Lasers in Surgery and Medicine 39:571–582 (2007)

Interstitial Photodynamic Therapy for aSymptom-Targeted Treatment of Complex VascularMalformations in the Head and Neck Region

Christian S. Betz , Dr. Med.,1,2* H. Rolf Jager, MD, FRCR,3,4 Jocelyn A.S. Brookes, MRCP, FRCR,4

Robin Richards, PhD,5 Andreas Leunig, Priv. Doz.,2 and Colin Hopper, MD, FRCS1,6

1Department of Oral and Maxillofacial Surgery, University College London Hospital NHS Foundation Trust,Mortimer Market, London WC1E 6AU, United Kingdom2Department of Otorhinolaryngology, Head and Neck Surgery, Klinikum Grosshadern atthe Ludwig Maximilian University, Marchioninistr. 15, 81377 Munich, Germany3Lysholm Department of Neuroradiology, The National Hospital for Neurology and Neurosurgeryand Institute of Neurology, 8–11 Queen Square (3rd floor), London WC1N 3BG, United Kingdom4Department of Radiology, University College London Hospital NHS Foundation Trust, 235 Euston Road,London NW1 2BU, United Kingdom5Department of Medical Physics and Bio-Engineering, Malet Place Engineering Building,University College London, Gower Street, London WC1E 6BT, United Kingdom6Eastman Dental Hospital and Institute, University College London, 256 Gray’s Inn Road,London WC1X 8LD, United Kingdom

Background and Objectives: Photodynamic therapy isbased on an interaction of a drug and light in oxygenatedtissue. The photosensitizing drug Foscan1 is licensed in theEU for the treatment of advanced head and neck cancer.The light can be applied by surface illumination or directlyinto tumour tissue by optical fibres. One interesting featureof PDT is that it does not cause major damage to nerves andmajor blood vessels. This raises the possibility of using thistherapy in the treatment of benign neoplasms in the headand neck.Study Design/Materials and Methods: A total of 11patients with lymphatic [8] or venous malformation [3]were treated on 25 occasions. The treatments were carriedout using Temoporphin (Foscan1) 0.15 mg/kg; the drug-light-interval was 4 days. Illumination was performed at652 nm delivered interstitially through bare tip fibres at atotal light dose of 20 J per fibre. Multiple fibres werepositioned either image guided [13] or clinically [12] toensure accurate targeting of tissue while avoiding damageof the surrounding and overlying tissue.Results: In all cases there was a significant reduction inthe volume of abnormal tissue without damage to theoverlying skin; the results were objectified using MRI-imaging, CT-volumetry and surface optical scanning. Thebest results were obtained with lymphatic malformations,especially for those that had not undergone previoussurgery. Post-treatment pain and swelling were success-fully controlled with steroids and a variety of analgesics(opioids and non-steroidal anti-inflammatories). No vascu-lar or neurological signs were encountered.Conclusion: This minimally invasive approach to treatcomplex benign neoplasias seems promising. The treat-ment is safe, effective and repeatable and merits furtherevaluation. Lasers Surg. Med. 39:571–582, 2007.� 2007 Wiley-Liss, Inc.

Key words: lymphatic malformation; PDT; vascularmalformation; venous malformation

INTRODUCTION

Vascular lesions are considered to be among the mostcommon congenital or neonatal abnormalities. Tradition-ally, the nomenclature and classification of these lesionsdates back to the German Anatomy Professor Virchow, whosubdivided these lesions into either haemangiomas orlymphangiomas [1]. Each of these was additionally (andaccording to their anatomical and histological appearance)termed as either ‘‘simplex’’, ‘‘cavernosum’’ or ‘‘racemato-sum’’.

Nowadays, a modern classification first introduced byMulliken and Glowacki in the 1980s is generally acceptedand has replaced the classical terminology [2]. Vascularlesions are thereby subdivided into haemangiomas, whichare characterized by endothelial proliferation, and vascularmalformations with normal endothelial turnover. Whereashaemangiomas only seldomly require treatment as theyusually undergo an involution following their proliferativephase, vascular malformations tend to increase in volumethroughout lifetime due to progressive ectasia of theinvolved vessels triggered by trauma, infection or hormonalchanges [3]. If the lesions become symptomatic, treatmentis usually indicated. Common symptoms of vascular

*Correspondence to: Christian S. Betz, Med., Department ofOtorhinolaryngology, Ludwig Maximilian University Munich,Klinikum Großhadern, Marchioninistr. 15, 81377 Munich,Germany. E-mail: christian.betz@med.uni-muenchen.de

Accepted 19 July 2007Published online in Wiley InterScience(www.interscience.wiley.com).DOI 10.1002/lsm.20535

� 2007 Wiley-Liss, Inc.

malformations in the head and neck region comprisecosmetic issues as well as functional problems such asobstructive airway compromise, dysphagia, chronic pain orrecurrent bleeding. Treatment recommendations for vas-cular malformations are dependent on the main type ofvessels involved:

* Capillary malformations are usually located super-ficially and are easily and comprehensively treated bylaser coagulation.

