Ch. Fontolliet

Photodetection and photodynamic therapy of "early" squamous cell carcinomas of the pharynx, oesophagus and tracheo-bronchial tree

The efficacy of photodynamic therapy (PDT) alone was evaluated on 41 ‘early’ squamous cell carcinomas of the pharynx (10), oesophagus (15) and tracheo-bronchial tree (16). All lesions but two were synchronous second primaries in ENT-patients suffering from a more extensive cancer, governing the overall oncological prognosis.Photofrin I (3 mg/kg) or Photofrin II (2 mg/kg) were injected 72 h prior to the red light irradiation, supplied by an argon pumped dye laser. A diffusing cylinder was used to obtain a homogeneous light distribution at the tumour site (60 J to 150 J/cm2). In the oesophagus and bronchi, the results are good for cancers staged in situ or microinvasive at endoscopy (two recurrencies for 23 lesions treated). For more advanced cancers (submucosal in the oesophagus or invading the bronchial cartilage), the results are less satisfactory (three recurrencies for eight lesions treated). In the pharynx where light dosimetry is more difficult, the rate of recurrencies is higher (3/10 lesions treated). In the bronchi (one case) and oesophagus (one case), the longest disease-free survival is now 5 years.The irradiation of a non-cancerous zone of normal buccal mucosa on 25 patients having received HPD showed necrosis in all cases with light doses as low as 50mW/cm2 for 20 min (60 J cm−2), even with Photofrin II.We encountered six complications (three cicatricial stenosis, two fistulae, one severe sunburn), most of them resulting from the lack of selectivity of HPD. According to these experiments, PDT is efficient at destroying early squamous cell carcinomas in the pharynx, oesophagus and bronchi, but the tumour selectivity of HPD is poor in the digestive tract lined with squamous cell epithelium. The only hope for the future lies in the synthesis of a more selective and more stable photosensitizer. This discussion reviews possible directions of research for the development of new dyes (cationic dyes, dyes attached to monoclonal antibodies, etc), for PDT and hyperthermia, for photodetection of early cancers using a fluoro-endoscope, and finally, for tumour depth profiling in hollow organs using lasers of different wavelengths.

La nouvelle classification de Savary des œsophagites de reflux

RésuméComme la classification de Savary-Miller dont elle adopte l’essentiel, la classification de l’œsophagite par refluxen 5 types de Savary-Monnier repose sur une analyse rigoureuse et précise des lésions endoscopiques. Ses principales qualités sont d’être simple, complète, logique et souple. Son impact sur la pratique est certain puisqu’elle a une excellente valeur pronostique et qu’elle permet de choisir la bonne stratégie thérapeutique. De plus, en isolant les cicatrices cylindriques (seules précancéroses à surveiller à long terme) elle permet de les utiliser pour préciser la topographie des œsophagites de reflux.SummaryThe Savary- Monnier classification of reflux oesophagitis into 5 types relies on the rigorous and accurate analysis of endoscopic lesions. It is based for the essentials on the earlier Savary- Miller grading (1974). It has the advantage to be simple, exhaustive, logic and adaptable. Its impact on clinical practice is undeniable since it has an excellent prognostic value and indicates the best choice of therapeutic strategy. Moreover, by setting apart the cylindric cell scars (the only precancerous lesions needing a long term surveillance), this grading allows to specify the topography of reflux oesophagitis.ResumenComo la clasificación de Savary- Miller de la cual adopta lo esencial, la clasificaeión de la esofagitis por reflujo en 5 tiposde Savary- Monnier reposa sobre un análisis riguroso y preciso de las lesiones endoscópicas. Sus principales cualidades son la de ser simple, completa, lógica y flexible. Su impacto en la práctica es efectiva ya que tiene un excelente valor pronóstico y permite escoger la correcta estrategia terapéutica. Además, excluyendo las cicatrices cilindricas (solo las precancerosas de vigilancia a largo plazo), ella permite utilizarla para precisar la topografia de las esofagitis por reflujo.ZusammenfassungWie die Klassifikation nach Savary- Miller, wovon sie die wesentlichen Punkte übernimmt, basiert die Einteilung der Refluxösophagitis in 5 Stadien nach Savary- Monnier auf einer strengen und genauen endoskopischen Untersuchung der Läsionen. Ihre grundlegenden Eigenschaften sind die Einfachheit, Vollständigkeit, der logische Aufbau und die Anpassungsfähigkeit. Ihre Bedeutung für die Praxis ist gegeben, da sie eine hervorragenden prognostischen Wert besitzt und so die Auswahl der geeigneten therapeutische Strategie erlaubt.Darüberhinaus erlaubt sie Präzisierung der Topographie der Refluxösphagitis im Fall von Narben im Bereich des Zylinderepithels (der einzigen Präkanzerose, die über lange Zeit beobachtet werden muβ .RiassuntoLa nuova classificazione della esofagite da reflusso in 5 stadidi Savary- Monnier deriva come quella di Savary- Miller da una analisi rigorosa e precisa delle lesioni endoscopiche. Le sue caratteristiche peculiari sono la semplicità, la completezza, la logica e la sua adattabilitànella tipizzazione delle varie lesioni. Il suo valore prognostico permette, da un punto di vista pratico, di scegliere la strategia terapeutica piùadatta al tipo di lesione. In più, isolando le cicatrici di forma cilindrica (le sole da sorvegliare a lungo termine per la loro potenzialitàprecancerosa) essa permette di utilizzarle nel precisare correttamente la topografia delle lesioni dell’esofagite da reflusso.

