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18.4.1.2 MRI

Evidence is growing that complementary information from alternative imaging modalities could help decrease the variability encountered for GTV delineation. MRI shows several potential advantages over CT, such as better discrimination between tumour and normal tissues in many organs. Rash et al. (1997) studied the potential impact of the combined use of CT and MRI on tumour volume delineation in advanced head and neck cancer. Four observers outlined the GTV in six patients with advanced cancers with extension to the base of skull on CT, axial MRI, and coronal or sagittal MRI. They found that MRI-de- rived GTVs are smaller (difference of 30%) and have less interobserver variation than CT-derived GTVs. The ability to obtain images in any anatomical plane and the superior soft tissue contrast of MRI has led to its use in target delineation in nasopharyngeal carcinoma (NPC). Enami et al. (2003) examined the use of MRI and CT in eight NPC patients. Compared with CT, the MRI-based targets were 74% larger, more irregularly shaped, and did not always include the CTV targets. On average, the composite CT+MRI GTV was 10% larger than the GTV drawn from MRI alone. Therefore, the use of CT-based targets may lead to underdosing of some regions of the tumour. Image fusion allows one to use both CT and MRI information in drawing the target volumes. The authors concluded that fusion of MRI and CT images is recommended in treatment planning for NPC, because it significantly reduces the possibility of missing parts of the tumour volume. This was confirmed by Chung et al. (2004) who studied the impact of MRI versus CT on NPC in 258 patients. They found that MRI was superior to detect intracranial infiltration since in 40.3% of patients this was detected by MRI, whereas CT showed negative findings. Detection of pterygopalatine fossa involvement accompanying intracranial invasion was higher with MRI than CT (96.1% vs. 56.9%).

18.4.1.3 PET

A recent literature survey on the use of 18FDG PET in HNC indicates that when compared with CT, PET has a higher sensitivity (87% vs. 62%) and specificity (89% vs. 73%) for staging cancer, higher sensitivity (93% vs. 54%) and specificity (83% vs. 74%) for imaging recurrences, and higher sensitivity (84% vs. 60%) and specificity (95% vs. 39%) for monitoring effects

of therapy (Gambhir et al. 2001). However, 18FDG is not a specific marker for cancer since other normal tissues, including salivary gland, skeletal muscle, brain, and heart can have increased tracer uptake. In addition, activated macrophages and areas of inflammation also show high tracer uptake, which can lead to false-positive examinations.

The impact of PET imaging on target delineation in radiotherapy for HNC has recently been investigated. The utility of PET further improved by the introduction of combination PET/CT scanners. Syed et al. (2005) examined the impact of combined FDG PET/ CT in HNC in 24 patients and concluded that PET/ CT significantly increases interobserver agreement and improved the confidence in disease localisation of FGD-avid lesions with 51%. However, one crucial remark must be made concerning the interpretation of the PET images. If we want to use PET to delineate volumes, we must define the way the PET images are viewed. For example, changing the window setting changes the interpretation of lesion margins; the optimal window setting for radiotherapy contouring applications has yet to be determined. Until now, every study uses its own threshold, or even does not comment on which threshold was used, which makes it difficult to compare the data.

Scarfone et al. (2004) evaluated the influence and accuracy of FDG-PET in target volume definition as a complementary study to CT. Six HNC patients were studied. Tumours were delineated on CT and modified based on the PET data. The resulting PET-CT GTV was larger than the original CT volume by an average of 15%. The final lymph node volume based on PET+CT was on average 17% larger than the initial CT volume. The authors concluded that PET can act as a complementary modality, providing information on target viability not visible by CT. Koshy et al. (2005) also examined the use of FDG PET in radiotherapy planning for HNC. A total of 36 patients with HNC received PET-CT as part of their treatment planning. In 38% of patients, PET-CT fusion altered the TNM score. Radiotherapy volumes and dose were altered in five patients (14%) and four patients (11%), respectively. Paulino et al. (2005) compared the GTV identified on CT to that obtained from FDG-PET in 40 patients with HNC. They found that the PET-GTV was smaller, the same size, and larger than the CTGTV in 75%, 8% and 18% of cases, respectively. In approximately 25% of patients, the primary GTV would have been underdosed when the CT-GTV was used for IMRT planning. The authors therefore recommend using both CTand PET-defined primary tumour in determining the GTV for IMRT. Ciernik

