Accepted Manuscript Title: Contrast-enhanced ultrasound for diagnosis of an enlarged cervical lymph node in a patient with oropharyngeal cancer: a case report Author: Shalva R Gvetadze, Ping Xiong, Jiang Li, Mingming Lv, Jun Li, Xin Yang, Konstantin D Ilkaev, Jian Sun PII: DOI: Reference:
S2212-4403(17)31024-6 http://dx.doi.org/doi: 10.1016/j.oooo.2017.08.007 OOOO 1821
To appear in:
Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Received date: Revised date: Accepted date:
11-6-2017 6-8-2017 10-8-2017
Please cite this article as: Shalva R Gvetadze, Ping Xiong, Jiang Li, Mingming Lv, Jun Li, Xin Yang, Konstantin D Ilkaev, Jian Sun, Contrast-enhanced ultrasound for diagnosis of an enlarged cervical lymph node in a patient with oropharyngeal cancer: a case report, Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology (2017), http://dx.doi.org/doi: 10.1016/j.oooo.2017.08.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
CEUS imaging of enlarged neck lymph node
Contrast-enhanced ultrasound for diagnosis of an enlarged cervical lymph node in a patient with oropharyngeal cancer: a case report Shalva R Gvetadze1,2, PhD, DDS, Ping Xiong3, PhD, MD, Jiang Li4, PhD, DDS, Mingming Lv 1, PhD, DDS, Jun Li1, DDS, Xin Yang1, PhD, DDS, Konstantin D Ilkaev5, MD, Jian Sun1*, PhD, MD 1. Department of Oral Maxillofacial – Head Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, Shanghai, China; 2. Central Research Institute of Dentistry and Maxillofacial Surgery, Moscow, Russia; 3. Department of Ultrasound, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; 4. Department of Oral Pathology, Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; 5. Department of Head and Neck Surgery, NN Blokhin Russian Cancer Research Center, Moscow, Russia.
*-
Corresponding author. Professor Sun Jian PhD, MD, Department of Oral Maxillofacial – Head Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, 639 Zhizaoju Road, Shanghai 200011, China; E-mail: [email protected]
The work conducted done in the 9th People’s Hospital, Shanghai Jiao Tong University School of Medicine, Department of Oral Maxillofacial – Head Neck Oncology and Department of Ultrasound. No grants were issued for financing of the study. The case was not prior presented elsewhere. No conflict of interest is declared among the authors. Abstract word count: 111 words. Manuscript word count: 1741 words. Number of references: 22 papers. Four figures, no tables.
Key words: oropharyngeal cancer; contrast enhanced ultrasound; sentinel lymph node; CT; ultrasound.
Page 1 of 12
CEUS imaging of enlarged neck lymph node
Abstract In oral and oropharyngeal cancer the presence of regional neck metastasis strongly influences treatment planning and survival prognosis. A number of imaging techniques can be utilized in the clinic for diagnosis and staging. A patient with oropharyngeal cancer was staged T2cN1 after clinical examination, CT, and FDG/PET-CT. Contrast-enhanced microbubble imaging was applied for diagnosis of a lymph node suspected of harboring a metastasis. The result of the microbubble procedure showed the suspicious node to be tumor-negative, which was later confirmed by frozen section and serial step section of the harvested node. Contrastenhanced ultrasound with intravenous microbubble contrast introduction may be of benefit in staging oropharyngeal cancer patients with enlarged neck lymph nodes.