Time‐dependent Biodistribution of Tetra(m‐hydroxyphenyl)chlorin and Benzoporphyrin Derivative Monoacid Ring A in the Hamster Model: Comparative Fluorescence Microscopy Study

The pharmacokinetics of the photosensitizer used play a key role in the understanding of the mechanism of photodynamic therapy‐induced damage. Fluorescence microscopy was used to compare time‐dependent biodistribution of tetra(m‐hydroxyphenyl)chlorin (mTHPC) and benzoporphyrin derivative monoacid ring A (BPD‐MA) in different hamster tissues, including an early, chemically induced, squamous cell carcinoma. Following injection of 0.5 mg/kg body weight of mTHPC and 2.0 mg/kg BPD‐MA, groups of three animals were sacrificed at different time points and a series of fluorescence micrographs from different excised organs were analyzed. The highest fluorescence intensities of mTHPC were observed at 96 h for squamous epithelia and skin and at 48 h for smooth muscle. There is no real peak of BPD‐MA fluorescence between 30 min and 3 h in the basal epithelial layers, fibroconnective tissue, muscles or blood vessels. At 4 h after injection, the fluorescence level of BPD‐MA decreased and at 24 h it had returned to background level in all observed tissues. The significantly faster clearance of BPD‐MA is the principal advantage as compared to mTHPC. However, similar localization patterns in different tissues with essentially vascular affinity represent a possible disadvantage for treating early malignancies with BPD‐MA as compared to mTHPC, which is mainly localized in various epithelia. For both photosensitizers no significant selectivity between early squamous cell carcinoma and healthy mucosae is seen. Pharmacokinetic studies of different photosensitizers in an appropriate animal model are essential for selecting new‐generation photosensitizers with the most favorable localization for photodynamic therapy of early malignancies in hollow organs.

Localization of tetra(m-hydroxyphenyl)chlorin (Foscan) in human healthy tissues and squamous cell carcinomas of the upper aero-digestive tract, the esophagus and the bronchi: a fluorescence microscopy study

To date, little is known about precise time-dependent distribution and histological localization of tetra(m-hydroxyphenyl)chlorin (mTHPC) in human healthy tissues and squamous cell malignancies in the upper aero-digestive tract. A fluorescence microscopy study was performed on 50 healthy tissue biopsies and on 13 tumors (graded from Tis to T1 SCC) from 30 patients. Tissue samples were taken between 4 h and 11 days following injection of 0.15 mg/kg mTHPC. A fairly comparable distribution pattern in various tissues was observed over time in different patients. Vascular localization of mTHPC fluorescence predominates at a short delay, whereas the dye is essentially located in the tumoral and healthy mucosa after longer delays. A much lower uptake and retention of mTHPC fluorescence was noted in striated muscle and cartilage as compared to neoplastic lesions. No significant selectivity was found between healthy and tumoral mucosa. The obtained data are important to confirm drug-light interval that have been selected for effective PDT for early SCC malignancies while minimizing the risks of over- or under-treatment. The low fluorescence level in striated muscle provides the opportunity to develop interstitial PDT as a treatment modality for invasive SCC of unfavorable locations in the oral cavity or pharynx, such as the base of the tongue.

