Diagnosis of lymph node metastases of head and neck cancer and evaluation of effects of chemoradiotherapy using ultrasonography

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1 Int J Clin Oncol (2010) 15:23 32 DOI /s REVIEW ARTICLE Diagnosis of lymph node metastases of head and neck cancer and evaluation of effects of chemoradiotherapy using ultrasonography Madoka K. Furukawa Masaki Furukawa Received: 30 November 2009 / Published online: 29 January 2010 Ó Japan Society of Clinical Oncology 2010 Abstract Background Ultrasonographic diagnostic criteria were established to detect cervical metastatic lymph nodes including those up to 10 mm in thickness. Ultrasonography can diagnose not only cervical metastatic lymph nodes but can also be used to evaluate treatment-induced changes in lymph node metastases, one by one or degeneration of metastatic lesion in remaining lymph nodes after chemoradiotherapy. Methods A high-frequency probe of 7.5 MHz or higher was used in the ultrasonographic diagnosis of cervical lymph node metastases, using B-mode, Doppler blood flow imaging, and tissue elasticity imaging. Cervical lymph node metastases of head and neck squamous cell carcinoma were diagnosed according to ultrasonographic lymph node metastasis criteria. These criteria consist of the thickness of a lymph node (more than 6 mm or not), and existence of intra-lymph nodal occupying lesions suspected as a metastatic focus or not. Furthermore, metastatic lymph nodes remaining without regression after chemoradiotherapy were also evaluated according to therapeutic effect, using ultrasonography, and we examined the efficacy of ultrasonography to predict clinical outcomes. Results These diagnostic criteria enabled the accurate diagnosis of metastatic lymph nodes that were up to 10- mm-thick; such nodes are difficult to diagnose by M. K. Furukawa (&) Department of Head and Neck Surgery, Kanagawa Cancer Center, Nakao, Asahi-ku, Yokohama, Kanagawa , Japan madoka@yokohama. .ne.jp M. Furukawa Division of Medical Informatics, Yokohama City University Medical Center, Yokohama, Japan computed tomography (CT) or magnetic resonance imaging (MRI). Moreover, examination of therapeutic effects such as decreased blood flow into a metastatic focus, and softening of a lymph node, by evaluating B-mode dynamic images or employing tissue elasticity imaging, was also useful to determine the effectiveness of chemoradiotherapy and a favorable outcome. Conclusion Ultrasonographic diagnostic criteria for cervical metastatic lymph nodes enabled accurate diagnosis. Ultrasonographic evaluation of therapeutic effects on cervical lymph node metastases revealed not only the control of metastasis in the cervical region but also the clinical course and control of the primary site. Keywords Ultrasonography Diagnostic criteria Lymph node metastasis Head and neck cancer Introduction In the diagnosis of lymph node metastases of head and neck cancer, ultrasonography can evaluate enlarged lymph nodes one by one. By using ultrasonography, the presence or absence of metastases is determined from the same perspective as neck dissection. Ultrasonography allows the evaluation of not only lymph nodes that are 10 mm diameter or more [1], which are generally diagnosed as cervical lymph node metastasis-positive by computed tomography (CT) or magnetic resonance imaging (MRI), but also lymph nodes of less than 10 mm diameter, based on sufficient image information. Thorough preventive and radical dissection had been recommended to be performed regardless of the result of preoperative diagnosis, because all lymph node metastases less than 10 mm in diameter had been considered as potential lymph node metastasis

2 24 Int J Clin Oncol (2010) 15:23 32 because of the low diagnostic accuracy of CT or MRI. Although radical neck dissection can decrease the rate of secondary lymph node metastases or relapse, it may induce in patients various postoperative pains and disorders due to cervical dysfunction [2]. Thus, the role of ultrasonography will take on greater importance in the future. The number of cases in which chemoradiotherapy is selected with the aim of preserving organs has been increasing among patients with head and neck cancer, including those with cervical lymph node metastasis. Although it has been considered difficult to control cervical lymph node metastasis by radiotherapy alone, the number of patients in whom satisfactory efficacy has been obtained even against cervical lymph node metastasis by combining chemotherapy with radiotherapy has been increasing. Ultrasonographic evaluation of therapeutic effects on cervical lymph node metastases is necessary to choose the patients who do not need additional neck therapy, to avoid shoulder