Introduction It is well recognized that patients with early oral and oropharyngeal squamous cell carcinoma (SCC) tend to benefit from execution of sentinel lymph node (SLN) biopsy for diagnostic and staging purposes. In a situation where there is a choice between wait-and-see follow up or neck dissection, SLN detection and pathologic exam may spare the patient from morbidities linked to regional lymphadenectomy [1, 2]. Several classic (blue dye injections, lyphoscintigraphy and
SPECT-lymphoscintigraphy)
and
new
evolving lymphographic
techniques (CT-lymphography, MRI-lymphography, near-infrared fluorescence imaging, etc.) are used for SLN visualization in different clinical settings [3]. Among these novel means is 2 Page 2 of 12
CEUS imaging of enlarged neck lymph node
contrast enhanced ultrasound (CEUS) which was introduced for SLN biopsy in the staging of breast cancer [4]. High diagnostic efficiency results of the method have been reported since then [5]. Microbubble contrast agents that are used for CEUS can be delivered intravenously or injected into soft tissues peritumorally. Intravenous delivery allows preoperative differentiation of the status of nodes that are considered suspicious for metastasis [6]. Local (intradermal, subcutaneous, or submucous) peritumoral injections are done for tracing and identification of the SLN [7]. More recently, CEUS has been applied for SLN mapping in patients with T1-2cN0 oral tongue SCC [8]. Here we present a case in which CEUS was successfully utilized for imaging and diagnosis of an enlarged lymph node in a patient with early oropharyngeal SCC. Case 1 A male 52 year-old patient was referred to the department with a recent experience of odynophagia. There was no history of smoking or alcohol abuse. CT of the head and neck revealed a 1.7x2.1x2.1 cm sized tumor occupying the right vallecula and nearly totally obstructing the right part of the oropharyngeal orifice at the level of the third cervical vertebra (Fig.1A). In the right neck an enlarged lymph node was spotted in level III at the anterior border of the sternocleidomastoid muscle (Fig. 1B). Pharyngoscopy-assisted biopsy specimens exhibited poorly differentiated SCC. PET-CT showed two zones of increased heterogeneous fludeoxyglucose (FDG) uptake: one in the primary site in the oropharynx and another in the right neck in level III. The presence of a metastatic deposit was suspected. The patient then was subjected to ultrasound for further neck evaluation. During grey-scale ultrasound the enlarged 3.0x1.2x1.9 cm lymph node that had been seen during CT was visualized on the right side in level III. The hilum was intact and no signs of cortical thickening were present (Fig. 2A). Greyscale ultrasound and CEUS were performed using the Esaote MyLabTM Twice (Esaote SpA, 3 Page 3 of 12
CEUS imaging of enlarged neck lymph node
Italy) device. As the primary site in the oropharynx was problematic to reach for peritumoral contrast injection, an intravenous delivery was chosen for CEUS imaging of this particular node to establish its status. The SonovueTM contrast agent (Bracco Imaging, Milan, Italy) was used in this case. The dry medium powder was mixed with 5 ml of normal sterile saline. The ampule was firmly shaken before every injection to establish a homogeneous suspension of microbubbles. The prepared contrast was delivered intravenously in a 2.5 ml bolus, immediately followed by 5 ml of saline. Two injections were carried out. Enhancement of the node started 15 seconds after injection and the contrast washout began after 90 seconds. A uniform filling pattern without perfusion defects was recognized. The contrast was distributed inside the lymph node equally (Fig. 2B). According to this finding, the node was judged metastasis-free. The patient received surgical treatment: right lateral suprahyoid pharyngotomy for primary tumor excision; a modified radical neck dissection with preservation of internal jugular vein, sternocleidomastoid muscle and accessory nerve removal on the right side, and a selective supra-omohyoid neck dissection on the left side of the neck. In the operating room the examined lymph node was dissected off the surgical specimen and was bisected along the axis (Fig. 3A, B). One half of the node was submitted for frozen section exam and the second half was reserved for routine paraffin serial step sectioning. The frozen section reported no signs of malignancy, which was later supported by serial step section results, describing a picture characteristic for reactive nodal inflammation (Fig. 4). No metastatic nodes were found elsewhere in the bilateral surgical specimens, therefore staging the patient as T2pN0. The postoperative period was uneventful and three months postoperatively no signs of local or regional recurrence were observed.
Discussion 4 Page 4 of 12
CEUS imaging of enlarged neck lymph node
