Survival analysis in patients with cutaneous malignant melanoma

INTRODUCTION: Cutaneous malignant melanoma (MM) takes only 3% of all malignant tumours of the skin, but for reason of its increased frequency and pronounced tendency to rapid growth and metastases, it causes 60% of total lethal outcomes due to malignant tumours of the skin [1]. Primary MM is a diagnostic problem because of the great variety of its clinical features. Asymmetric configuration, irregular border, speckled color(r)diameter of more than 6 mm, and elevation of the surface, suggest suspicion of malignant alteration, but even then misdiagnosis is possible. For the final diagnosis of MM histopathological confirmation is necessary. The method to use is the extensive excisional biopsy of the lesion and its borders [2]. Histopathological diagnosis is based on microscopic findings which include: histogenetic type of MM, tumour thickness according to Breslow, level of invasion according to Clark, presence of ulceration, grade of lymphocyte infiltration, mitote rate, type of cells, presence of melanin in cells [2, 3]. PATIENTS AND METHODS: A five-year survival of patients with cutaneous malignant melanoma (MM) was studied according to sex, age and distinct features of the tumour: site, type of initial therapy, stage of the disease, time from the first signs of the disease to diagnosis of MM, histological findings (histogenetic type, Breslow's tumour thickness, Clark's level of invasion, presence of ulceration, degree of lymphocyte infiltration, number of mitoses, type of cells, intensity of pigmentation) and presence of metastases. The retrospective study included 336 patients with cutaneous MM. There were 185 female (55.1%) and 151 male patients (44.9%), aged 14-83 years, mean age 48.8 years, who were treated at the institute of Oncology and Radiology in Belgrade from 1978 to 1990. The mean follow-up was 60 months (1-144 months). Melanoma in situ had 16 (4.1%) patients. Stage I had 45 patients (14.1%), stage II 163 (48.5%), stage III 83 (24.7%) and stage IV 29 (8.6%) patients. Acral location on hands and feet had 40 (11.9%) patients, on head and neck 36 (10.7%), on the trunk 146 (43.5%) and on the extremities (except hands and feet) 114 (33.9%) patients. Nodular melanoma (NM) was the most frequent histogenetic type revealed in 150 (44.6%) patients, superficial spreading melanoma (SSM) in 105 (31.1%) patients, acral melanoma (AM) in 39 (11.5%) and lentigo malignant melanoma (LMM) in 32 (9.4%) patients (Table 1). Five-year survival rate was calculated according to Kaplan-Meier's method and significance of the difference between some categories was tested by Long-Rank's test; the significance less than 0.05 was accepted. RESULTS: Statistically highly significant differences in a five-year survival (p < 0.01) were related to sex p = 0.0005, age p = 0.0017, tumour site p = 0.0025, initial therapy p = 0.0036, stage of MM p = 0.0000, histological features of the tumour p = 0.0000 and presence of metastases p = 0.0000. A better five-year survival prognosis was found in female patients (64.5%) compared to male patients 44.5%, aged 27-46 years (87.3%) compared to patients younger than 26 years (43.5%); patients with melanoma on the extremities (except hands and feet) had a better five-year survival (66.7%) compared to patients younger than 26 years (43.5%); patients with melanoma on the extremities (except hands and feet) had a better five-year survival (65.7%) compared to patients with melanoma on the trunk or acral melanoma (47.3%). Higher survival was recorded in the group of patients with the tumour 1.5-3 mm thick, in whom the tumours was excised and regional nodes dissected as the primary therapy (66.9%) compared to those who underwent excision of the tumor only (48.8%). A five-year survival of patients with MM in situ was 100% for those in stage I; 85% in stage II; 42% in stage III, 16% and 0% in stage IV. The patients in whom the diagnosis of MM was established within 10 months after the first signs of the disease had significa     

Prediction of outcome for patients with cutaneous melanoma

Correct evaluation of the venous network before arterial revascularization is required to avoid unsuccessful explorations, underestimation of calibre because of spastic reactions to dissection and use of defective veins with unrecognized parietal or intraluminal lesions. The homolateral internal saphenous vein cannot be used in 10 to 30% of cases. Success of venous bypass is 30 to 40% greater than with prosthetic implants. Other veins can be used including the contralateral internal saphenous vein, external saphenous veins and veins from the upper limbs. Clinical evaluation is insufficient. Phlebography provides good results but is an aggressive exploration with certain limitations compared with duplex Doppler. Its potential complications are also absent with ultrasound exploration. Duplex Doppler is thus the first-line choice. Close coordination between the angiologist and the surgeon is essential to compare the exact measurements obtained preoperatively and the surgical findings, particularly concerning the venous calibre. Correction coefficients may then be established.     

