Henrik B. Hellquist

Photo-oxidative disruption of lysosomal membranes causes apoptosis of cultured human fibroblasts.

Acridine orange (AO) is a lysosomotropic weak base, a metachromatic fluorochrome, and a photosensitizer, as well. Living cells that are exposed for a short period of time to this compound at low concentration, and under ordinary culture conditions, accumulate the drug within their acidic vacuolar compartment, giving rise to a mainly red, granular fluoresence upon excitation with blue light. When AO-loaded cells are irradiated with intense blue light, AO soon starts to leak from late endosomes and lysosomes, partially shifting the fluorescence to a green, nuclear and diffuse cytosolic, one. This AO-relocalization is a consequence of photo-oxidation of the lysosomal membranes, which initially results in disruption of their proton-gradients and later, in leakage into the cytosol of a host of hydrolytic enzymes--as was here demonstrated by immunocytochemistry--which are capable of causing cellular damage. Most fibroblasts survived minor photo-oxidation, with a period of reparative autophagocytosis. Severe photo-oxidation, which resulted in severe lysosomal damage, caused cellular necrosis; whereas moderate stress, resulting in only partial lysosomal leakiness lead to apoptosis with TUNEL-positive nuclei and shrunken cytoplasm. The findings of the present study show that photo-oxidative damage to the membranes that surround the acidic vacuolar compartment, is an event that results in release of proteolytic and DNA-fragmenting enzymes into the cytosol, which may induce either necrosis, apoptosis, or reparable sublethal damage, depending on the magnitude of lysosomal rupture. Furthermore, the results strongly suggest that proteases and endonucleases of lysosomal origin may induce apoptosis if relocalized from the acidic vacuolar compartment into the cytosol.

Adenocarcinoma of the ethmoid sinuses. A review of 28 cases with special reference to wood dust exposure

Adenocarcinoma makes up only a small percent of all nasal and paranasal sinus carcinomas, and is most often found in the ethmoid sinuses. Adenocarcinoma of the ethmoid sinuses is known to be associated with exposure to wood dust. Twenty‐eight patients with ethmoid adenocarcinomas were collected, mainly during the last decade from a region with approximately 900,000 inhabitants and with a large amount of furniture industries. There were 4 women and 24 men in the study. Twenty of the men were exposed to dust from hardwood for 20 to 55 years (mean, 40 years) which is in accord with other reports and supports data on the increased risk for workers of developing adenocarcinoma of the ethmoid sinuses when exposed to dust from hardwood. Radiologic diagnosis is necessary to delineate the extent of these tumours, and computerized tomography (CT) especially furnishes important information. Most patients received preoperative radiotherapy followed by surgery, 50% of them survived 5 years, which is in accord with other reports.

The So-Called ‘Allergic’ Nasal Polyp

A series of 95 consecutive patients who have had a polypectomy was investigated with regard to clinical history and the morphology of the polyps. The results were compared with a series of 203 patients with allergy, of whom 12 had been polypectomized. The study revealed that a high percentage of the 95 patients had subjective complaints, particularly nasal congestion, nasal discharge, sneezing, headache, snoring and a loss of smell. The latter was present in nearly 58% of the patients, and persisted long after the operation in a third of the cases. More than 50% of the 95 patients had had 3 or more polypectomies. Rather few patients suffered from allergy-like conditions. Eighty-two of the 95 polyps were of the ordinary, oedematous, eosinophilic type; 7 were neutrophilic, fibro-inflammatory; 5 showed pronounced hyperplasia of the seromucinous glands, and 1 was a so-called polyp with atypical stroma. Only 6% of the 203 patients with allergy had had a polypectomy. Ten of the 12 polyps removed from the series of patients with allergy were of the ordinary type and 2 of the fibro-inflammatory type. A review of the literature is done concerning the association between nasal polyp and different diseases. The results of the present study support the concept that allergy is not the only cause for nasal polyps and that the accumulation of eosinophilic granulocytes observed in most polyps is often not related to allergy.

Expression of Epidermal Growth Factor Receptor in Laryngeal Dysplasia and Carcinoma

The immunoreactivity of epidermal growth factor receptor (EGFR) was studied in laryngeal biopsy specimens from 24 patients. The study comprised 5 cases of normal laryngeal mucosa, 5 cases of dysplasia, 7 cases of well differentiated squamous cell carcinoma, and 7 cases of poorly to moderately differentiated squamous cell carcinoma. EGFR was in general not expressed in normal and dysplastic epithelia, whilst all carcinomas showed a rather strong positive immunoreactivity. There was no significant difference in staining patterns between the well and poorly to moderately differentiated carcinomas. The results suggest that EGFR constitutes a component of neoplastic, but probably not preneoplastic, laryngeal disease. The study failed to reveal any difference in staining pattern between different types of laryngeal squamous cell carcinoma.

Oncocytic lesions of the larynx.

Oncocytic cysts of the larynx, comprising 0.5–1 % of all laryngeal specimens, are benign lesions with a tendency to multifocal involvement occurring in patients over the age of 50. The pathological findings should be interpreted as oncocytic metaplasia with or without ductal or adenomatous hyperplasia. Surgical excision is the treatment of choice. Seven laryngeal oncocytic cysts are reported.