Squamous cell carcinoma is the most common malignant tumor of the oral cavity and oropharynx and has a high potency for secondary spread to the regional lymph nodes. The existence of lymph node metastasis is the most important predictive factor that influences survival prognosis and indicates the necessity and extent of neck dissection. The conventional imaging techniques of CT and MRI possess low sensitivity for detecting neck metastasis in nodes less 3 mm in size; up to 40% of cN0 necks are left with unidentified occult disease. To overcome these conditions, the concept of SLN was developed and used in the clinic for cancers in different regions of the body [9, 10, 11]. Several techniques for SLN mapping are currently in use. Their features have evolved to achieve higher quality of anatomical visualization, less invasiveness, and easy reproducibility [12]. Experimental studies have demonstrated the prospects of CEUS with microbubble contrast agents in SLN detection [12, 13]. Sulfur hexafluoride microbubbles are the most widely used contrast agent for CEUS and they act as an inert gas in vivo. The agent is created from hexafluoride gas encased by phospholipoid-stabilized microbubbles with mean diameter of 2.5µm, which is smaller than that of an erythrocyte (mean 7.2µm). This allows the bubbles to pass through the capillaries and lymphatic micro-vessels and assures real-time identification and clearance. CEUS lymphography with microbubbles injected intradermally for SLN identification was introduced in breast cancer staging by Sever et al. (4). The authors described a combo method of preoperative CEUS and intraoperative lymphoscintigraphy and reported 89% overall sensitivity of the microbubble technique [4]. Rautiainen et al. documented 66.7% sensitivity, 100% specificity, 100% positive predictive value, 93.8% negative predictive value, and overall accuracy of 94.4% for CEUS detection and SLN biopsy in invasive breast cancer [5]. A pilot study of CEUS with local peritumoral injection was executed in T1-2cN0 oral tongue SCC 5 Page 5 of 12
CEUS imaging of enlarged neck lymph node
patients [8]. The method was deemed feasible and high patient tolerance of the procedure was witnessed. SLNs were identified in 11 out of 12 patients (91.7%). SLNs were detected in level IA (6.7%), level IB (73.3%), and level IIA (20%). Preliminary studies suggest that intravenous CEUS can improve the differential diagnosis of malignant lymph nodes from reactive nodes and provide a more accurate selection of nodes to be submitted to fine-needle aspiration biopsy [14, 15, 16]. A large study on 460 patients implementing intravenous CEUS for superficial melanoma lymph node metastases was conducted by Rubaltelli et al. [6]. Using the accepted ultrasonographic signs of hilum echogenicity, round shape (a ratio of longitudinal to transverse diameter of less than 2), cortical thickening, and CEUS-specific lymph node perfusion patterns, the authors reported sensitivity of 100% and specificity of 99.5%. During intravenous CEUS examination, specific characteristics are useful in differentiation of intact or reactive inflamed lymph nodes from metastatic nodes. The non-metastatic normal lymph node gets its blood supply through the artery of the hilum, which divides into small branches in the medulla to reach the size of capillaries at the cortex [17]. After injection of the SonovueTM microbubble agent, hilum enhancement starts at 10-15 seconds with further homogenous enhancement of the cortex. The washout starts at 40-45 seconds and typically finishes after 60-90 seconds. In the metastatic nodes, tumor cells produce distortion of the vascular structure of the hilum. Tumor infiltration of the cortex is combined with angiogenesis and enlargement of the capsular vessels, which leads to peripheral hypervascularisation with tortuous and aberrant vessels supplying the tumor foci. After injection of the SonovueTM contrast in a metastatic node, enhancement starts at 10-15 seconds, with perfusion defects identified in the hilum zone. Heterogeneous enhancement of the cortex with
6 Page 6 of 12
CEUS imaging of enlarged neck lymph node
local hypo-intensive zones which represent metastatic deposits is seen from 15 to 20 seconds. After 40-60 seconds the washout of the contrast begins [18]. PET-CT applies fluorine-18 fludeoxyglucose (18F-FDG) as a tracer. This technique makes possible the visualization of glucose metabolic activity by scrutinizing the intensity of positron emission. The injected tracer gets transferred into cells where it is not further metabolized after it is phosphorylated to
18
F-FDG-6- phosphate. This leads to cellular accumulation of fluorine-18.
In head and neck cancers, FDG-PET/CT can be used in different settings with unequal efficiency. While it is highly favorable for distant metastasis and recurrent disease exploration, its benefit in early stage neck node assessment is doubtful. A limited sensitivity of the technique with a high number of false-negative results was demonstrated in patients with cN0 with metastatic nodal deposits ≥3 mm [19, 20]. Hence, 18FDG-PET/CT is currently not recommended for cN0 neck evaluation owing to its low negative-predictive value (around 80%) [21]. Common false-positive PET/CT errors are the consequences of high FDG uptake through normal physiological activity, benign thyroid nodules, inflammatory processes, recent chemotherapy, radiotherapy, and surgery [22]. The present paper describes a case of T2 oropharyngeal SCC with controversial results of different imaging techniques concerning the condition of the neck. Both CT and FDG-PET/CT suggested the presence of a metastatic lymph node in level III of the ipsilateral neck, therefore staging the regional lymphatic basin as cN1. During preoperative grey-scale ultrasound and CEUS with intravenous microbubble introduction, the lymph node was considered metastasisfree, thereby leading to staging of the neck as cN0. The frozen section and serial step section pathology of the exposed lymph node exhibited reactive inflammation of the node with no signs
7 Page 7 of 12
CEUS imaging of enlarged neck lymph node
of metastatic disease. Further clinical research is required to establish the proper position of CEUS in management of oral and oropharyngeal cancer patients.