* High-flow malformations (arterial- and arteriovenousmalformations, arteriovenous fistulas) are best treat-ed by embolization followed by surgical resection.

* Venous malformations are classically treated bysclerotherapy using high percentage ethanol orsodium tetradecyl sulphate (Sotradecol) which is (inlarger lesions) followed by ablative and reconstructivesurgery. Some authors also recommend interstitiallaser coagulation for treatment [4].

* Lymphatic malformations usually require surgicaldebulking or removal. Sclerotherapy with Bleomycinand OK-432, a lyophilized streptococci mixture thatcauses a host-mediated inflammation leading tosclerosis and subsequent shrinking have recentlybeen described as an alternative treatment option.

Whereas these recommendations are reasonable forsmaller lesions, large and infiltrating or deep seated venousor lymphatic malformations are often difficult to treatwithout causing major tissue defects and damage toneurovascular structures. Therefore, it would be desirableto have a treatment option at hand to gently reducesymptomatic tumour bulk whilst avoiding the above-mentioned adverse effects.

Photodynamic therapy (PDT) is a novel treatment optionthat causes tissue destruction via an interaction of lightand a photosensitizing drug (Fig. 1). In the head andneck area, the photosensitizer Temoporphin (mTHPC,Foscan1) is licensed in the European Union for palliativetreatment of patients with advanced head and necksquamous cell carcinoma failing prior therapies andunsuitable for other therapies [5]. As PDT is known toreduce tissue volumes without larger amounts of scarringand without damaging intact neurovascular structures[6,7], this treatment modality also seems well suitable forthe treatment of vascular malformation in the head andneck area. We have therefore conducted a clinical feasi-bility study to assess the possible benefits of such a therapyin a small group of patients.

MATERIALS AND METHODS

Between March 2001 and March 2007, a total of 25mTHPC-PDTs were performed in 11 patients (8� lym-phatic malformation, 3� venous malformation), whereasthe number of treatments per patient varied from 1 to 10.All lesions were deep seated and had a complex structure,whereas the size varied from only a few cubic centimetres tolesions extending from the cervical or facial skin all the wayinto the pharynx, virtually replacing normal soft tissuestructures. All patients presented with one or more disease-related symptoms that are summarized in Table 1. Thephotodynamic treatments were symptom-targeted and notprimarily aimed to achieve complete tumour regression. Alltreatments were conducted at the University CollegeLondon Hospital (UCLH) after having been grantedapproval by the Institutional Board Review.

Treatment parameters were chosen according to thoserecommended for tumour palliation with an intravenously

Fig. 1. Schematic illustration of the mode of action in photo-

dynamic therapy. If photosensitizing molecules (e.g. mTHPC)

become excited by light of a certain wavelength, their outer shell

electrons reach a higher, unstable state of energy. In these

special molecules, they pass a semi-stable, so called triplet-state

before returning into the stable ground state. In this state, there

is the possibility for an energy transfer from the photosensitizer

to oxygen (O2) or other molecules (M), which are thereby trans-

formed into highly reactive radicals. Via various routes such as

intracellular oxidation which leads to cellular necrosis or

apoptosis, vascular shutdown and immune-modulatory effects,

this eventually leads to the anticipated tissue destruction.

572 BETZ ET AL.

applied photosensitizer dose of 0.15 mg/kg, (Foscan1,Biolitec Pharma Ltd., Edinburg, Scotland), a drug-light-interval of 96 hours and an applied energy density of 20 Jper fibre and position (200 seconds at 0.1 W). A four-channel, multiport diode laser emitting at 652 nm (Multi-port PDT Laser 652 nm, Biolitec AG, Jena Germany) wasused for illumination in combination with single-use BFSF403 DL fibres supplied by CeramOptec GmbH (Bonn,Germany) with bare polished tips and a core diameter of400 mm. From the time of injection, all patients followed astrict regimen of controlled re-exposure to light at anincremental rate of 100 lx per day with return to normallight exposure at 2–3 weeks.

Illuminations were all performed interstitially, and theused bare tip fibres were placed parallel in a triangular gridwith an edge length of 1.5 cm either clinically (12/25treatments) or under image-guidance (13/25 treatments) indeeper-seated malformations with more complex geome-tries. In nine cases, the fibres were placed under MRI-guidance using MRI-compatible epidural catheter needles(MREyeTM, Cook UK Ltd., Letchwork, UK) for introductionof the fibres (Fig. 2). CT-guidance (Fig. 3) and ultrasoundguidance were applied in two cases each, with CT beingpreferentially used in cases where bony structures are‘‘shielding’’ the lesion and need to be bypassed by theneedles and Doppler ultrasound when the malformationsshowed a fair amount of flow. In order to treat three-dimensionally, illuminations were performed with consec-utive, 1 cm pullbacks (Fig. 4). In total, a range of 40–1,600 Jwere applied in 20 J steps within each treatment, with theamount of energy deposited being determined by the size ofthe lesion to treat and the areas considered of importancefor patient-specific relief of symptoms.

