cervical metastasis

7/29/2019 Cervical Metastasis

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Cervical metastasis by a tumor is firm statement of its aggressive malignant nature. Nothing ismore controversial than the management of cervical metastatic disease. This is not surprisingconsidering the lack of knowledge of carcinogenesis, pathophysiology of metastases, andimplications of tumor spread. Fortunately, great strides have been made in the understanding of the intricate processes related to metastatic disease. Proper understanding of anatomy and the

detection of cervical metastatic disease is crucial to this process. Forthcoming techniques willalso facilitate the detection of primary and metastatic disease.

For excellent patient education resources, visit eMedicine's Cancer and Tumors Center . Also, seeeMedicine's patient education article Cancer of the Mouth and Throat .

Photograph showing an aspirate being placed on a glass slide.After the 20-mL disposable syringe with an attached 21-gauge needle is placed under the skinsurface and the mass is aspirated, a small drop of aspirated fluid is placed on a glass slide.N

The lymphatic system has 3 components: the capillaries, vessels, and nodes.

Capillaries

Larger than arteriovenous capillaries, lymphatic capillaries are thin-walled, with a single layer of endothelial cells. Lymphatic capillaries are found in all tissues; however, they are more abundantin the upper respiratory and GI tracts. Pooled capillaries drain lymphatic fluid into lymphaticvessels, which have 3 layers.

Vessels

As in the capillaries, the vessels have a single layer of endothelial cells surrounded by an inner,longitudinal elastic layer. This first muscle layer is surrounded by a circular smooth musclelayer, which, in turn, is enveloped by an outer connective tissue layer. Lymphatic vessels containmany more valves than the venous system, with the lymph circulation entirely dependent oncompression by surrounding muscles. Lymphatic vessels drain into lymph nodes.

Nodes

These nodules of tissue are of variable size. Typically, as many as 75 nodes are located on eachside of the neck. Nodes contain a subcapsular sinus below a prominent capsule, into whichlymphatic fluid drains. This capsule is often the first site of metastatic growth. The fluidpermeates the substance of the node (composed of a cortex and a medulla) and exits through the
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hilum to enter more lymphatic vessels. These nodes are located between the superficial cervicaland prevertebral fascia and, thus, are very amenable to surgical removal. The lymphatic fluideventually enters the venous system at the junction of the internal jugular and subclavian veins.Many nodal descriptions exist today; Rouvire's is the classic model. The following describes themain cervical node groups:

The occipital nodes are in the superficial group, which includes 3-5 nodes. This group of nodes islocalized between the sternocleidomastoid (SCM) and trapezius muscles, at the apex of theposterior triangle. These nodes are superficial to the splenius capitis.

The deep posterior cervical group includes 1-3 nodes. This group of nodes is located deep to thesplenius capitis and follows the course of the occipital artery. These nodes drain the scalp, theposterior portion of the neck, and it's the deep muscular layers of the neck.

The postauricular nodes vary in number from 2 to 4; they are located in the fibrous portion of thesuperior attachment of the SCM muscle to the mastoid process. Postauricular nodes drain the

posterior parietal scalp and the skin of the mastoid region.

The parotid nodes can be divided into intraglandular and extraglandular groups. Theextraglandular parotid nodes are located outside but adjacent to the parotid gland, where theydrain the frontolateral scalp and face, the anterior aspects of the auricle, the external auditorycanal, and the buccal mucosa. Embryologically, the lymphatic system develops before theparotid gland, which surrounds the intraglandular nodes as it develops. This explains why theparotid gland contains lymphoid tissue. The intraglandular nodes drain the same regions as theextraglandular nodes, to which they interconnect and then drain into the upper jugular group of lymph nodes. As many as 20 parotid nodes may be found.