dysfunction or swallowing disturbance caused by excess neck therapy. is approximately identical to the diameter of a lymph node measured on the horizontal section by CT or MRI (Fig. 1). Cervical lymph node metastases in patients with head and neck squamous cell carcinoma were diagnosed according to ultrasonographic lymph node metastasis criteria, prepared based on the standard thickness, changes in the internal structure, and blood flow of a lymph node (Table 1; Figs. 2, 3). A lymph node with a thickness of 6 mm or more is defined as suspected of being positive for metastasis. Even normal or reactive lymphadenopathies can have a thickness of 6 mm or more; those with no occupying lesions, suspected to be a metastatic focus, must Major axis Y Z β α Skin X Materials and methods Thickness Minor axis A high-frequency probe of 7.5 MHz or higher (about 10 MHz) is used in the diagnosis of cervical lymph node metastases; focus, gain, and depth are adjusted to the cervical region to obtain the best image [3]. Studies of Doppler blood flow imaging and other techniques are performed concomitant with B-mode observation. Three-dimensional size measurement should be performed for this procedure. When an image of a maximum section of a lymph node is obtained by placing the probe on the body surface toward the body axis direction, the distance of the lymph node in this direction is defined as the thickness. In the cervical region, lymph node thickness Body axis Fig. 1 Measurement of the size of a lymph node using threedimensional ultrasonography. Upon measurement of a lymph node, the maximum transverse section of a lymph node is defined as the a(x Z) plane and the maximum transverse section normal to a is defined as the b(y Z) plane. This is done to enable three-dimensional measurement with a lymph node taken as an ellipsoid. When a probe is held against the body surface to the body axis direction, the distance of a lymph node in the direction from the body surface to the body axis is defined as lymph node thickness. In the cervical region, lymph node thickness is approximately identical to the diameter of a lymph node measured on the horizontal section by computed tomography (CT) or magnetic resonance imaging (MRI) Table 1 Diagnosis of cervical lymph node metastases (head and neck squamous cell cancer) using ultrasonography B mode Color or power Doppler Thickness of lymph node 6 mm or more Thickness of lymph node less than 6 mm Thickness of lymph node 6 mm or more Thickness of lymph node less than 6 mm Metastasis-positive in principle Those with unlocalized fatty hilum identified Metastasis-negative in principle Those nearly spherical in shape, with fatty hilum not identified or localized Metastasis-positive in principle Those with blood flow distributed uniformly through the hilum of a lymph node to the entire lymph node Metastasis-negative in principle Those nearly spherical in shape with perfusion defect or disturbed blood flow detected from blood flow distribution through the hilum to the entire lymph node Metastasis-positive Metastasis-negative Node-negative Metastasis-positive Metastasis-positive Metastasis-negative Metastasis-negative Metastasis-positive

3 Int J Clin Oncol (2010) 15: Fig. 2 Flow chart for the ultrasonographic (B-mode) diagnosis of cervical lymph node metastasis (head and neck squamous cell cancer). Cervical lymph node metastases in patients with head and neck squamous cell carcinoma were diagnosed according to the ultrasonographic lymph node metastasis criteria prepared based on the standard thickness and changes in the internal structure Thickness of lymph node: 6 mm or higher Metastatic lymph node with unlocalized fatty hilum identified Thickness of lymph node: than 6 mm less Metastatic lymph node nearly sphere in shape with fatty hilum not identified or localized metastasispositive metastasisnegative metastasisnegative metastasispositive Fig. 3 Flow chart for the ultrasonographic color or power Doppler diagnosis of cervical lymph node metastases (head and neck squamous cell cancer). If Doppler blood flow imaging was available, cervical lymph node metastases were diagnosed according to the ultrasonographic lymph node metastasis criteria prepared based on the thickness, changes in the internal structure, and blood flow of a lymph node, using B-mode and Doppler blood flow imaging Thickness of lymph node: 6 mm or higher Metastatic lymph node with blood flow traversing the hilum and distributed uniformity to the entire lymph node Thickness of lymph node: less than 6 mm Metastatic lymph node nearly sphere in shape with perfusion defect or disturbed blood flow detected in blood flow distribution through the hilum to the entire lymph node metastasis-positive metastasispositive