Significance of serum protein S100 levels in screening for melanoma metastasis: does protein S100 enable early detection of melanoma recurrence?

A number of recent reports suggest serum protein S100 as a prognostic parameter in patients with metastatic melanoma. In the present study, serum protein S100 was investigated as a tumour marker for screening for melanoma metastasis in patients attending regular follow-up examinations. During the period from September 1997 to December 1998, serum protein S100 levels were measured by an immunoluminometric assay in 411 consecutive high risk melanoma patients (666 samples) and in 120 control subjects. Melanoma patients with resected primary tumours with a tumour thickness of 1.5 mm or more with resected metastasis were included in the study. Overall, 41 of the 411 patients developed metastasis during the period of observation. According to the distribution of protein S100 levels, the following different cut-off values were examined: 0.08 microg/l (95 percentile of the control group) and 0.13 microg/l (95 percentile of the group of melanoma patients without metastasis). The test efficiency for protein S100 as a diagnostic test for the detection of metastasis was highest for the cut-off value of 0.13 microg/l. In eight of the 41 patients (19.5%), elevation of protein S100 was the first sign of recurrence. Of the 41 patients with metastatic disease, 13 had elevated protein S100, giving a sensitivity of 0.32. The specificity for the detection of metastasis was 0.96. In eight of the 14 patients (57%) who developed distant metastasis, elevated S100 values were the first sign of tumour progression. In conclusion, determination of serum protein S100 levels enables earlier detection of distant metastasis in patients at high risk for metastasis. The impact on survival time needs to be investigated in follow-up studies.

Ultrasound examination of regional lymph nodes significantly improves early detection of locoregional metastases during the follow-up of patients with cutaneous melanoma: results of a prospective study of 1288 patients.

BACKGROUND: In regional lymph node metastasis of cutaneous melanoma, the number and volume of involved lymph nodes are the most important prognostic factors. Several studies have revealed that palpation of the lymphatic drainage area(s) and regional lymph nodes has a high rate of false-negative results during follow-up. The aim of the current study was to assess the sensitivity and specificity of ultrasound versus clinical diagnosis in the detection of subcutaneous and regional metastases. METHODS: During a period of 42 months, a total of 6328 lymphatic drainage areas were examined clinically and by ultrasound (7.5-10 MHz) in 1288 melanoma patients at 4435 follow-up consultations. When an ultrasound finding was suggestive of metastasis, surgery and histopathologic evaluation were performed. The results of clinical examination, ultrasound examination, and histopathologic findings were compared. RESULTS: In 504 ultrasound examinations performed on 235 patients, metastatic disease was diagnosed in 263 examinations following surgery (179 patients). Due to advanced disease or rejection, an additional 56 patients did not undergo surgery. In 239 of the 263 positive findings (90.9%), metastases from melanoma were histopathologically confirmed. In 8 cases (3%) a second malignancy and in 16 cases (6. 1%) benign lymphadenopathy was histopathologically diagnosed. Palpation of subcutaneous lymph nodes and lymph nodes gave false-negative results in 68 of the 238 cases of histopathologically proven metastases (28.6%). Clinical examination was least sensitive in the supraclavicular, axillary, and infraclavicular regions. The sensitivity and specificity for ultrasound examination were 89.2% and 99.7%, respectively, and 71.4% and 99.7% for clinical examination, respectively. CONCLUSIONS: For early diagnosis of in-transit and regional lymph node metastases in cutaneous melanoma, ultrasound scanning is distinctly superior to clinical examination. Controlled follow-up studies are proposed to examine the possible beneficial effects on survival time resulting from the ultrasound examinations of the lymphatic drainage area(s) and regional lymph nodes.

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

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 humoral 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.

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.

Patterns of local horizontal spread of melanomas: consequences for surgery and histopathologic investigation.

Understanding local spreading patterns of melanomas is a precondition for the localized surgical treatment and histopathologic investigation. We used hematoxylin and eosin-stained paraffin sections for a two-phase, cellular and microscopic study of patterns of lateral spread in superficial spreading melanomas (SSMs), nodular melanomas (NMs), lentigo maligna melanomas (LMMs), and acral lentiginous melanomas (ALMs). Complete histologic examination of vertical excisional margins was carried out with paraffin sections 5 mm beyond the clinical tumor border of 1395 SSMs, 376 NMs, 179 LMMs, 46 ALMs, and 37 acrally located SSMs or NMs. Further sections of embedded material were analyzed when tumor-positive margins were found. In case of continuous tumor spread, reoperations were continued until the tissue was free of tumor cells. In case of noncontinuity, a final excision was made to a minimum safety margin of 10 to 20 mm. Concentrically consecutive, 5-microm thick hematoxylin and eosin-stained sections were taken from the outside of a 10-mm safety margin inward to the clinical borders of 34 SSMs, five NMs, 10 LMMs, and five ALMs. Noncontinuous subclinical spread was found in all SSMs and NMs in the form of few isolated cell nests at the epidermis-dermis junction. Ninety-two percent of these were located within 6 mm of the central tumor. All LMMs and ALMs showed a clearly demonstrable, uninterrupted spread into the periphery at the epidermis-dermis junction, too, usually in groups of outgrowths. The probability of finding these outgrowths 5 mm beyond the clinical tumor border was 54% in LMM and ALM. Complete histologic examination of vertical excisional margins (micrographic surgery) is therefore the therapy of choice only for LMM and ALM and is inefficient for SSM and NM.

Extent and consequences of physician delay in the diagnosis of acral melanoma.