The submandibular nodes are divided into 5 groups: preglandular, postglandular, prevascular,postvascular, and intracapsular. The preglandular and prevascular groups are located anterior tothe submandibular gland and facial artery, respectively. The postglandular and postvasculargroups are posterior to these structures. Differing from the parotid gland in embryologicaldevelopment, there is no true intraglandular node; however, occasionally, a node has beenidentified inside the capsule of the gland. The submandibular nodes drain the ipsilateral upperand lower lip, cheek, nose, nasal mucosa, medical canthus, anterior gingiva, anterior tonsillarpillar, soft palate, anterior two thirds of the tongue, and submandibular gland. The efferentvessels drain into the internal jugular nodes.

For the submental nodes, 2-8 nodes are located in the soft tissues of the submental trianglebetween the platysma and mylohyoid muscles. These nodes drain the mentum, the middleportion of the lower lip, the anterior gingiva, and the anterior third of the tongue. The efferentvessels drain into both the ipsilateral and contralateral submandibular nodes or into the internal

jugular group.

The sublingual nodes are located along the collecting trunk of the tongue and sublingual glandand drain the anterior floor of the mouth and ventral surface of the tongue. These nodessubsequently drain into the submandibular or jugular group of nodes.


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The retropharyngeal nodes are divided into a medial and lateral group, located between thepharynx and the prevertebral fascia. The lateral group, located at the level of the atlas near theinternal carotid artery, consists of 1-3 nodes, which may extend to the skull base. The medialgroup extends inferiorly to the postcricoid level. This group drains the posterior region of thenasal cavity, sphenoid and ethmoid sinuses, hard and soft palates, nasopharynx, and posterior

pharynx down to the postcricoid area. Management of these nodes must be considered if anymalignancy arises from the mentioned drainage areas.

The anterior cervical nodes are divided into the anterior jugular chain and the juxtavisceral chainof nodes. The anterior jugular chain nodes follow the anterior jugular vein, located superficial tothe strap muscles. These nodes drain the skin and muscles of the anterior portion of the neck, andthe efferent vessels empty into the lower internal jugular nodes.

The juxtavisceral nodes are separated into the prelaryngeal, prethyroid, pretracheal, andparatracheal nodes. Prelaryngeal nodes are located from the thyrohyoid membrane to thecricothyroid membrane and drain the larynx and the thyroid lobes. A single delphian node is

often found overlying the thyroid cartilage.

The pretracheal group consists of nodes between the isthmus of the thyroid gland down to thelevel of the innominate vein. Varying from 2-12 in number, these nodes drain the region of thethyroid gland and the trachea and receive afferent flow from the prelaryngeal group. Thepretracheal efferents empty in the internal jugular group and the anterior superior mediastinalnodes.

The paratracheal nodes lie near the recurrent laryngeal nerve and drain the thyroid lobes,parathyroid glands, subglottic larynx, trachea, and upper esophagus. The efferent vessels travelto the lower jugular group or directly toward the junction of the internal jugular vein and the

subclavian vein. The anterior nodes drain bilaterally because the midline of the neck has nodivision. Treatment must be planned accordingly when a tumor is located in subjacent drainingareas.

The lateral cervical nodes are divided into superficial and deep groups. The superficial groupfollows the external jugular vein and drains into either the internal jugular or transverse cervicalnodes of the deep group.

The deep group forms a triangle bordered by the internal jugular nodes, the spinal accessorynodes, and the transverse cervical nodes. The transverse cervical nodes, forming the base of thetriangle, follow the transverse cervical vessels and may contain as many as 12 nodes. Thesenodes receive drainage from the spinal accessory group and from collecting trunks of the skin of the neck and upper chest. The spinal accessory chain follows the nerve of the same name andmay account for as many as 20 nodes. This chain receives lymph from the occipital,postauricular, and suprascapular nodes and from the posterior aspect of the scalp, nape of theneck, lateral aspect of the neck, and the shoulder.

The internal jugular chain consists of a large system covering the anterior and lateral aspects of the internal jugular vein, extending broadly from the digastric muscle superiorly to the


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subclavian vein inferiorly. As many as 30 of these nodes may exist, and they have beenarbitrarily divided into upper, middle, and lower groups. The efferents of these nodes eventuallypass into the venous system via the thoracic duct on the left and multiple lymphatic channels onthe right. These nodes drain all the other groups mentioned. Direct efferents may be present fromthe nasal fossa, pharynx, tonsils, external and middle ear, eustachian tube, tongue, palate,

laryngopharynx, major salivary glands, thyroid, and parathyroid glands.

