[Evidence of a modification of the profile of addictive drugs consumption through the study of patients consulting a psychiatric emergency room]. / Mise en evidence d'une modification des habitudes de consommation de substances psychoactives au travers du suivi d'une activité d'urgence psychiatrique.

The consumption of psychoactive drugs is frequently the reason of consultation in a psychiatric emergency unit. We present here the evolution over time of the consumption pattern of patients consulting the psychiatric emergency unit of the Brugmann University Hospital. Major modifications were observed during this period. Mainly, problematic consumption of opiates was progressively overwhelmed by this of cannabis, psychostimulants and recently synthesis drugs. We suggest that this reflects the situation of psychoactive drugs consumption in the general population. This implicates a modification of prevention and treatment attitudes in drug consuming persons.

Overexpression of p53 is a late event in the development of malignant melanoma.

Overexpression of the p53 gene product has been observed in a high percentage of malignant melanomas. To evaluate the role of this protein in the development of melanoma, we examined p53 expression in benign, premalignant, and malignant melanocytic lesions. Using the antibodies DO-7 and 1801, which recognize both wild-type and most mutant forms of the p53 protein, we analyzed by immunohistochemical staining 26 benign nevi, 34 dysplastic nevi from patients at low risk for the development of melanoma, 22 dysplastic nevi from patients at high risk for the development of melanoma, 61 primary melanomas (including 15 that arose from dysplastic nevi), and 10 metastatic melanomas. Expression of the p53 protein was not observed in any of the benign or dysplastic nevi. Of the primary melanomas only 3 (5%) demonstrated nuclear staining, whereas 70% of the metastatic melanomas showed a positive reaction for p53. These data suggest that overexpression of the p53 gene product is a late event in the progression of melanoma and consequently indicate that expression of this protein cannot be used as a marker to identify patients at high risk for the subsequent development of melanoma.

Lack of germline CDK6 mutations in familial melanoma.

Germline mutations in genes encoding several components of the retinoblastoma pathway have been linked with inherited predisposition to melanoma. Most commonly, such mutations involve CDKN2A, a cyclin-dependent kinase inhibitor of two kinases, CDK4 and CDK6, which phosphorylate the retinoblastoma protein (pRB) and thereby promote passage through the G1/S cell-cycle restriction point. Less frequently, germline mutations in the CDK4 gene have also been linked with an increased risk of melanoma. Despite the sequence and functional homology between CDK4 and CDK6, the role of germline mutations in CDK6 in melanoma predisposition is unknown. We detected no CDK6 mutations within the p16 (CDKN2A) binding domain in index cases from 60 melanoma-prone kindreds that lacked germline mutations in the coding regions of either CDKN2A or within the entire CDK4 coding region. We conclude that germline mutations in CDK6 do not make a significant contribution to melanoma predisposition.

MIB-1 proliferative activity is a significant prognostic factor in primary thick cutaneous melanomas.

Although the Breslow measurement of tumor thickness of melanoma is the most significant predictor of survival, the biologic behavior of thick lesions remains unpredictable. MIB-1, a monoclonal antibody to a Ki-67 epitope, recognizes all proliferating cells. Unlike Ki-67 antibody, which requires frozen tissue, MIB-1 can be used on formalin-fixed tissue. Proliferation, measured by MIB-1 expression and mitotic index, was assessed as a prognostic factor in a group of patients with clinical stage I thick cutaneous melanoma (tumor thickness 4 mm or greater), for which predicted survival is low. From a melanoma data base, 97 patients with this type of melanoma were identified. Of these, 64 had lesional tissue available for study. The median follow-up time was 3.8 years (range 0.42-13.6 years). The percentage of MIB-1 reactivity was scored as low at less than 10% (n = 33), intermediate at 10% to 20% (n = 17), and high at greater than 20% (n = 14). Melanomas with high MIB-1 reactivity were associated with significantly poorer cause-specific survival compared with tumors with intermediate (p < 0.0001) or low MIB-1 reactivity (p = 0.0025). Multivariate analysis demonstrated that MIB-1 reactivity was a significant independent prognostic factor related to cause-specific survival (p = 0.0002) and was more sensitive than tumor thickness or mitotic index in this select group of high-risk patients. Identification of individuals with stage I thick cutaneous melanoma who are at risk of recurrent disease may improve patient management as new therapeutic modalities become available.

