11.08.2019

Cancer Of The Head And Neck Myers Pdf Reader

Cancer Of The Head And Neck Myers Pdf Reader 3,2/5 5485 votes
  1. Head And Neck Anatomy Muscles
  2. Daniele Lecis

Frequently on head and neck skin, which is consistent with its propensity for sites with intermittent sun exposure, such as the trunk 14. Myers(.) Department of Head and Neck Surgery, UT MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1445, Houston, TX, USA e-mail: jmyers@mdanderson.org Chapter 37 Head and Neck Melanoma.

Published online 2004 Jun 8. doi: 10.1038/sj.bjc.6601877
PMID: 15188012
This article has been cited by other articles in PMC.

Surgical therapy of the lymphatic basins in head and neck malignancies has been evolved from radical neck dissection to modified radical neck dissection in order to reduce the morbidity of the procedure and to preserve as much function and quality of life as possible for the patient while still maintaining an oncologic sound result (Suárez, 1962). With the same objective proponents of a further limitation favour a selective neck dissection in the presence of initial cervical disease (Traynor et al, 1996; Ambrosch et al, 2001). While there are efforts to reduce the surgical approach in the presence of metastases, there is even more reason to do so if a neck has been staged N0. The problem arises from the fact that current staging methods cannot reliably exclude small metastases. A risk of occult metastatic disease exceeding 15–20%, therefore, is considered an indication for elective neck dissection (Steiner and Hommerich, 1993; Pitman et al, 1997). If occult metastases are detected in the neck dissection specimen, adjuvant radiotherapy will usually be indicated while in case of a neck without metastatic disease there are no therapeutic consequences. However, patients experience a loss of quality of life due to the morbidity of the neck dissection. To preserve quality of life while aiming for an oncologic sound result, the sentinel lymph-node concept was established. Sentinel lymph nodes are defined as the first nodes to drain a tumour. Thus, they carry the highest risk of metastatic disease. Based on this apriority, the hypothesis of the sentinel node concept is that the oncologic status of the sentinel node has diagnostic value for the total lymphatic basin. The intriguing idea is that a sentinel node free of tumour may make an elective lymphonodectomy of the lymphatic basin unnecessary. The sentinel node concept has been introduced in malignant melanomas and breast cancer (Morton et al, 1992; Giuliano et al, 1994). While there have been early studies on malignant melanomas in the head and neck (Morton et al, 1993), there is only limited experience in head and neck squamous cell carcinoma. It was the aim of this study to assess the diagnostic value of the sentinel node method in head and neck cancer.

PATIENTS AND METHODS

Patients

From May 2000 until May 2003, 40 male and 10 female patients with previously untreated squamous cell carcinomas of the upper aerodigestive tract were included in this study. The study was conducted in accordance to the Revised Declaration of Helsinki (2000). Informed written consent was obtained from each patient. Tumours were located in the larynx in 12 cases. In all, 11 patients suffered from carcinoma of the tonsil, 10 patients of the mobile tongue, eight of the floor of the mouth, three of the base of the tongue, four of the palate, one of the dorsal oropharyngeal wall and one of the hypopharynx (Table 1 ). One more patient with a tumour of the base of the tongue and three more patients with laryngeal tumours who were all initially thought feasible for the study were not included because it was not possible to expose the caudal rim of the tumours and to perform a peritumoral injection of the tracer. Thus, the patients received only part of the injections.

Table 1

NDNumber and level of SLNsNumber and level of SLNs with tumorLevel of metastases
No.Site of primaryMidlineT-statusIpsiContraIpsiContraIpsiContrapN-statusIpsiContra
1TongueNo1I–IIII-IIIII, 8xIIIIII0
2LarynxNo3II–IVII-IVII00
3LarynxNo3II–IVII-IVI, II, III00
4LarynxNo3II-IVII-IVII, 2xIII, 2xV00
5TongueNo2I–III4xIIIIII1III
6TonsilNo2I–IVI-IV3xI, 3xIII, 5xV0I1I
7LarynxNo3I–IIIII0
8TongueNo2I–IVII, 5xIII, IV, 1xIV0
9LarynxNo3I–VII-IVI, II, 2xIII00
10TonsilNo4I–V5xII0
11TonsilNo2I–VI, 2xII0
12FOMNo2I–IIII0
13BOTNo3I–IVII, VII1II
14FOMNo2I–V4xII0
15TongueNo2I–IVII, III, V0
16LarynxNo1I–IVII, III0
17LarynxNo3I–IIII-IIIIIII0
18TonsilNo2I–IV2xII2xII2b2xII
19TonsilNo2I–IVIIII2bI, 2xII, III
20TonsilNo1I–VII0
21TongueNo1I–IV4xIIII1II
22TongueNo2I–IV4xII, 2xIII2xII2b2xII
23FOMYes2I–IVI-IVII2xII, 3xIII0
24LarynxYes3I-IIII-IIIIIIII, 2xIII0
25PalateYes2II–IIIII-IIIIIIII0
26BOTNo1I–IVI-IVI, II, 2xIII00
27LarynxNo3II–IVII-IV4xII00
28TongueNo2I–IIII, 2xIII0
29TongueNo1I–III2xIII0
30FOMYes2I–IIII–IIIIIII0
31FOMYes3I–IVI–III2xIII, II0
32BOTNo3II–IVII–IV2xII00
33TonsilNo2I–IVIIII2b3xII
34OrophaYes2II–VII–VIIII0
35FOMNo2I–IVI–IVI, II00
36LarynxNo1II–IV2xIII0
37PalateYes3II–IVII–IVII2xII12cII
38TonsilNo2I–IV00
39TongueNo2I–III3xII, 3xIIIII, III2bII, III
40TonsilNo2II–IVIIII1II
41TongueNo2I–IVI, II, IIIIII2b2xI, III
42TongueNo3I–IIIII, III, IV0
43PalateNo2II–III00
44TonsilNo2II–III2xII0
45FOMNo1I–IIII–III, II0
46HypopharynxNo4II–IVII–IVII0
47PalateNo2II–III01II
48LarynxYes3II–IIIII–IIIII, 2xIII0
49LarynxNo3II–III00
50TonsilNo1II–IVII, 2xIII, IV0
Midline signifies a tumour crossing the midline. FOM=floor of the mouth; BOT=base of the tongue; oropha=posterior oropharyngeal wall; ND=levels of neck dissection; Ipsi=ipsilateral; Contra=contralateral; SLN=sentinel lymph node. Roman numbers indicate the levels of the neck.

Staging of the neck was based on ultrasound examination of the neck. In 19 patients, an ultrasound-guided fine-needle aspiration cytology was performed. In each case, the N0-status of the neck was confirmed as a prerequisite for study inclusion.

Methods

Up to a total of 50 MBq 99Tc-colloid (Solco®Nanocoll, Solco, Basel, Switzerland) dissolved in 0.2 ml saline solution was injected peritumorally with a minimum of four injections depending on the location and size of the tumour. Particle size of the tracer was less than 80 nm in diameter. The injection was given on the day of resection of the primary tumour and elective neck dissection. In 11 patients with accessible tumours peritumoral injection was given preoperatively and lymphoscintigraphy was performed. Planar images were acquired using a large-field-of-view-gamma camera equipped with a LEAP-collimator (Gammadiagnost Tomo, Philips, Hamburg, Germany). The sequence for the first 10 min was 30 s per frame from a frontal, left or right lateral view. Then, 5-min images were acquired up to 30 min post injection from different views. Lymphatic drainage was assessed by visual inspection. Lymph nodes accumulating tracer were marked on the skin. Initially, only in cases with difficult to access tumours such as carcinomas of the base of the tongue, larynx and in some tumours of the oropharynx injection was performed intraoperatively. After May 2002, all tumours were injected intraoperatively. In these cases a lymphoscintigraphy to visualise the sentinel lymph node preoperatively was not possible. In patients with laryngeal tumours a microlaryngoscopy was performed to expose the tumour. Peritumoral injection was given by using a butterfly-cannula.