All treatments were performed under general anaesthe-sia for optimal patient comfort and pain managementduring introduction of fibres and illumination. In all caseswhere PDT was performed close to the upper aero digestivetract, nasogastric feeding tubes were introduced in theoperating theatre prior to illumination. Post-treatment,tube feeding was commenced and continued until patientswere able to swallow adequate amounts for a balancednutrition under protection of the airways as assessed by theSpeech and Language Therapy Team at UCLH. Twopatients with treatment sites closely related to the upperairways underwent temporary, prophylactic tracheostomy

at the time of illumination and remained canulated for atotal duration of 5 days. In order to prevent or antagonizepost-PDT swelling, all patients received three intravenousdoses of 8 mg Dexamethasone over 24 hours starting atthe time of illumination. For control of post-treatment pain,an analgesic protocol was devised in accordance with thePain Management Team at UCLH which was based onretrospective data from previous PDT patients anddeployed for all patients in this study. All patients receivedregular doses of Paracetamol (1 g QDS), Diclofenac (50 mgTDS) and Codeine Phosphate (30–60 mg QDS). Theywere also put on an ‘‘as required’’ scheme of Tramadol(50–100 mg QDS PRN) and oral Morphine Sulphate (10 mg2/24 PRN). Complete analgesia was anticipated in all cases.Weaning of the regularly administered drugs was initiatedas soon as the patient did not require additional ‘‘asrequired’’ analgetics anymore.

All outcomes were assessed clinically, whereas some ofthe outcomes additionally required more sophisticated,objective measures for assessment.

To quantify the effect of PDT on the patients’ facialcontours, surface optical scans (SOS) were performed pre-and post-PDT at the department of Medical Physics in fiveout of eight patients with reduced facial cosmesis. Themethod has been described in detail elsewhere [8], and itprovides three-dimensional surface images of the face ingreat details. Following computerized registering of bothsurfaces in 3D, a differential, false-colour image wasgenerated representing radial differences from a computedcommon axis of the two surfaces. Thereby, unchangedareas are coloured in light blue, positive differences inwarm colours (from green over yellow to deep red) and

Fig. 2. Coronal T1-weighted MR image during needle place-

ment for iPDT of an extensive lymphatic malformation of the

left face, neck and pharynx. Using an oblique, submandibular

approach, the needles were placed parallel to each other to

ensure a homogeneous light distribution within the lesion

during the treatment via illumination fibres inserted though

these hollow needles.

TABLE 1. Distribution of Symptoms in the Patient

Population Evaluated

Symptom

Percentage of

patients

Patient

fraction

Unsatisfactory cosmesis 73 8/11

Recurrent bleeding 36 4/11

Pain 27 3/11

Dysphagia 18 2/11

Obstructive Sleep Apnea

Syndrome (OSAS)

9 1/11

Obstructive snoring 9 1/11

INTERSTITIAL PHOTODYNAMIC THERAPY 573

negative differences in cold colours (dark blue to deeppurple), with a quantitative colour scale in units mm.Additionally, changes in facial asymmetry could be deter-mined by establishing differential, false colour images ofthe affected sides of the face from the contour image of thesame and the mirror contour image of the opposite side bothpre- and post-PDT.

To estimate the effect of PDT treatment on obstructivedisorders of the upper airways such as obstructive snoring(n¼ 1) and obstructive sleep apnea syndrome (OSAS,n¼ 1), the lumen of the airways before and after treatmentwas compared on MRI images acquired in three planes(coronal, axial and sagittal). Additional, special efforts weretaken to assess the treatment outcome in the patient with

OSAS. CT data served as an input for a 3D reconstruction ofthe upper airways before and after PDT, and the corre-sponding airway volumes were determined. Additionally,the patient underwent nocturnal pulse oximetry studiesproceeding and following PDT counting the average dips inoxygen saturation (i.e. saturation declines of�4%) per houras an approximation for the severity of his OSAS.

RESULTS

The overall outcome from Foscan1-PDT in this caseseries is presented in Table 2. All outcomes were assessedclinically, whereas some of the outcomes additionallyrequired other methods for assessment as defined in theMaterials and Methods section. Concerning the cosmetic

Fig. 3. Placement of illumination fibres under CT guidance. a: Axial CT image of a lymphatic

malformation post- and retromandibular on the right side. b: Three dimensional reconstruc-

tion of CT images using a bone window setting with illumination fibres in place.

Fig. 4. Illustration of the ‘‘pullback-method’’ for the treatment of three dimensional tissue

volumes. a: Treatment (20 J/cm2) of the anterior chin area in a large lymphatic malformation

with four clinically introduced, parallel fibres. b: After pullback of 1 cm per fibre, the next

treatment (again with 20 J/cm2) is performed lateral to the first one. This procedure is

continued until approximately 1.5 cm beneath the point of entry.