Managing cutaneous melanoma

Cutaneous melanoma represents the main cause of death among skin cancers. Early diagnosis gives, for the time being, the only possibility for high rate of curative treatment. Diagnosis is based on pathological findings, and at primary tumor stage. Breslow thickness of the lesion is the best prognostic index. At local stage of the disease, treatment is precisely codified by international recommendations and consensus conferences. Follow-up after surgical treatment is also well codified. Treatment of lymph node invasion or metastatic disease is, on the other hand, less codified. Despite recent advances, especially in immunotherapy, treatment of advanced stages of melanoma remains difficult.     

Narrow resection of cutaneous melanoma

We report the case of a young pregnant woman with a malignant tumour of the kidney suggestive of oncocytoma. Because of the pregnancy, preoperative staging consisted of abdominal ultrasound and magnetic resonance imaging. Caesarean section was performed. Several days later, surgical exploration of the kidney was performed with tumourectomy and frozen section analysis: radical nephrectomy was finally performed. The definitive histology was chromophobe renal cell carcinoma. This is a rare tumour of the kidney, with its own characteristics allowing histopathological diagnosis and with a better prognosis than renal cell carcinoma. In the literature, pregnancy, a situation of immune depression, does not increase the prevalence of malignant neoplasms.     

Blockage of mesenteric lymphatic flow in rats

An experimental model of blockage of the mesenteric lymphatic flow (MLF) in rats was designed, and morphologic changes of mesenteric lymphatic vessels (MLV) and lymph nodes were investigated by mesenteric lymphangiography and histopathologic examination. Body weight in rats with blockage of MLF did not increase normally. Mesenteric lymphangiography revealed dilation of the MLV, reverse flow into the peripheral MLV, and leakage of contrast medium, resulting in chylous ascites. Remarkable dilation of the lymphatic sinuses and dilated and increased rough endoplasmic reticulum in lymphocytes in the mesenteric lymph nodes due to lymph stagnation were observed by light and electron microscopic examination, respectively.     

Molecular genetics of familial cutaneous melanoma

PURPOSE: A family history of melanoma is a significant risk factor for the disease, and recently several loci that determine susceptibility to the development of melanoma have been identified. The most important of these is p16/CDKN2A. We attempted to determine the degree to which the p16/CDKN2A gene has been implicated in the development of melanoma, and to identify other genetic factors that play a role as well. METHODS: We reviewed the literature published since the isolation of p16/CDKN2A and identified 13 studies that report the status of the gene in melanoma samples and 12 reports that examine p16/CDKN2A in melanoma kindreds. We also reviewed associated studies on CDK4 and RB1 involvement in melanoma, and examined the role of p16/CDKN2A in other inherited cancers. RESULTS: The evidence strongly implicates p16/CDKN2A in determining predisposition to malignant melanoma. Overall, approximately 20% of families that have been studied show mutations in the gene. However, because of clustering of sporadic cases in families, and potentially because of technical factors, this is likely an underestimate of the proportion of the genetic predisposition for melanoma that is due to p16/CDKN2A mutation. Rare families carry a mutated CDK4 gene that is also responsible for inherited melanoma. CONCLUSION: The gene p16/CDKN2A is an important determinant of melanoma risk. A commercial test is presently available to assess the status of this locus. However, because of uncertainties regarding the interpretation of the results of p16/CDKN2A genetic testing, we do not recommend routine clinical use of this test at this time.     

Clinical characteristics of early cutaneous melanoma

Clinical characteristics of the primary tumor in 786 patients with superficial spreading melanoma were studied in a prospective sequential series of patients from the Melanoma Clinical Cooperative Group. The most useful features for early diagnosis were change in size and change in color, present in 71% and 55% respectively of patients with level II lesions. Increase in height of lesion correlated with more advanced disease. Ulceration and bleeding were predominantly found in advanced primary lesions and are consequently of limited use in early recognition. Awareness of the historical and clinical features of the primary tumor should result in early recognition and cure of most primary superficial spreading melanomas.     