et al. (2003) used integrated PET-CT for target volume definition in 39 patients with various solid tumours, 12 were HNC. They detected an increase in PET-GTV of >=25% compared to CT-GTV in 17% of patients, while the GTV was reduced >=25% in 33% of patients. In patients with nasopharyngeal (n, 9) and oropharyngeal (n, 12) tumours, Nishioka et al. (2002) found that PET-CT detected 39 positive nodes in contrast to only 28 nodes detected by clinical examination and CT/MRI. In four patients, the nodal status was increased, which impacted on target delineation. Parotid sparing became possible in 71% of patients whose upper neck areas near the parotid glands were tumour free on PET-CT, and, except for one patient, no recurrences were seen at 18 months when the PET-CT defined volumes were used as GTV. In general, all studies conclude that PET adds extra information to both CT and MRI concerning target delineation.

However, we must keep in mind that the majority of FDG-PET findings lack corresponding pathology data. A small study by Schwartz et al. (2005) compared FDG-PET findings with the pathology findings in 20 patients undergoing neck dissection. FDG-PET/CT showed a high nodal staging sensitivity and specificity of 96% and 98.5%, respectively. FDG-PET/CT detected nodal disease in two patients considered to have node-negative disease by CT alone. Daisne et al. (2004) compared CT, MR and FDG-PET in 29 patients with stages II–IV HNC. Nine patients underwent total laryngectomy. PET volumes were delineated based on a specific tumour to background ratio (Daisne et al. 2003). The key finding of this study was that, in comparison with the surgical specimen used as reference, all the imaging modalities tended to result in overestimation of the tumour extension. For anatomical imaging, average GTVs were up to 107% larger, whereas for functional imaging, a 46% overestimation was still observed. Despite this finding, all three imaging modalities failed to depict a small fraction of the subclinical tumour extension, which thereby revealed their insufficient resolution.

Overall, two general questions remain unsolved concerning the use of FDG-PET in radiotherapy treatment planning:

•What is the optimal PET volume for radiation therapy? To the contouring physician, the edges of tumours on PET are fuzzy, unlike CT. As discussed above, some authors arbitrarily define the FDG-avid volume as the region encompassed by the 50% intensity level relative to the tumour maximum (e.g. Paulino et al. 2005; Scarfone et al.

2004; Koshy et al. 2005), others use certain signal- to-background ratio’s (e.g. Daisne et al. 2004) as threshold.

•Will treatment of PET-defined tumour improve outcome? In theory, better delineation of the target should mean better tumour coverage and hence better local control. Whether this better treatment planning will have an impact on clinical outcome, either by improving local tumour control or by reducing toxicity remains to be determined.

Clinical studies with optimal follow-up will hopefully bring clarity in these issues.

18.4.2

Target Delineation: Biological Information

Besides the location, size and extent of the tumour, knowledge about biological features of the tumour might be useful in the management of head and neck cancer. Treatment selection may be based on this information, dose-painting can be applied, or response prediction can be extrapolated from these data.

The concept of biological target volume (BTV) was therefore introduced (Ling et al. 2000). This implies the integration of physical and biological conformality, leading to multidimensional conformal radiotherapy. The concept of gross, clinical, and planning target volume (GTV, CTV, and PTV), as proposed by the International Commission on Radiation Units and Measurements Report No. 50 (ICRU 50), is currently used in radiotherapy treatment design. In general, CT, MRI and sometimes FDG-PET are used to delineate the GTV and CTV, and radiation portals are designed to entirely cover the volumes and deliver a uniform dose distribution to it. Recent interest has been developed to create nonuniformity within the targets, more specifically to increase dose to certain tumour subregions in order to increase local control (so-called dose-painting). IMRT has the ability to deliver nonuniform dose distributions, but the question remains how to track the regions of interest. Therefore, there has been a lot of interest in developing imaging modalities to deliver molecular and biological information regarding hypoxia, proliferation, apoptosis, angiogenesis and receptor status of tumours (Chapman et al. 2003). Biological imaging can be of value, but still a lot of research and clinical studies are needed before this can be realized in clinical routine.