Tenascin differentiates dermatofibroma from dermatofibrosarcoma protuberans: comparison with CD34 and factor XIIIa.

Differentiation of dermatofibroma (DF) from dermatofibrosarcoma protuberans (DFSP) can be difficult. CD34 and Factor XIIIa have been used to differentiate DF from DFSP. However, there is overlap and lack of specificity of their expression. Tenascin is an extracellular matrix glycoprotein that is involved in embryogenesis, carcinogenesis, and wound healing. The aim of the study was to assess the role of tenascin in DF and DFSP and compare the results with those obtained with CD34 and Factor XIIIa. Immunohistochemical staining was performed on 20 cases each of DFSP and DF, using antibodies to tenascin, CD34 and Factor XIIIa, and the streptavidin biotin technique. Positivity for all 3 antibodies was assessed within the tumors. Tenascin expression was also assessed at the dermal-epidermal junction. Strong tenascin positivity was noted at the dermal-epidermal junction overlying the lesion in 20 of 20 cases of DF (100%) and was negative over the lesion in 20 of 20 cases DFSP (100%). Tenascin was noted within the lesion of 80% of both DF and DFSP (16/20 cases). CD34 was strongly expressed in 16 of 20 (80%) DFSP and 5 of 20 (25%) DF, whereas Factor XIIIa was strongly expressed in 19 of 20 (95%) DF and 3 of 15 (15%) DFSP. Although CD34 was expressed in 80% DFSP and Factor XIIIa in 95% of DF, there was overlap in their expression in the 2 types of tumors. The increased expression of tenascin at the dermal-epidermal junction overlying the lesion in DF but not in DFSP, differentiated these 2 tumors. In contrast, tenascin expression within the lesion did not differentiate DF from DFSP.

Origin of the desmoplasia in desmoplastic malignant melanoma.

Four cases of desmoplastic malignant melanoma were examined light microscopically and immunohistochemically. Electron microscopy was performed in three cases. Light microscopy showed that all tumors were composed of neoplastic spindle cells that infiltrated between mature collagen bundles in the reticular dermis. Some of the spindle cells had bizarre nuclei, whereas other spindle cells resembled normal fibroblasts. Melanin could not be demonstrated in any of the tumors by histochemical techniques. Electron microscopic examination of the spindle cells showed prominence of rough endoplasmic reticulum, which was dilated and filled with flocculent material and occasional collagen fibrils. The same cells contained aggregates of non-membrane-bound melanin granules and pre-melanosomes. Some cells also showed features of myofibroblasts. Immunoperoxidase staining with anti-S100 protein antibody demonstrated positivity of the spindle cells as well as of melanocytes in the basal layer of the epidermis. Scar tissue and fibroblasts did not stain. These findings show that the desmoplastic component of these malignant melanomas derives from melanocytes that have undergone adaptive fibroplasia. Therefore, in assessing depth of invasion in a malignant melanoma, measurements should include the desmoplastic areas.

Atypical Spitz nevi/tumors: lack of consensus for diagnosis, discrimination from melanoma, and prediction of outcome.