Referances 1. Leusink FK, van Es RJ, de Bree R, et al. Novel diagnostic modalities for assessment of the clinically node-negative neck in oral squamous-cell carcinoma. Lancet Oncol. 2012; 13: e554-61. 2. Cousins A, Thompson SK, Wedding AB, Thierry B. Clinical relevance of novel imaging technologies for sentinel lymph node identification and staging. Biotechnol Adv. 2014; 32: 269-79. 3. Xiong L, Engel H, Gazyakan E, Rahimi M, Hunerbein M, Sun J, et al. Current techniques for lymphatic imaging: state of the art and future perspectives. Eur J Surg Oncol. 2014; 40: 270-6. 4. Sever AR, Mills P, Jones SE, Cox K, Weeks J, Fish D, Jones PA. Preoperative sentinel node identification with ultrasound using microbubbles in patients with breast cancer. AJR Am J Roentgenol. 2011; 196(2):251-6. 5. Rautiainen S, Sudah M, Joukainen S, Sironen R, Vanninen R, Sutela A. Contrastenhanced ultrasound-guided axillary lymph node core biopsy: Diagnostic accuracy in preoperative staging of invasive breast cancer. Eur J Radiol. 2015; 84:21306.
8 Page 8 of 12
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6. Rubaltelli L, Beltrame V, Scagliori E, et al. Potential use of contrast-enhanced ultrasound (CEUS) in the detection of metastatic superficial lymph nodes in melanoma patients. Ultraschall Med. 2014; 35:67-71. 7. Xie F, Zhang D, Cheng L, et al. Intradermal microbubbles and contrast-enhanced ultrasound (CEUS) is a feasible approach for sentinel lymph node identification in early stage breast cancer. World J Surg Oncol. 2015; 13:319. 8. Gvetadze SR, Xiong P, Lv M, Li J, Hu J, Ilkaev KD et al. Contrast-enhanced ultrasound mapping of sentinel lymph nodes in oral tongue cancer – a pilot study. Dentomaxillofac Radiol. 2017; 46(3): 20160345. 9. Cabanas RM. An approach for treatment of penile carcinoma. Cancer. 1977; 39: 456-66. 10. Borgstein PJ, Meijer S, Pijpers R. Intradermal blue dye to identify sentinel lymph-node in breast cancer. Lancet. 1997; 349: 1668-9. 11. Monroe MM, Pattisapu P, Myers JN, Kupferman ME. Sentinel lymph node biopsy provides prognostic value in thick head and neck melanoma. Otolaryngol Head Neck Surg. 2015; 153: 372-8. 12. Goldberg BB, Merton DA, Liu JB, et al. Contrast-enhanced sonographic imaging of lymphatic channels and sentinel lymph nodes. J Ultrasound Med. 2005; 24(7):953-65. 13. Goldberg BB, Merton DA, Liu JB, et al. Sentinel lymph nodes in a swine model with melanoma: contrast-enhanced lymphatic US. Radiology. 2004; 230:727-34.
9 Page 9 of 12
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14. Yu M, Liu Q, Song HP, Han ZH, Su HL, He GB et al.: Clinical application of contrastenhanced ultrasonography in diagnosis of superficial lymphadenopathy. J Ultrasound Med. 2010; 29: 735–740. 35. 15. Yang WT, Metreweli C, Lam PK, Chang J: Benign and malignant breast masses and axillary nodes: evaluation with echo-enhanced color power Doppler US. Radiology. 2001; 220: 795–802. 16. Cui X, Ignee A, Nielsen MB, Schreiber-Dietrich D, De Molo C, Pirri C, et al. Contrast enhanced ultrasound of sentinel lymph nodes. J Ultrason. 2013; 13(52): 73-81. 17. Willard-Mack Cl. Normal structure, function, and histology of lymph nodes. Toxicol Pathol. 2006; 34:409-24. 18. Sencha AN, Mogutov MS, Patrunov JuN, et al. Ultrasound assessment using contrast agents. Moscow: Vidar-M, 2015 (in Russian). 19. Nahmias C, Carlson ER, Duncan LD, Blodgett TM, Kennedy J, Long MJ, et al. Positron emission tomography/computerized tomography (PET/CT) scanning for preoperative staging of patients with oral/head and neck cancer. J Oral Maxillofac Surg. 2007; 65: 2524–35. 20. Schoder H, Carlson DL, Kraus DH, Stambuk HE, Gonen M, ¨ Erdi YE, et al. 18F-FDG PET/CT for detecting nodal metastases in patients with oral cancer staged N0 by clinical examination and CT/MRI. J Nucl Med. 2006; 47: 755–62.
10 Page 10 of 12
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21. Manca G, Vanzi E, Rubello D, Giammarile F,Grassetto G, Wong KK, et al. (18)F-FDG PET/CT quantification in head and neck squamous cell cancer: principles, technical issues and clinical applications. Eur J Nucl Med Mol Imaging. 2016; 43: 1360–75. 22. Purohit BS, Ailianou A, Dulguerov N, Becker CD, Ratib O, Becker M. FDG-PET/CT pitfalls in oncological head and neck imaging. Insights Imaging. 2014; 5(5): 585-602.