Although fairly consistent, these drainage patterns are subject to alteration with malignantinvolvement or after radiotherapy. In such cases, rerouting is possible, with metastases arising inunusual sites. Metastases have also been shown to skip first-echelon nodes and manifest in thelower internal jugular group.

Spread patterns of cancer from various primary sites in the head and neck to the cervical nodeshave been documented in retrospective analyses of large groups of patients undergoing neck dissections. Since the first descriptions of nodal groups, various classification systems have beendescribed.

To address surgical management of early-stage neck metastases via neck dissection, variousauthors have proposed a number of classification schemes. This lack of uniformity andstandardization results in redundancy, misinterpretation, and confusion among clinicians. Themost widely accepted terminology was originally described by a group of head and neck surgeons at Memorial Sloan-Kettering Hospital. This classification uses neck levels or zones anddivides each side of the neck into 6 separate regions. This system is still used today.

Level I is bordered by the body of the mandible, anterior belly of the contralateraldigastric muscle, and anterior and posterior bellies of the ipsilateral digastric muscle.Two nodal subgroups are found. The submental group (Ia) is found in the submental

triangle (anterior belly of the digastric muscles and the hyoid bone), and thesubmandibular group (Ib) is found within the submandibular triangle (anterior andposterior bellies of the digastric muscle and the body of the mandible).

The nodes found in level II are located around the upper third of the internal jugular vein,extending from the level of the carotid bifurcation inferiorly to the skull base superiorly.The lateral boundary is formed by the posterior border of the SCM muscle; the medialboundary is formed by the stylohyoid muscle. Two subzones are also described; nodeslocated anterior to the spinal accessory nerve are part of level IIa, and those nodesposterior to the nerve are located in level IIb.

The middle jugular lymph node group defines level III. Nodes are limited by the carotidbifurcation superiorly and the cricothyroid membrane inferiorly. The lateral border isformed by the posterior border of the SCM muscle; the medial margin is formed by thelateral border of the sternohyoid muscle.

Level lV contains the lower jugular group and extends superiorly from the omohyoidmuscle to the clavicle inferiorly. The lateral border is formed by the posterior border of the SCM muscle; the medial margin is formed by the lateral border of the sternohyoidmuscle.

The lymph nodes found in level V are contained in the posterior neck triangle, borderedanteriorly by the posterior border of the SCM muscle, posteriorly by the anterior border


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of the trapezius, and inferiorly by the clavicle. Level V includes the spinal accessory,transverse cervical, and supraclavicular nodal groups.

Level VI lymph nodes are located in the anterior compartment. These nodes surround themiddle visceral structures of the neck from the level of the hyoid superiorly to thesuprasternal notch inferiorly.

A complete understanding of these anatomic relationships allows various practitioners toexchange information in an unbiased fashion and is critical in the decision-making processesinvolved in management of nodal metastases.

The current hypotheses on the development of malignancies relate to alterations in the normalmechanisms of cellular proliferation and differentiation and a failure of cell death (apoptosis).This loss of growth control is the result of genetic mutations, including the activation of proto-oncogenes and/or inactivation of tumor suppressor genes. The resulting phenotypic changesprovide cancer cells a growth advantage, including loss of response to normal growth controls,defects in response signals for programmed cell death, resistance to cytotoxicity, and defects in

terminal differentiation.

Proposed by Fidler, the concept of tumor heterogeneity suggests that tumors are composed of heterogeneous subpopulations of cells differing in immunogenicity, invasiveness, cellular growthkinetics, sensitivity to cytotoxic drugs, and ability to metastasize. The local tumor environmentmay favor the development of more aggressive clones in the formation of metastases. Althoughthe size of individual clones with metastasizing potential in a given tumor is significant, only avery small percentage of circulating cells lead to the development of metastatic colonies.