For intraoperative detection of the sentinel lymph nodes, cutaneous flaps were raised and the sternomastoid muscle was retracted. A straight 14-mm diameter γ-probe (Navigator GPS, RMD, Watertown, MA, USA) was used to localise lymph nodes accumulating tracer. Counts of the primary tumour, background activity and sentinel lymph nodes were documented for a 10-s-period each by the γ-probe. All lymph nodes accumulating activity were harvested and initially termed sentinel nodes. A definition of the true sentinel node was to be based on the results. After separate resection of the sentinel lymph nodes neck dissection was continued. It was carried out unilaterally in 39 patients and bilaterally in 21 patients. The extent of the neck dissection was depending on location and size of the primary tumour. In three patients with a tumour not crossing the midline sentinel nodes were observed on both sides of the neck. A bilateral neck dissection had been determined before the sentinel node procedure. Therefore no change in policy was necessary. If feasible, the primary tumour was excised before neck dissection in order to reduce the shine-through and scatter from the injection site, which can significantly hinder the detection of the sentinel lymph node. Location of sentinel lymph nodes, metastases and extent of neck dissection are described according to the terminology of the American Academy of Otolaryngology – Head and Neck Surgery (Robbins et al, 2002).

Neck dissection specimens and sentinel nodes were fixed in 10% neutral buffered formalin. For pathological examination, nodes were bisected along the axis. All nodes including sentinel lymph nodes were evaluated by a hematoxylin–eosin (H&E)-stained single section. If the single slices of the sentinel lymph nodes were free of tumour cells, they were further examined by step serial sections in 2 mm intervals in 18 patients. Of each block three sections were cut. One slice was stained with H&E and a second one immunohistochemically with cytokeratin antibody Lu5 (BMA, Augst, Switzerland). Results of the pathohistological examination of the sentinel lymph nodes and the respective neck dissection specimens were compared.

RESULTS

In 46 out of 50 patients, there was a lymphatic drainage of the radiocolloid into at least one sentinel lymph node. In four patients, a sentinel lymph node could not be detected. Of 42 patients with a tumour not crossing the midline, 35 had an ipsilateral and three a bilateral drainage into sentinel lymph nodes while four did not reveal any sentinel nodes. Of eight patients with a tumour crossing the midline, seven had a bilateral and one a unilateral lymphatic drainage. The number of lymph nodes accumulating tracer and being biopsied intraoperatively varied from 1 to 11. The average number of lymph nodes accumulating the tracer was 3.2 (Table 1). There was no correlation between time interval between injection of the tracer and localisation of the sentinel nodes to the number of nodes detected.

Three of 11 patients with preoperative lymphoscintigraphy did not reveal a lymphatic drainage during scintigraphy, while in these three patients radiolabelled sentinel lymph nodes were detected intraoperatively with the γ-probe. In two of them an occult metastasis was found. In the remaining eight patients, a lymphatic drainage was observed by scintigraphy. The drainage into the levels of the neck was identical to the location of sentinel lymph nodes detected with the γ-probe. In six cases, however, there were more sentinel nodes detected with the probe than visualised by scintigraphy.

In 34 patients pathohistological examination did neither show occult metastases in the sentinel nodes nor in lymph nodes of the neck dissection specimens. In 12 patients at least one sentinel lymph node was found to harbour occult metastastic disease. In nine of these patients metastases in the sentinel lymph nodes were the only ones, whereas in three patients additional metastases were found in nonsentinel lymph nodes. Thus, the status of the neck had to be changed from N0 to pN1 in five patients, to pN2b in six patients and due to a contralateral metastasis to pN2c in one patient. All sentinel nodes containing occult metastases were within the first five nodes of highest activity in each patient (Table 2 ). None of the patients with tumour-free sentinel lymph nodes revealed metastases in nonsentinel lymph nodes.

Table 2

Background activity and count rate of radiolabelled sentinel lymph nodes

No.Background counts1. SLN2. SLN3. SLN4. SLN5. SLN6. SLN7. SLN8. SLN9. SLN10. SLN11. SLN
537369827341368750
612159014071364665519404403346274265221
1340181160
1871990578
1917121
215197520414291
22612509455421129876
3322744
37181926651
392908950453712
40441
Lymph nodes marked in bold letters signify occult metastatic disease. SLN=sentinel lymph node.

In three patients without detectable sentinel lymph nodes, no metastases were found by pathohistologic examination. In one patient without accumulation of the tracer in lymph nodes a single metastasis was detected in the neck dissection specimen.

In two of 12 patients, occult metastases were detected only after additional sections had been stained with H&E. In one patient, the metastasis was found by immunohistochemical staining only.

Of the four patients in whom a peritumoral injection was not possible and who received only part of the injection, two patients with laryngeal carcinomas were staged pN0 after pathohistologic examination. In the remaining two patients lymph nodes accumulating tracer were tumour-free whereas in each case a node without tracer accumulation harboured metastatic disease.

DISCUSSION

The sentinel node concept offers the chance to stage the neck with less morbidity than an elective selective neck dissection. Attempts in assessing the diagnostic value of the sentinel node by fine-needle aspiration cytology offering the least possible morbidity, though at first promising, were not successful (Colnot et al, 2001; Höft et al, 2002; Nieuwenhuis et al, 2002). The method does not reliably detect occult metastatic disease as the sample of the sentinel lymph node is too small. Achieving a valid diagnosis mandates a pathohistological examination of a complete sentinel node. In order to determine the diagnostic value of the sentinel lymph-node concept, we compared the pathohistological results of sentinel nodes with the respective neck dissection specimens.

In our group of patients, the pathological exclusion of occult metastases in sentinel lymph nodes was predictive for the pathological status of the neck in each patient. Based on the limited number of patients in this study, the sentinel lymph node seems to have a high diagnostic value in head and neck cancer. This is in accordance with the literature. The first biopsy of a radiolabelled sentinel lymph node in head and neck cancer was performed by Alex and Krag (1996). Initial investigations of the sentinel lymph-node concept in head and neck cancer were disappointing using blue dye only (Alex and Krag, 1996; Pitman et al, 1998; Shoaib et al, 1999). Studies applying a radiolabelled tracer with or without additional blue dye, however, were promising. The majority of the studies reported results favouring the sentinel lymph-node concept (Koch et al, 1998; Shoaib et al, 1999, 2001; Alex et al, 2000; Zitsch et al, 2000; Mozzillo et al, 2001; Stoeckli et al, 2001, 2002; Barzan et al, 2002; Werner et al, 2002a, 2002b). Groups who worked with blue dye report of an extravasation of the blue dye into the tissue (Pitman et al, 2002). Other authors detected stained sentinel nodes only in a minority of their patients (Stoeckli et al, 2001). Additionally, blue dye will stain the area around the primary tumour. This hinders a resection of the primary tumour and might alter the absorption of the laser energy that is frequently used to resect oral, pharyngeal and laryngeal tumours. Therefore, most groups in contrast to groups treating malignant melanomas or breast cancer prefer a radioactive tracer without using blue dye.

We excluded four patients from our study in whom a peritumoral injection of the caudal rim of the tumour was not possible. Since the tracer had already been injected, nodes accumulating tracer were localised. Pathohistological comparison revealed occult metastatic disease in two of the patients. However, the nodes that had accumulated the tracer were free of metastases. Thus, if a complete peritumoral injection of the tracer is not possible, the patient is not eligible for the sentinel node method.

In four of our patients, no sentinel node could be detected. Reasons might be a wrong technique by injecting the tracer too deep into the tissue not close enough to the mucosa. Another reason might be that in-transit metastases diverted or in this case blocked the drainage of the radiocolloid into the sentinel node (Civantos et al, 2003).

In 10 of 13 patients with occult metastases, the initial H&E staining was sufficient to detect the metastases. In two of the patients, however, they were discovered exclusively after additional sections had been stained with H&E. In another case, tumour cells were found by immunohistochemical staining only. An intensive sectioning and standard H&E staining as well as immunohistochemical staining will reveal more metastases than standard single-block examination of a lymph node (Ambrosch et al, 1995; van den Brekel et al, 1996). Thus, performing a sentinel node-biopsy and basing the therapy of the neck on the status of the sentinel lymph node mandates an intensive and profound patho- and immunohistochemical work-up.

In one patient 10 and in another patient 11 radioactive lymph nodes were found. It is obvious that not all these nodes were sentinel lymph nodes. A high number of nodes accumulating activity poses a problem as the aim of the sentinel node concept is to keep the surgical morbidity to a minimum. Yet, also in other studies up to nine nodes accumulating tracer have been detected (Alex et al, 2000; Shoaib et al, 2001). There have been different approaches to limit the number of nodes to be biopsied by defining the sentinel lymph node by its activity. Alex et al (2000) suggested that an activity three times higher than the background should classify a sentinel lymph node. Zitsch et al (2000) adopted a definition used in malignant melanomas defining the sentinel node as having two times the background activity count rate. Werner et al (2002a) characterised sentinel lymph nodes as the three nodes with the highest activity emitting at least 10 times the background counts. As depicted in Table 2, all sentinel lymph nodes with occult metastases were among the five nodes with the highest activity. Yet, even if we had limited ourselves to harvesting the three nodes with the highest activity, we still would have detected all patients with occult metastatic disease. Thus, defining the sentinel nodes as the three nodes with the highest activity seems to be sufficient to reduce the number of nodes to be resected while achieving an oncologic sound result.

