Ulf Ellwanger

Tumor Lymphangiogenesis : A Novel Prognostic Indicator for Cutaneous Melanoma Metastasis and Survival

Malignant melanomas of the skin are distinguished by their propensity for early metastatic spread via lymphatic vessels to regional lymph nodes, and lymph node metastasis is a major determinant for the staging and clinical management of melanoma. However, the importance of tumor-induced lymphangiogenesis for lymphatic melanoma spread has remained unclear. We investigated whether tumor lymphangiogenesis occurs in human malignant melanomas of the skin and whether the extent of tumor lymphangiogenesis may be related to the risk for lymph node metastasis and to patient survival, using double immunostains for the novel lymphatic endothelial marker LYVE-1 and for the panvascular marker CD31. Tumor samples were obtained from clinically and histologically closely matched cases of primary melanomas with early lymph node metastasis (n = 18) and from nonmetastatic melanomas (n = 19). Hot spots of proliferating intratumoral and peritumoral lymphatic vessels were detected in a large number of melanomas. The incidence of intratumoral lymphatics was significantly higher in metastatic melanomas and correlated with poor disease-free survival. Metastatic melanomas had significantly more and larger tumor-associated lymphatic vessels, and a relative lymphatic vessel area of >1.5% was significantly associated with poor disease-free and overall survival. In contrast, no differences in the density of tumor-associated blood vessels were found. Vascular endothelial growth factor and vascular endothelial growth factor-C expression was equally detected in a minority of cases in both groups. Our results reveal tumor lymphangiogenesis as a novel prognostic indicator for the risk of lymph node metastasis in cutaneous melanoma.

Metastatic pathways and time courses in the orderly progression of cutaneous melanoma

Summary Background  It is known that two‐thirds of patients who develop clinical metastases following treatment of a primary cutaneous melanoma initially present with locoregional metastases and one‐third initially present with distant metastases. However, few reports in the literature give detailed figures on different metastatic pathways in cutaneous melanoma.

Prospective Evaluation of a Follow-Up Schedule in Cutaneous Melanoma Patients: Recommendations for an Effective Follow-Up Strategy

PURPOSE To prospectively examine and evaluate the results of follow-up procedures in a large cohort of cutaneous melanoma patients. PATIENTS AND METHODS This was a prospective study in 2,008 consecutive patients with stage I to IV cutaneous melanoma from 1996 to 1998 on the yield of stage-appropriate follow-up examinations according to the German guidelines. Documentation of patient and follow-up data comprised patient demography, primary tumor specifics, and any clinical and technical examinations performed. The detection of metastasis was classified as early or late, and the means of their detection and the resulting overall survival probabilities were examined. RESULTS A total of 3,800 clinical examinations and 12,398 imaging techniques were documented. Sixty-two second primary melanomas in 46 patients and 233 disease recurrences in 112 patients were detected during this time. In stage I to III disease, physical examination was responsible for the discovery of 50% of all recurrences. In the primary tumor stages, 21% of all recurrences were discovered by lymph node sonography, with the majority being classified as early detection. Forty-eight percent of the recurrences were classified as early detection, and these patients had a significant benefit of overall survival probability. CONCLUSION The results of our study suggest that an elaborated follow-up schedule in cutaneous melanoma is suitable for the early detection of second primary melanomas and early recurrences. The intensity of clinical and technical examinations can be reduced during follow-up of patients in the primary tumor stages and may be intensified in locoregional disease. Recommendations for an effective follow-up strategy are outlined.

Digital image analysis for diagnosis of cutaneous melanoma. Development of a highly effective computer algorithm based on analysis of 837 melanocytic lesions.

Background  Digital image analysis has been introduced into the diagnosis of skin lesions based on dermoscopic pictures.

Diagnostic value and prognostic significance of protein S-100β, melanoma-inhibitory activity, and tyrosinase/MART-1 reverse transcription-polymerase chain reaction in the follow-up of high-risk melanoma patients

Cutaneous melanoma is the most aggressive form of skin carcinoma in humans, frequently with a rapid progression of disease. To detect early developing metastasis, laboratory tests to determine levels of lactate dehydrogenase (LDH) and alkaline phosphatase (AP) form part of the regular follow‐up, but often cannot discover recurrent disease at a sufficiently early stage.

Prognostic impact of the type of anaesthesia used during the excision of primary cutaneous melanoma.