18.4.2.1 Hypoxia

Hypoxia is believed to be a major determinant in tumour response to radiation and their subsequent outcome. Hypoxic cells are 2.5–3 times more resistant to ionising irradiation than well-oxygenated cells. Identifying and quantifying tumour hypoxia may predict outcome and identify patients who could benefit from more aggressive radiotherapy to overcome the hypoxic effect. Escalating the dose to these tumour regions might improve outcome. A variety of methods have been used to measure oxygenation of tumours. Clinical studies have been performed using polarographic needle electrodes (Eppendorf, Hamburg, Germany) (e.g. Nordsmark and Overgaard 2004). This, however, is an invasive technique and no discrimination is possible between necrotic tissue and viable hypoxic tissue. Moreover, the presence of tumour heterogeneity prompts the question as to whether these measurements are representative for the entire tumour.An additional drawback is the fact that this technique is only useful for accessible tumours by electrodes. Other noninvasive techniques have gained interest in recent years.

Tumour perfusion and tumoral oxygen concentration are factors that are usually strongly linked, although tumour oxygenation also depends on oxygen consumption by the tumour cells. The tumour perfusion rate can be determined noninvasively by dynamic CT. Hermans et al. (2003) used dynamic CT in 105 patients, treated with radiotherapy, to determine the rate of tumour perfusion. Therefore, a contrast agent bolus was rapidly injected i.v., while during the first pass a dynamic data acquisition was performed at the level of the largest axial tumour slice. The perfusion was calculated by using the time-density curve of the tumour and the maximal value in arterial density. When the patients were stratified according to the median perfusion value, those with lower perfusion rate had a significantly higher local failure rate. The authors concluded that CT-determined tumour perfusion rate was an independent predictor of local outcome in irradiated HNC.

Tissue perfusion can be estimated using MRI from the increase in the T1 signal after the bolus administration of a gadolinium-based contrast medium. Echo-planar dynamic imaging (EPI) can track the uptake of the contrast agent using fast pulse sequences. The derived parametric image can yield pixel by pixel information on blood volume, blood perfusion, diffusion, extravascular space, etc. These techniques can be applied to assess tumour grade and type, treatment

response and prognosis. Hoskin et al. (1999) used dynamic contrast enhanced MRI in 13 patients with advanced HNC before and after completion of radiotherapy. The authors found that tumours with diminished tumour perfusion at the end of therapy are those most sensitive to radiotherapy and that those tumours which show greater tumour enhancement after radiotherapy are likely to fail locally. Schmitt et al. (2003) used noninvasive MR spin-labeling techniques to quantify tissue perfusion in HNC patients before and during radiation therapy. Ten patients were examined before radiotherapy, five of them were investigated twice during radiotherapy. In four of five patients studied at the start and end of radiotherapy, perfusion decreased, while in one patient there was an increase. Tumours with high initial perfusion tended to be smaller in size and showed a better response than those showing weak pre-treatment perfusion. Tissue oxygen levels can be assessed noninvasively by blood–oxygen level-dependent (BOLD) fMRI (Krishnan et al. 1988; Taylor et al. 2001; Landuyt et al. 2001) This technique is based on the paramagnetic property of deoxygenated hemoglobin that induces magnetic inhomogeneities, enhances the relaxation of the adjacent water molecules, and thereby decreases the T2* signal adjacent to the blood vessels. Studies by Kaanders et al. (2002) showed that treatment results in advanced HNC can be improved by accelerated radiotherapy with carbogen breathing (a hyperoxic hypercapnic gas mixture) and nicotinamide (ARCON). The mechanism of action of carbogen and nicotinamide is thought to be an increase in tumour oxygenation and thus a reduction of hypoxic regions in the tumour. Rijpkema et al. (2002) investigated tumour vascularity and oxygenation by dynamic gadolinium contrast-enhanced MRI and BOLD MRI, respectively, in 11 HNC patients. Patients were investigated twice, with and without breathing the hyperoxic hypercapnic gas mixture. BOLD MRI revealed a significant increase of the MRI time constant of transverse magnetization decay (T2*) in the tumour during hypercapnic hyperoxygenation, which correlates to a decrease of the deoxyhemoglobin concentration. No changes in overall tumour vascularity were observed, as measured by the gadolinium contrast uptake rate in the tumour. Multiple gradient-echo MRI may thus be an important tool for the assessment of the local oxygenation status of tumours and may assist in the prediction of responses to therapy.