Counts of the background and of the sentinel nodes varied considerably. This might be due to individual differences, although the technique has been standardised as described. Depth of injection might differ slightly resulting in a reflux of the tracer out of the tissue causing a higher background from the pharynx. Also less tracer will reach the lymph nodes. Patients 39 and 40 had small tumours. Therefore, less than 50 MBq was injected. Consequently, this might result in a reduced count both of the sentinel nodes and of the background. No correlation of the varying counts in respect to time interval between injection and detection of the sentinel nodes was found. However, since sentinel nodes are defined as the three nodes with the highest activity and not in relation to the average counts of all patients differences to the average do not have an impact on the individual patient.

Preoperative lymphoscintigraphy did not improve the procedure of identifying the sentinel nodes: in two patients without scintigraphic drainage sentinel nodes containing occult metastases were localised by the γ-probe. In the other patients more radiolabelled nodes were detected intraoperatively by the γ-probe than visualised by scintigraphy. In these cases, scintigraphy did not reduce the number of nodes to be biopsied as all were located in the same levels of the neck as the nodes visualised preoperatively. Thus, there seems to be little help by preoperative lymphoscintigraphy and we do not apply it on a regular basis any longer. An argument in favour of preoperative lymphoscintigraphy is the existence of aberrant drainage patterns to the contralateral side of the neck. However, careful percutaneous scanning with the γ-probe should detect radiolabelled lymph nodes there, too.

The average incidence of occult metastatic disease was 26% based on staging by ultrasound and ultrasound-guided fine-needle aspiration cytology. These results are comparable to the findings of other groups also applying radiological criteria for staging (Stoeckli et al, 2001; Barzan et al, 2002; Werner et al, 2002a). The better the staging methods are in detecting small metastases, the less occult metastases will be overlooked and the more valuable will be the impact of an additional sentinel lymph-node procedure. Consequently, it is important not to replace standard staging methods by the sentinel lymph-node concept, but to perform it in addition to the best possible staging procedures.

In the present group, no patient with tumour-free sentinel nodes was found to have a metastasis in a nonsentinel lymph node. Therefore, one could argue that if we had performed a sentinel biopsy only, an elective neck dissection could have been avoided in 34 of our 50 patients. Yet, data are too limited to permit this step. So far, only Ross et al (2002) have reported on a study of a true biopsy of the sentinel lymph node without elective neck dissection. In case of occult metastatic disease, therapeutic neck dissection is performed. However, so far, there have been no sufficient follow-up data. A validation of the sentinel lymph-node method mandates that patients with a mere biopsy of the sentinel nodes should have equal regional control rates as patients after elective neck dissection. The consequence of a tumour-positive sentinel lymph node has to be discussed, too. A subsequent therapeutic neck dissection will be delayed by several days until sentinel nodes have been examined intensively by patho- and immunohistology. Revision neck dissection will cause additional morbidity. Alternatively, radiotherapy could be applied. This again would cause severe morbidity. Intraoperative examination of the sentinel nodes would enable an instant decision whether or not to perform a therapeutic approach to the neck and to avoid a second surgical step. Frozen section examination of the sentinel lymph nodes has been performed in breast cancer and malignant melanomas. However, sensitivity especially for micrometastases is low and therefore frozen section examination is not recommended in these tumours (Turner et al, 1999; Koopal et al, 2000). Likewise, Civantos et al (2003) discovered only six of 10 occult metastases of squamous cell carcinomas of the oral cavity by frozen section examination. Thus, at present, there are still a number of problems to be solved before sentinel lymph-node biopsy can be integrated into clinical routine. Further studies with a combined sentinel node biopsy and elective neck dissection will have to clarify whether or not early metastases can be detected by sentinel node biopsy only. If this can be proven, more studies will be necessary to determine whether or not regional control after sentinel biopsy is equivalent to elective neck dissection and whether or not sentinel node biopsy with a possible secondary therapeutic neck dissection results in less morbidity than a primary limited selective elective neck dissection.