The events surrounding the initiation of local tumor invasion by epithelial tumors include a lossof cellular adhesion to surrounding tumor cells and basement membrane, invasion by malignant

cells of the subjacent connective tissues by the production of cellular enzymes and growthmediators, cellular attachment to extracellular membrane molecules, neovascularization, andentry or exit from the circulation through the attachment to endothelial cell ligands. A repeat of these events occurs at metastatic sites.

In the case of head and neck squamous cell carcinomas, malignant cells may progress fromcarcinoma in situ, to microinvasive carcinoma, to a deeply invasive tumor with lymphaticmetastases. Interestingly, a head and neck squamous cell carcinoma has the ability to manifest atboth extremes of histopathological development in the same anatomic location. The critical stepin the transition from carcinoma in situ to microinvasive and invasive carcinoma is thedestruction of the basement membrane. This destruction is accomplished by the production of specific proteolytic molecules by tumor cells, including matrix metalloproteinases, collagenases,and plasminogen activators.

Angiogenesis is the growth of new capillaries by sprouting from established vessels. In normaltissues, self-limiting angiogenesis is part of reproduction and organogenesis in addition to woundrepair and healing. Conversely, pathological angiogenesis is not autoregulated, but results fromalterations in growth-control mechanisms of disease processes (eg, malignant transformation).Various tumor-derived factors (eg, prostaglandin E2, platelet-derived growth factor,


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transforming growth factor-beta, transforming growth factor-alpha, beta-fibroblast growth factor)are still being investigated for their propensity to facilitate endothelial cell proliferation.

Recent research looking specifically at the production of cytokines regulating immune,inflammatory, and angiogenetic responses in patients with laryngeal squamous cell cancer has

revealed higher serum concentrations of the cytokines interleukin-6, interleukin-8, and vascularendothelial growth factor. These agents may be important in proinflammatory andproangiogenetic responses of tumor cells.

The ability of a tumor to stimulate an angiogenic response should directly determine thecapability of a tumor to metastasize and ultimately kill the host. A clear correlation betweentumor angiogenesis and nodal metastasis has been demonstrated in early and invasive breastcarcinoma, ovarian and endometrial carcinoma, non small-cell carcinomas, prostatic carcinoma,adenocarcinoma of the colon, and squamous cell carcinoma of the esophagus.

The literature notes conflicting reports regarding microvessel density and nodal metastasis in

head and neck squamous cell carcinomas. Tumor sites of varying origins with differentvascularization patterns at their primary sites may behave differently. Malignancies of the headand neck, especially head and neck squamous cell carcinomas, are the result of a series of geneticmisadventures of squamous epithelial cells leading to malignant transformation. Variable geneticsusceptibility, prolonged tobacco and alcohol exposure, viruses, and immune suppression all canfacilitate these genetic derangements.

Tumors invade local connective tissues by the production of proteinases and the expression of surface markers that facilitate attachment to extracellular matrix components. Tumor growth andsize being limited by available nutrients from the surrounding milieu, recruitment of hostcapillaries leads to the formation of an intratumoral blood supply. Capillary and lymphatic

invasion by tumor cells allow malignant cell dissemination and the establishment of histologically identical tumors at distant sites.

Most recently, the expression of vascular endothelial factor-D in a mouse tumor model wasfound to lead to the lymphatic spread of tumor cells, tumor angiogenesis, and tumor growth.Further research in this area will likely provide more details in the multiple steps involved in thelymphatic spread of squamous cell cancer.

The dissemination of tumor cells beyond the primary site unfortunately remains the mostsignificant factor in prognosis and needs further study.

Evaluation of the Neck for Cervical Metastases: Physical Examination

Evaluating neck metastases based on physical examination findings has been the classic methodfor patients with new tumors in the head and neck. The single most important factor indetermining prognosis is whether nodal metastasis is present. Survival rates decrease by 50%when nodal metastases are present. Furthermore, the presence of cervical adenopathy has beencorrelated with an increase in the rate of distant metastasis.


