1st International ESTP Expert Workshop: “Larynx squamous metaplasia”. A re-consideration of morphology and diagnostic approaches in rodent studies and its relevance for human risk assessment

Invited international experts participated in a 2-day workshop organized by the European Society of Toxicologic Pathology (ESTP) to evaluate and discuss spontaneous and induced laryngeal lesions in rodents. The main purpose of the workshop was to agree upon the terminology and relevance of a range of laryngeal changes that varied from very subtle epithelial alterations up to severe metaplastic or neoplastic lesions. The workshop experts concluded that minimal, focal epithelial changes of the laryngeal epithelium, predominantly occurring at the base of the epiglottis, should be given the descriptive term of “epithelial alteration” and assessed as “non-adverse”. Although observed as induced effects they may also occur in non-treated animals and were not considered to have a potential for a laryngeal dysfunction. Also, cases of minimal to slight laryngeal squamous metaplasia that are not observed diffusely could occur spontaneously or as treatment-induced lesions and should be assessed as “non-adverse”. Cases of moderate to severe laryngeal squamous metaplasia observed diffusely in multiple levels should be regarded as “adverse”, as there is a potential for dysfunction of the larynx. The occurrence of dysplasia or cellular atypia linked to laryngeal squamous metaplasia should always be reported separately and described in detail. In the evaluation of treatment-related effects of the larynx in studies utilizing aged animals, it has to be considered that moderate or even severe cases of focal laryngeal squamous metaplasia may occasionally be found as age-related, spontaneous lesions. Although inhalation exposure of rodents to non-genotoxic compounds may cause laryngeal squamous metaplasia, none of the workshop experts were aware of any reported cases of tumor induction in the larynx with a non-genotoxic compound. Therefore, for non-genotoxic compounds, the workshop experts did not regard laryngeal squamous metaplasia by itself as a precancerous lesion.