemotherapy and radiation and suspending one while delivering the other [29]. and (4) radiation enhancement or sensitization: cytotoxic effects of chemotherapy further reduce the ability of tumor cells to repair radiation-induced cellular damage.034) [23]. morbidity and mortality associated with treatment [13]. and (3) increased cost. There were no differences in survival between patients treated in the two arms and larynx preservation without compromise of survival was observed in 42% of patients. Treatment of the neck in patients receiving concurrent chemoradiation has been reported by Lavertu and Adelstein [35–37] from the Cleveland Clinic. duration.

However.62:226–233 Petruzzelli/Emami . As in the VA Larynx Study. Advances in Radiation Oncology In addition to advances in timing. the fusion of magnetic resonance image (MRI) data into the treatment planning systems significantly increases the accuracy of the target volume and prevents maginal or gross misses in certain head and neck tumors (e. altered fractionation. 39] and Weisman et al. none had pathologically demonstrable tumor and there were no recurrences. Although 3D-CRT is CTbased. physical examination and evaluation of surgical pathology specimens. In a similar study. Close attention to detail is paid to delineating tumor volumes and normal structures based on imaging. Twenty-one of the patients in this study had less than a complete response and 18 underwent neck dissection. [41] treated 22 patients presenting with N2/N3 disease with high-dose intra-arterial cisplatin and concurrent RT. radioprotection agents. Six of 20 evaluable patients underwent neck dissection after having a fine needle aspiration biopsy (FNAB) of a persistent neck mass. high linear energy transfer (particle-beam) techniques. 3D treatment planning is performed on CT databases. while in the 17 less than complete responders. 1 of which was positive and 1 was ‘suggestive’ of persistent carcinoma on FNAB. In an attempt to overcome cisplatin resistance and enhance the locoregional effects of concurrent chemoradiotherapy. The mathe- 230 ORL 2000. 4 had viable tumor in the specimen. Of the 18 complete responders undergoing neck dissection. Increasing the dose (total dose and dose per fraction) and the size of the target field increases the probability of collateral damage to normal structures. several dramatic advances have been made in the field of radiation oncology. This protocol involves selective intra-arterial administration of high-dose cisplatin (150 mg/m2) with concurrent RT (1. Although addition of neck dissection reduces the risk of local recurrence.8– 2 Gy standard external beam !35 fractions) and systemic neutralization of cisplatin by intravenous infusion of sodium thiosulfate. and salivary glands. the most important of these advances in head and neck radiation oncology is the development of three-dimensional (3D) conformal radiation therapy. dose escalation and increased locoregional control can be achieved without placing adjacent normal structures at significantly higher risk [43]. In a recent report of this protocol in patients with N2 or N3 disease. nasopharynx).g. Unlike traditional two-dimensional treatment plans drawn from plain films. Fourteen patients had viable tumor in the neck dissection specimens and there was 1 local recurrence following neck dissection. The high doses delivered to exact 3D volumes require extreme accuracy in constructing target volumes and precision in dose delivery [44].went neck dissection. Local control at 2 years was reported in 20 of 22 patients. dose escalation and biological modulation of chemotherapeutic agents. The development of remote afterloading brachytherapy. 8 had viable tumor. carotid artery. 3D treatment planning and 3D dose delivery. by more precisely targeting the treatment volume. The end result of the treatment plan is a 3D reconstruction of target volumes and adjacent normal anatomy which can be viewed as the entire plan or from the perspective on an individual beam. [38. The effectiveness of radiation therapy in controlling a given tumor volume is determined by the dose delivered to that volume. These authors also advocate planned neck dissection following chemoradiotherapy in patients with advanced nodal disease based on posttreatment FNAB at 8 weeks. Robbins et al. a complete response in the neck was associated with increased disease-free survival. [39] demonstrated a complete clinical response in 33 of 56 evaluable patients. [40. Two of the 3 partial responders who did not have neck dissection died of locally uncontrolled disease. 41] have reported separate institutional experiences with simultaneous RT and intra-arterial cisplatin. Specifically of concern in the head and neck are the optic apparatus. Based on this. Substantial computational power and imaging support are required for the two components of 3D-CRT. 3D conformal radiation therapy (3D-CRT) was developed to more efficiently target the 3D volume at greatest risk which minimizes the damage to adjacent uninvolved tissue. chemosensitizing drugs. it does not increase overall survival. brain and spinal cord. and radiation-targeted gene therapy are all being tested in the clinical arena [42]. Of the 16 patients with complete response undergoing neck dissection. Robbins et al. intraoperative RT. Neck dissections for 2 patients demonstrated viable cancer. the authors recommended neck dissection for all N2/N3 patients regardless of the therapeutic response in the neck. Weisman et al. The dose delivered is limited by the tolerance of adjacent normal uninvolved tissues.