Endoscopic Findings of 100 Early-Stage Esophageal Cancers

The morphologic analysis of 100 early squamous cell carcinomas of the esophagus has shown that the barely visible or invisible forms (erythroplakias and occult forms) are predominant. This explains the poor yield of upper gastrointestinal (GI) endoscopies in detecting early cancers, at least in Western countries. Leucoerythroplakias correspond to the most advanced form of early cancers (submucosal invasion in approximately 38% of cases). Pure erythroplakias and occult forms correspond to in situ or intramucosal cancers in over 90% of the cases. Accurate endoscopic staging is possible using morphologic criteria, superficial spread, and rigidity of the wall as parameters. In a prospective study, we show that the degree of accuracy of this staging system reaches 95% for an experienced endoscopist. T1aN0 cancers can benefit from an endoscopic treatment (mucosectomy or photodynamic therapy), because the risk of lymph node metastasis is low (6%). In T1bN0 cancers, the best treatment option is an esophageal resection with extensive mediastinal lymph node dissection for good surgical candidates; PDT combined with adjuvant radiotherapy is a reasonable option for inoperable patients.

Is their prevalence in patients with Barrett’s esophagus overestimated?

The prevalence of adenocarcinoma in patients with Barrett’s esophagus ranges from 7% to 40% in patients undergoing endoscopy (Table 1) [2], and from 37% up to 85% in patients undergoing surgery [9, 12, 13].

Staging endoscopique du carcinome épidermoïde «précoce» pour la voie digestive supérieure

RésuméCe travail réquite de deux études.La première, rétrospective, a analysé de manière détaillée les correspondances mascroscopiques et histo-pathologiques de 190 carcinomes épidermoïdes précoces de la voie digestive supérieure. Selon une liste de critères morphologiques basés sur la couleur de la muqueuse, la localisation des lésions, leur extension en surface ainsi que la souplesse pariétale, il nous paru possible de prédire le degré ďinvasion carcinomateuse intra-pariétale de ces lésions lors de ľendoscopie.Cette présmption a été vérifiée de manière prospective lors ďune seconde étude, toujours en cours, portant actuellement sur 64 carcinomes épidermoïdes précoces de la voie digestive supérieure. Ľendoscopiste établit un staging histologique présumé de la lésion selon les critères morphologiques décrits ci-dessus. Son diagnostic endoscopique est transmis au pathologue par I’intermédiaire ďun code chiffré secret. Apres exérèse in toto de la lésion, cette dernière est examinée par coupes histologiques seriées. La corrélation entre le staging histologique présumé établi par ľendoscopeur et le diagnostic histologique s’est révé1ée exacte ou surrévaluée (faux positif) dans 95 % des cas. Le taux ďerreur par sous-évaluation entraînant une éventuelle conséquence thérapeutique est de 5 % (faux négatif). Par rapport aux données de la littérature concernant le staging pré-opératoire des carcinomes épidermoïdes précoces de ľœsophage par ultrasonographic endoscopique, cette méthode paraît plus précise pour un endoscopiste entraîné. Ľultrasonographie endoscopique garde toute sa valeur pour la détection des adénopathies médiastinals.SummaryThis paper is the result of two studies.The first was a retrospective study which made a detailed analysis of the macroscopic and histopathological relationships of 190 early squamous cell cancers of the upper digestive tract. It appeared possible to use endoscopy to predict the degree of intra-parietal cancerous invasion of the lesions by using a list of morphological criteria based on the colour of the mucosa, the localisation of the lesions, their surface extensions as well as parietal flexibility.This presumption was verified in a second study, still in progress, on 64 early squamous cell carcinomas of the upper digestive tract. The endoscopist set up a histological staging which was based on the morphological criteria of the lesion as described above. This endoscopic diagnosis was transmitted to the pathologist via a secret code number. After the exeresis of the entire lesion, it was examined by histological serial sectioning. The correlation between the presumed histological staging established by the endoscopist and the histological diagnosis is shown to be over-evaluated (false positive) if not exact in 95 % of cases. The rate of error caused by under-evaluation entailing a possible therapeutic consequence stands at 5 % (false negative). In relation to the findings in articles concerning the pre-operational staging of early squamous cell carcinomas of the eosophagus by means of an ultra-sonic endoscopy, it would seem that this method is more appropriate for a trained endoscopist. Ultrasonography is also a valuable means in the detection of mediastinal adenopathies.ResumenEste trabajo es el resultado de dos estudios.El primero, retrospectivo, ha analizado de manera detallada las correlaciones macroscopicas e histopatológicas de 190 carcinomas epidermoides precoces de la via digestiva superior. Según una lista de criterios morfológicos basados sobre el color de la mucosa, la localizatión de las lesiones, su extensión en superficie así como la elasticidad parietal, nos ha parecido posible predecir el grado de invasión carcinomatosa intraparietal de las lesiones después de la endoscopia.Esta presunción ha sido verificada de manera prospectiva en un segundo estudio en desarrollo, actualmente sobre 64 carcinomas epidermoides precoces de la vóa digestiva superior. El endoscopista presume una clasificación histológica según los criterios morfológicos aquí descritos. Su diagnóstico endoscópico es transmitido al patólogo por intermedio de un código secreto cifrado. Después de la resectión « in toto » de la lesión, esta última es examinada por cortes histológicos seriados. La correlatión entre la clasificación histológica presuntiva establecida por el endoscopista y el diagnóstico histológico ha sido exacta o sobrediagnosticada (falso positivo) en el 95 % de los casos. El margen de error por sub-evaluatión que implica una eventual consecuencia terapéutica es del 5 % (falso negativo). En relatión a los datos de la literatura concernientes a la clasificación pre-operatoria de los carcinomas epidermoides precoces del esófago por ultrasonografía endoscópica, este método parece más preciso para un endoscopista entrenado. La ultrasonografía endoscópica mantiene todo su valor para la detectión de las adenopatías mediastinales.