574 BETZ ET AL.

outcome, all patients concerned (8 out of 11) showed asubjective as well as clinical improvement of the facialcontours of various degrees. SOS objectively provednegative surface changes and mirror imaging showedimprovement in facial symmetry in all five patients thatwere examined in this fashion. Recurrent bleeding epi-sodes, which four of the treated patients suffered fromoriginally, all resolved completely. Chronic or recurrentpain prior to PDT was a main issue in three patients, andresolved in two of these and considerably improved in theremaining case after treatment. Obstructive symptoms ofthe upper aero digestive tract such as dysphagia (mostpronounced in solid food), obstructive snoring and OSAS allshowed a considerable improvement as well.

All patients tolerated the procedure well and the usedanalgesic protocol proved suitable for an adequate paincontrol in all patients. Normal oral feeding was reachedwithin a week post-PDT in all patients included in thisseries; the tracheostomy canulas could be removed after5 days without any problems. Adverse events were seen in 8out of 25 treatments altogether. They comprised mildphototoxic reactions (mild sunburns) in four cases, massivelocal swellings within the treated areas in three cases and apinpoint breakdown of skin covering the treated area in onecase. All affected skin healed without remarkable scarring.Two out of three cases with massive post-therapeuticswellings experienced a clinically remarkable yet conser-vatively manageable airway compromise (Fig. 5). No otheradverse events such as vascular or neurological complica-tions were encountered.

Case Presentation 1

Patient DT first presented to the Department of Oral andMaxillofacial Surgery at UCLH in 2001 at the age of 47 witha large lymphatic malformation of the lower face and theupper aero digestive tract practically replacing the normalsoft tissues. He had undergone various surgical debulkingprocedures, but was still suffering from a severe disfigure-ment of his facial contours and an OSAS. Between March2001 and December 2006, the patient underwent 10 coursesof interstitial mTHPC-PDT. Five of these were restricted tothe outside face, and the illumination fibres were placedclinically. The other five treatments were targeted at both

facial cosmesis and expansion of the upper airways; thefibre placement was performed under MRI-guidance. Intwo instances, PDT was accompanied by a surgicaldebulking within the oral cavity. For one PDT withextensive illumination of the upper airways, the patientunderwent temporary tracheostomy.

The patient tolerated the procedures very well, and thepost-PDT pain levels were remarkably low. One time, thepatient sustained a mild phototoxic reaction of his face andhands as he did not strictly adhere to the recommendedlight precautions.

During the course of the treatments, both main symp-toms showed stepwise improvements. In a controlled andbloodless way, the facial contours were ameliorated bygenerally decreasing the facial tumour bulk and by nearlyrestoring symmetry within the chin area. In Figure 6, aSOS differential image shows efficient left mental tissuereduction of approximately 6 mm in radial surface followingthe first course of PDT in 2001. All five treatments of the

TABLE 2. Treatment Outcomes and Its Assessments With Regards to the Different

Symptoms Encountered in the Patient Population Evaluated

Symptom Outcome Assessment

Unsatisfactory cosmesis Improvement 100% 8/8 Clinical, SOS

Recurrent bleeding Resolution 100% 4/4 Clinical

Pain Resolution 67% 2/3 Clinical

Improvement 33% 1/3

Dysphagia Improvement 100% 2/2 Clinical

OSAS Improvement 100% 1/1 Clinical, MRI,

CT-volumetry, HI

Obstructive snoring Resolution 100% 1/1 Clinical, MRI

Fig. 5. Severe swelling of treated area (lymphatic malforma-

tion of right neck, tongue and floor of mouth) 1–4 days post-

PDT. Conservative measures (systemic steroids, adrenaline

nebulizers) were sufficient to control this side effect; no

invasive measures became necessary.

INTERSTITIAL PHOTODYNAMIC THERAPY 575

airway showed various degrees of success. Figure 7 showsthe treatment effect on the upper airways on a comparative,axial MRI plane at the level of the mandibular symphysisand body before and after the patient’s 3rd course of PDT inOctober 2002. In March 2006, the patient underwent his9th course of PDT which was most aggressively aimed at awidening of the patient’s upper airways using a total of 36illumination sites at 20 J/cm2 each. Figure 8 shows theresults of a three planar and three dimensional airwayreconstruction pre- and post-PDT, with an increase of thecalculated upper airway volume from 20.5 to 26.5 cm3. Overthe course of treatments, the patient’s average oxygensaturation dips (saturation declines �4%) at night werereduced from 36 to 16 per hour.

Case Presentation 2

In summer 2001, the 22-year-old patient SG firstpresented to the Department Oral and MaxillofacialSurgery at UCLH with an aesthetically unpleasantswelling of the left cheek which had been histologicallydefined as a lymphatic malformation. The patient had noother disease-related symptoms. From December 2001until January 2005, the patient underwent three coursesof Foscan1-PDT; the fibres were placed under MRI-guidance in the first two cases and clinically for the last

treatment. In April 2004, the patient additionally under-went a surgical left maxillary trimming procedure, as partof the left sided swelling was caused by an additionalasymmetry of the facial bones.