Urocanic acid isomers in patients with basal cell carcinoma and cutaneous malignant melanoma

Urocanic acid (UCA) is a major chromophore for ultraviolet (UV) radiation in the skin. On UV exposure, the naturally occurring trans-isomer converts to the cis-isomer in a dose-dependent manner. Accumulating evidence indicates that cis-UCA acts as an initiator of the UV-induced suppression of certain skin immune functions. This immunomodulation is recognized as an important factor in the development of skin cancer. In this study, pigmentation and UCA isomers were measured in 29 patients with previous basal cell carcinoma (BCC), 23 patients with previous cutaneous malignant melanoma (MM), and 32 healthy controls. Measurements were performed on UV-exposed (forehead, upper back) and UV non-exposed (buttock) skin. No significant differences in pigmentation percentage, total UCA concentration, relative (%) or absolute (nmol/cm2) cis-UCA concentration were observed between the groups in any of the body sites studied. The net production of cis-UCA after irradiation with a single test UV dose was evaluated. The relative production of cis-UCA following irradiation was significantly higher in both cancer groups when compared with the control group, while no significant difference was found between the BCC and the MM patients.     

Expression of apoptosis regulators in cutaneous malignant melanoma

Metastatic malignant melanoma (MM) is usually incurable and responds poorly to chemotherapy. Because many cytotoxic drugs cause cell death by inducing apoptosis, an imbalance of apoptosis regulatory proteins may contribute to MM treatment resistance. We have previously shown reduced expression of Bcl-2 protein, a negative regulator of apoptosis, in MM as compared with benign nevi. It is hypothesized that other apoptosis regulators may be involved in survival of MM cells. We examined the expression of Bax, Bcl-2, Bcl-X, and Mcl-1 in human benign nevi, primary MM, and metastatic MM using immunohistochemistry. Results were confirmed with Western blotting. The proapoptotic protein, Bax, was surprisingly overexpressed in all MM samples compared with benign nevi. Interestingly, in most MM samples there was overexpression of Mcl-1 or Bcl-XL, both negative regulators of apoptosis. Increased expression of Mcl-1 and Bcl-XL was first observed in thin primary melanomas, suggesting that up-regulation of these proteins represents a relatively early event associated with malignant transformation in MM. As published previously, the majority of primary and metastatic MM exhibited reduced Bcl-2 levels. We conclude that the apoptosis inhibitors Bcl-XL or Mcl-1, alone or in combination, may circumvent the normal cell death pathway, contributing to the pathogenesis and treatment resistance in metastatic MM.     

Epidemiology of primary cutaneous malignant melanoma in Jordan

Juvenile xanthogranuloma of parotid gland is reported in a 9-year-old boy. This kind of tumor is thought to be very rare in salivary glands. Histological, immunohistochemical and ultrastructural data showed characteristic features and excluded a Langerhans cell histiocytosis. Follow-up was uneventful after 18 months.     

The risk of subsequent primary carcinoma of the pancreas in patients with cutaneous malignant melanoma

BACKGROUND: Carcinoma of the pancreas is the fifth leading cancer in the U.S. and has the poorest survival rate of the major malignancies. Recent studies have reported an increased risk of carcinoma of the pancreas in malignant melanoma-prone kindreds and have suggested a link between malignant melanoma and pancreas carcinoma and mutations in the p16INK4 gene. This study evaluates the risk of carcinoma of the pancreas in a population-based cohort of patients with malignant melanoma. METHODS: The malignant melanoma patients were identified from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute. The cohort was followed within the SEER system to ascertain the occurrence of subsequent microscopically confirmed primary carcinoma of the pancreas from January 1973 through December 1993. The time of follow-up was expressed as person-years of observation. Standardized incidence ratios (SIR) and 95% confidence intervals (95% CI) were calculated. RESULTS: There were 43,781 malignant melanoma patients providing 263,528 person-years of follow-up. A nearly 2-fold increased risk of subsequent carcinoma of the pancreas in patients diagnosed with malignant melanoma before age 50 years was observed (SIR = 1.76; 95% CI = 0.80-3.34) and the greatest estimated risk occurred in young white females (SIR = 2.27; 95% CI = 0.73-5.30). CONCLUSIONS: These results provide some evidence in support of observations in recent studies that not only a family history of malignant melanoma but also malignant melanoma diagnosed at an early age may be associated with the subsequent development of carcinoma of the pancreas. Further research with larger numbers of melanoma patients is necessary to explore these potential associations.     