The biological nature of Spitz nevi/tumors and their diagnostic distinction from, or relationship to, melanoma remain unresolved issues. In this report, a series of 30 melanocytic lesions removed from 28 patients, including atypical Spitz nevi/tumors and metastasizing Spitzoid tumors/melanomas, were evaluated by a panel of dermatopathologists to evaluate interobserver diagnostic concordance and to assess the prognostic power of histological criteria. For inclusion in the study, each lesion had to display some criteria for the Spitz nevus, and in addition one of the following was required: (1) definitive clinical outcome such as metastasis or death of disease, or (2) long-term follow-up if the patient remained disease free. Each lesion was reviewed independently and blinded as to the clinical data by 10 pathologists, who categorized them as (1) typical Spitz nevus/tumor, (2) atypical Spitz nevus/tumor, (3) melanoma, (4) tumor with unknown biological potential, or (5) other melanocytic lesion. There was limited discussion of criteria before the review. Evaluation of 17 Spitzoid lesions yielded no clear consensus as to diagnosis; in only one case did six or more pathologists agree on a single category, regardless of clinical outcome. Notably, however, some lesions that proved fatal were categorized by most observers as either Spitz nevi or atypical Spitz tumors. Conversely, seven or more pathologists scored 13 lesions as melanoma. These results illustrate (1) substantial diagnostic difficulties posed by many Spitz tumors, especially those with atypical features, even among experts, and (2) the lack of objective criteria for their distinction from melanoma and for gauging their malignant potential. Nevertheless, our observations do suggest that a biological relationship exists between the Spitz nevus/tumor and melanoma.

The effects of open leaf burning on spirometric measurements in asthma.

The purpose of our study was to determine the effects of open leaf burning on asthmatic subjects. Seven subjects with known asthma of varying severity, along with three normal control subjects, were walked 0.5 mile with and without exposure on the same day, under very similar environmental conditions. An acute spirometric broncho-constrictive response was observed within 30 min of exercise with exposure to leaf burning in two of the seven asthmatic subjects. Five of the seven showed an overall drop in parameters measured. No significant change in the FEV1 was seen in the normal subjects with either protocol, nor in the asthmatic subjects during low level exercise alone. The results of our study suggest that open leaf burning under normal community-allowed conditions may represent a significant health hazard for some asthmatic subjects.

Palisaded encapsulated neuromas. A clinicopathologic study.

Reed et al described the clinical and light-microscopic findings of palisaded encapsulated neuromas in 1972, but few cases have been reported since. We have studied 81 consecutive tumors. Clinically, these were solitary, asymptomatic, 2- to 6-mm, flesh-colored papules, usually located on the face of middle-aged patients. The correct diagnosis was rarely made; the lesion was most often mistaken for a basal cell epithelioma, melanocytic nevus, or other benign tumor. Light microscopy revealed single or multiple encapsulated dermal lobules composed of interlacing Schwann cells. Variable numbers of fine axons and myelin sheath remnants were present. Palisading of nuclei was not a prominent feature. Electron microscopy demonstrated substantial numbers of class C fibers (mostly nonmyelinated) only partially enveloped by Schwann cell cytoplasm. Pathologically, palisaded encapsulated neuromas are distinctive true neuromas resembling those seen in the multiple mucosal neuroma syndrome. Electron-microscopic findings are similar to those seen in peripheral nerve regeneration, suggesting that palisaded encapsulated neuromas may be traumatic in origin, and could represent regeneration following local minor injury to the skin.

Removal of congenital nevi--cons.

Reviews of the literature support the view that melanomas arise in LCHN as well as other types of nevi and normal skin. The cases reported in the literature show a pediatric predominance. It is impossible to develop predictable figures by combining incidences of nevi with historical data from case reports. A long-term registry and follow-up are needed. In the meantime, each case should be treated individually, keeping in mind that especially in LCHN, it may be impossible to remove all melanocytes both in skin and in the CNS. Associated neuromelanosis may be present. Whether or not surgery is done, the patient must be carefully followed. Large nevi may be observed and changes that are noted should be biopsied early. Even with biopsy, the diagnosis may be unclear because some changes may be pseudomalignancies rather than true malignancies. Parents of infants should be informed of all possibilities and the complications of surgery adequately outlined. The adult with a LCHN should be informed that there is some risk. (It has been our experience that most adults prefer cosmetic revision of small areas and elect observation rather than excision.) As new techniques such as tissue expanders and more refined investigations to delineate extent of the nevus are found, it may be possible to adequately ablate more lesions in the future if a prospective study shows a convincing incidence of melanoma.

Diagnosis and management of long-standing benign oral ulceration.