References

  • Alex JC, Krag DN. The gamma-probe-guided resection of radiolabeled primary lymph nodes. Surg Oncol Clin N Am. 1996;5:33–41. [PubMed] [Google Scholar]
  • Alex JC, Sasaki CT, Krag DN, Wenig B, Pyle PB. Sentinel lymph node radiolocalization in head and neck squamous cell carcinoma. Laryngoscope. 2000;110:198–203. [PubMed] [Google Scholar]
  • Ambrosch P, Kron M, Fischer G, Brinck U. Micrometastases in carcinoma of the upper aerodigestive tract: detection, risk of metastasizing, and prognostic value of depth of invasion. Head Neck. 1995;17:473–479. [PubMed] [Google Scholar]
  • Ambrosch P, Kron M, Pradier O, Steiner W. Efficacy of selective neck dissection: a review of 503 cases of elective and therapeutic treatment of the neck in squamous cell carcinoma of the upper aerodigestive tract. Otolaryngol Head Neck Surg. 2001;124:180–187. [PubMed] [Google Scholar]
  • Barzan L, Sulfaro S, Alberti F, Politi D, Marus W, Pin M, Savignano MG. Gamma probe accuracy in detecting the sentinel lymph node in clinically N0 squamous cell carcinoma of the head and neck. Ann Otol Rhinol Laryngol. 2002;111:794–798. [PubMed] [Google Scholar]
  • Civantos FJ, Gomez C, Duque C, Pedroso F, Goodwin WJ, Weed DT, Arnold D, Moffat F. Sentinel node biopsy in oral cavity cancer: correlation with PET scan and immunohistochemistry. Head Neck. 2003;25:1–9. [PubMed] [Google Scholar]
  • Colnot DR, Nieuwenhuis EJ, van den Brekel MW, Pijpers R, Brakenhoff RH, Snow GB, Castelijns JA. Head and neck squamous cell carcinoma: US-guided fine-needle aspiration of sentinel lymph nodes for improved staging – initial experience. Radiology. 2001;218:289–293. [PubMed] [Google Scholar]
  • Giuliano AE, Kirgan DM, Guenther JM, Morton DL. Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg. 1994;220:391–398.[PMC free article] [PubMed] [Google Scholar]
  • Höft S, Muhle C, Brenner W, Sprenger E, Maune S. Fine needle aspiration cytology of the sentinel lymph node in head and neck cancer. J Nucl Med. 2002;43:1585–1590. [PubMed] [Google Scholar]
  • Koch WM, Choti MA, Civelek AC, Eisele DW, Saunders JR. Gamma probe-directed biopsy of the sentinel node in oral squamous cell carcinoma. Arch Otolaryngol Head Neck Surg. 1998;124:455–459. [PubMed] [Google Scholar]
  • Koopal SA, Tiebosch AT, Albertus Piers D, Plukker JT, Schraffordt Koops H, Hoekstra HJ. Frozen section analysis of sentinel lymph nodes in melanoma patients. Cancer. 2000;89:1720–1725. [PubMed] [Google Scholar]
  • Morton DL, Wen DR, Foshag LJ, Essner R, Cochran A. Intraoperative lymphatic mapping and selective cervical lymphadenectomy for early-stage melanomas of the head and neck. J Clin Oncol. 1993;11:1751–1756. [PubMed] [Google Scholar]
  • Morton DL, Wen DR, Wong JH, Economou JS, Cagle LA, Storm FK, Foshag LJ, Cochran AJ. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg. 1992;127:392–399. [PubMed] [Google Scholar]
  • Mozzillo N, Chiesa F, Botti G, Caraco C, Lastoria S, Giugliano G, Mazzarol G, Paganelli G, Ionna F. Sentinel node biopsy in head and neck cancer. Ann Surg Oncol. 2001;8 Suppl 9:103S–105S. [PubMed] [Google Scholar]
  • Nieuwenhuis EJ, Castelijns JA, Pijpers R, van den Brekel MW, Brakenhoff RH, van der Waal I, Snow GB, Leemans CR. Wait-and-see policy for the N0 neck in early-stage oral and oropharyngeal squamous cell carcinoma using ultrasonography-guided cytology: is there a role for identification of the sentinel node. Head Neck. 2002;24:282–289. [PubMed] [Google Scholar]
  • Pitman KT, Johnson JT, Brown ML, Myers EN. Sentinel node biopsy in head and neck squamous cell carcinoma. Laryngoscope. 2002;112:2101–2113. [PubMed] [Google Scholar]
  • Pitman KT, Johnson JT, Edington H, Barnes EL, Day R, Wagner RL, Myers EN. Lymphatic mapping with isosulfan blue dye in squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg. 1998;124:790–793. [PubMed] [Google Scholar]
  • Pitman KT, Johnson JT, Myers EN. Effectiveness of selective neck dissection for management of the clinically negative neck. Arch Otolaryngol Head Neck Surg. 1997;123:917–922. [PubMed] [Google Scholar]
  • Robbins KT, Clayman G, Levine PA, Medina, Sessions R, Shaha A, Som P, Wolf GT. Neck dissection classification update: revisions proposed by the American Head and Neck Society and the American Academy of Otolaryngology-Head and Neck Surgery. Arch Otolaryngol Head Neck Surg. 2002;128:751–758. [PubMed] [Google Scholar]
  • Ross G, Shoaib T, Soutar DS, Camilleri IG, Gray HW, Bessent RG, Robertson AG, MacDonald DG. The use of sentinel node biopsy to upstage the clinically N0 neck in head and neck cancer. Arch Otolaryngol Head Neck Surg. 2002;128:1287–1291. [PubMed] [Google Scholar]
  • Shoaib T, Soutar DS, MacDonald DG, Camilleri IG, Dunaway DJ, Gray HW, McCurrach GM, Bessent RG, MacLeod TI, Robertson AG. The accuracy of head and neck carcinoma sentinel lymph node biopsy in the clinically N0 neck. Cancer. 2001;91:2077–2083. [PubMed] [Google Scholar]
  • Shoaib T, Soutar DS, Prosser JE, Dunaway DJ, Gray HW, McCurrach GM, Bessent RG, Robertson AG, Oliver R, MacDonald DG. A suggested method for sentinel node biopsy in squamous cell carcinoma of the head and neck. Head Neck. 1999;21:728–733. [PubMed] [Google Scholar]
  • Steiner W, Hommerich CP. Diagnosis and treatment of the N0 neck of carcinomas of the upper aerodigestive tract. Eur Arch Otorhinolaryngol. 1993;250:450–456. [PubMed] [Google Scholar]
  • Stoeckli SJ, Steinert H, Pfaltz M, Schmid S. Sentinel lymph node evaluation in squamous cell carcinoma of the head and neck. Otolaryngol Head Neck Surg. 2001;125:221–226. [PubMed] [Google Scholar]
  • Stoeckli SJ, Steinert H, Pfaltz M, Schmid S. Is there a role for positron emission tomography with 18F- fluorodeoxyglucose in the initial staging of nodal negative oral and oropharyngeal squamous cell carcinoma. Head Neck. 2002;24:345–349. [PubMed] [Google Scholar]
  • Suárez O. Le probleme chirurgical du cancer du larynx. Ann Otolaryngol. 1962;79:22–34.[Google Scholar]
  • Traynor SJ, Cohen JI, Gray J, Andersen PE, Everts EC. Selective neck dissection and the management of the node-positive neck. Am J Surg. 1996;172:654–657. [PubMed] [Google Scholar]
  • Turner RR, Hansen NM, Stern SL, Giuliano AE. Intraoperative examination of the sentinel lymph node for breast carcinoma staging. Am J Clin Pathol. 1999;112:627–634. [PubMed] [Google Scholar]
  • van den Brekel MW, van der Waal I, Meijer CJ, Freeman JL, Castelijns JA, Snow GB. The incidence of micrometastases in neck dissection specimens obtained from elective neck dissections. Laryngoscope. 1996;106:987–991. [PubMed] [Google Scholar]
  • Werner JA, Dunne AA, Ramaswamy A, Folz BJ, Brandt D, Kulkens C, Moll R, Lippert BM. Number and location of radiolabeled, intraoperatively identified sentinel nodes in 48 head and neck cancer patients with clinically staged N0 and N1 neck. Eur Arch Otorhinolaryngol. 2002b;259:91–96. [PubMed] [Google Scholar]
  • Werner JA, Dunne AA, Ramaswamy A, Folz BJ, Lippert BM, Moll R, Behr T. Sentinel node detection in N0 cancer of the pharynx and larynx. Br J Cancer. 2002a;87:711–715.[PMC free article] [PubMed] [Google Scholar]
  • Zitsch RP, III, Todd DW, Renner GJ, Singh A. Intraoperative radiolymphoscintigraphy for detection of occult nodal metastasis in patients with head and neck squamous cell carcinoma. Otolaryngol Head Neck Surg. 2000;122:662–666. [PubMed] [Google Scholar]
Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK
Published online 2010 Mar 3. doi: 10.1007/s11912-010-0087-2
PMID: 20425597
This article has been cited by other articles in PMC.

Abstract

Rapid advances in the ability to produce nanoparticles of uniform size, shape, and composition have started a revolution in the sciences. Nano-sized structures herald innovative technology with a wide range of potential therapeutic and diagnostic applications. More than 1000 nanostructures have been reported, many with potential medical applications, such as metallic-, dielectric-, magnetic-, liposomal-, and carbon-based structures. Of these, noble metallic nanoparticles are generating significant interest because of their multifunctional capacity for novel methods of laboratory-based diagnostics, in vivo clinical diagnostic imaging, and therapeutic treatments. This review focuses on recent advances in the applications of nanotechnology in head and neck cancer, with special emphasis on the particularly promising plasmonic gold nanotechnology.

Keywords: Nanotechnology, Gold nanoparticles, Nanorods, Cancer, Head and neck

Introduction

Nanobiotechnology represents the convergence of multiple scientific fields including chemistry, engineering, physics, and molecular biology. Nanoparticles are generating a revolution within the scientific community as the race to develop clinically useful structures progresses. Elements restricted to the nanoscale in various forms demonstrate previously unseen physical properties (electronic, optical, magnetic, catalytic) []. Due the appropriate size match and facile surface chemistry allowing conjugation to biologically active molecules, several nanoparticles are potentially exploitable for a wide range of applications in biology and medicine. Nanotechnology has generated significant investment from the National Institutes of Health (NIH)/National Cancer Institute and is expected to create a paradigm-shift in the detection, treatment, and prevention of cancer [].

A plethora of nanostructures have been described with varying composition (eg, gold, iron oxide, carbon, dielectric materials, molecular, liposomal) and shapes including solid nanoparticles (eg, spheres, rods, triangles, cubes), nanoshells (within inner and outer cores), nanocages, nanowire, nanotubes, branched dendrimers, and polymeric and organic lipid nanoparticles []. Inorganic nanoparticles are particularly interesting because of their unique electronic, magnetic, optical, photothermal, or catalytic properties at the nanoscale. Of the array of nanostructures currently available, plasmonic gold nanoparticles are especially promising because of their simple fabrication, multifunctional nature, facile surface chemistry [–6••], biodistribution properties, and relatively low toxicity [•, 8, ].

Gold nanoparticles can be applied therapeutically for photothermal therapy [], intravascular drug/gene delivery [], and ionizing radiation enhancement []. This new technology has impending clinical application toward head and neck cancer as evidenced by the initiation of two phase 1 human trials investigating gold conjugated tumor necrosis factor (TNF) treatment of solid tumors [12] and photothermal therapy of refractory head and neck cancer [13]. A discussion of gold nanotechnology provides a foundation to understand the unique possibilities created by the emerging nanosciences.

Why Nanobiotechnology?

Nanotechnology is expected to provide a range of devices for diagnosis and treatment in medicine. On the size scale of 1 to 200 nm, nanoparticles are well matched in size to biologic molecules and structures found inside living cells []. Typical mammalian cells range in size from 2000 nm to 10,000 nm, whereas cellular organelles are about 100 nm to 300 nm and intracellular proteins and molecules are about 10 nm to 50 nm. Nanoparticles appear the appropriate size range for imaging and manipulation at the molecular level. The ability to control the nanoparticle surface chemistry allows conjugation to various ligands for interactions at the molecular level. Furthermore, gold nanoparticles produce greatly enhanced spectral signals that are detectable above the background noise of cells and extracellular tissue.

Head and Neck Cancer: Room for Improvement

Cancer is the second-leading cause of mortality in the United States, responsible for one in every four deaths [15]. Cancers of the head and neck—including the salivary glands, thyroid, and the mucosal lining of the oral cavity, pharynx, nasopharynx, and larynx—account for 2% to 6% of all malignancies in the United States [16]. The mainstay of treatment for head and neck cancer is surgery, radiation, chemotherapy, antibody-blocking therapy, or a combination of therapies. The most important advance in the management of head and neck cancer has been the increasing role of chemotherapy, or antibody-blocking therapy, for use in conjunction with radiation therapy to achieve cure with organ preservation [17, ]. Despite these advances, survival rates for head and neck cancer have improved little in the past 50 years. Current treatments have significant functional and cosmetic impact and significant attention is focused on improving the quality of life of these patients [17].