Complete regression of primary cutaneous malignant melanoma

While partial spontaneous histopathological regression is a common finding in invasive primary melanoma, proven complete regression is rare, with only 33 cases having been documented. None of the patients in these reported cases had a biopsy specimen taken from the original lesion, which would unequivocally prove the diagnosis of complete regressing melanoma. Over 4 years, we saw a 62-year-old white man who refused treatment of a biopsy specimen-proved superficial spreading melanoma (Breslow thickness, 0.7 mm) that eventually regressed completely. A biopsy specimen confirmed complete histopathological regression. There was no clinical evidence of regional or distant metastases throughout the 4 years. To our knowledge, this is the first documented case of a biopsy specimen-proved primary melanoma completely regressing. We present sequential photographic documentation and review the literature about this phenomenon. While the prevalence of such an event is unknown, evidence is presented that it may be more common than previously thought.     

Clinical diagnosis and therapy of cutaneous melanoma in situ

BACKGROUND: The frequency of in situ melanoma is increasing, and it is often diagnosed fortuitously by histology. METHODS: We retrospectively reviewed 121 melanomas in situ in 113 patients with the aim of identifying the clinical features of, and optimal surgical treatment for this cutaneous malignancy. Treatment was limited surgery with 3 mm margins of excision in 69 cases (57%) and wider margins of excision (more than 3 mm) in 52 cases (43%). The lesions had a median diameter of 1 cm (range, 2-35 mm) and were generally macular (92% of cases) asymmetric (87%), with an irregular border (88%) and nonuniform pigmentation (98%), usually in shades of brown (41%) and black (48%). These features had permitted a clinical diagnosis of melanoma or suspected melanoma in 62% of cases and of doubtful nevus in an additional 18% of cases. RESULTS: At a median follow-up of 4 years, there were six local recurrences (three treated by limited surgery and three by wider excision), all in situ melanomas. CONCLUSIONS: The typical clinical features of melanoma in situ, which are similar to those of early invasive melanoma, are usually sufficiently distinctive to suggest the clinical diagnosis of melanoma or suspected melanoma. Except for large size and superficially extended lesions (larger than 2 cm), adequate treatment is excision with 3 mm margins, although larger lesions (larger then 2 cm) may have an appreciable incidence of local recurrence.     

Technique of lymphatic mapping and sentinel node biopsy for melanoma

AIM: To evaluate the effect of PD Plus on weekly Kt/Vurea and creatinine clearance (Kcr) among patients undergoing CAPD/CCPD (continuous ambulatory peritoneal dialysis/continuous cyclic peritoneal dialysis). METHODS: The kinetic studies of 92 CAPD and 18 CCPD patients who transferred to PD Plus were analyzed. All patients underwent CAPD/CCPD and PD Plus for a minimum of 3 months. Standard collection methods were used and kinetic indices calculated with the Pack PD Kinetic Modeling program. 57 patients had transport data and were modeled for a target weekly Kt/Vurea >/=2.1 using PD Plus with /=2.1 and 47% a Kcr >/=60 liters/1.73 m2 with PD Plus, but only 20% did so with CAPD/CCPD. A close correlation between the supervised patients and modeled therapy was observed. CONCLUSIONS: Adequate dialysis is possible by using higher fill volumes, the supine position, and optimal dwell times (PD Plus) in most patients. The discrepancy between modeled and achieved dose is likely due to poor compliance with therapy, inadequate training, or poor specimen collection.     