metastasisnegative metastasisnegative be excluded. Therefore, when there are no obvious occupying lesions, the hilum of a lymph node can be clearly identified by B mode, or uniformly distributed blood flow to the lymph node through the hilum can be observed. Although lymph nodes with a thickness of less than 6 mm are considered metastasis-negative, they were judged as metastasis-positive when the presence of occupying lesions suspected to be a metastatic focus within the lymph node was doubtful. From these contexts, lymph nodes that were spherical, those in which the hilum could not be identified by B mode, or those that were irregularly localized, and those with a perfusion defect or disturbance in blood flow distribution through the hilum were defined as metastasis-positive even though their thickness was less than 6 mm. Because additional treatment of the cervical region is associated with problems such as post-treatment dysfunction, accurate evaluation of the therapeutic effect is necessary in determining the necessity for additional treatment. If metastatic lymph nodes have disappeared upon evaluation of the therapeutic effects of chemoradiotherapy by B-mode ultrasonography, the therapy may be considered to have been effective; however, a lymph node may clearly appear to remain even if it is not defined on

4 26 Int J Clin Oncol (2010) 15:23 32 Lymph node metastases Evaluation of treatment effect based on size and number of lymph nodes Disappeared/scarred Regression Unchanged Worsening Evaluation of treatment effect based on the presence or absence of degeneration With degeneration Without degeneration A favorable prognosis can be expected Fig. 4 Evaluation of treatment effect on cervical metastatic lymph node using ultrasonography. Disappeared or scarred indicates effacement of metastatic lymph nodes or only scars remaining. Regression indicates metastatic lymph nodes have regressed and remain (bidirectional regression rate: 50% or higher). Unchanged indicates metastatic lymph nodes have not regressed (bidirectional Additional treatments should be considered regression rate: less than 50%). Worsening indicates metastatic lymph nodes have enlarged, with the emergence of neopathies. Regression and Unchanged are further classified based on the presence or absence of degeneration. Changes in blood flow (Doppler blood flow imaging) and changes in hardness (B mode, tissue elasticity imaging) are used for the diagnosis of degeneration Fig. 5 Ultrasound images of lymph node metastases and dissected lymph nodes. Ultrasound images of metastatic lymph nodes of 10 and 20 mm thickness, the latter resulting in replacement of the whole internal structure of the lymph node by the metastatic focus and allowing the diagnosis of metastasis using the ultrasonographic diagnostic criterion (the scale shows 10 mm)

5 Int J Clin Oncol (2010) 15: Fig. 6 Evaluation of treatment effect on metastatic lymph node using power Doppler echography. Lymph nodes with disappearance of blood flow to a metastatic focus were judged to have become degenerated and this indicated a favorable outcome Fig. 7 Pre- and postchemoradiotherapy metastatic lymph node elastography. Tissue elasticity imaging displays different hardness of tissues in different colors through calculation of the differences in the distortions of tissues. Hard tissues are displayed in blue and soft tissues in red in this figure. The images show that a metastatic lymph node, or a hard mass, which can be observed to be predominantly blue prior to treatment, changes to a soft mass, seen to be a blend of green and red after treatment. The lymph node can be judged as being degenerated due to treatment effects palpation. Nonetheless, if there are favorable treatment effects, the remaining lymph node becomes soft with no blood flow to the metastatic focus within the metastatic lymph node (as demonstrated on ultrasound images) due to the degeneration occurring within the lymph node. The ultrasonographic evaluation procedure for determining the effects of treatment on cervical lymph node metastasis is shown in Fig. 4. Evaluation of the effects of concurrent chemoradiotherapy with cisplatin (CDDP) and 5-fluorouracil (FU), using ultrasonography, was performed in 51 patients positive for cervical lymph node metastases of