The procedures were well tolerated and no adverseevents encountered apart from a pinpoint breakdown ofthe skin in the posterior part of the treated area whichhealed without a visible scar following the last course ofPDT.

Even though the PDT treatments resulted in a fairamount of tissue reduction in the posterior and inferior partof the lesion with a radial surface loss of approximately4 mm, the anterior and superior part bordering the noseremained rather unchanged (Fig. 9). Therefore, a surgicalsoft tissue debulking in this area was performed in July2006. The removed tissue showed some scarring anddegenerative signs of the skeletal muscle where thelymphatic malformation was originally located in and asmall focus of remaining lymphatic malformation withdisrupted endothelial lining which was interpreted as aPDT-effect (Fig. 10). The final cosmetic outcome was muchimproved as rated by both patient and physician.

Case Presentation 3

Patient JD was seen in early 2005 at the age of 61 at theoutpatient clinic of the Department Oral and MaxillofacialSurgery at UCLH with an extensive venous malformationof the left neck, tongue and pharynx that was affecting thepatient’s swallowing function and facial cosmesis. Headditionally suffered from obstructive snoring. The lesionhad been slowly but permanently increasing in size duringearly childhood, and two previous therapeutic interven-tions (low dose radiotherapy in 1960 and a CO2-Laserdebulking in 1997) had only led to an intermittentslowdown of tissue expansion.

Between February 2005 and February 2007, the patientunderwent three PDT-procedures, whereby the first andthird were directed against tumour masses of the left neckand pharynx (i.e. the fibres were placed under MRI-guidance) and the second course was for tissue reductionof the external parts of the left neck and the left side of thetongue with the fibres placed clinically. For the first PDT, aprophylactic tracheostomy was performed.

PDT was well tolerated and post-therapeutic pain levelswere low. Following the first PDT including an easydecanulation on the fifth post-treatment day, the patientdeveloped a partly obstructing, oropharyngeal swelling4 weeks post-PDT. Under conservative treatment, thisswelling was quickly reducing and no invasive measuresbecame necessary.

Concerning the outcome, the left neck swelling as well asthe dilated subcutaneous vessels showed a stepwiseimprovement. In clinical assessment, the dysphagia hasgreatly improved and the obstructive snoring has resolved.For an objective assessment, MRI scans were performedbefore and after the treatments. Figure 11 shows coronalMRI images from the first PDT with an impressivewidening of the upper aero digestive tract as a result ofthe treatment.

Fig. 6. Differential image of surface optical scans (SOS) pre-

and post-PDT in patient DT with a large lymphatic malforma-

tion of the left face, neck and oropharynx. ‘‘Warm’’ colours

(yellow! red) represent gain of radial surface, whereas ‘‘cold’’

colours (dark blue!purple) suggest loss. The presented image

proves a significant reduction of tissue (approximately 6 mm

loss in radial surface) within the left mandibular area.

576 BETZ ET AL.

DISCUSSION

General Discussion Concerning Aim ofStudy, Materials and Methods and Results

Following on from the encouraging results of interstitialPDT for advanced head and neck cancer, it was shown thatthe therapy was well tolerated with no neurologicalcomplications. This gave us the confidence to treat a varietyof benign diseases as described in this study. The approachchosen seems ethically justifiable as (a) currently recom-

mended treatment options such as surgery, sclerotherapyor laser coagulation do not offer reliably high rates ofsymptom control whilst carrying great risks for severeadverse events (see below) and (b) the anticipated rate forsevere side effect of interstitial mTHPC-PDT (especiallyconcerning neurovascular structures) was exceptionallylow. The later assumption is based on both clinicalobservations as well as on animal studies. Kubler et al. [6]published an experimental study on the effect of mTHPC-PDT on rabbit blood vessels and nerves. Even though the

Fig. 7. Axial T1-weighted MR images pre- and post-PDT demonstrating the treatment effect

on the upper aero digestive tract in patient DT with a large lymphatic malformation of the left

face, neck and oropharynx. (right): (taken 5 weeks after the procedure) shows a significantly

wider airway at the height of the mandibular symphysis and body as compared to the pre-

treatment image (left).

Fig. 8. Three planar and three-dimensional reconstructions of volumetric CT images pre- and

post-PDT for the assessment of the treatment effect on the upper airway in patient DT. The pre-

treatment image (a) shows a very tight airway which is nearly completely occluded at the

height of the epiglottis, whereas the post-treatment image (b) shows a significant widening.

The airway volume [determined from the 3D reconstructions in the upper left corners of (a,b)]

has thereby increased from 20.5 to 26.5 cm3. [Figure can be viewed in color online via

www.interscience.wiley.com.]