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During the clinical evaluation, careful palpation of the neck, with specific attention to location,size, firmness, and mobility of each node, is noted. Attention is particularly directed to nodes thatappear fixed to underlying neurovascular structures, visceral organs, or nodes that demonstrateskin infiltration. The description of each node becomes an important part of the medical record,which can be used to assess the response to treatment or the progression of the disease.

Unfortunately, clinical palpation of the neck demonstrates a large variation of findings amongvarious examiners. Although both inexpensive to perform and repeat, palpation findings aregenerally accepted as inaccurate. Both the sensitivity and specificity are in the range of 60-70%,depending on the tumor studied. Because of the known low sensitivity and specificity of palpation, a neck side without palpable metastases is still at risk of harboring occult metastasis,with the risk determined by the characteristics of the primary tumor. The incidence of false-negative (occult) nodes based on physical examination findings varies in the literature from 16-60%. Before the introduction of diagnostic imaging, particularly CT scan, clinical palpation wasshown to be inadequate for detecting cervical metastasis. Soko et al reported that only 28% of occult cervical metastases were found by clinical palpation. Martis reported a 38% prevalence of

occult metastasis based on clinical examination findings.

Detection of Cervical Metastasis: Radiological Investigations

Debate persists over the relative merits of imaging in the evaluation of the neck for metastaticdisease .[1] Studies that correlate radiologic and histopathologic findings show that earlymicroscopic metastases can be present in nodes smaller than 10 mm that demonstrate no stigmataof neoplasia (ie, central necrosis, extracapsular spread). Evidence of early metastatic disease inclinically occult nodes is minimal and may evade the efforts of the pathologist and radiologist.

Ultrasound

Ultrasound is reported superior to clinical palpation for detecting lymph nodes and metastases.The advantages of ultrasound over other imaging modalities are price, low patient burden, andpossibilities for follow-up.

Sonographs of metastatic lymph node disease characteristically find enlargement with a sphericalshape. Commonly, nodes are hypoechoic, with a loss of hilar definition. In cases of extranodalspread with infiltrative growth, the borders are poorly defined. Common findings of metastasesfrom squamous cell carcinoma are extranodal spread and central necrosis together with liquidareas in the lymph nodes. Lymph node metastases from malignant melanoma and papillarythyroid carcinoma have a nonechoic appearance that mimics a cystic lesion. Sonography may

also be useful for assessing invasion of the carotid artery and jugular vein.

Because lymph nodes of borderline size cannot be reliably diagnosed using ultrasound alone,ultrasound-guided fine-needle aspiration and cytologic examination of the nodes in question canbe easily performed. The result of the aspirate examination depends on the skill of theultrasonographer and the quality of the specimen (ie, harboring an adequate number of representative cells). Using this technique, most studies report that a sensitivity of up to 70% canbe obtained for the N0 neck .
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Photograph showing the smear technique for plating a sample aspirate. After asmall drop of fluid is placed on a glass slide, a second slide is used to smear the aspirate evenly over thesurface of the slide. The slide is then prepared for cytologic evaluation.

Photograph showing an aspirate being placed on a glass slide. Afterthe 20-mL disposable syringe with an attached 21-gauge needle is placed under the skin surface and themass is aspirated, a small drop of aspirated fluid is placed on a glass slide.

CT scan

Since its debut in the 1970s, CT scans have been an invaluable tool in all fields of medicine,including the evaluation of head and neck cancer. Since the advent of high-resolution systemsand specific contrast media, fine-cut CT scanning has allowed the detection of pathologicalcervical nodes of smaller size that may be missed by clinical examination. CT scanning is nowused routinely for the preoperative evaluation of the neck because, presumably, it helps decreasethe incidence of occult cervical lymphadenopathy .[2]

Introduced in 1998, multiple-spiral CT scanning promises further improvement of temporal andspatial resolution (in the longitudinal axis). This technique permits rapid scanning of largevolumes of tissue during quiet breathing. The volumetric helical data permit optical multiplanarand 3-dimensional reconstructions. Improvement of the assessment of tumor spread and lymph

node metastases in arbitrary oblique planes is another advantage of the spiral technique.