11 Page 11 of 12
CEUS imaging of enlarged neck lymph node
Fig. 1. A. Tumor occupying the right vallecula and nearly totally obstructing the right part of the oropharyngeal orifice in the CV III level. B. The enlarged lymph node was spotted in level III at the anterior border of the sternocleidomastoid muscle.
Fig. 2. A. A grey-scale ultrasound exam of the suspicious lymph node (margins outlined with arrows) showed no signs of malignancy, with the hilum intact (asterisk) and no cortical thickening. B. In CEUS imaging, the contrast was equally distributed within the node, confirming the benign nature of the enlargement of the node.
Fig. 3. A. The lymph node dissected off the surgical specimen. B. The node bisected along axis for frozen section and paraffin serial step section analysis.
Fig. 4. The serial step section exhibited an inflamed reactive lymph node without any signs of malignancy.
12 Page 12 of 12
S2212-4403(17)31024-6 http://dx.doi.org/doi: 10.1016/j.oooo.2017.08.007 OOOO 1821
To appear in:
Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Received date: Revised date: Accepted date:
11-6-2017 6-8-2017 10-8-2017
Please cite this article as: Shalva R Gvetadze, Ping Xiong, Jiang Li, Mingming Lv, Jun Li, Xin Yang, Konstantin D Ilkaev, Jian Sun, Contrast-enhanced ultrasound for diagnosis of an enlarged cervical lymph node in a patient with oropharyngeal cancer: a case report, Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology (2017), http://dx.doi.org/doi: 10.1016/j.oooo.2017.08.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
CEUS imaging of enlarged neck lymph node
Contrast-enhanced ultrasound for diagnosis of an enlarged cervical lymph node in a patient with oropharyngeal cancer: a case report Shalva R Gvetadze1,2, PhD, DDS, Ping Xiong3, PhD, MD, Jiang Li4, PhD, DDS, Mingming Lv 1, PhD, DDS, Jun Li1, DDS, Xin Yang1, PhD, DDS, Konstantin D Ilkaev5, MD, Jian Sun1*, PhD, MD 1. Department of Oral Maxillofacial – Head Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, Shanghai, China; 2. Central Research Institute of Dentistry and Maxillofacial Surgery, Moscow, Russia; 3. Department of Ultrasound, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; 4. Department of Oral Pathology, Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; 5. Department of Head and Neck Surgery, NN Blokhin Russian Cancer Research Center, Moscow, Russia.
*-
Corresponding author. Professor Sun Jian PhD, MD, Department of Oral Maxillofacial – Head Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, 639 Zhizaoju Road, Shanghai 200011, China; E-mail: [email protected]
The work conducted done in the 9th People’s Hospital, Shanghai Jiao Tong University School of Medicine, Department of Oral Maxillofacial – Head Neck Oncology and Department of Ultrasound. No grants were issued for financing of the study. The case was not prior presented elsewhere. No conflict of interest is declared among the authors. Abstract word count: 111 words. Manuscript word count: 1741 words. Number of references: 22 papers. Four figures, no tables.
Key words: oropharyngeal cancer; contrast enhanced ultrasound; sentinel lymph node; CT; ultrasound.
Page 1 of 12
CEUS imaging of enlarged neck lymph node
Abstract In oral and oropharyngeal cancer the presence of regional neck metastasis strongly influences treatment planning and survival prognosis. A number of imaging techniques can be utilized in the clinic for diagnosis and staging. A patient with oropharyngeal cancer was staged T2cN1 after clinical examination, CT, and FDG/PET-CT. Contrast-enhanced microbubble imaging was applied for diagnosis of a lymph node suspected of harboring a metastasis. The result of the microbubble procedure showed the suspicious node to be tumor-negative, which was later confirmed by frozen section and serial step section of the harvested node. Contrastenhanced ultrasound with intravenous microbubble contrast introduction may be of benefit in staging oropharyngeal cancer patients with enlarged neck lymph nodes.
