Background Patients with head-and-neck cancers who are free of disease after local therapy remain at high risk for both recurrent and second primary tumors Retinoids have proved efficacious in the treatment of premalignant oral lesions and are promising agents for the prevention of epithelial carcinogenesis Methods We prospectively studied 103 patients who were disease-free after primary treatment for squamous-cell cancers of the larynx, pharynx, or oral cavity After completion of surgery or radiotherapy (or both), these patients were randomly assigned to receive either isotretinoin (13-cis-retinoic acid) (50 to 100 mg per square meter of body-surface area per day) or placebo, to be taken daily for 12 months Results There were no significant differences between the two groups in the number of local, regional, or distant recurrences of the primary cancers However, the isotretinoin group had significantly fewer second primary tumors After a median follow-up of 32 months, only 2 patients (4

https://www.nejm.org/doi/pdf/10.1056/NEJM199009203231205

Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck.

13-cis-Retinoic acid has been reported to be effective in treating oral leukoplakia. We randomly assigned 44 patients with this disease to receive 13-cis-retinoic acid (24 patients) or placebo (20), 1 to 2 mg per kilogram of body weight per day for three months, and followed them for six months. There were major decreases in the size of the lesions in 67 percent (16 patients) of those given the drug and in 10 percent (2 patients) of those given placebo (P = 0.0002); dysplasia was reversed in 54 percent (13 patients) of the drug group and in 10 percent (2 patients) of the placebo group (P = 0.01). The clinical response to the drug correlated with the histologic response in 56 percent (9 of 16) of the patients evaluated. Relapse occurred in 9 of 16 patients two to three months after treatment ended. The toxic effects of the drug were acceptable in all but two patients. Cheilitis, facial erythema, and dryness and peeling of the skin were common; conjunctivitis and hypertriglyceridemia also occurred. All adverse reactions could be reversed by reducing the dose or temporarily discontinuing the drug. We conclude that 13-cis-retinoic acid, even in short-term use, appears to be an effective treatment for oral leukoplakia and has an acceptable level of toxicity.

13-cis-retinoic acid in the treatment of oral leukoplakia.

https://iopscience.iop.org/article/10.1088/0031-9155/35/9/001/pdf

Physics of thermal processes in laser-tissue interaction

The concept that cells can become malignant upon the elimination of parts of chromosomes inhibiting cell division dates back to Boveri in 1914. Deletions occurring in tumor cells are therefore considered a first indication of possible locations of tumor suppressor gene. Approaches used to localize and identify the paradigm of tumor suppressors, RB1, have also been applied to localize tumor suppressor genes on 3p, the short arm of chromosome 3. This review discusses the methodological advantages and limitations of the various approaches. From a review of the literature on losses of 3p in different types of solid tumors it appears that some tumor types show involvement of the same region, while between others the regions involved clearly differ. Also discussed are results of functional assays of tumor suppression by transfer of part of chromosome 3 into tumor cell lines. The likelihood that a common region of deletions would contain a tumor suppressor is strongly enhanced by coincidence of that region with a chromosome fragment suppressing tumorigenicity upon introduction in tumor cells. Such a situation exists for a region in 3p21.3 as well as for one or more in 3p12-p14. The former region is considered the location of a lung cancer suppressor. The same gene or a different one in the same region may also play a role in the development of other cancers including renal cell cancer. In the latter cancer, there may be additional roles of the VHL region and/or a 3p12-p14 region. The breakpoint region of a t(3;8) originally found to be constitutively present in a family with hereditary renal cell cancer now seems to be excluded from such a role. Specific genes on 3p have been suggested to act as suppressor genes based on either their location in a common deletion region, a markedly reduced expression or presence of aberrant transcripts, their capacity to suppress tumorigenicity upon transfection in to tumor cells, the presumed function of the gene product, or a combination of several of these criteria. A number of genes are evaluated for their possible role as a tumor suppressor according to these criteria. General agreement on such a role seems to exist only for VHL. Though hMLH1 plays an obvious role in the development of specific mismatch repair-deficient cancers, it cannot revert the tumor phenotype and therefore cannot be considered a proper tumor suppressor. The involvement of VHL and MLH1 also in some specific hereditary cancers allowed to successfully apply linkage analysis for their localization. TGFBR2 might well have a tumor suppressor function. It does reduce tumorigenicity upon transfection. Other 3p genes coding for receptor proteins THRB and RARB, are unlikely candidates for tumor suppression. Present observations on a possible association of FHIT with tumor development leave a number of questions unanswered, so that provisionally it cannot be considered a tumor suppressor. Regions that have been identified as crucial in solid tumor development appear to be at the edge of synteny blocks that have been rearranged through the chromosome evolution which led to the formation of human chromosome 3. Although this may merely represent a chance occurrence, it might also reflect areas of genomic instability.

Deletions of the short arm of chromosome 3 in solid tumors and the search for suppressor genes