INTERSTITIAL PHOTODYNAMIC THERAPY 577

drug doses were doubled as compared to the clinical use,they did not witness a breakdown or rupture of the majorvessel walls or any clinically apparent neurological symp-toms. Only histologically, they were able to prove changessuch as oedemas and media-hyperplasia of the vessel wallsor partial demyelisation of nerve structures. The authorsconcluded that their experiments suggest mTHPC to be aclinically safe procedure concerning neurovascular struc-

tures. In an ongoing clinical study at the MaxillofacialDepartment of UCLH, a total of 105 interstitial photo-dynamic treatments using Foscan1 have been performedso far in 73 patients with progressive head and neckmalignancies. Following PDT, none of the patients treatedso far suffered from any clinically apparent neurologicaldeficits. Concerning vascular events, there was one patientwho sustained a lethal carotid blowout 14 days after PDT. Apost-mortem observation, however, revealed that thecommon carotid artery had been infiltrated over a largedistance by the recurrent tumour, and a tumour necrosisinduced by PDT had subsequently led to a rupture of thevessel. In the case of benign malformations, infiltrations ofvessels do not occur and the likelihood for such an adverseevent was therefore thought to be extremely low.

Because conventional therapies are well suited forsmaller, easily accessible lesions, the inclusion into thiscase series was restricted to patients with complex, deep-seated vascular malformations of the head and neck area.As comprehensive tissue destruction of complex vascularmalformations, which is easily possible using mTHPC-PDT, would lead to major tissue defects that wouldrequire secondary reconstruction and would not guaranteeto aesthetically or functionally benefit the patients, a lessaggressive approach was undertaken that was primarilydriven by the patients’ main symptoms. Therefore, morethan one treatment was required in 4 out of 11 patients inorder to reach the anticipated effects. Even though thisresults in a higher average cost per patient, we still feel thatthis proceeding is justified as it should provide for thehighest patient benefits with the lowest rate of adverseevents.

The treatment protocol (drug dose, drug light interval,illumination per fibre position) was the same as used inpalliative head and neck tumour treatments [7]. Thedecision to do so was based mostly on the fact that light–tissue interactions and soft tissue treatment volumesfollowing interstitial PDT with mTHPC have been studiedto a reasonable degree only for this combination of

Fig. 9. Differential image of SOS pre- and post-PDT in patient

SG with a lymphatic malformation of the left cheek area.

Whereas the posterior inferior part of the lesion shows the

wanted tissue reduction of approximately 4 mm in the radial

surface, no obvious surface change could be proven for the

anterior superior part.

Fig. 10. H&E stained histopathological slides from resected tissue from the anterior superior

part of the lymphatic malformation in patient SG following PDT. a: Shows scarring and

degeneration of the skeletal muscle the lymphangioma was contained in at a 200�magnification. b: Shows a small focus of remaining lymphatic tissue within the resection

specimen (taken at 100�); even though there are lymphatic spaces, the endothelial lining looks

disrupted.

578 BETZ ET AL.

parameters. Monte Carlo simulations performed at theNational Medical Laser Centre in London, UK, suggest thateach single illumination with 20 J via bare fibre should leadto a spherical volume of tissue necrosis with a diameter ofapproximately 1 cm. While this might not be true for allcases (numerous authors have pleaded for in vivo dosimetryto rule out intra- and inter-individual differences [9]), wehave so far achieved reasonable outcomes with anextremely low rate of adverse events by relying on thisassumption. Nevertheless, we are aware of this short-coming and anticipate introducing novel optical- or othermethods such as functional BOLD-MRI for a detailed invivo dosimetry in the near future.

In order to reach adequate treatment effects in our studypopulation, interstitial illumination seemed to be a basicpre-requisite. Fibre placement could only be performedclinically if the lesions (though complex in structure) wereeasily accessible from the outside and the outlines wereclearly determinable clinically. This was the case in nearlyhalf of the cases treated (12 out of 25). Treatment guidance,especially using MRI, had already proved to be a highlyhelpful tool in interstitial fibre placement in an earlierstudy on palliative PDT in head and neck tumour cases [10],and this could be confirmed in the present study. In all caseswith image-guided placement of fibres (n¼ 13), the treat-ment could be most accurately focussed on the areas ofconcern while sparing vital structures. In our opinion, MRor CT guidance have significantly contributed in achievinga very low incidence of adverse events even though highlycomplex and deep-seated malformations were commonlytreated. The choice of image guidance method has beendescribed above and is dependent on the type and the site ofthe lesion. The only downside to image guidance is cost, butthis is justified by the good outcomes that are expectable inthe face of the difficult cases treated.

The above described regimen for the management ofpost-PDT pain, nutrition issues and airway patency wasbased on previous experience with interstitial PDT inpalliative tumour cases. In the presented series of patients,it seemed to provide for sufficient patient safety andcomfort during the post-procedural period. The rate of

adverse events was low (8 out of 25 treatments), and theywere mostly mild and all fully reversible. In the two cases oftreatment-induced, airway compromising swellings only,the severity must be rated as intermediate. These twoevents did not, however, require more than conservativemeasures (steroids, adrenaline nebulizers) for successfulmanagement. All in all, the PDT protocol should thereforebe rated as being a safe procedure when compared withconventional treatment options for the lesions concerned(see below).