Malignant melanoma of the ear

This paper reports on 16 cases of primary malignant melanoma of the external ear and the patients were followed up for two to 116 months. Fourteen patients had surgical excision with wide margins as initial treatment, whilst two had an amputation performed. Eleven patients had no recurrences, two died of other diseases, and four died of malignant melanoma. The five patients who developed recurrences received further surgery and two also radiotherapy. Seven of the cases were histologically of the nodular type, six were superficial spreading, two were in situ melanoma, and one was a lentigo maligna. The thickness ranged from 0.15 to 11.5 mm. Classification according to Clark et al. (1969) revaled that as many as nine cases were Clark level IV or more. Immunostaining with PCNA yielded strong positivity in all cases, however, statistical analysis did not reveal any differences that could be correlated to the prognosis. Estimation of the vascularization at the base of the tumours by means of immunostaining with CD31 did not reveal any significant differences either. We concluded that in our material the thickness of the tumour is of greater prognostic value than the estimation of proliferation by PCNA and vascularization by CD31. The value of PCNA and CD31 as possible prognostic parameters needs to be evaluated in a larger series. It is emphasized that malignant melanoma of the external ear is a highly malignant tumour, and that four of our 16 patients died of their disease, three of them within a year after diagnosis. Malignant melanoma of the external ear is readily inspected and thereby an early diagnosis should be possible.

Histological Changes in the Nasal Mucosa in Persons Occupationally Exposed to Formaldehyde Alone and in Combination with Wood Dust

In the nasal mucosa of rodents, both formaldehyde and wood dust have proved to be carcinogenic. Wood dust is also a well-known nasal carcinogen in man. The effects of long-term exposure of humans to formaldehyde, however, are more obscure. In this investigation two groups of workers with well-defined exposure to formaldehyde and to formaldehyde and wood dust, respectively, were compared with a control group regarding histological changes in nasal specimens from the middle turbinate. Significant changes were found in the formaldehyde group but not in the group exposed to both formaldehyde and wood dust. No correlation was found between histological changes and duration of exposure, doses of exposure or smoking habits.

Carcinoma in Situ and Severe Dysplasia of the Vocal Cords: A Clinic pathological and Photometric Investigation

Premalignant lesions of the vocal cords vary in their gross appearance. and diagnosis invariably relies on microscopic examination. This retrospective clinicopath-ological and photometric study of 20 cases of severe dysplasia and carcinoma in situ showed that various degrees of squarnous cell differentiation may he recognized for laryngeal premalignant lesions and that such distinction may be of prognostic significance. Carcinoma in situ is widely accepted as a premalignant lesion. while there has been an uncertainty about the histological criteria and the biological nature of severe dyasplasia. None of the cases of carcinoma in situ of classic type recurred. whereas well differentiated severe dysplasia had a high recurrence rate and development of invasice carcinoma. A classitlcation of severe dysplasia into well and moderately, to poorly differentiated is proposed. Photometric examination proved to be of value in the assessment of nuclear atypia. which was sometinies masked. and especislly in the case o...

Nasal cuboidal metaplasia with dysplasia. Precursor to adenocarcinoma in wood-dust-exposed workers?

The histological study of the non-tumours nasal mucosa in 22 wood-workers with ethmoidal adenocarcinoma was carried out and special attention was paid to the presence of cuboidal metaplasia with or without dysplasia. The workers had been exposed to wood dust for an average of 38 years (range 18 to 55 years). In 19 cases cuboidal metaplasia was found and 16 of these also had dysplasia. In 10 cases there was a transitional zone with dysplastic cuboidal epithelium in continuity with the tumour. In 5 cases there was squamous metaplasia. The results indicate cuboidal metaplasia with dysplasia being a possible precursor to nasal adenocarcinoma in workers exposed to wood dust, similar to the findings of squamous metaplasia and squamous cell carcinoma in nickel workers.

Positive identification in situ of mRNA expression of IL-6, and IL-12, and the chemotactic cytokine RANTES in patients with chronic sinusitis and polypoid disease. Clinical relevance and relation to allergy

Interleukins 6 (IL-6) and 12 (IL-12), and the chemoattractant chemokine RANTES were studied in ethmoidal mucosa, using reverse transcriptase polymerase chain reaction. The 49 patients had chronic sinusitis or nasal/paranasal polyposis, and some also allergy. To the best of our knowledge, this is the first study that demonstrates RANTES and IL-12 on mRNA level in human sinonasal mucosa in situ. mRNA for IL-6, IL-12 and RANTES were detected in 2, 8 and 6 patients with chronic sinusitis, respectively, and in mucosa from patients with polyposis a positive expression was observed in 4, 14 and 10 cases. There were no statistically significant differences. Analysing the entire group of 49 patients, disregarding type of mucosal disease, the number of patients with positive RANTES was significantly higher than that for IL-6. Similarly, IL-12 positivity was more frequently expressed than IL-6. mRNA for IL-6 was expressed in only 2 of the allergic patients. The cytokine production studied thus seems to be unrelated to the clinically defined entities. There is thus a local production in human diseased sinonasal mucosa of RANTES, as well as of IL-6 and IL-12. The local production of RANTES is an important prerequisite for recruitment and migration of inflammatory cells into the tissue. IL-12 is a co-stimulator of antigen-specific responses of established T helper 1 (Th1) clones, and regulates the responsiveness of the clones to a number of T cell growth factors. The study supports a shift towards Th1 cells in these disease entities.