6 28 Int J Clin Oncol (2010) 15:23 32 Worsened 0 (January 2000 December 2006) Unchanged 11 Stage III 4 patients Stage IVa 45 patients Stage IVb 2 patients Regressing15 Disappeared/ scarred25 Patients with regressing/unchanged lymph node: 26 Survival(%) (25 patients) (15 patients) p= p= (11 patients) Disappeared/scarred Regressing Unchanged Survival(%) ( 9 patients) p= (17 patients) With degeneration Without degeneration Time Year Time Year Fig. 8 Ultrasonographic evaluation of chemoradiotherapy effect on metastatic lymph node, and prognosis. Evaluation of the effects of concurrent chemoradiotherapy with cisplatin (CDDP) and 5-fluorouracil (5-FU), using ultrasonography, were performed in 51 patients positive for cervical lymph node metastases of hypopharyngeal cancer. Lymph nodes disappeared or were scarred in 25 patients. The prognosis of patients with disappeared or scarred lymph nodes was favorable. The prognosis of patients with regressing/unchanged lymph nodes was favorable even when there was degeneration within the lymph node (Otolaryngology 54:S14 S19 [6]) hypopharyngeal cancer, and the clinical outcomes in these patients were evaluated according to the therapeutic effect observed with ultrasonography without additional planned neck dissection. Results Ultrasonography presents significant advantages for detecting metastatic lymph nodes of approximately 10 mm thickness when using the ultrasonographic cervical lymph node diagnostic criterion by ultrasonography for examination of cervical lymph node metastases of head and neck squamous cell carcinoma. The rigorous differentiation of an approximately 10-mm-thick lymph node is thus defined as the objective of this diagnostic criterion. Figure 5 shows ultrasound images of metastatic lymph nodes of 10 and 20 mm thickness, the latter resulting in replacement of the whole internal structure of the lymph node by the metastatic focus and allowing the diagnosis of metastasis using the ultrasonographic diagnostic criterion. When the entire inner part of a lymph node is replaced by a metastatic focus, the thickness of the lymph node increases to about mm. By the time the thickness reaches approximately 20 mm, the lymph node would have already developed necrotic areas, often allowing easy diagnosis of a metastatic lymph node by CT or MRI. Although metastatic lymph nodes which are less than 10 mm thick are observed frequently in the clinical scene of head and neck cancer, they are often overlooked due to the impossibility of detection by palpation, CT, or MRI. The careful diagnosis of lymph nodes of this size using ultrasonography is considered to be of great value. Evaluation of the therapeutic effect of chemoradiotherapy, based on the size and number of metastatic lymph nodes and prognosis, was performed in 51 patients positive for cervical lymph node metastases of hypopharyngeal cancer. The results were as follows: lymph nodes disappeared or were scarred in 25 patients; the treatment thereof was regarded as sufficiently effective and presented a favorable outcome. In 15 patients, metastatic lymph nodes regressed and in 11 patients the lymph nodes remained stable, indicating arrested growth; in these 26 patients, the internal blood flow or the hardness of metastatic lymph nodes was observed in order to classify the nodes depending on the presence or absence of degeneration. In nine patients, lymph nodes were judged to have become degenerated and to have presented a favorable outcome, with the disappearance of blood flow to a metastatic focus (Fig. 6) and obvious change in the hardness, the lymph nodes being softer than prior to treatment. Although the softness of lymph nodes can be judged by the observation of B-mode ultrasound images by adding pressure-release, tissue elasticity imaging (elastography) is useful for recording softness or hardness as objective data (Fig. 7) [4, 5]. Ultrasonographic evaluation of treatment effects on cervical lymph node metastasis not only shows metastasis control in the cervical region but also indicates the clinical

7 Int J Clin Oncol (2010) 15: No changes in the size or form of the lymph node are evident. Thickness is first affected (6 mm or higher in thickness) The capsule also becomes thicker The metastatic focus extends beyond the capsule of the lymph node into surrounding tissues. The border becomes poorly demarcated. Lymph node and its capsule A metastatic focus occupies almost the entire lymph node. A border is clearly observed (10-20 mm in thickness; can be identified even by CT). Although the entire lymph node becomes enlarged, the capsule is retained Fatty hilum composed of fatty tissues surrounding the hilum and medulla of a lymph node Metastatic focus Necrotic area within the metastatic focus Fig. 9 Process of development of a metastatic lymph node and its ultrasound image (for squamous cell cancer). À A normal lymph node is flat and ellipsoidal; an ultrasound image shows a fatty hilum composed of fatty tissues surrounding the hilum and medulla of a lymph node appearing as a linear or ellipsoidal high-echo image. ` As metastatic cancer cells invade a lymph node through afferent lymphatic vessels, a metastatic focus is initially formed in