PET scanning can be used to identify and quantify hypoxia in solid tumours. Several tracers have been tested so far, both imidazole and non-imidazole containing agents. 18F fluorinated misonidazole (FMISO)

and 123I-arabinoside act as bioreductive molecules which are reduced and incorporated into the cells under hypoxic conditions (Chapman et al. 1983; Koh et al. 1992). In a study of Rasey et al. (1996), using FMISO-PET, 36 of the 37 patients investigated had hypoxic regions, with fractional hypoxic volumes of 9%. Eschmann et al. (2005) compared the uptake of FMISO of HNC with clinical outcome after treatment. A total of 26 patients with HNC were scanned before radiotherapy and FMISO uptake was quantified using standardized uptake values (SUV) and tumour- to-background ratios. The authors found that patients with local recurrence could be separated from disease-free patients by SUV 4h after injection (all recurrences had SUV>2). All patients with tumour- to-muscle ratio>1.6 presented with tumour recurrence. The authors also found that the activity curve of FMISO was prognostic: tumours with a rapid washout showed no recurrences in contrast to tumours with an accumulation curve. However, FMISO distribution over timed seemed not to be constant. As a consequence, tumour regions defined as hypoxic on the basis of the cutoff values shifted. If one wants to use these data for radiotherapy planning, regional kinetic analysis that takes into account early as well as late FMISO data are needed.

Newer generations of nitroimidazoles have been studied including 18F-labeled fluoroerythronitroimidazole (FETNIM), fluoroetanidazole (FETA) and 2-(2-nitro-1[H]-imidazol-1-yl)-N-(2,2,3,3,3-pen- tafluoropropyl)-acetamide (EF5). FETNIM and FETA are both more stable to non-oxygen dependent metabolism and have higher tumour-to-background contrast secondary to their increased hydrophilicity (Yang et al. 1995; Lehtio et al. 2001; Rasey et al. 1999). EF5 has already been used for immunohistochemical detection of hypoxia, creating the opportunity to correlate PET findings with immunohistochemistry (Ziemer et al. 2003). A possible drawback of EF5 is the low tumour-to-background ratio due to nonspecific binding caused by its lipophilic nature. FETNIM has already been used clinically to determine the oxygenation status of HNC in patients undergoing radiotherapy. Lehtio et al. (2004) studied 21 patients who underwent multitracer PET scans with FETNIM to evaluate the oxygenation status and [15O2] H2O to measure the blood flow. PET findings were correlated with the radiotherapy outcome and survival. The authors concluded that tumours with a high blood flow were associated with poor survival. A high FETNIM tumour/plasma ratio or fractional hypoxic volume had no significant relationship with survival in this small series.

Other non-imidazole agents like 62Cu-diacetylbis (N-4-methyl-thiosemicaarbazone; Cu-ATSM) are being evaluated. Cu-ATSM is a potentially good marker for hypoxia because of its rapid uptake, activity ratio, rapid blood clearance and washout from normally oxygenated cells. Chao et al. (2001) examined the feasibility of dose-escalation to hypoxic areas using IMRT by co-registration of Cu-ATSM PET to CT images for treatment planning. This planning study showed that 80 Gy could be delivered in 35 fractions to the hypoxic target volume, with 70 Gy in 35 fractions delivered to the rest of the clinical target volume.

However, temporal stability might be a concern for hypoxia imaging. Intermittent opening and closure of vessels can cause microscopic changes in oxygenation, so-called acute hypoxia (Chaplin et al. 1986). In addition, reoxygenation of hypoxic regions occurs during the 6- to 7-week period of fractionated radiotherapy. Studies on the temporal stability of tumour hypoxia mapping are therefore necessary (Fig. 18.5).

Although these new tracers have promise, much more work remains to be done before they can be used to influence treatment decisions for these patients. The difficult challenge is to validate the correlation with marker uptake and the presence of viable hypoxic cells. This validation is difficult, however, because no gold standard for measuring these tumour properties exists.