Introduction It is well recognized that patients with early oral and oropharyngeal squamous cell carcinoma (SCC) tend to benefit from execution of sentinel lymph node (SLN) biopsy for diagnostic and staging purposes. In a situation where there is a choice between wait-and-see follow up or neck dissection, SLN detection and pathologic exam may spare the patient from morbidities linked to regional lymphadenectomy [1, 2]. Several classic (blue dye injections, lyphoscintigraphy and
SPECT-lymphoscintigraphy)
and
new
evolving lymphographic
techniques (CT-lymphography, MRI-lymphography, near-infrared fluorescence imaging, etc.) are used for SLN visualization in different clinical settings [3]. Among these novel means is 2 Page 2 of 12
CEUS imaging of enlarged neck lymph node
contrast enhanced ultrasound (CEUS) which was introduced for SLN biopsy in the staging of breast cancer [4]. High diagnostic efficiency results of the method have been reported since then [5]. Microbubble contrast agents that are used for CEUS can be delivered intravenously or injected into soft tissues peritumorally. Intravenous delivery allows preoperative differentiation of the status of nodes that are considered suspicious for metastasis [6]. Local (intradermal, subcutaneous, or submucous) peritumoral injections are done for tracing and identification of the SLN [7]. More recently, CEUS has been applied for SLN mapping in patients with T1-2cN0 oral tongue SCC [8]. Here we present a case in which CEUS was successfully utilized for imaging and diagnosis of an enlarged lymph node in a patient with early oropharyngeal SCC. Case 1 A male 52 year-old patient was referred to the department with a recent experience of odynophagia. There was no history of smoking or alcohol abuse. CT of the head and neck revealed a 1.7x2.1x2.1 cm sized tumor occupying the right vallecula and nearly totally obstructing the right part of the oropharyngeal orifice at the level of the third cervical vertebra (Fig.1A). In the right neck an enlarged lymph node was spotted in level III at the anterior border of the sternocleidomastoid muscle (Fig. 1B). Pharyngoscopy-assisted biopsy specimens exhibited poorly differentiated SCC. PET-CT showed two zones of increased heterogeneous fludeoxyglucose (FDG) uptake: one in the primary site in the oropharynx and another in the right neck in level III. The presence of a metastatic deposit was suspected. The patient then was subjected to ultrasound for further neck evaluation. During grey-scale ultrasound the enlarged 3.0x1.2x1.9 cm lymph node that had been seen during CT was visualized on the right side in level III. The hilum was intact and no signs of cortical thickening were present (Fig. 2A). Greyscale ultrasound and CEUS were performed using the Esaote MyLabTM Twice (Esaote SpA, 3 Page 3 of 12
CEUS imaging of enlarged neck lymph node
Italy) device. As the primary site in the oropharynx was problematic to reach for peritumoral contrast injection, an intravenous delivery was chosen for CEUS imaging of this particular node to establish its status. The SonovueTM contrast agent (Bracco Imaging, Milan, Italy) was used in this case. The dry medium powder was mixed with 5 ml of normal sterile saline. The ampule was firmly shaken before every injection to establish a homogeneous suspension of microbubbles. The prepared contrast was delivered intravenously in a 2.5 ml bolus, immediately followed by 5 ml of saline. Two injections were carried out. Enhancement of the node started 15 seconds after injection and the contrast washout began after 90 seconds. A uniform filling pattern without perfusion defects was recognized. The contrast was distributed inside the lymph node equally (Fig. 2B). According to this finding, the node was judged metastasis-free. The patient received surgical treatment: right lateral suprahyoid pharyngotomy for primary tumor excision; a modified radical neck dissection with preservation of internal jugular vein, sternocleidomastoid muscle and accessory nerve removal on the right side, and a selective supra-omohyoid neck dissection on the left side of the neck. In the operating room the examined lymph node was dissected off the surgical specimen and was bisected along the axis (Fig. 3A, B). One half of the node was submitted for frozen section exam and the second half was reserved for routine paraffin serial step sectioning. The frozen section reported no signs of malignancy, which was later supported by serial step section results, describing a picture characteristic for reactive nodal inflammation (Fig. 4). No metastatic nodes were found elsewhere in the bilateral surgical specimens, therefore staging the patient as T2pN0. The postoperative period was uneventful and three months postoperatively no signs of local or regional recurrence were observed.