Oral squamous cell carcinoma (OSCC) represents an excellent model for both head and neck cancer and solid malignancies in general. Nearly 85% of all malignancies are of epithelial origin including the skin, oral cavity, nasopharyngeal, laryngeal, lung, gastrointestinal, colon, and bladder cancer [15]. OSCC is an aggressive malignancy that invades local tissue, spreads to regional and distant sites, and has an overall 5-year survival of 60% [15]. About 80% to 90% of OSCC overexpress a surface antigen important to tumor growth and proliferation, epithelial growth factor receptor (EGFR) [19]. Analogous surface receptors exist on other solid tumors, making EGFR an excellent model for investigation of antibody-based targeting of tumors. EGFR-blocking therapies have enjoyed recent success as adjuvant treatment to radiation with significant reduction in associated toxicity for patients []. Detection of OSCC primary or recurrent tumors is possible with direct visual inspection because of surface-exposed location in the body. As a result of these factors, OSCC has been the focus of several early studies of nanotechnology.

Find a Role for Nanotechnology in Cancer Management?

Nanotechnology appears poised to provide devices capable of 1) sensitive and specific anatomic, molecular, and biologic imaging; 2) selective therapy of tumors; and 3) relatively low toxicity. The physical properties of several nanostructures strongly suggest that these goals are attainable and will result in a significant improvement over the current standard of care. Patients with head and neck cancer require staging assessments, invasive treatments, and post-treatment monitoring with physical examination and routine imaging for 5 years. The mainstay of imaging modalities for diagnosis and follow-up head and neck cancer patients are MRI, CT, ultrasonography, and positron emission tomography (PET). These techniques have limited resolution and cannot detect microscopic or molecular changes. Further, interpretation of findings can be complicated by difficult anatomy, edema or inflammation, scarring from prior treatment, and loss of detail because of patient movement or dental implants. False-positive findings can occur on PET imaging because of inflammatory or infectious processes. Furthermore, the imaging techniques are quite poor for detection of small surface lesions. Definitive diagnosis still requires tissue diagnosis with biopsy or needle aspiration. Intraoperative diagnosis of tumor at the surgical margins can be difficult. Developing sensitive and specific noninvasive molecular tests for staging, screening, and intraoperative diagnosis would significantly improve patient care.

Currently available therapies for head and neck cancer suffer significant limitations. In the head and neck, surgical resection is limited by several adjacent important structures such as the carotid artery, eye, and brain. Residual tumor may be left behind near vital structures or because it has spread beyond the surgical margin, making adjuvant treatments necessary to achieve cure of the residual disease. Radiation therapy has a high failure rate for advanced tumors, and toxicity limits the amount that can be given to one full course treatment. Chemotherapy in head and neck cancer is limited to a supportive role in combination with radiation. Nanotechnology may provide a new tool for clinicians by offering the potential of molecular diagnostic probes and novel therapeutic devices, such as photothermal and magneto-thermal probes, drug- and gene-delivery vectors, and radiation enhancers.

Application of Gold Nanotechnology in Head and Neck Cancer

Three properties of gold nanoparticles are important at the biologic level. First, the small size of the particles creates a large surface area to volume. Based on the large surface area, chemical reactions occur on the surface of the nanoparticles at a significantly increased rate, creating actively enhanced catalytic agents. The catalytic properties have not yet found application in cancer therapy. Second, nanoparticles happen to be the correct size for intravascular transport and accumulation inside many tumor beds for selective tumor targeting and drug delivery. Third, gold particles take on optical properties useful for imaging and photothermal therapy.

Gold Nanoparticles as a Drug-Delivery Vector

When hidden from the human immune system, gold nanoparticles ranging from 10 nm to 140 nm will accumulate inside tumors because of the enhanced permeability and retention effect []. Passivating the nanoparticle surface can be easily achieved with polymers such as polyethylene glycol (PEG). Accumulation in solid tumors occurs because of filtration through the poorly formed, leaky vasculature associated with tumor angiogenesis []. Paciotti et al. [8] demonstrated PEG bound gold conjugated with TNF rapidly accumulated in MC-38 colon carcinoma tumor-bearing mice with little uptake in other organs [8]. The PEG coating shields the complex from the immune responses and is vital for successful drug delivery. Paciotti et al. [8] discovered gold nanoparticles with targeting ligands lacking a passivating agent are taken up within minutes by the reticuloendothelial system. Because gold readily bonds to sulfur atoms, gold nanoparticles can be easily conjugated to a range of molecules through thiol chemistry. Loading gold with toxic chemicals or molecules, such as TNF, allows selective delivery of large doses of toxins. By adding PEG in addition to selected toxins, selective accumulation in the tumor reduces toxicity of the treatment drug by avoiding the other healthy host organs. Interestingly, the targeting ligand TNF appears to increase uptake of the gold into the tumor, suggesting that active ligands can improve selective tumor targeting. As a result of these findings, gold-based drug delivery is the first NIH funded human “nano” trial initiated and has completed patient accumulation in its phase 1 trial []. Several potential targeting ligands exist to improve tumor uptake including folate, transferrin, arginine–glycine–aspartic acid peptide, antibodies, or antibody fragments to cell surface receptors [].

Optical Properties of Gold Useful for Imaging and Therapy

Plasmons

Noble metal nanoparticles such as solid gold, silver, and silica-core gold nanoshells exhibit dramatic optical properties useful for ultrasensitive sensing and photothermal therapy. When stimulated by light, all the conduction band electrons in the gold nanoparticles oscillate coherently on the particle surface, creating a phenomena known as the surface plasmon resonance (SPR). According to the Mie theory, when light strikes gold nanoparticles smaller than 200 nm, energy is lost due to two processes: light scattering and light absorption [6].

Light scattering occurs as energy from the light stimulates the electrons on the particle surface to oscillate and subsequently emit photons at the same frequency (color) or at a shifted frequency. When light is absorbed, the energy is converted efficiently into heat. The nanoparticles have a particular (resonance) frequency, or color, in which they scatter and absorb the maximum amount of light. The “peak frequency” is sensitive to the size, shape, composition and surrounding environment. By changing the size or shape, gold nanoparticles are tunable over the visible and infrared region of light. Particles 30 nm to 100 nm in size scatter intensely and can be detected by commercial microscopes with darkfield illumination. Using a darkfield microscope, particles 40 nm in size can be detected by eye at a concentration of 10−14 M. A single 60 nm nanosphere is 105 times brighter than a fluorescein molecule [, ]. Changing the electric field of the nanoparticles, such as by bringing two particles in close proximity to each other, changes the peak frequency by shifting the color toward the red region. A few nanoparticles will cause a shift of a few nanometers, whereas aggregation of several particles causes a larger red shift of up to 100 nm. If the nanoparticle is coated with a substance, such as an antibody, the light must pass through that substance, resulting in a small red shift of the peak frequency. The attributes are useful for plasmonic based imaging [].

Plasmonic Cancer Imaging

In addition to direct interaction with light, the SPR creates a source of energy on the particle surface that can affect optical properties of molecules on its surface. Gold nanotechnology appears useful for biomedical imaging in many optical domains including fluorescence [], light absorption and scattering [, , ], photoacoustic imaging [], photothermal imaging [28], and surface-enhanced Raman scattering [29]. Based on the SPR, diagnostic imaging with gold nanospheres and nanorods has been achieved in vivo in animal models using multiphoton imaging of single nanorods [], photoacoustic imaging of tumors and sentinel nodes [, 32], near infrared absorption imaging [•, ], surface-enhanced Raman spectroscopy [••], and confocal endoscopy [].