&NA; The prognostic value of the type of anaesthesia used for the excision of malignant tumours has been a subject of controversy. Cell‐mediated as well as humoural immune responses can be compromised after general anaesthesia, and recurrences may therefore occur more frequently. On the other hand, excision of primary tumours under local anaesthesia might also influence the prognosis unfavourably. The aim of the present study was to determine the prognostic impact of general and local anaesthesia for the primary excision of cutaneous melanoma. Follow‐up data of 4329 patients on the Central Melanoma Registry of the German Dermatological Society were analysed. Cox proportional hazards analysis was performed to evaluate the independent significance of the prognostic factors, and survival probabilities were calculated for matched pairs using Kaplan‐Meier estimates. Statistical analysis revealed an independent significant effect on survival for tumour thickness, ulceration, level of invasion, anatomical site and gender. General anaesthesia for primary excision of melanoma was associated with a decrease in the survival rate (relative risk 1.46, P < 0.0001). This study revealed a slight but significantly increased risk of death for patients treated with general anaesthesia for the primary excision of melanoma. Therefore local anaesthesia should be preferred for the treatment of primary melanoma.

Detection of melanoma micrometastasis in sentinel nodes by reverse transcription-polymerase chain reaction correlates with tumor thickness and is predictive of micrometastatic disease in the lymph node basin.

The sentinel node has been reported to be representative for the presence or absence of metastatic melanoma in the draining lymph node basin. In this study, for the first time sentinel nodes and adjoining nonsentinel nodes were analyzed for micrometastatic disease using tyrosinase reverse transcription-polymerase chain reaction (RT-PCR) in comparison with standard immunohistochemistry. Successful identification of the sentinel nodes using a gamma probe-guided surgery was achieved in 73 (92%) of 79 patients with cutaneous stage I and II melanoma (tumor thickness > or =0.75 mm). A total of 794 regional lymph nodes, 148 sentinel nodes, and 646 adjoining nonsentinel nodes were evaluated. Tyrosinase RT-PCR was shown to increase the sensitivity for melanoma cell detection in sentinel nodes significantly (49% positivity) as compared with immunohistochemistry using antibodies against HMB-45 antigen and S-100 protein (18% positivity). Examination of sentinel nodes was highly predictive in determining the presence of regional lymph node micrometastasis by immunohistochemistry (99%) and RT-PCR (89%). Interestingly, detection of nodal micrometastasis by RT-PCR showed a strong positive correlation with tumor thickness of primary cutaneous melanoma. These results suggest the clinical significance and emphasize the importance of tyrosinase RT-PCR for detection of melanoma micrometastasis in sentinel nodes.

LYMPH NODE MICROMETASTASES OF CUTANEOUS MELANOMA: INCREASED SENSITIVITY OF MOLECULAR DIAGNOSIS IN COMPARISON TO IMMUNOHISTOCHEMISTRY

The presence of regional lymph node metastases is one of the most significant prognostic factors for predicting survival in patients with clinical stage I or II cutaneous melanoma. For accurate staging of the primary tumor a sensitive technique is required to detect occult nodal micrometastases. This prospective diagnostic study was designed to evaluate the incidence of nodal micrometastases using nested reverse transcription‐polymerase chain reaction (RT‐PCR) for tyrosinase in comparison to immunohistochemical examination. Furthermore, the incidence of melanoma micrometastases detected by RT‐PCR was analysed in correlation to major prognostic factors. A total of 466 regional lymph nodes from 79 patients with primary cutaneous melanoma (tumor thickness > 0.75 mm) were investigated. In 49 lymph nodes from 31 patients immunohistochemistry demonstrated melanoma metastases. Using tyrosinase RT‐PCR, nodal micrometastases were detected in 136 lymph nodes from 52 patients including all lymph nodes positive by immunohistochemical examination. Out of the 417 lymph nodes negative by immunohistochemistry, 87 nodes (21%) were identified to express tyrosinase by the RT‐PCR technique. Among the 48 patients negative by immunohistochemical assessment, 21 (44%) had nodal micrometastases (n = 40) using RT‐PCR. All 68 lymph nodes from 46 non‐melanoma patients serving as negative controls for tyrosinase RT‐PCR were negative. The detection of melanocytic nodal micrometastases by tyrosinase RT‐PCR is a highly specific method with a sensitivity significantly higher than that achieved by immunohistochemistry (p < 0.0001). Patients with nodal micrometastases identified exclusively by RT‐PCR had significantly higher tumor thickness as compared to patients with negative results by RT‐PCR (p < 0.01). Int. J. Cancer (Pred. Oncol.) 79:318–323, 1998.