Discussion 4 Page 4 of 12
CEUS imaging of enlarged neck lymph node
Squamous cell carcinoma is the most common malignant tumor of the oral cavity and oropharynx and has a high potency for secondary spread to the regional lymph nodes. The existence of lymph node metastasis is the most important predictive factor that influences survival prognosis and indicates the necessity and extent of neck dissection. The conventional imaging techniques of CT and MRI possess low sensitivity for detecting neck metastasis in nodes less 3 mm in size; up to 40% of cN0 necks are left with unidentified occult disease. To overcome these conditions, the concept of SLN was developed and used in the clinic for cancers in different regions of the body [9, 10, 11]. Several techniques for SLN mapping are currently in use. Their features have evolved to achieve higher quality of anatomical visualization, less invasiveness, and easy reproducibility [12]. Experimental studies have demonstrated the prospects of CEUS with microbubble contrast agents in SLN detection [12, 13]. Sulfur hexafluoride microbubbles are the most widely used contrast agent for CEUS and they act as an inert gas in vivo. The agent is created from hexafluoride gas encased by phospholipoid-stabilized microbubbles with mean diameter of 2.5µm, which is smaller than that of an erythrocyte (mean 7.2µm). This allows the bubbles to pass through the capillaries and lymphatic micro-vessels and assures real-time identification and clearance. CEUS lymphography with microbubbles injected intradermally for SLN identification was introduced in breast cancer staging by Sever et al. (4). The authors described a combo method of preoperative CEUS and intraoperative lymphoscintigraphy and reported 89% overall sensitivity of the microbubble technique [4]. Rautiainen et al. documented 66.7% sensitivity, 100% specificity, 100% positive predictive value, 93.8% negative predictive value, and overall accuracy of 94.4% for CEUS detection and SLN biopsy in invasive breast cancer [5]. A pilot study of CEUS with local peritumoral injection was executed in T1-2cN0 oral tongue SCC 5 Page 5 of 12
CEUS imaging of enlarged neck lymph node
patients [8]. The method was deemed feasible and high patient tolerance of the procedure was witnessed. SLNs were identified in 11 out of 12 patients (91.7%). SLNs were detected in level IA (6.7%), level IB (73.3%), and level IIA (20%). Preliminary studies suggest that intravenous CEUS can improve the differential diagnosis of malignant lymph nodes from reactive nodes and provide a more accurate selection of nodes to be submitted to fine-needle aspiration biopsy [14, 15, 16]. A large study on 460 patients implementing intravenous CEUS for superficial melanoma lymph node metastases was conducted by Rubaltelli et al. [6]. Using the accepted ultrasonographic signs of hilum echogenicity, round shape (a ratio of longitudinal to transverse diameter of less than 2), cortical thickening, and CEUS-specific lymph node perfusion patterns, the authors reported sensitivity of 100% and specificity of 99.5%. During intravenous CEUS examination, specific characteristics are useful in differentiation of intact or reactive inflamed lymph nodes from metastatic nodes. The non-metastatic normal lymph node gets its blood supply through the artery of the hilum, which divides into small branches in the medulla to reach the size of capillaries at the cortex [17]. After injection of the SonovueTM microbubble agent, hilum enhancement starts at 10-15 seconds with further homogenous enhancement of the cortex. The washout starts at 40-45 seconds and typically finishes after 60-90 seconds. In the metastatic nodes, tumor cells produce distortion of the vascular structure of the hilum. Tumor infiltration of the cortex is combined with angiogenesis and enlargement of the capsular vessels, which leads to peripheral hypervascularisation with tortuous and aberrant vessels supplying the tumor foci. After injection of the SonovueTM contrast in a metastatic node, enhancement starts at 10-15 seconds, with perfusion defects identified in the hilum zone. Heterogeneous enhancement of the cortex with
6 Page 6 of 12
CEUS imaging of enlarged neck lymph node
local hypo-intensive zones which represent metastatic deposits is seen from 15 to 20 seconds. After 40-60 seconds the washout of the contrast begins [18]. PET-CT applies fluorine-18 fludeoxyglucose (18F-FDG) as a tracer. This technique makes possible the visualization of glucose metabolic activity by scrutinizing the intensity of positron emission. The injected tracer gets transferred into cells where it is not further metabolized after it is phosphorylated to
18
F-FDG-6- phosphate. This leads to cellular accumulation of fluorine-18.
In head and neck cancers, FDG-PET/CT can be used in different settings with unequal efficiency. While it is highly favorable for distant metastasis and recurrent disease exploration, its benefit in early stage neck node assessment is doubtful. A limited sensitivity of the technique with a high number of false-negative results was demonstrated in patients with cN0 with metastatic nodal deposits ≥3 mm [19, 20]. Hence, 18FDG-PET/CT is currently not recommended for cN0 neck evaluation owing to its low negative-predictive value (around 80%) [21]. Common false-positive PET/CT errors are the consequences of high FDG uptake through normal physiological activity, benign thyroid nodules, inflammatory processes, recent chemotherapy, radiotherapy, and surgery [22]. The present paper describes a case of T2 oropharyngeal SCC with controversial results of different imaging techniques concerning the condition of the neck. Both CT and FDG-PET/CT suggested the presence of a metastatic lymph node in level III of the ipsilateral neck, therefore staging the regional lymphatic basin as cN1. During preoperative grey-scale ultrasound and CEUS with intravenous microbubble introduction, the lymph node was considered metastasisfree, thereby leading to staging of the neck as cN0. The frozen section and serial step section pathology of the exposed lymph node exhibited reactive inflammation of the node with no signs
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of metastatic disease. Further clinical research is required to establish the proper position of CEUS in management of oral and oropharyngeal cancer patients.