Criteria for the identification of questionable nodes are also evolving as technology advances.Central necrosis remains the most specific finding suggestive of nodal involvement, but itsabsence does not exclude metastasis. Unfortunately, metastasis is usually quite rare or not visiblein small lymph nodes, where detection would be crucial. Because of the higher imagingresolution, various studies have reduced the traditional values of 10-15 mm for a node to besuggestive. Many authors have proposed a minimal axial diameter of 11 mm for the
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submandibular triangle and 10 mm for the rest of the neck. Other criteria include the presence of groups of 3 or more borderline nodes and the loss of tissue planes.

An imaging-based classification has also been proposed by Som et al ,[3] and due to its specificity,has also been endorsed by clinicians managing head and neck cancer. The boundaries of the

nodal levels were easily discerned by radiologists and yielded consistent nodal classifications.

For an evaluation of the diagnostic abilities of Ga-SPECT, see Kotani et al .[4]

Magnetic resonance imaging

The value of MRI is its excellent soft tissue resolution. MRI has surpassed CT scanning as thepreferred study in the evaluation of cancer at primary sites such as the base of the tongue and thesalivary glands. The sensitivity of MRI exceeds that of clinical palpation in detecting occultcervical lymphadenopathy. Size, the presence of multiple nodes, and necrosis are criteria sharedby CT scanning and MRI imaging protocols .[5, 6]

Many reports indicate that CT scanning still has an edge over MRI for detecting cervical nodalinvolvement. Advances in MRI technology (eg, fast spin-echo imaging, fat suppression) have notyet surpassed the capacity of CT scanning to identify lymph nodes and to define nodalarchitecture. Central necrosis, as evaluated by unenhanced T1- and T2-weighted images, hasbeen shown to provide an overall accuracy rate of 86-87% compared with CT scanning, whichhas an accuracy rate of 91-96% .[7] The use of newer contrast media, especially supramagneticcontrast media agents, hopefully will improve the sensitivity of MRI.

Positron emission tomography imaging

This new imaging modality has been increasingly studied in the staging of head and neck cancer .[8, 9] The technique relies on the uptake of 2-fluoro-2-deoxy-D-glucose (FDG) inmetabolically-active lesions. The study may also be fused to a corresponding CT scan tofacilitate the localization of the lesion of concern.

In comparing the usefulness in the detection of cervical metastasis, PET/CT fusion images havebeen found to be superior and more accurate for the detection of cervical metastasis, compared toPET alone, as well as conventional imaging modalities. In addition, PET can contribute to thedetection of residual or early recurrent tumors, leading to the institution of earlier salvagetherapy .[2]

Conclusions

None of the currently available imaging techniques can help depict small tumor deposits insidelymph nodes. Characteristics of metastatic lymph nodes that can be depicted are the size andpresence of noncontrast-enhancing parts inside metastatic lymph nodes caused by tumornecrosis, tumor keratinization, or cystic areas inside the tumor. Only rarely does tumoral tissueenhance more than reactive lymph node tissue; in these rare cases, the tumor can be visualizedwithin a reactive lymph node.


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Patients who need an evaluation for a possible nodal malignancy require a comprehensivemultidisciplinary evaluation of all potential sites of drainage to that node to identify its primarysource. This includes a thorough evaluation of potential primary sites using endoscopictechniques. When appropriate, include laryngoscopy, esophagoscopy, bronchoscopy, andexamination of the nasopharynx. If no primary source is identified, taking blind mucosal biopsy

samples of the most likely head and neck subsites is essential .[10]

PET/CT techniques have a promising role; however, greater clinical experience is needed priorto making this modality the standard for the detection of metastasis in head and neck cancer.

Complete documentation of nodal characteristics by clinical examination and palpation guide theexaminer in using adjunctive radiological tools to exclude occult nodal metastasis.

cervical metastasis

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