18.4.2.2 Proliferation

Uncontrolled proliferation is one of the hallmarks of cancer. Imaging the amount of proliferation may be predictive for tumour response, and regions of high cell proliferation may benefit from dose escalation. Slowly proliferating tumours generally show less FDG uptake than rapidly proliferating tumours. FDG uptake in cells, however, is not an absolutely specific measure of tumour growth or proliferative activity, because regions of inflammation, musculature, are known to take up FDG. Because of this, more specific tracers have been studied. Radiolabeled nucleosides can be used to quantify DNA synthesis and radiolabeled amino acids to infer protein synthesis. The most studied nucleoside tracers is 18F-labeled fluorothymine (FLT), a pyrimidine analogue, which measures indirectly DNA synthesis via the DNA salvage pathway. FLT has high specific activity and good tumour-to-background ratio (Shields et al. 1998). Cobben et al. (2004) studied the use of FLT-PET for visualization of laryngeal cancer in 21 patients and

c

Fig. 18.5a–c. Temporal change in hypoxia.A 57-year-old patient presented with a squamous cell carcinoma of the oropharynx, stage T3N2b. A base-line FDG-PET (a) shows uptake at the primary tumour (black arrow) and regional adenopathy (black arrowhead). A FMISO-PET (b) was acquired 1 day later and shows uptake both in the primary tumour (white arrow) and the adenopathy (white arrowhead), demonstrating the presence of hypoxia. The repeat FMISO-PET after 4 weeks of radiotherapy (c) shows a loss in the FMISO uptake suggesting a temporal change in hypoxia

compared these data with FDG-PET. The authors detected an equal amount of tumours with FLT and FDG-PET. In laryngeal cancer, they detected a higher uptake of FDG than FLT. Therefore, the authors concluded that FLT-PET seems less adequate for the detection of laryngeal cancer but further research is warranted. Sensitivity of FLT imaging, however, is not optimal because DNA synthesis is not as robust as glucose uptake and less tracer is taken up (Buck et al. 2003).

The most studied amino acid tracers are 11C-me- thionine (MET) and 11C-tyrosine. One advantage of using amino acid tracers over FDG is that they can better discriminate between tumour and inflammatory tissue because inflammatory cells have lower protein metabolism than glucose metabolism (Kubota et al. 1995). Geets et al. (2004) studied the role of MET-PET for the delineation of the tumour volume in pharyngolaryngeal squamous cell carcinoma. In all, 23 patients received CT, FDG-PET and MET-PET before treatment (radiotherapy or surgery). The authors found that the MET volumes did not differ from the CT volumes, while the FDG vol-

Apoptosis can be a marker for radiosensitivity and prognosis for radiotherapy treatment outcome because apoptosis is a major form of cell death after ionising irradiation. Annexin V binds to membranebound phosphatidyl serine and is selectively exposed on the surface of cells as they undergo apoptosis. 99mTc-radiolabeled annexin V is therefore being tested to measure apoptosis (Green and Steinmetz 2002). Annexin accumulation has been imaged successfully using 99mTc-SPECT and near infrared fluorescence (NIRF) in several tumoral sites. van de Wiele et al. (2003) performed a quantitative tumour apoptosis imaging using 99mTc-radiolabeled annexin V and SPECT. A total of 20 patients with HNC underwent CT, 99mTc-radiolabeled annexin V SPECT and subsequent surgical resection. Quantitative 99mTc-ra- diolabeled annexin V tumour uptake values correlated well with the number of apoptotic cells derived from TUNEL assays (detects apoptosis-induced DNA fragmentation), if only tumour samples with no or minimal amounts of necrosis are considered. The authors conclude that radiolabeled annexin V can be used to monitor treatment response, if the treatment does not alter the diffusion-related uptake of the peptides. 99mTc-radiolabeled annexin V scintigraphy has already been used successfully in monitoring radiation-induced apoptotic cell death in follicular lymphoma patients (Haas et al. 2004). Data on HNC are missing.

18.4.2.4

Receptor Status/Molecular Imaging

Proliferation of certain tumours is regulated by growth factors and hormones that bind to membrane or intracellular receptors to activate signal

transduction pathways. In vivo imaging of the receptor status might provide relevant information concerning prognosis and choice of therapy. One example is epidermal growth factor receptor (EGFr) imaging using SPECT and NIRF optical imaging. EGFr is a transmembrane glycoprotein involved in activating several pathways associated with proliferation, migration, stromal invasion, angiogenesis and resistance to cell death-inducing signals (Dancey 2004). EGFR is overexpressed in nearly all HNC (80%–100%) (Grandis et al. 1996), and this overexpression is associated with both increased metastatic potential and poor prognosis (Ang et al. 2002). Optical contrast agents to visualise EGFr are under development.