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6. Rubaltelli L, Beltrame V, Scagliori E, et al. Potential use of contrast-enhanced ultrasound (CEUS) in the detection of metastatic superficial lymph nodes in melanoma patients. Ultraschall Med. 2014; 35:67-71. 7. Xie F, Zhang D, Cheng L, et al. Intradermal microbubbles and contrast-enhanced ultrasound (CEUS) is a feasible approach for sentinel lymph node identification in early stage breast cancer. World J Surg Oncol. 2015; 13:319. 8. Gvetadze SR, Xiong P, Lv M, Li J, Hu J, Ilkaev KD et al. Contrast-enhanced ultrasound mapping of sentinel lymph nodes in oral tongue cancer – a pilot study. Dentomaxillofac Radiol. 2017; 46(3): 20160345. 9. Cabanas RM. An approach for treatment of penile carcinoma. Cancer. 1977; 39: 456-66. 10. Borgstein PJ, Meijer S, Pijpers R. Intradermal blue dye to identify sentinel lymph-node in breast cancer. Lancet. 1997; 349: 1668-9. 11. Monroe MM, Pattisapu P, Myers JN, Kupferman ME. Sentinel lymph node biopsy provides prognostic value in thick head and neck melanoma. Otolaryngol Head Neck Surg. 2015; 153: 372-8. 12. Goldberg BB, Merton DA, Liu JB, et al. Contrast-enhanced sonographic imaging of lymphatic channels and sentinel lymph nodes. J Ultrasound Med. 2005; 24(7):953-65. 13. Goldberg BB, Merton DA, Liu JB, et al. Sentinel lymph nodes in a swine model with melanoma: contrast-enhanced lymphatic US. Radiology. 2004; 230:727-34.
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14. Yu M, Liu Q, Song HP, Han ZH, Su HL, He GB et al.: Clinical application of contrastenhanced ultrasonography in diagnosis of superficial lymphadenopathy. J Ultrasound Med. 2010; 29: 735–740. 35. 15. Yang WT, Metreweli C, Lam PK, Chang J: Benign and malignant breast masses and axillary nodes: evaluation with echo-enhanced color power Doppler US. Radiology. 2001; 220: 795–802. 16. Cui X, Ignee A, Nielsen MB, Schreiber-Dietrich D, De Molo C, Pirri C, et al. Contrast enhanced ultrasound of sentinel lymph nodes. J Ultrason. 2013; 13(52): 73-81. 17. Willard-Mack Cl. Normal structure, function, and histology of lymph nodes. Toxicol Pathol. 2006; 34:409-24. 18. Sencha AN, Mogutov MS, Patrunov JuN, et al. Ultrasound assessment using contrast agents. Moscow: Vidar-M, 2015 (in Russian). 19. Nahmias C, Carlson ER, Duncan LD, Blodgett TM, Kennedy J, Long MJ, et al. Positron emission tomography/computerized tomography (PET/CT) scanning for preoperative staging of patients with oral/head and neck cancer. J Oral Maxillofac Surg. 2007; 65: 2524–35. 20. Schoder H, Carlson DL, Kraus DH, Stambuk HE, Gonen M, ¨ Erdi YE, et al. 18F-FDG PET/CT for detecting nodal metastases in patients with oral cancer staged N0 by clinical examination and CT/MRI. J Nucl Med. 2006; 47: 755–62.
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21. Manca G, Vanzi E, Rubello D, Giammarile F,Grassetto G, Wong KK, et al. (18)F-FDG PET/CT quantification in head and neck squamous cell cancer: principles, technical issues and clinical applications. Eur J Nucl Med Mol Imaging. 2016; 43: 1360–75. 22. Purohit BS, Ailianou A, Dulguerov N, Becker CD, Ratib O, Becker M. FDG-PET/CT pitfalls in oncological head and neck imaging. Insights Imaging. 2014; 5(5): 585-602.
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Fig. 1. A. Tumor occupying the right vallecula and nearly totally obstructing the right part of the oropharyngeal orifice in the CV III level. B. The enlarged lymph node was spotted in level III at the anterior border of the sternocleidomastoid muscle.
Fig. 2. A. A grey-scale ultrasound exam of the suspicious lymph node (margins outlined with arrows) showed no signs of malignancy, with the hilum intact (asterisk) and no cortical thickening. B. In CEUS imaging, the contrast was equally distributed within the node, confirming the benign nature of the enlargement of the node.
Fig. 3. A. The lymph node dissected off the surgical specimen. B. The node bisected along axis for frozen section and paraffin serial step section analysis.
Fig. 4. The serial step section exhibited an inflamed reactive lymph node without any signs of malignancy.
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![[The magnetic resonance tomographic differential diagnosis between reactively enlarged lymph nodes and cervical lymph node metastases].](/assets/img/hold.png)