Background. —Deletions in the short arm of chromosome 3 (3p) are present in most lung carcinomas. Objective. —To investigate the role of these chromosome 3p deletions in the pathogenesis of non—small cell lung carcinomas. Design. —Seven archival, paraffin-embedded, surgically resected lung cancer specimens were studied. Fifty precisely identified malignant and preneoplastic lesions present in bronchi, bronchioles, and alveoli were microdissected from stained slides and analyzed for allele loss using polymerase chain reaction—based assays for dinucleotide repeat polymorphisms at three chromosome 3p loci (3p14,3p21.3, and 3p25). Setting. —University-based medical center and affiliated hospitals. Subjects. —Samples were analyzed from seven patients who underwent surgical resection with curative intent for non—small cell lung cancer and whose specimens included extensive multifocal areas of preneoplastic lesions (hyperplasia, metaplasia, dysplasia, or noninvasive cancer). Results. —Lymphocytes from all seven cases were heterozygous (ie, informative) for all three microsatellites analyzed. Six (86%) of seven invasive cancers had loss of heterozygosity at one or more chromosome 3p sites. In the accompanying preneoplastic lesions, loss of heterozygosity was detected in none of two normal bronchioles, 13 (76%) of 17 hyperplasias, six (86%) of seven dysplasias, and four (100%) of four noninvasive cancers. Loss of heterozygosity was detected throughout the respiratory tract, in bronchi, bronchioles, and alveoli. In 18 (78%) of 23 preneoplastic lesions, the specific alleles lost were identical to those lost in the corresponding carcinomas. The probability of this happening by chance is 5.3×10-3. Conclusions. —Deletions in the short arm of chromosome 3 occur at the earliest stage (hyperplasia) in the pathogenesis of lung cancer and involve all regions of the respiratory tract. Allele loss is highly specific, but its mechanism remains unknown. Our findings may be of considerable biologic, prognostic, and clinical significance. (JAMA. 1995;273:558-563)

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=jama&articleId=387010&pdfFileName=jama_273_7_030.pdf

Allele-specific chromosome 3p deletions occur at an early stage in the pathogenesis of lung carcinoma

The sequence of histological change induced by CO2 laser irradiation was discussed in terms of two factors: the physiomechanical factor and the physiochemical factor. At sufficiently high heat energy levels, the immediate findings are characterized by crater formation resulting from rapid vaporization of the water and ejection of the solid component. In the immediate vicinity of the crater edge, the maximum tissue temperature rise is 65 degrees C above the 32 degrees C ambient tissue temperature and it decreases to the primary tissue temperature within a distance of 2 mm. The healing process of CO2 laser induced lesions proceeds with minimal delay. The lymphatic and vascular channels are occluded in the marginal area of coagulation resulting in a marked hemostatic effect. This sealing effect increases the margin of safety in preventing possible dissemination of tumor cells. By selecting the appropriate power, time, and focus cone angle, precise destruction of preselected areas of tissue can be achieved with an extraordinary hemostatic effect without damaging the underlying tissue. These advantages are especially helpful in function-preserving surgery.

Laser surgery in otolaryngology: interaction of co2 laser and soft tissue

Field cancerization of the mucous membranes of the aerodigestive tract frequently develops in response to tobacco and alcohol usage; it is characterized by a variety of premalignant and frankly malignant epithelial changes that may lead to the development of multiple primary cancers of the aerodigestive tract. Field cancerization can be demonstrated by supravital staining with toluidine blue or by electron microscopic study of random biopsies taken from apparently normal mucosa. Field cancerization should be taken into account in treatment planning of a patient with cancer so that all treatment options, including the use of radiation therapy, be kept open for as long as possible in the event that the patient may develop multiple primary tumors.

Field cancerization in the aerodigestive tract--its etiology, manifestation, and significance.

THE EARLY diagnosis and management of carcinoma of the oral cavity and pharynx continues to present a great challenge. Carcinoma in an early stage of development is hard to detect because the lesion may be impalpable and the color changes not very different from the color of the surrounding mucosa. When the tumor is still intraepithelial, the only evidence may be an area of "erosion" where the thin covering layer of keratin or flattened cells is missing. Because carcinoma in the oral cavity, pharynx, and larynx is often multicentric in origin, it is common to find satellite tumors adjacent to the main tumor mass; the satellite tumor may be inconspicuous and overlooked during definitive therapy. Many carcinomas of the oral cavity start out as surface lesions which spread over the mucosa much more than they infiltrate1; the margins of the tumor may be hard to define, especially if there is

Toluidine blue in the management of carcinoma of the oral cavity.

Keratosis, atypia, carcinoma in situ, and microinvasive cancer occurring as white or red patches on the vocal cords are part of the diathesis of cancer of the aerodigestive tract and represented a sequential continuum. Excisional biopsy is the preferred treatment for identification and potential cure of the lesion. If the margins of excision are inadequate, further treatment options are either reexcision or radiotherapy. Radiotherapy should be used only when the need for voice conservation prevails. Cessation of smoking does not remove the potential for progression of the disease, therefore, all patients must be followed indefinitely. Excisional biopsy of keratosis, carcinoma in situ, and microinvasive cancer of the larynx offers an excellent prognosis for voice preservation and survival.

Natural history and management of keratosis, atypia, carcinoma-in situ, and microinvasive cancer of the larynx.

Since 1960, 15 patients with histologically proven inverted papilloma of the nose and paranasal sinuses have been treated at the University Hospital, City Hospital, and V. A. Hospital in Boston. Eight of these patients have been found to have squamous cell carcinoma in the pathological specimens; four of these patients have died of carcinoma. Wide surgical excision, usually through a lateral rhinotomy with exenteration of the invaded sinus as indicated, was the therapy of choice. In spite of the published incidence of carcinoma in inverted papilloma of approximately 7-24 per cent, we have found a much higher rate. We therefore, suggest that meticulous microscopic examination of multiple sections of inverted papilloma specimens be carried out in a search for evidence of squamous cell carcinoma. Inverted papilloma should be treated as a premalignant lesion by appropriate radical surgery.

Joseph Incze

Papers

Laser surgery in otolaryngology: interaction of co2 laser and soft tissue

Field cancerization in the aerodigestive tract--its etiology, manifestation, and significance.

Toluidine blue in the management of carcinoma of the oral cavity.

Natural history and management of keratosis, atypia, carcinoma-in situ, and microinvasive cancer of the larynx.

Inverted papilloma and squamous cell carcinoma.