As optical sensors, gold nanoparticles are multifunctional probes that provide several new types of information for medical imaging at the subcellular, biochemical, and molecular level. Silica-gold nanoshells and solid gold nanoparticles, as spheres and rods, can be selectively targeted to OSCC using antibodies directed against EGFR. Sokolov et al. [] demonstrated in vitro immunoconjugated gold nanospheres are intense contrast agents using a red laser pointer with a portable confocal endoscopy unit. El-Sayed et al. [] demonstrated the colorimetric attributes of immunotargeted gold nanoparticles for imaging anatomic location and molecular sensing of OSCC with light scattering and absorption. Imaging of gold nanospheres revealed colored particles with much greater affinity for the malignant cell lines. Particles about 25 nm in size could easily be detected above the background scattering of the cellular components. Light absorption was measured from single cells revealing characteristic absorption spectra of the gold nanospheres. The authors reported measurement of a shift in the color frequency by approximately 10 nm when the antibody-gold conjugated bound the EGFR. Furthermore, the amount of nanoparticles on the cell surface could be quantified as binding to the malignant cell line is 600% more than to the control cells, consistent with expected values of overexpression of EGFR on the cell lines []. Huang et al. [] subsequently demonstrated gold nanorods as near-infrared (NIR) imaging probes in the same OSCC cell line model using light scattering and absorption. Plasmonic imaging was subsequently performed in vivo using light scattering. The authors found about a 100 nm red shift of the particles color (from green to red) on the cell surface. The imaging characteristics and color change are thought to be caused by the aggregation of the nanoparticles induced by the clustering of overexpressed EGFR on the cancer cell surface.

Fluorescence Imaging of Gold Nanoparticles

The SPR can further enhance other optical processes of molecules in close proximity to the nanoparticles. For instance, gold nanoparticles quench fluorescence of molecules when covalently bound to the molecule, but enhance the scattering and fluorescence of molecules on their surface is separated from the nanoparticles by a distance sufficient to minimize quenching. In OSCC cell culture models, El-Sayed et al. [] found that gold nanoparticles quench cellular autofluorescence approximately 15% when incubated or immunoconjugated to cells. This effect was interpreted to be due to intense light absorption of the particles that were restricted in cellular compartments from accessing strong cellular fluorophores.

Molecular Detection with Surface-enhanced Raman Scattering

Surface-enhanced Raman scattering (SERS) is a powerful technology potentially useful for single-cell study and clinical medical diagnostics in vivo. Raman scattering of light occurs as a result of modulating the scattered light by the vibrational frequencies of the irradiated molecules. This produces a so-called fingerprint spectrum specific to the molecule. Because of the typically weak signals, use of Raman spectroscopy has been limited in medical applications. However, the gold SPR strongly enhances Raman scattering of adjacent molecules, creating a surface-enhanced Raman spectroscopy, known as SERS. Gold SPR enhances the Raman scattering by orders of magnitude (more than a million times) [] and has been reported for the use of SERS for single molecule detection [] and in vivo detection of cancer in a murine model. Gold nanospheres tagged with colored dyes and covalently bound to anti-EGFR single chain variable fragment (Sc-Fv) B10 antibodies produced strong SERS spectra of the dyes using a 20 mW laser at 9 mm from the skin. The dyes were 200 times brighter than the fluorescence emitted by the comparison group labeled with quantum dots []. Furthermore, SERS spectra have been obtained from nanoparticles targeted to the cytoplasm, nucleus [], and cell surface []. Huang et al. [] identified a possible molecular signature of EGFR overexpression using antibody-conjugated gold nanorods. The anti-EGFR nanorod SERS produced a strong, polarized spectra. The great intensity of signals created by gold nanorods results from the overlapping gold plasmonic fields of the rods lined lengthwise that would not occur with haphazard alignment on the cell surface. The lengthwise arrangement of the nanorods is postulated to result from tight packing of some of the rods in close proximity because of overexpression, clustering, and dimerization of EGFR receptors on the cancer cell surface [].

Plasmonic Photothermal Therapy

Another useful application of light absorption by gold nanoparticles is generation of heat for plasmonic photothermal therapy (PPTT). By changing the size, shape, or composition of the nanoparticles, the color of light that absorbs maximal energy can be tuned over the visible and NIR spectra. The NIR region from 650 nm to 900 nm is a desirable optical window in human tissue for deep penetration of light. Whereas gold spheres are tunable across the visible spectrum, the nanoshells and nanorods are both tunable across the NIR spectrum. The main determining factor of nanorod peak absorption is the aspect ratio of the particle: the relation of the length to width. By changing the aspect ratio (ratio of the short end to long end), gold nanorods are tunable over the near IR region from 650 nm to 1000 nm, where tissue penetration of human tissue by light is maximal. Although light penetration of human tissue is limited to a few millimeters in the visible region, microwatt laser NIR light can penetrate 10 cm into breast tissue and 4 cm into skull/brain or deep muscle tissue. Higher power US Food and Drug Administration class 3 lasers can penetrate through 7 cm of muscle and neonatal skull/brain []. From a surgeon’s perspective, in practical use, light delivery and nanoparticle selection can be tailored to specific lesions. Light and nanoparticles can be delivered externally, within the tumor by intravascular canalization, direct needle-guided placement, or into a postoperative field for residual tumor cells.

Kulms

Gold nanoshells, a first generation nanotechnology with a silica core surrounded by a gold shell, have been successfully tested in vitro [, ], in vivo in animal models [], and are currently initiating human trials for NIR photothermal therapy in refractory head and neck cancers [13]. However, based on modeling of heating efficiencies of gold nanospheres, nanorods, nanoshells and molecular dyes, gold nanorods seem to be far superior agents [].

Selective targeting with PPTT of OSCC was demonstrated in vitro in the visible range with immunoconjugated gold nanospheres []. Using a laser in the visible region at 442 nm, gold nanospheres were efficiently heated and killed the cells in two malignant OSCC cell lines at 19 W/cm2 (HOC 313 clone 8) and 25 W/cm2 (HSC 3) at much lower energy compared to the nonmalignant cell line (HaCat) at 57 W/cm2 []. However, visible light only penetrates human tissue on the order of a few millimeters and nanospheres would be limited to surface applications.

By changing the shape to a rod, or using a nanoshell, the peak absorption wavelength can be tuned to the NIR spectrum. Gold nanoshells targeted to breast cancer [] and gold nanorods targeted to OSCC in the NIR [] have been reported for combined imaging and photothermal therapy at 800 nm using a Ti:sapphire laser []. Nanorods achieve tumoricidal effect with less energy than either nanoshells or nanospheres. Nanoshells caused cell death at 35 W/cm2 for 7 min exposure [], whereas immunotargeted gold nanorods achieved cell death with 3 min exposure at 10 W/cm2 in vitro [7].

Based on heating and modeling experiments, gold nanoparticles can generate temperatures of 70°C to 80°C in these cells using far lower laser powers than conventional dyes []. Temperatures of 70°C to 80°C celsius are hot enough to denature proteins and disrupt protein, DNA, and RNA. Image analysis suggest cell death occurs because of blebbing formation of the cell wall and loss of membrane integrity []. Cell injury is likely related to both necrosis and cell membrane rupture.

Comparison of gold nanospheres, nanorods, and nanoshells reveals the gold nanoparticles absorb light at 104 times better than the best molecular dyes. Gold nanorods absorb a similar amount of energy as gold nanoshells at one third the size because the entire nanorod is composed of gold []. Furthermore, nanorods absorb the most energy per particle volume of all the particles. To compare particles across a range of sizes, a volumetric coefficient, expressed as a per micron absorption coefficient uabs can be calculated. Examining the nanoshell configuration used in vivo for photothermal trials (inner core, 60 nm; outer core, 70 nm) [, ], the nanoshells have a uabs of 35.62 with a peak absorption at 892 nm. At 11.4 nm, the nanorods uabs = 1000.87 at 863 nm, roughly 30 times more than the nanoshells (Table 1) [].

Table 1

Comparison of absorption coefficient of nanorods and nanoshells

ParticleaDimensionλmaxnmμа
Silica-goldR1 = 40 nm84350.61
R2 = 70 nm
Silica-goldR1 = 50 nm70420.57
R2 = 70 nm
Silica-goldR1 = 90 nm98411.07
R2 = 105 nm
NanorodsAR = 3.1, reff = 11.43 nm797907.09
NanorodsAR = 3.9, reff = 11.43 nm8631003.87
NanorodsAR = 3.9, reff = 8.74 nm788986
NanorodsAR = 3.9, reff = 21.86 nm842449.34

aGold nanorods have about 30 times more absorption of light in the size range of particles under study for photothermal applications.

AR aspect ratio; λmax wavelength where particle has maximal absorption and scattering (extinction); μа per micron absorption coefficient; R1 outer gold core; R2 inner silica core; reff effective radius of nanorod.

(Adapted from Jain et al. [], with permission.)