18.4.3

Treatment Verification

Treatment guiding and verification refer to the use of imaging to ensure that the field of irradiation is appropriate throughout the entire treatment period, taking into consideration factors such as changes in tumour size and shape, patient positioning and organ movement. Today, the treatment fields are routinely verified using the accelerator beam and conventional film or, in modern systems, using 2D electronic portal image detectors (EPID) as detectors (Fig. 18.3). As with portal films, electronic portal images are compared with some reference image. The latter can be a digitized simulator film or a digitally reconstructed radiograph in case of 3D treatment planning. Recently, cone beam CT has been introduced for verification of treatment fields in 3D view. To create these fields, an extra tube is mounted on the accelerator producing a divergent X-ray beam, which is captured using a portal detector, opposed to the CT tube. Both make a 360° rotation around the patient. This allows a 3D visualisation of the treatment field in relation to organs of interest.

Recently, the next generation in radiation oncology has been developed, called four-dimensional (4D) conformal radiotherapy (CRT), a logical regression from 3D-CRT. During a course of radiotherapy, when successful, tumours shrink. Patients may also lose weight which will further alter their geometry and dosimetry (Barker et al. 2004). 4D CRT accounts for these geometrical changes. In radiotherapy, spatio-temporal instability of target and normal structures, and/or geometric uncertainty of patient positioning are one of the reasons for treatment failure. Especially in sophisticated radiotherapy such as

IMRT, devices and methods of increasing precision and accuracy are needed. Latest generation linear accelerators are therefore equipped with CT and/or fluoroscopy modes. A CT-based image guidance system can visualize soft-tissue structures while fluoroscopy can be used to track fiducial markers e.g. during breathing. The recent development of megavoltage cone beam CT (MVCT) will allow the reconstruction of the actual daily-delivered dose based on patient’s anatomy in real time (Pouliot et al. 2003; Ghilezan et al. 2004). By acquiring a low-dose megavoltage CT image on the treatment machine immediately prior to therapy, the patient position – including soft tissue anatomy – can in principle be verified on-line. The same imaging device can then be used to record the portal dose during treatment. By converting this portal dose to primary fluence at the plane of the detector and back projecting through the MVCT model of the patient, the 3D dose delivered at the time of treatment can be obtained. This may lead to ‘adaptive radiotherapy’ with modulation of prescription and delivery based on the actual delivered dose, as opposed to planned dose (Welsh et al. 2002). Further studies are ongoing to optimize MVCT imaging and better define its utility in patients.

18.5

Conclusion and Future Challenges

The use of multimodality imaging, both anatomical and functional, has already led in several cancer centers to improved staging of disease, as well as to improved treatment planning, by better dose delivery to GTV while sparing critical normal structures. The development of imaging markers associated with prediction of radioresistance and/or outcome could impact significantly on treatment planning. Such information could be used in the (near) future to design conformal dose distributions, ‘paint’ additional dose to specific tumour regions, or rationally describe adjuvant therapy targeted to specific tumour phenotype and genotype.

The ability to predict the ultimate outcome early in treatment would have tremendous implications for patients. Functional imaging could identify nonresponders early, which allows for a switch in therapy.

There still remain some hurdles to be overcome, including imaging pathological validation, timing of post-treatment imaging, and accounting for spatial and temporal tumour motion during radiation therapy.

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However, we must keep in mind that no single imaging modality can provide us the entire picture of tumour profiling. Anatomical and functional imaging fusion will be essential. Knowledge about the capabilities and especially limitations of all the imaging modalities remains essential in their clinical use.

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Subject Index

Subject Index

361

H

Hand-Schüller-Christian disease 253

Hashimoto’s thyroiditis (chronic lymphocytic thyroiditis)

human immunodeficiency virus (HIV) 3, 230, 295

I

image-guided radiotherapy (IGRT) 345 intensity-modulated radiation therapy (IMRT) 338, 346

Kaposi’s sarcoma 3, 75

Subject Index

L

Langerhans cell histiocytosis 253 laryngeal necrosis 71 laryngectomy

– frontal 65

– horizontal supraglottic 65

–hypopharyngeal 85 lymphadenitis

–bacterial 295

lymphangioma 173, 228 lymphatic malformations 107 lymphoepithelial cysts 324 lymphoepithelial lesion

M

malignant fibrous histiocytoma 74, 182, 212