Concerning treatment outcome, all patients were eitherrelieved from their symptoms or at least experienced amarked improvement of their disease-related symptoms(see Table 2). The assessment of treatment outcomes wasthereby based on subjective and objective factors. Theoutcome was always clinically assessed and the patients’views were recorded. Comparing Surface Optical Scanningbefore and after treatment has proved to be a feasible way toquantitatively objectify influences of the treatment on thefacial contours and to estimate improvements in facialsymmetry. Whether or not these values, however, reliablyreflect our personal conception of facial aesthetics isanother matter. Further arguments for the use of the laserscanner for monitoring changes include the ease, low costand non-invasiveness of the procedure. In order to measurethe treatment effect of PDT on obstructive diseases such asdysphagia, obstructive snoring and OSAS, pre- and post-treatment imaging studies (CT, MRI) were performed intwo patients. Both showed a measurable widening ofthe upper aero digestive tract over the course of time. Thefunctional effect, however, was only estimated in thepatient suffering from OSAS by performing nocturnalpulse oximetry studies. Even though Polysomnography isthe generally accepted gold standard for diagnosing OSAS,there is scientific evidence that simple oximetry aloneincreases the probability of sleep apnea, especially ifperformed in an attended setting [11] (as in the patientpresented in Case Presentation 1). It is therefore very likelythat this patient suffered from OSAS when he firstpresented and that his severity of the disease was positivelyinfluenced by the treatment.

Fig. 11. Coronal T2-weighted MR images pre- and post-PDT for the assessment of treatment

effects on patient JD. Whereas the pre-treatment MRI image (a) shows a near occlusion of the

upper aero digestive tract by the hyperintense venous malformation, the situation is

significantly improved on the post-treatment image with some restoration of the aero

digestive tract lumen (b).

INTERSTITIAL PHOTODYNAMIC THERAPY 579

Comparison of PDT to Conventional Therapiesfor Venous Malformations

Sclerotherapy is a first choice option for the treatment ofvenous malformations, and it is often rated as a simple andeffective procedure. After injection of a sclerosing agent,sludging of erythrocytes occurs, and this is followed by athrombosis of the vessels. Subsequently, the lesion shrinksdown in size due to permanent obliteration of vessels byorganized thrombi, intimal necrosis and adventitial fib-rosis. The method seems to be especially effective ifthe draining vessels of the malformation are of normalcalibre and do not show dilatation or ectatic changes [12].The favoured sclerosing agent used in this setting isabsolute ethanol, for which good results with limitedcomplications rates (e.g. transient facial nerve palsies)have been reported in rather large study populations (e.g.[13,14]). Another classic, but still frequently used sclero-sant is sodium tetradecyl sulfate (Sotradecol), which yieldsa slightly increased incidence of recurrence with a margin-ally decreased risk of systemic toxicity. However, thistherapeutic approach should be restricted to the lower thirdof the face and the neck, however, as ‘‘facial veins have novalves and the venous drainage may well pass through thecavernous sinus’’ [15]. A further drawback of the method isthe amount of scarring that is induced within the treatedtissue which may impede further surgical interventions.Concluding from our observations, PDT seems to comparefavourably with this therapeutic option, as it is notrestricted to certain areas of the head and neck region,and in those patients that underwent a surgical procedurefollowing one or more courses of PDT (n¼ 5), no excessivescarring of the treated areas that had a negative influenceon the surgical performance was detected. Furthermore, atleast in our study population PDT did in none of the casesinduce transient nerve palsies, which are rather common insclerotherapy.

Surgery in venous malformations of the head and neckarea is usually not recommended as a monotherapy, butrather in a combined approach with sclerotherapy (whichproceeds surgical intervention). The indications are large,infiltrating malformations that are difficult to delineate,and the surgery usually requires ablative and reconstruc-tive steps. In this subset of patients, however, completesurgical extirpation is often difficult to achieve, andsubtotal resection is performed to relieve pain, reducetumour bulk or improve function. Side effects of surgery inthis setting are dependent on the radicalness of resectionand comprise neurological deficits, vascular events (i.e.haemorrhages) and local as well as systemic infections.PDT may offer a good alternative as a monotherapy, aslarge and complex venous malformations seem to betreatable with good outcomes concerning symptom-reliefand only minor chances for adverse events (especiallyconcerning neurovascular structures).