Both nanorods and nanoshells are tested in vivo with PPTT. Hirsch et al. [] found a maximal temperature rise of 37°C using 4 to 6 min of laser exposure in a murine model of transmissible venereal tumor with 10- to 25-fold less laser energy than needed for indocyanine green dye []. In an OSCC murine model, PEGylated nanorods were successfully imaged in OSCC implanted murine tumors using an infrared light source and charge coupled device digital camera (Fig. 1). Treatment with an 808 nm LED laser with a 6 mm beam achieved a 22°C temperature rise and a 25% (intravenous route) and 57% (direct injection into tumor) reduction of tumor compared with the sham treatment group after 13 days. Imaging revealed the direct injection group had 2.18 times greater absorption of light in the tumor than the intravenous injection group and 4.35 greater than the control group at 2 min (Fig. 1).

Near infrared absorption imaging with gold nanorods in mice treated with tumors (top). Extinction spectra (bottom) reveal that direct injection achieves nearly twice the absorption of intravascular injection of the nanorods. PBS—phosphate buffered saline. (From Dickerson et al. [•], with permission.)

The biodistribution of gold nanorods appears similar to other nanoparticles and can be delivered intravascularly to tumors. In vivo mice studies demonstrated PEG-nanorods accumulates about one third of the gold in the tumor [, ], making gold nanorods very attractive for PPTT applications in the head and neck.

Radiation Enhancement

Gold nanotechnology is potentially useful to augment current ionizing radiation techniques through two avenues: tissue hyperthermia and radiation enhancement. Gold is strong absorber of radiographs. Hainfeld et al. [] calculated that radiation doses could be enhanced locally around gold nanoparticles loaded into tumors by more than 200%. Tumor-burdened mice treated with gold nanoparticles and radiation demonstrated 86% 1-year survival in gold nanoparticle treatment group compared with only 20% in group treated with radiation alone []. In addition, the effectiveness of ionizing radiation can be improved with local tissue hyperthermia during treatment. This effect can be achieved using photothermal techniques [].

Other Technologies

Other nanotechnologies clearly have significant potential for application in the diagnosis and management of head and neck cancer, such as carbon nanotubes, iron oxide (magnetic) nanoparticles, and dendrimers [, , ]. For instance, iron-based nanoparticles work on similar principles to gold nanoparticles as magnetically active probes for imaging, therapy, and drug carrying []. A variety of additional ligands have been attached to nanoparticles to selectively target cancer cells. Other classes of nanoparticles can serve as drug or gene carries. As later generations of nanotechnology develop, such as combined magnetico-optico particles [], integrated particles comprising “nanosystems” are expected to be developed capable of performing complex actions.

Conclusions

Nanotechnology is poised to create a paradigm shift in the diagnosis and management of head and neck cancer through the creation of multifunctional devices capable of sensitive, specific diagnosis and simultaneous therapy. Whereas several nanoparticles have been developed, plasmonic gold nanoparticles appear particularly interesting because of their facile surface chemistry, relatively limited toxicity, and novel optical properties useful for concurrent imaging and therapy. Gold nanotechnology brings forth ultrasensitive optical imaging and multiple therapeutic options that may be potentially used in unison. As a drug delivery agent, toxicity of attached drugs is significantly reduced. Photothermal therapy adds a new treatment that can be used in addition to other forms of treatment. Enhancement of radiation could significantly improve delivery of appropriate radiation doses with reduced toxicity to surrounding tissue. Although much work is still required to understand the toxicity and best applications, compared with the limitations and toxicities of existing treatment, nanotechnology may significantly advance management of head and neck cancer.

Head And Neck Anatomy Muscles

Disclosure

No potential conflicts of interest relevant to this article were reported.

Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

1. El-Sayed MA. Some interesting properties of metals confined in time and nanometer space of different shapes. Acc Chem Res. 2001;34:257–264. doi: 10.1021/ar960016n. [PubMed] [CrossRef] [Google Scholar]
2. Pridgen EM, Langer R, Farokhzad OC. Biodegradable, polymeric nanoparticle delivery systems for cancer therapy. Nanomed. 2007;2:669–680. doi: 10.2217/17435889.2.5.669. [PubMed] [CrossRef] [Google Scholar]
3. Huang X, Jain PK, El-Sayed IH, El-Sayed MA. Gold nanoparticles: interesting optical properties and recent applications in cancer diagnostics and therapy. Nanomed. 2007;2:681–693. doi: 10.2217/17435889.2.5.681. [PubMed] [CrossRef] [Google Scholar]