Urinary flow rates in hypospadias

OBJECTIVES: To determine long-term results of patients who underwent primary ligament repair and delayed reconstruction for lateral ligament instability. DESIGN: Retrospective. SETTING: Outpatient clinic. PATIENTS/PARTICIPANTS: Patients who had undergone acute repair or delayed reconstruction at this institution between 1958 and 1977, excluding patients who were deceased or who could not be located. INTERVENTION: Forty-eight patients (fifty-three ankles) underwent twenty-two primary ligament repairs and thirty-one delayed reconstruction operations. MAIN OUTCOME MEASUREMENTS: Clinical results graded with clinical scale and radiologic results based on stress radiographs and plain film radiographs. RESULTS: At an average of twenty years after operation (range 12 to 33 years), patients were satisfied with forty-nine ankles, satisfied with reservations with two ankles, and dissatisfied with two ankles. Clinical results after repair were excellent in twenty ankles, good in one, fair in none, and poor in one. After reconstruction, the results were excellent in twenty-one ankles, good in six, fair in one, and poor in three. In the primary repair group, the mean talar tilt with stress testing improved from 20.7 +/- 10.7 degrees before operation to 2.8 +/- 3.0 degrees after operation. In the reconstruction group, the mean talar tilt improved from 20.7 +/- 8.4 degrees before operation to 2.8 +/- 3.5 degrees after operation. CONCLUSIONS: Clinical and radiologic results were similar in the repair and reconstruction groups. The majority of severe (Grade III) ankle sprains may be treated nonoperatively, but if residual instability occurs, late reconstruction should achieve satisfactory results.     

Metastatic cutaneous melanoma promoted by ultraviolet radiation in mice with transgene-initiated low melanoma susceptibility

An inbred-strain (C57BL/6) transgenic (Tyr-SV40E) mouse model of ultraviolet radiation (UVR)-induced metastatic cutaneous melanoma was produced without the use of chemical carcinogens and without resulting in other skin malignancies. Expression of this transgene occurs specifically in melanocytic-lineage cells. In untreated hemizygous mice of transgenic line 12 there are no skin melanomas, and the oncogenic sequence, which is expressed at a very low level, functions solely as a weak initiating stimulus. UVR [including 65% ultraviolet B (280-320 nm wavelength)] supplied the necessary promoting stimulus leading to melanomas. Of various trial protocols, eight were successful and involved exposure of 112 mice for a limited time on each of 3-10 days starting at 2-3 days of age and totalling 1.1-3.7 J/cm2 UVR. Fourteen of these animals developed a total of 15 invasive skin melanomas on the head and body, arising between 37-115 weeks of age and, therefore, often after a relatively long latency. The tumors were melanotic and in five of the mice they yielded macrometastases in regional and distant sites. The single most favorable protocol (1.9 J/cm2 total UVR, at 0.38 J/cm2/day for 5 days starting at 3 days of age) led to the highest incidence of melanoma (5 of 19 mice) and one of the lowest mortality rates (2 of 19). No melanomas occurred in UVR-treated nontransgenic C57BL/6 controls. Benign skin keratoacanthomas arose and often regressed in treated transgenic as well as nontransgenic mice. This new transgenic mouse model introduces many novel possibilities for experimental analysis of the melanoma-promoting mechanisms of UVR and also of the ability of specific genetic changes to impede or facilitate the UVR effect.     

Importance of microscopic vascular invasion in primary cutaneous malignant melanoma

Invasion into blood vessels by malignant melanoma at the primary cutaneous site is a superior discriminant for an adverse prognosis. However, until the question of relative prognostic values is resolved conclusively, surgical pathologists should document the collection of histopathologic observations recommended by McGovern and co-conferees.     

Analysis of p53 in human cutaneous melanoma cell lines

Mutations in the p53 tumour suppressor gene have been detected in a variety of human malignancies. Mutations have been found predominantly in conserved regions two to five. Our aim was to analyse p53 at the protein and DNA level in seven melanoma cell lines of cutaneous origin (HMB-2, DX3, LT5.1, MJM, SK23, A375P and A375M), including two parental/metastatic derivatives (A375P and A375M; DX3 and LT5.1). By immunohistochemical staining with three mouse monoclonal antibodies and a rabbit polyclonal serum, it was possible to observe differential nuclear expression of p53. The quantitation of p53 protein levels by ELISA correlated with the nuclear staining pattern. Western blotting showed an intact p53 protein in all cell lines; p53 was polymorphic in three cell lines (MJM, A375P and A375M). DNA sequencing studies showed that all cell lines had wild type p53. These results suggest that p53 is unlikely to play a significant role in the genesis of cutaneous melanoma.