Advanced Metastatic Disease ORL 2000. The more advanced version of 3D-CRT is intensitymodulated radiation therapy (IMRT).matical relationships between the doses delivered to the tumor and specified adjacent tissues can be interpolated into a dose volume histogram [43. Combined chemoradiation therapy appears to offer higher response rates than single modality radiation in advanced metastatic disease. namely xerostomia. no data has clearly demonstrated their contribution a superior quality of life in comparison to surgical treatments. Nineteen of 20 patients had a complete response at the completion of radiation therapy. thus providing the capability for multiple treatment fields in a single therapy session. The delivery of ionizing radiation to complex 3D targets while sparing normal uninvolved tissues requires the use of multiple coplanar and non-coplanar beams. contralateral parotid glands. etc. In a recent report by Eisbruch et al. The principal difference between 3D-CRT and IMRT is that in the former. the dose is determined by the radiation oncologist and a plan is created by a team of dosimetrists/radiation oncologists (trial and error as well as experience) to achieve the conformity of the prescribed dose to the target volume in three dimensions. the intensity of the individual beams are usually not modulated and are of similar intensity whereas in IMRT the individual beam intensities are modulated (both in planning and delivery) by the computer to achieve the desired goal.62:226–233 231 . etc. [47] on utilization of 3D-CRT in treatment of 15 patients with unresectable head and neck cancer. have significantly improved the capability of highly precise dose delivery [46]. heavy and less optimal cerrobend blocks for beam shaping. In 3D-CRT. spinal cord.. the authors have significantly reduced the dose to the salivary glands without compromising the coverage of tumor target volumes. In summary. Overall toxicity was acceptable with the majority of patients (80%) completing treatment in 40 days without treatment break. 44]. Patients were treated over 5 weeks to a total dose of 60 Gy to the primary and 50 Gy to the secondary targets. such as the mandible. and spinal cord. This device is placed at the beam exit of the linear accelerator and can create multiple irregular shaped fields under computer control within seconds. such as enhanced dynamic wedges. has been shown by other authors [48]. Similarly. the nonsurgical treatment of advanced (N2/N3) metastatic disease continues to evolve. Review of the dosimetry reveals significant sparing of the mandible. thus eliminating one of the most debilitating long-term complications of head and neck RT. through millions of iterations will create the best plan to achieve the goal of conformity. asymmetric jaws. Total allowable Medicare charges for treatment were less than those for either conventional or accelerated fractionation RT. Nine patients reported symptomatic xerostomia during treatment and no patient had higher than grade 2 salivary toxicity. 46]. Whereas in IMRT the dose is specified by the radiation oncologist (both to target volumes as well as normal tissues) and the specialized computer. Patients in whom chemoradiation is not effective in eradicating cervical metastases will still need to be offered neck dissection as salvage. At our institution every effort is made to coordinate the delineation of target volumes with both the surgical and radiation oncologists. Use of the MLC has eliminated the need for traditional cumbersome.. Integral to the precise delivery of these beams is the multileaf collimator (MLC) [45]. Twenty patients with head and neck carcinoma (including 3 cases of nasopharyngeal carcinoma) were treated with IMRT-based simultaneous modulated accelerated radiation therapy (SMART). such as wedges and tissue compensators [44. While nonsurgical treatments do not appear to influence survival positively or negatively. Other 3D-CRT delivery accessories. Utilization of IMRT eliminated the use of traditional accessories. as less than complete responders will need some surgical treatment of the primary site. An initial experience with IMRT has recently been reported by Butler et al. the significant potential of 3D-CRT in sparing uninvolved normal structures. [49].

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217 Smith. 2000 Alexiou. 226 Rinaldo. 204. 217 Silver.M. 199 Curtin. 199 Subject Index Vol.A. No. 217 – – metastases 178. C.L.O. 204. A.karger. 177.com/journals/orl . 212 Stimmer.Author Index Vol. 226 Ferlito. S. R. 177. H. 199 Mancuso. 217 Som. H. 186.D. 212.V.J. P. 62. 186 Mondin. 2000 Advanced cervical metastases 226 Angiogenesis 178 Cancer invasion 178 Cervical node metastases 204 Chemotherapy 226 Classification 212 Computed tomography 186. 204 Devaney. Basel Accessible online at: www. 217 Pathology 204 Positron emission tomography 199 Radiotherapy 226 Specimen processing 204 Ultrasound 199 ABC Fax + 41 61 306 12 34 E-Mail karger@karger. 4. B. K. 186 Devaney. No. 204 Emami. 217 Kau. G.karger. W. V.ch www. 4.E. 62. A. 178. 199 Arnold. 212.J. C. R. Karger AG.com © 2000 S. 199 Head and neck cancer 212 – – – neoplasms 186 Laryngeal cancer 199 Larynx 217 Lymph node(s) 186. 212 Petruzzelli. A. 199 Lymphatic metastasis 186 Magnetic resonance imaging 199 Metastasis 217 Neck dissection 212.