Interstitial laser coagulation is another treatmentoption that is favoured by various authors for the treat-ment of deep seated, complex venous malformations, andgood treatment outcomes have generally been reported

[4,16,17]. The most widely used system for this indicationis the Nd:YAG laser with bare fibres, but other systemssuch as diode lasers or intense pulsed light (IPL) flashlamp systems have also been described. It is usuallyrecommended to use low light intensities of 1–2 W for500–1,000 seconds per fibre, which leads to a sphericalarea of necrotic tissue around the fibre tip with a diameterof 16 mm [15]. The number of spots per treatment islimited as they correlate with the amount of post-treat-ment swelling. Therefore, several treatment sessions areusually required to reach the desired effect. Adverseeffects include scarring, hyper- and hypopigmentation,mild atrophy and a wrinkled texture of the overlying skin[18]. Even though PDT also often needs to be performedmore than once in order to treat these lesions compre-hensively, adverse events seem to occur at a far lower ratethan after laser therapy.

Comparison of PDT to ConventionalTherapies for Lymphatic Malformations

The gold standard for the treatment of lymphaticmalformations is surgery [19,20]. A complete excision isthereby always to be anticipated, as recurrence ratesfollowing incomplete resection vary between 35% and100% [21]. In a retrospective study performed by Riechel-mann et al. [22] on 21 patients with large cervico-faciallymphatic malformations, disease control was achieved in13 out of 14 cases with (sub)total removal of the lesion,whereas this was true for only one out of seven cases whohad undergone partial removal. In smaller, easily acces-sible lesions this seems an excellent option. In clinicalreality as well as in the patient series presented here,however, lymphatic malformations often present with amore complex structure with an intimate involvement ofimportant adjacent structures. In these cases, high com-plication rates are to be expected for radical surgery, andthis has been confirmed by numerous publications. Forexample, Padwa et al. [23] published a retrospective reviewon the clinical course and the long-term outcomes of 17patients with large, symptomatic cervico-facial lymphaticmalformations. Following a mean of four surgical inter-ventions per patient, the authors witnessed a permanentdamage to the facial nerve in 76% and to the hypoglossalnerve in 24% of the cases. Other, frequently occurringcomplications include other neurological deficits, haemor-rhages due to an injury of vascular structures, seromas,would infections and sepsis [21]. If the lesion is situated inclose proximity to the upper aero digestive tract, surgicalresections go along with an increased risk of an acute orpersistent airway compromise. Therefore, several authorshave proposed a less aggressive and more symptom-basedsurgical approach or other techniques such as limitedradiofrequency ablation for these cases [22,24]. Finally,surgical interventions tend to leave a fair amount ofscarring, so that subsequent procedures might be hinderedand the complication rate might rise even more. Eventhough the presented case series does not reach any kind ofstatistical significance as for the low number of patientsexamined, PDT seems to produce less serious side effects

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than surgery if complex lymphatic malformations aretreated while treatment benefits for the patients aresimilar. This is especially true for neurovascular struc-tures, as there were no such side effects encountered. Afurther advantage of PDT in this setting seems to be thepossibility to retreat without raising the chances for sideeffects as scarring does not adversely affect this treatmentmodality.

Even though surgery is still seen as the gold standard oftherapy for extratruncular lymphatic malformations,sclerotherapy has also been investigated as a treatmentoption in recent years especially if the lesions arelocated in surgically inaccessible or challenging areas.As sclerosing agents, attention has been mostly drawnto Bleomycin, a chemotherapeutic antibiotic isolatedfrom the fungus Streptomyces verticillus, and OK-432(Picibanil1, Chogai Pharmaceutical Co., Tokyo, Japan), alyophilized mixture of a low virulence strain of group AStreptococcus pyogenes incubated with benzylpenicillin,and good clinical results in single cystic and macrocysticlesions have been reported for both [25–27]. Because theformer carries the more serious risk of developingpulmonary fibrosis, however, it cannot be recommendedfor this benign indication without hesitation. Side effectsof the latter are common but usually less severeand comprise swelling, pain, influenza-like syndromes,haemorrhage, neuritis and (in rare cases) airwaycompression secondary to cyst enlargement followinginjection of the sclerosant. The preferred sclerosing agentfor the treatment of lymphatic malformations is thereforePicibanil1, and it seems useful as a monotherapy for thetreatment of single cystic and macrocystic lesions [27,28].Again, the use of PDT should be advantageous oversclerotherapy, as side effects are usually low and theapplication should not be restricted to a certain subgroupof lesions only. This, however, has not been provendirectly by the current series, as the histopathologicalsubtypes of lymphatic malformations within the patientpopulation were not determined by default, but is ratheran assumption derived from the fact that drug and lightdistribution (which are of utmost importance for the PDTeffect) should be comparable in macro- and microcysticlesions.

CONCLUSION

Interstitial PDT with mTHPC as a photosensitizer seemsto be a safe, effective, symptom-targeted treatment optionfor complex benign vascular lesions. Depending on theextent and site of the lesion, fibre placement may beperformed clinically or under image guidance. The methodcompares favourably with conventional treatment modal-ities because of its universal applicability in the head andneck field concerning lesion sites and types, its nearlyunlimited repeatability and its apparent lack of neuro-vascular side effects. As the presented number of patientstreated so far is low, however, these results need to beconfirmed in a larger trial with considerable higher patientnumbers.

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