the peripheral region remote from the hilum of the lymph node. As the metastatic focus becomes larger, the displaced fatty hilum becomes localized. Changes in the entire lymph node subsequently occur in response to the metastatic foci within the lymph node. In this case, firstly, the thickness of the lymph node increases, where the course and control of the primary metastatic focus in relation to changes in size, and the presence or absence of degeneration (Fig. 8) [6]. Ultrasonographic findings are expected to provide important information for investigating the necessity for neck dissection or other additional therapy after chemoradiotherapy. Discussion Although lymph node micrometastases which cannot be observed macroscopically may be present at the cellular level, and although there may be small lesions which cannot be detected even by ultrasonography, it is very important to perform pretreatment ultrasonographic assessment of lymph nodes less than 10 mm in diameter which cannot be assessed by CT or MRI in diagnostic procedures for cervical lymph node metastases of head and neck cancer. This suggests that ultrasonography is indispensable for metastasis evaluation. capsule of the lymph node becomes thicker. Þ When the entire lymph node is replaced by the metastatic focus, the fatty hilum cannot be identified. Under this condition, the thickness of the lymph node increases to about mm. Notably, at approximately 20 mm thickness, the inner part of the lymph node would have developed necrotic areas, creating an image that allows easy diagnosis of lymph node metastases by CT or MRI. At this time, the capsule of the lymph node is still retained and a clear border of the lymph node is shown. þ Further progression of the metastatic focus culminates in the involvement of the lymph node capsule, resulting in a poorly demarcated lymph node border It is necessary to have a clear understanding of the formation of lymph node metastases to arrive at an accurate diagnosis. Because the form of a metastatic lymph node or the mode of metastasis formation varies slightly among the histologic types of cancer, descriptions of the most common histologic types of head and neck cancer, particularly squamous cell cancer, are provided. The process by which a metastatic lymph node enlarges and its ultrasound images are shown in Figs. 9 and 10. In the ultrasound image of a normal lymph node, a fatty hilum, composed of fatty tissues in the peripheral region of the hilum, and the medulla appear as a linear or elliptical high-echo image. Changes occur in the form and internal structure of a lymph node following cancer cell invasion of its marginal zone via afferent lymphatic vessels; metastatic foci are formed in the marginal zone remote from the hilum and then they start to enlarge (Fig. 9). In a normal lymph node, blood flow distributed to the organ through the hilum can be confirmed by blood flow imaging using color or power Doppler technology. The appearance of metastatic

8 30 Int J Clin Oncol (2010) 15:23 32 Blood flow through the hilum of a lymph node distributes around the metastatic focus, resulting in increased blood flow. Lymph node capsule involvement eventually creates blood flow from the surrounding tissues to the metastatic focus. The capsule of the lymph node becomes thickened where new blood flow appears. Blood flow that is randomly distributed from the capsule to the metastatic focus appears. Lymph node and its capsule Fatty hilum composed of fatty tissues surrounding the hilum and medulla of a lymph node Metastatic focus Necrotic area within the metastatic focus Fig. 10 Process of development of lymph node metastases and blood flow imaging within a lymph node (ultrasonic color or power Doppler; for squamous cell cancer). À Observation of blood flow within a lymph node using color or power Doppler technology allows confirmation of blood flow distributed through the hilum and fatty hilum to the inner part of a normal lymph node. ` As cancer cells invade a lymph node through afferent lymphatic vessels, a metastatic focus is initially formed in the peripheral region remote from the hilum of the lymph node. When the metastatic focus becomes larger, blood flow through the hilum of the lymph node is not uniformly distributed, such that blood flow surrounding the metastatic focus or Blood flow localized blood flow appears. The capsule of the lymph node becomes thicker, new blood flow emerges in the capsule, and blood supply flows randomly into the metastatic focus. Þ When the entire lymph node is replaced by a metastatic focus, the fatty hilum or blood flow through the hilum of a lymph node cannot be identified. The inner part the lymph node would have developed necrotic areas with only randomly