The authors formed a Mouth Clinic at Sunnybrook Hospital in 1973 since when there have been 3025 patient visits. Those patients with chronic ulceration present a challenge, the diagnosis sometimes being difficult and therapy not rapidly effective. The differential diagnosis includes lichen planus, pemphigus vulgaris, benign mucous membrane pemphigoid, discoid lupus erythematosus, erythema multiforme, aphthous ulcers, Behcets disease, periadenitis mucosa necrotica recurrens, specific infections and iatrogenic causes. It is possible to reach a definite diagnosis in virtually every case by means of a good history and careful clinical examination supplemented by biopsies and in some cases direct and indirect immunofluorescent studies. Treatment emphasizes scrupulous attention to oral hygiene with baking soda mouthwashes and careful teeth cleaning to minimize the accumulation of dental plaque. Specific therapy includes topical steroids in lichen planus, intra muscular gold in benign mucous membrane pemphigoid, a previously unreported treatment which considerably improved seven out of ten patients, and tetracycline mouthwashes in aphthous ulcers.

Ultrasound backscatter microscope analysis of mouse melanoma progression.

The incidence and mortality rate of cutaneous melanoma continue to increase throughout the world, making the study of melanoma biology an important area of current research. While recent breakthroughs in transgenic mouse technology have led to promising mouse skin models of melanoma, there is presently no technique available for quantitatively studying subsurface melanoma progression, in vivo. We demonstrate the first application of an imaging method called ultrasound backscatter microscopy (UBM) for imaging early murine melanomas with spatial resolution of 30 microns axial and 60 microns lateral. Murine B16 F10 melanomas have been imaged from their earliest detection, over several days, until they are 2 to 5 mm in diameter. Melanoma dimensions measured by UBM were found to be in excellent agreement with those determined histopathologically on the excised tumours. The relative rms errors in UBM-determined melanoma height and width were found to be 8.7% and 4.2%, respectively. The mean rate of increase in tumour height of early murine melanoma was found to be 0.37 +/- 0.06 mm/day. Computer-generated volumetric renderings of melanomas have been produced from three-dimensional image data, allowing quantitative comparisons of tumour volumes to be made. Using a priori assumptions of ellipsoid tumour shape, the relative error in UBM-determined volume was shown to be less than 17%. These results should be of considerable interest to investigators studying melanoma biology using mouse skin models, and have implications in the use of high frequency ultrasound imaging for the clinical assessment of cutaneous melanoma.

A 40-100 MHz B-scan ultrasound backscatter microscope for skin imaging.

There is a growing interest in high resolution, subsurface imaging of cutaneous tissues using higher frequency ultrasound, and several commercial systems have been developed recently which operate at 20 MHz. Some of the possible applications of higher frequency skin imaging include tumour staging, boundary definition, and studies of the response of tumours to therapy, investigations of inflammatory skin conditions such as psoriasis and eczema, and basic studies of skin aging, sun damage and the effects of irritants. Investigation of these areas is quite new, and the role of ultrasound skin imaging is continuing to evolve. Lateral resolution in the 20 MHz imaging systems ranges from 200 to 300 microns, which limits imaging applications to cutaneous structures which are relatively large in size. In this paper, a real-time ultrasound backscatter microscope (UBM) for skin imaging is described which operates in the 40-100 MHz range, providing axial resolution between 17 and 30 microns and lateral resolution between 33 and 94 microns. This improvement in resolution over current skin ultrasound systems should prove useful in determining the margins of small skin lesions, and in obtaining more precise, in vivo skin thickness measurements to characterize nonmalignant skin disease. Example images of normal skin, seborrhoeic keratosis and malignant melanoma illustrate the imaging potential of this system.

Poorly differentiated skin tumors. Beyond hematoxylin-and-eosin staining.

Although many tumors may be diagnosed by light microscopy alone, a few require further investigation. Selective use of antibodies by immunohistochemical techniques solves most diagnostic problems. The explosive discovery of many new antibodies often raises more questions than it answers, and electron microscopy still plays a significant role when used judiciously. It is important to recognize that every new antibody must be adequately assessed in the clinical situation and that its specificity, or lack thereof, is appreciated by both clinician and pathologist. With every new antibody, we increase our knowledge of basic disease processes. In the future, antibodies will be part of the pathologist's armamentarium for predicting disease outcomes. Not only will the cell of origin be identified but proliferation rates and production of various factors that influence metastatic potential will be delineated.