Les œsophagites « primitives » ďorigine médicamenteuse a propos de 978 observations (1970-1990)

RésuméLa prévalence et ľincidence des œsophagites directement induites par des médicaments sont probablement sous-estimées. Les principaux agents responsables sont les antibiotiques, le bromure ďémépronium et les anti-inflammatoires. Le principal facteur favorisant est ľingestion du médicament sans eau et/ou de sa prise en position allongée. Ľendoscopie est indispensable pour le diagnostic; elle révèle habituellement des érosions localisées au niveau des deux-tiers supérieurs de ľœsophage. Ľévolution des lésions œsophagiennes est généralement favorable aprés ľarrêt du médicament incriminé. Des complications graves (sténose, perforation, hémorragie), parfois mortelles (6 cas), ne sont pas exceptionnelles.SummaryThe prevalence and incidence of oesophagitis directly caused by drug is probably underestimated. The principal causal agents are the antibiotics, emepronium bromide and the anti-inflammatory drugs. The principal propitious factor is the ingestion of the drug without water and/or in a reclining position. Endoscopy is essential for the diagnosis; it usually reveals localized erosions in the upper two thirds of the oesophagus. The evolution of these oesophageal erosions is generally favourable, as soon as the incriminated medication is withdrawn. However, serious complications (stenosis, perforation, haemorrhage), and sometimes even death (6 cases), are not exceptional.ResumenLa prevalencia y la incidencia de esofagitis directamente inducida por medicamentos estan probablemente sub-estimadas. Los principales agentes responsables son los antibióticos, el bromuro de emepronio y los anti-inflamatorios. El principal factor favorecedor es la ingestión del medicamento sin agua y/o su toma en posición horizontal. La endoscopia es indispensable para el diagnóstico; ella revela habitualmente las erosiones localizadas a nivel de los dos tercios superiores del esófago. La evolución de la lesiones esofágicas es generalmente favorable después de suspender el medicamento incriminado. Complicaciones graves (estenosis, perforación, hemorragia), algunas veces mortales (6 casos), no son excepcionales.

Possibilités et limites des traitements endoscopique et photodynamique pour le carcinome épidermoïde précoce des voies aérodigestives supérieures, des bronches et de ľœsophage