distributed blood flow observed in the area other than the said necrotic areas. þ Further progression of the metastatic focus culminates in the involvement of the lymph node capsule, where blood flow is distributed from the surrounding tissues to the metastatic focus foci within a lymph node alters the internal blood flow [7], and ultrasonography enables the early detection of these changes (Fig. 10). When metastatic foci are formed within a lymph node and they start to enlarge, the thickness of the lymph node increases. Given this factor, thickness should be used as a criterion for evaluating whether a lymph node is nodepositive or node-negative, and the standard thickness should be set at approximately 6 7 mm [8]. Diagnostic criteria were prepared based on the standard thickness, changes in the internal structure, and blood flow of a lymph node. There are two modes underlying the treatment effects of chemoradiotherapy, as shown in Fig. 11. In the case where there is a metastatic focus within a lymph node, with the lymph node structure still retained, and when favorable treatment effects are observed, the metastatic focus within the lymph node would disappear, resulting in a normal lymph node structure (Fig. 11, left). In contrast, as shown in Fig. 12, in the case where the entire lymph node is replaced by a metastatic focus with the obliteration of the normal lymph node structure, the shape of the lymph node metastasis remains for some time, with the metastatic focus remaining necrotic and degenerative (Fig. 11, right). If the lymph node is dissected at this time, the inner part of the lymph node is replaced by necrotic tissues with no remaining cancer cells (Fig. 12). In the latter case, the metastatic lymph node will finally disappear while the course is observed without dissecting it. Recently, the aim has been to minimize invasion triggered by treatment and surgery. Thus, the role of ultrasonography will take on greater importance. On the other hand, the limitations of ultrasonography are as follows. It is not possible to make a definitive diagnosis from a site that is not observed. The test method and diagnostic level are variable depending on the testers. Accordingly, to maximize the usefulness of ultrasonography, it is necessary to completely observe the entire cervical region, to master basic diagnostic techniques, and to establish criteria for the

9 Int J Clin Oncol (2010) 15: A case showing the lymph node structure still retained A case showing the lymph node structure destroyed A metastatic lymph node is often in this condition at the time of evaluation of treatment effect after completion of therapy The metastatic focus within a lymph node becomes necrotic A metastatic lymph node returns to the normal lymph node structure. Fig. 11 Process of degeneration of a metastatic lymph node with chemoradiotherapy (case showing complete response). In the case where there is a metastatic focus within a lymph node with the lymph node structure still retained, and when favorable treatment effects were observed, the metastatic focus within the lymph node would disappear, resulting in a normal lymph node structure (left). In The metastatic focus becomes necrotic with destruction of the lymph node structure The metastatic focus is taken up by surrounding scar tissue contrast, as shown in Fig. 12, in the case where the entire lymph node is replaced by a metastatic focus with the obliteration of the normal lymph node structure, the shape of the lymph node metastasis remains for some time, with the metastatic focus remaining necrotic and degenerative (right) Fig. 12 Doppler blood flow imaging showing perfusion defect within a metastatic focus. In the case where the entire lymph node is replaced by a metastatic focus with the obliteration of the normal lymph node structure with favorable treatment effects, the shape of the lymph node metastasis remains for some time, with the metastatic focus remaining necrotic and degenerative (the scale shows 10 mm) diagnosis of metastases in order to reduce disparities in the diagnostic levels between testers. Conclusion Although the previous method for the diagnosis of cervical lymph node metastasis was palpation, ultrasonography can be seen as an extension of this traditional palpation method, and it would definitely be easy to adopt it into the daily routine of medical practice. Because ultrasonographic diagnostic standards are a major factor underlying thestandardization of treatment for cervical lymph node metastasis of head and neck cancer, ultrasonography is considered to play a major role in achieving a definitive diagnosis and evaluating treatment outcomes. Conflict of interest statement None.

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