Das Zentralregister Malignes Melanom der Deutschen Dermatologischen Gesellschaft in den Jahren 1983–1993 Epidemiologische Entwicklungen und aktuelle therapeutische Versorgung des malignen Melanoms der Haut**

ZusammenfassungDas Zentralregister Malignes Melanom der Deutschen Dermatologischen Gesellschaft hat seine Arbeit 1983 aufgenommen und sich seitdem zu einem kontinuierlich fortgeführten multizentrischen Projekt entwickelt. Insgesamt wurden bis Juni 1994 die Daten von 19.250 Patienten aus 41 Kliniken der alten Bundesländer, 14 Kliniken der neuen Bundesländer, zwei Kliniken aus Österreich und einer Klinik aus der Schweiz gemeldet. Die Auswertung der Daten läßt mehrere epidemiologische Trends im Zeitraum von 1983–1993 erkennen. a) Es fand sich eine kontinuierliche Zunahme des Anteils der Männer an den Melanom-Patienten, der im Mittel von 38% im Jahre 1983 auf 46% im Jahre 1993 anstieg. b) Die Früherkennung maligner Melanome wurde im untersuchten Zeitraum verbessert. Die Diagnosen im Stadium des Primärtumors stiegen im untersuchten Zeitraum an. Die mittlere Tumordicke nach Breslow nahm in den alten Bundesländern von 1,8 mm auf 1,3 mm und in den neuen Bundesländern von 2,5 mm auf 1,7 mm ab. Entsprechend verringerte sich der Anteil nodulärer Melanome in den alten Bundesländern im Mittel von 29,3% auf 14,1% und in den neuen Bundesländern von 40,6% auf 22,6%. In den Jahren 1990–1993 wurden in den alten Bundesländern 64% und in den neuen Bundesländern 34,2% aller primären malignen Melanome zweizeitig operiert. Insgesamt wurden 73,7% der Patienten in Lokalanästhesie operiert. In den letzten Jahren wurde vermehrt in Lokalanästhesie und zweizeitig operiert, wobei entsprechend der Abnahme der Tumordicke die endgültige Versorgung häufiger mit kleinerem Sicherheitsabstand erfolgte. Die vorliegende Analyse zeigt, daß das Zentralregister Malignes Melanom ein wichtiges Instrument zur Untersuchung von Entwicklungen der klinischen Epidemiologie und der Therapie des malignen Melanoms im deutschsprachigen Raum ist.SummaryThe Central Malignant Melanoma Registry of the German Dermatological Society was founded in 1983 and has meanwhile developed into a major continuously updated multicentre project. Up to June 1994, 19250 reports of cutaneous melanoma had been received, from 41 departments of dermatology in the former Federal Republic of Germany, from 14 departments in the former German Democratic Republic, from 2 departments in Austria, and from 1 department in Switzerland. Analysis of the data revealed some epidemiological trends over time during the years 1983 to 1993. (1) During the last 10 years the percentage of male patients has steadily increased, from an average of 38% in the year 1983 to 46% in 1993. (2) Early diagnosis of malignant melanoma improved during the period of time investigated. The percentage of diagnoses of primary tumour alone increased between 1983 and 1993. The mean tumour thickness (Breslow) decreased in the West Germany from 1.8 mm to 1.3 mm and in East Germany from 2.5 mm to 1.7 mm. The proportion of nodular melanoma decreased correspondingly from 29% to 14% in the former Federal Republic of Germany and from 40.6% to 22.6% in the former Germany Democratic Republic. During the years 1990 and 1993, 64% of melanoma patients with the primary tumour alone were operated on in two consecutive sessions in the former Federal Republic of Germany and 34.2% of those in the former Germany Democratic Republic. During this period 73.7% of all melanoma patients were operated on under local anaesthesia. In recent years surgical operations were more often performed in two consecutive sessions, mostly under local anaesthesia and with decreasing safety margins, in keeping with the decrease in tumour thickness. The present analysis shows that the Central Malignant Melanoma Registry is an important instrument for investigating trends in clinical epidemiology and treatment of malignant melanoma in the German-speaking countries.

Awareness and early detection of cutaneous melanoma: an analysis of factors related to delay in treatment

Factors associated with the detection of cutaneous melanomas and reasons for delay in diagnosis were investigated in 429 patients with histologically proven melanoma operated on between January 1993 and June 1996. Patients were interviewed using a standardized questionnaire. In 25% of patients, treatment was delayed for more than 1 year from the time they first noticed a suspicious pigmented lesion. Melanoma was detected by the patients themselves in 67% of women and 45% of men. The three predominant clinical symptoms of melanoma were change in colour (darker), increase in size and increase in elevation of a pigmented lesion. The role of sun exposure and of naevi as risk factors for melanoma, as well as the potential benefit of early treatment, were known by 87%, 66% and 82% of the patients, respectively. However, melanoma awareness had no impact on the time period between first observation of skin changes and treatment. Among the factors associated with delay in melanoma diagnosis, an initial incorrect diagnosis as a benign lesion by the physician first visited (in 18% of all cases) had the highest significance. Patients detecting their lesions themselves were treated significantly later than patients in whom others had remarked on changes in a naevus. Furthermore, melanomas of the head and neck were treated later than melanomas at other body sites. Further efforts to educate both the public and the medical profession are essential to ensure earlier treatment for cutaneous melanomas.