Predictive value of staging investigations in patients with clinical stage I malignant melanoma.

We reviewed the charts of 393 consecutive patients referred to the Toronto-Bayview Regional Cancer Centre and the Ontario Cancer Institute between January 1, 1978, and December 31, 1982, with clinical stage I malignant melanoma to determine the predictive value of routine staging investigations. The investigations reviewed included physical examination, liver function tests, radionuclide liver-spleen and bone scans, chest x-ray, whole-lung tomograms, CT chest scans, CT brain scans, and bipedal lymphangiograms. The clinical stage of nine patients was changed, eight as a result of physical examination and one as a result of lymphangiogram. No other investigations detected metastatic melanoma at referral. We recommend that staging investigations for patients referred with clinical stage I malignant melanoma be restricted to a complete physical examination and a baseline chest x-ray for all patients.

Role of immunohistochemistry in the diagnosis of undifferentiated tumors involving the skin.

Twenty undifferentiated skin tumors were examined by immunostaining in an attempt to achieve more precise identification. Light microscopy yielded only a differential diagnosis, whereas immunostaining of formalin-fixed, paraffin-embedded tissue sections with a panel of antibodies to intermediate filaments and other cell components led to a definitive diagnosis. Four cytokeratin-positive epithelial tumors were subtyped into squamous cell carcinomas and adenocarcinomas with the use of antibodies to different cytokeratin polypeptides. Fifteen vimentin-positive tumors were subdivided into malignant melanomas with the use of antibody to S-100 protein, lymphomas with the use of antibody to immunoglobulin, and mesenchymal tumors (angiosarcomas, atypical fibroxanthomas, dermatofibrosarcoma protuberans, and meningiomas) with the use of antibody to S-100 protein, factor VIII, and lysozyme. One desmin-positive tumor was diagnosed as a leiomyosarcoma of the skin. A scheme is presented for using immunohistochemistry to facilitate the diagnosis of undifferentiated tumors involving the skin.

Profile of malignant disease in the mouth clinic.

Between 1973 and 1981, 2,056 new patients were seen in the Mouth Clinic at Sunnybrook Hospital. Of these 109 proved to have malignant disease, with squamous cell carcinoma being the commonest type. Lower lip and floor of mouth were the most frequent sites. There was a high proportion of small tumors and local surgical excision was the most widely employed primary method of treatment. Radiation and combined treatment were used in larger lesions. Twenty-four patients have so far died of mouth cancer and the presence of enlarged lymph nodes at presentation was an ominous sign. Although containing the usual high proportion of heavy smokers and drinkers this group of patients at present exhibits a lower incidence of second primary malignancies than in some published series. It is concluded that surgery and radiotherapy have equivalent effectiveness in treating small primary lesions, where a policy of observation of the clinically negative neck appeared justified. The best treatment for large lesions and the most appropriate management of the clinically negative neck in intermediate size lesions has not been determined.

Lichen amyloidosus. Ultrastructure and pathogenesis.

The ultrastructure of six cases of lichen amyloidosus was studied with special attention to epidermal keratinocytes and the role of tonofilaments as precursors of fibrils of amyloid. Through the process of apoptosis, keratinocytes undergo degeneration and become filamentous cells and then filamentous masses or Civatte bodies. These bodies then drop into the dermis through a damaged basement membrane. In the papillary dermis, islands of amyloid become closely associated with Civatte bodies. In some cases, conversion to straight nonbranching filaments, characteristic of fibrils of amyloid, was found within whorled, densely packed filamentous masses. The transformation into fibrils of amyloid was not observed in keratinocytes or Civatte bodies situated in the epidermis. This final step of conversion may be aided by dermal fibroblasts that are frequently lodged around deposits of amyloid.