Daniele Lecis

4. Huang X, El-Sayed IH, Qian W, El-Sayed MA. Cancer cell imaging and photothermal therapy in the near-infrared region by using gold nanorods. J Am Chem Soc. 2006;128:2115–2120. doi: 10.1021/ja057254a. [PubMed] [CrossRef] [Google Scholar]
5. El-Sayed IH, Huang X, El-Sayed MA. Selective laser photo-thermal therapy of epithelial carcinoma using anti-EGFR antibody conjugated gold nanoparticles. Cancer Lett. 2006;239:129–135. doi: 10.1016/j.canlet.2005.07.035. [PubMed] [CrossRef] [Google Scholar]
6. Jain PK, El-Sayed IH, El-Sayed MA. Au nanoparticles target cancer. NanoToday. 2007;2:18–29.[Google Scholar]
7. Dickerson EB, Dreaden EC, Huang X, et al. Gold nanorod assisted near-infrared plasmonic photothermal therapy (PPTT) of squamous cell carcinoma in mice. Cancer Lett. 2008;269:57–66. doi: 10.1016/j.canlet.2008.04.026.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
8. Paciotti GF, Kingston DG, Tamarkin L. Colloidal gold nanoparticles: a novel nanoparticle platform for developing multifunctional tumor-targeted drug delivery vectors. Drug Dev Res. 2006;67:47–54. doi: 10.1002/ddr.20066. [CrossRef] [Google Scholar]
9. Niidome T, Yamagata M, Okamoto Y, et al. PEG-modified gold nanorods with a stealth character for in vivo applications. J Control Release. 2006;114:343–347. doi: 10.1016/j.jconrel.2006.06.017. [PubMed] [CrossRef] [Google Scholar]
10. Paciotti GF, Myer L, Weinreich D, et al. Colloidal gold: a novel nanoparticle vector for tumor directed drug delivery. Drug Deliv. 2004;11:169–183. doi: 10.1080/10717540490433895. [PubMed] [CrossRef] [Google Scholar]
11. Hainfeld JF, Slatkin DN, Smilowitz HM. The use of gold nanoparticles to enhance radiotherapy in mice. Phys Med Biol. 2004;49:N309–N315. doi: 10.1088/0031-9155/49/18/N03. [PubMed] [CrossRef] [Google Scholar]
12. Clinicaltrials.gov: TNF-bound colloidal gold in treating patients with advanced solid tumors, in, 2010. Available at http://clinicaltrials.gov/ct2/show/NCT00356980. Accessed January 2010.
13. Clinicaltrials.gov: Pilot study of AuroLase(tm) therapy in refractory and/or recurrent tumors of the head and neck, in, National Institute of Health, 2010. Available at http://clinicaltrials.gov/ct2/show/NCT00848042. Accessed January 2010.
14. Whitesides GM. The “right” size in nanobiotechnology. Nat Biotechnol. 2003;21:1161–1165. doi: 10.1038/nbt872. [PubMed] [CrossRef] [Google Scholar]
15. American Cancer Society: Cancer Facts and Figures, 2009. Available at http://www.cancer.org/downloads/STT/500809web.pdf. Accessed Januatry 2010.
16. Myers EN, Simental AA. Cancer of the oral cavity. In: Myers EN, Suen JY, Myers JN, Hanna EY, editors. Cancer of the Head and Neck. Philadelphia: Saunders; 2003. pp. 279–332. [Google Scholar]
17. Myers EN, Suen JY. Perspectives in head and neck cancer. In: Myers EN, Suen JY, Myers JN, Hanna EY, editors. Cancer of the Head and Neck. Philadelphia: Saunders; 2003. pp. 1–5. [Google Scholar]
18. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354:567–578. doi: 10.1056/NEJMoa053422. [PubMed] [CrossRef] [Google Scholar]
19. Lentsch EJ, Myers JN. Pathogenesis and progression of squamous cell carcinoma of the head and neck. In: Myers EN, Suen JY, Myers JN, Hanna EY, editors. Cancer of the Head and Neck. Philadelphia: Saunders; 2003. pp. 5–28. [Google Scholar]
20. Iyer AK, Khaled G, Fang J, Maeda H. Exploiting the enhanced permeability and retention effect for tumor targeting. Drug Discov Today. 2006;11:812–818. doi: 10.1016/j.drudis.2006.07.005. [PubMed] [CrossRef] [Google Scholar]
21. Goel R, Shah N, Visaria R, et al. Biodistribution of TNF-alpha-coated gold nanoparticles in an in vivo model system. Nanomed. 2009;4:401–410. doi: 10.2217/nnm.09.21.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
22. Pirollo KF, Chang EF. Does a targeting ligand influence nanoparticle tumor localization or uptake? Trends Biotechnol. 2008;26:552–558. doi: 10.1016/j.tibtech.2008.06.007. [PubMed] [CrossRef] [Google Scholar]
23. Yguerabide J, Yguerabide EE. Light-scattering submicroscopic particles as highly fluorescent analogs and their use as tracer labels in clinical and biological applications. I. Theory. Anal Biochem. 1998;262:137–156. doi: 10.1006/abio.1998.2759. [PubMed] [CrossRef] [Google Scholar]
24. El-Sayed I, Huang X, Macheret F, Humstoe JO, et al. Effect of plasmonic gold nanoparticles on benign and malignant cellular autofluorescence: a novel probe for fluorescence based detection of cancer. Technol Cancer Res Treat. 2007;6:403–412. [PubMed] [Google Scholar]
25. El-Sayed IH, Huang X, El-Sayed MA. Surface plasmon resonance scattering and absorption of anti-EGFR antibody conjugated gold nanoparticles in cancer diagnostics: applications in oral cancer. Nano Lett. 2005;5:829–834. doi: 10.1021/nl050074e. [PubMed] [CrossRef] [Google Scholar]
26. Sokolov K, Follen M, Aaron J, et al. Real-time vital optical imaging of precancer using anti-epidermal growth factor receptor antibodies conjugated to gold nanoparticles. Cancer Res. 2004;63:1999–2004. [PubMed] [Google Scholar]
27. Li PC, Wang CR, Shieh DB, et al. In vivo photoacoustic molecular imaging with simultaneous multiple selective targeting using antibody-conjugated gold nanorods. Opt Express. 2008;16:18605–18615. doi: 10.1364/OE.16.018605. [PubMed] [CrossRef] [Google Scholar]
28. Zharov VP, Lapotko DO. Photothermal imaging of nanoparticles and cells. IEEE J Selected Topics Quant Elect. 2005;11:733–751. doi: 10.1109/JSTQE.2005.857382. [CrossRef] [Google Scholar]
29. Nikoobakht B, Wang J, El-Sayed MA. Surface-enhanced Raman scattering of molecules adsorbed on gold nanorods: off-surface plasmon resonance condition. Chem Phys Lett. 2002;366:17–23. doi: 10.1016/S0009-2614(02)01492-6. [CrossRef] [Google Scholar]
30. Wang H, Huff TB, Zweifel DA, et al. In vitro and in vivo two-photon luminescence imaging of single gold nanorods. Proc Natl Acad Sci U S A. 2005;102:15752–15756. doi: 10.1073/pnas.0504892102.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
31. Song KH, Kim C, Maslov K, Wang LV. Noninvasive in vivo spectroscopic nanorod-contrast photoacoustic mapping of sentinel lymph nodes. Eur J Radiol. 2009;70:227–231. doi: 10.1016/j.ejrad.2009.01.045. [PubMed] [CrossRef] [Google Scholar]
32. Agarwal A, Huang SW, O’Donnell M, et al. Targeted gold nanorod contrast agent for prostate cancer detection by photoacoustic imaging. J Appl Phys. 2007;102:064701-064701-4.[Google Scholar]
33. Niidome T, Akiyama Y, Shimoda K, et al. In vivo monitoring of intravenously injected gold nanorods using near-infrared light. Small. 2008;4:1001–1007. doi: 10.1002/smll.200700438. [PubMed] [CrossRef] [Google Scholar]
34. Qian X, Peng XH, Ansari DO, et al. In vivo tumor targeting and spectroscopic detection with surface-enhanced Raman nanoparticle tags. Nat Biotechnol. 2008;26:83–90. doi: 10.1038/nbt1377. [PubMed] [CrossRef] [Google Scholar]
35. Aaron J, Nitin N, Travis K, et al. Plasmon resonance coupling of metal nanoparticles for molecular imaging of carcinogenesis in vivo. J Biomed. 2007;12:034007. [PubMed] [Google Scholar]
36. Kneipp J, Kneipp H, Kneippa K. SERS—a single-molecule and nanoscale tool for bioanalytics. Chem Soc Rev. 2008;37:1052–1060. doi: 10.1039/b708459p. [PubMed] [CrossRef] [Google Scholar]
37. Oyelere AK, Chen B, Huang X, et al. Peptide conjugated gold nanorods for nuclear targeting. Bioconjugate Chem. 2007;18:1490–1497. doi: 10.1021/bc070132i. [PubMed] [CrossRef] [Google Scholar]
38. Huang X, El-Sayed IH, Qian W, El-Sayed MA. Cancer cells assemble and align Gold nanorods conjugated to antibodies to produce highly enhanced, sharp and polarized surface Raman spectra: a potential cancer diagnostic marker. Nano Lett. 2007;7:1591–1597. doi: 10.1021/nl070472c. [PubMed] [CrossRef] [Google Scholar]
39. Weissleder R. A clearer vision for in vivo imaging. Nat Biotechnol. 2001;19:316–317. doi: 10.1038/86684. [PubMed] [CrossRef] [Google Scholar]
40. Loo C, Lowery A, Halas NJ, et al. Immunotargeted nanoshells for integrated cancer imaging and therapy. Nano Lett. 2005;5:709–711. doi: 10.1021/nl050127s. [PubMed] [CrossRef] [Google Scholar]
41. Hirsch LR, Stafford RJ, Bankson JA, et al. Nanoshell-mediated near-infrared thermal therapy of tumors under magnetic resonance guidance. Proc Natl Acad Sci U S A. 2003;100:13549–13554. doi: 10.1073/pnas.2232479100.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
42. Schwartz JA, Shetty AM, Price RE, et al. Feasibility study of particle-assisted laser ablation of brain tumors in orthotopic canine model. Cancer Res. 2009;69:1659–1667. doi: 10.1158/0008-5472.CAN-08-2535. [PubMed] [CrossRef] [Google Scholar]
43. Jain PK, Lee KS, El-Sayed IH, El-Sayed MA. Calculated absorption and scattering properties of gold nanoparticles of different size, shape, and composition: applications in biological imaging and biomedicine. J Phys Chem B. 2006;110:7238–7248. doi: 10.1021/jp057170o. [PubMed] [CrossRef] [Google Scholar]
44. Huang X, Jain PK, El-Sayed IH, El-Sayed MA. Determination of the minimum temperature required for selective photothermal destruction of cancer cells with the use of immunotargeted gold nanoparticles. Photochem Photobiol. 2006;82:412–417. doi: 10.1562/2005-12-14-RA-754. [PubMed] [CrossRef] [Google Scholar]
45. Lapotko D. Therapy with gold nanoparticles and lasers: what really kills the cells? Nanomed. 2009;4:253–256. doi: 10.2217/nnm.09.2. [PubMed] [CrossRef] [Google Scholar]
46. Akiyama Y, Mori T, Katayama Y, Niidome T. The effects of PEG grafting level and injection dose on gold nanorod biodistribution in the tumor-bearing mice. J Control Release. 2009;139:81–84. doi: 10.1016/j.jconrel.2009.06.006. [PubMed] [CrossRef] [Google Scholar]
47. Hainfeld JF, Dilmanian FA, Slatkin DN, Smilowitz HM. Radiotherapy enhancement with gold nanoparticles. J Pharm Pharmacol. 2008;60:977–985. doi: 10.1211/jpp.60.8.0005. [PubMed] [CrossRef] [Google Scholar]
48. Diagaradjane P, Shetty A, Wang JC, et al. Modulation of in vivo tumor radiation response via gold nanoshell-mediated vascular-focused hyperthermia: characterizing an integrated antihypoxic and localized vascular disrupting targeting strategy. Nano Lett. 2008;8:1492–1500. doi: 10.1021/nl080496z.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
49. Peng XH, Qian X, Mao H, et al. Targeted magnetic iron oxide nanoparticles for tumor imaging and therapy. Int J Nanomedicine. 2008;3:311–321.[PMC free article] [PubMed] [Google Scholar]
50. Wang C, Chen J, Talavage T, Irudayaraj J. Gold nanorod/Fe3O4 nanoparticle “nano-pearl-necklaces” for simultaneous targeting, dual-mode imaging, and photothermal ablation of cancer cells. Angew Chem Int Ed Engl. 2009;48:2759–2763. doi: 10.1002/anie.200805282. [PubMed] [CrossRef] [Google Scholar]