RésuméLe traitement photodynamique de 57 carcinomes épidermoïdes superficiels du pharynx [10], des bronches [21] et de ľœsophage [26] a été évalué chez 35 patients porteurs de polylocalisations carcinomateuses synchrones ou métachrones des voies aérodigestives supérieures.Ľirradiation laser a été effectuée 72 heures après injection intraveineuse du dérivé de ľhématoporphyrine (photofrin I ou II: 2 mg/kg ou lmg/kg), à une dose ďirradiation finalement fixée à 80-100 mWatt/cm2 pendant 20 minutes (100/120 joules/cm2) dans le rouge (630 nm) ou dans le vert (514 nm), en fonction du degré ďinfiltration carcinomateuse intra-pariétale.Les résultats obtenus sont bons pour les carcinomes in situ et micro-invasifs des bronches et de ľœsophage (3 récidives sur 37 lésions traitées). Dans le pharynx, où la géométrie est compliquée, et pour les carcinomes sous-muqueux, les résultats sont moins satisfaisants (6 récidives sur 17 lésions traitées). Le suivi des patients est supérieur à 3 ans pour plus de la moitié des cas (extrêmes: 6 à 82 mois).Les 6 complications observées ont eu lieu au début de notre expérience, lors des 29 premiers traitements jusqu’en 1987. Depuis lors, 28 nouvelles lésions ont été traitées sans complications, la maîtrise des doses ďirradiation, du choix de la longueur ďonde et de la quantité ďHpD injectée étant meilleure.SummaryThe photodynamic treatment of 57 squamous cell cancers of the pharynx [10], the bronchi [21] and the oesophagus [26] was assessed on 35 patients with synchronous or metachronous cancerous polylocalisations of the upper aero-digestive tract.Laser irradiation was carried out 72 hours after an intravenous injection of hematoporphyrine derivative (photofrin I or II: 2 mg/kg or 1mg/kg), to a dose of irradiation fixed at 80-100 m Watt/cm2 for a duration of 20 minutes (100/120 joules/cm2) in the red wavelength (630 nm) or in the green wavelength (514 nm), depending on the degree of intra-parietal penetration of the cancer.The tests carried out on the in situ and micro-invasive carcinomas of the bronchi and the oesophagus produced good results (for example, there were three relapses out of 37 treated lesions). However, for submucosal carcinoma and those in the pharynx where the geometry is more complicated, the results were less satisfying (6 relapses out of the 17 lesions that were treated). Patients are monitored for over 3 years in more than half of the cases (in more extreme cases: 6 to 82 months).The six complications observed here took place at the beginning of the experiment at the time of the first treatments up until 1987. Since then, however 28 new lesions have been treated without any further complications. This was due to an overall improvement in irradiation control, the choice of wavelength and the amount of HpD being injected.ResumenEl tratamiento fotodinámico de 57 carcinomas epidermoides superficiales de la faringe (10), de los bronquios (21) y del esófago (26) se han evaluado en 35 pacientes portadores de poli-localizaciones carcinomatosas sincronas o metacronas de las vías aéreo-digestivas superiores.La irradiación laser ha sido efectuada 72 horas después de la inyección intra-venosa de un derivado de la hematoporfirina (fotofrin 1 o 11: 2 mg/kg o 1 mglkg), a una dosis de irradiación finalmente fijada de 80-100 Watt/cm2 durante 20 minutos (100/ 120 joules/cm2) en el rojo (630 nm) o en el verde (514 nm), en función del grado de infiltración carcinomatosa intra-parietal.Los resultados obtenidos son buenos para los carcinomas in situ y microinvasivos de bronquios y del esofago (3 recidivas sobre 37 lesiones tratadas). En la faringe donde la geometría es complicada y para los carcinomas sub-mucosos, los resultados son menos satisfactorios (6 recidivas sobre 17 lesiones tratadas). El seguimiento de los pacientes es superior a 3 años para más de la mitad de los casos (extremos: 6 a 82 meses).Las 6 complicaciones observadas han tenido lugar al comienzo de nuestra experiencia, en los primeros 29 tratamientos hasta 1987. Después, las 28 nuevas lesiones han sido tratadas sin complicaciones; el dominio de las dosis de irradiación, la escogencia de la longitud de onda y de la cantidad de HpD han sido mejores.

Les dysphasies oesophagiennes en muqueuse malpighienne et cylindro-cellulaire : aspects histopathologiques

RésuméLe rôle de l’histopathologiste dans la définition et le diagnostic des lésions cancéreuses et précancéreuses de l’cesophage, sur muqueuse malpighienne ou cylindrique, est discuté sur la base de notre expérience personnelle et d’après les données de la littérature. Le diagnostic de dysplasie est un diagnostic fréquent et difficile, tant pour l’histologiste que pour le clinicien. Des méthodes de dépistage et un programme de surveillance du patient à risque sont proposés.SummaryThe role of the histopathologist in the definition and the diagnosis of precancerous and cancerous lesions originating in the squamous cell or columnar line mucosa of the esophagus are discussed on the basis of our experience and compared with the literature. The diagnosis of dysplasia is a frequent diagnosis but difficult to interpret both for the histopathologist as well as for the clinician. Screening methods and a monitoring programme for high risk patients are proposed.ResumenEl papel del histopatólogo en la definitión y el diagnóstico de las lesiones cancerosas y precancerosas del esófago, sobre mucosa malpigiana o cilindrica, es discutido sobre la base de nuestra experiencia personal y según la informatión de la literatura. El diagnóstico de displasia es un diagnóstico frecuente y diflcil tanto para el histólogo como para el clínico. Los métodos de investigatión y un programa de vigilancia del paciente de riesgo son propuestos.