The extent and consequences of professional delay in diagnosis were analysed in 83 patients with palmoplantar and subungual melanomas treated from January 1986 to March 1997 in our department. Seventeen (52%) out of 33 subungual melanomas and 10 (20%) out of 50 palmoplantar melanomas were clinically misdiagnosed by physicians. Three palmoplantar melanomas (6%) were initially misinterpreted by pathologists. In 23 of the 27 cases (85%) the clinical misdiagnosis was made by non-dermatologists. Misdiagnosis caused a median delay of 12 months in the diagnosis of palmoplantar melanomas and 18 months in the diagnosis of subungual melanomas. Delay in diagnosis was associated with increased tumour thickness, more advanced stage at time of melanoma diagnosis and a lower estimated 5-year survival rate (15.4% versus 68.9% for palmoplantar; 68.5% versus 90.9% for subungual). Acral melanomas are frequently misdiagnosed due to their less common locations and because plantar and subungual melanomas often do not fit the 'changing mole' pattern. To Improve the patient's prognosis it is necessary to increase the physicians' skill in the diagnosis of acral melanomas. Histological examination should always be performed in acral lesions that do not heal.

Metastatic melanoma of unknown primary origin shows prognostic similarities to regional metastatic melanoma: recommendations for initial staging examinations.

BACKGROUND: Metastatic melanoma of unknown primary origin accounts for approximately 2-6% of all melanoma cases. The prognostic significance of this diagnosis is still controversial. METHODS: Of 3258 patients with malignant melanoma recorded during the period 1976-1996, 2.3% had metastases of unknown primary origin. Anatomic distribution, clinical stage, and survival probabilities were evaluated. RESULTS: Thirty patients were classified as having cutaneous or subcutaneous in-transit metastases, and they showed a 5-year survival rate of 83%. Thirty-seven patients were classified as having lymph node metastasis, and their 5-year survival rate was 50%. Disseminated disease was diagnosed in only 8 patients, who had a median survival of 6 months. Comparison of survival probabilities for patients with in-transit metastases and unknown primary tumors with the probabilities for those with cutaneous primary tumors revealed a significant advantage for the former group. No significant differences were found for patients with lymph node metastasis when those with unknown primary tumors were compared with those who had cutaneous melanomas with regional lymph node metastasis. CONCLUSIONS: The clinical disease course of patients with metastatic melanoma of unknown primary origin is similar to that of patients with primary cutaneous melanoma when the same clinical stages of the disease are compared. Based on the assumption that the majority of regional metastases develop from completely regressed primary cutaneous melanoma, recommendations for initial staging examinations in patients with unknown primary tumors are given in this article.

Prolonged survival of 2 years or longer for patients with disseminated melanoma. An analysis of related prognostic factors.

BACKGROUND: Once melanoma has metastasized to distant sites, the prognosis is usually poor, showing an overall median survival of 6-8 months. Long term survival is extremely rare, and there is still controversy concerning the prognostic significance of therapeutic modalities. The aim of the current study was to identify important prognostic factors associated with Stage IV melanoma. METHODS: The current study was based on data for 3258 melanoma patients, for whom clinical, pathologic, and long term follow-up information was recorded during the period 1976-1996 at the Eberhard-Karls-University in Tuebingen. Germany. The attainment of 2 years' or longer survival time by patients with disseminated melanoma was addressed, and a multivariate analysis of related prognostic factors was performed by logistic regression. RESULTS: Four hundred forty-two patients (13.6%) developed distant metastasis. The median survival time was 7 months, and the 2-year, 5-year, and 10-year survival rates were 11.9%, 6.7%, and 4.7%, respectively. Forty-five patients had prolonged survival of 2 years or longer. Significantly more females belonged to the group of long term survivors (P = 0.0186). Of the modalities of therapy given, only surgery was associated with prolonged survival (P < 0.0001). Primary metastasis to the skin (P = 0.006), the brain (P = 0.015), more than a single metastatic site (P = 0.002), and Karnofsky performance status of less than 80 (P = 0.0035) were significantly related to short term survival. In addition, subsequent development of two or more new metastatic sites was also associated with short term survival (P = 0.0025). CONCLUSIONS: In the current analysis, prolonged survival of 2 years or longer for patients with disseminated melanoma was shown to depend on gender, site of primary metastasis, number of metastatic sites, and Karnofsky performance status. Of the modalities of therapy given, only surgery significantly influenced survival. However, in a small percentage of patients, long term complete remission was achieved with chemotherapy alone or in combination with surgery, suggesting that such regimens might be curative in selected cases.

[The difficulty of ultrasound diagnosis of lymph node metastases of malignant melanoma in protracted tumor growth]. / Zur Schwierigkeit der sonographischen Diagnose von Lymphknotenmetastasen des malignen Melanoms bei protrahiertem Tumorwachstum.

Lymph node ultrasound examinations are performed during the follow-up of cutaneous melanoma in order to early recognise regional metastases. The excision of regional metastases is the only way to inhibit disseminated metastasis in a certain percentage of cases. Lymph node ultrasound has a sensitivity of 95% in the diagnosis of pathological lymph node changes. Sonographic findings normally show typical features of malignancy; only in some doubtful cases are further control examinations warranted over a period of 4-6 weeks. In violation of this rule, two cases are presented with a delayed onset of metastases causing difficulties in the diagnosis of malignant transformation. Four years after the excision of a nodular melanoma with 0.8 mm tumor thickness at the right lower leg, a suspicious lymph node change in the right groin was sonographically detected which did not fulfill all criteria of malignancy. Control examinations over a period of 1 year found only a further growth of 3 mm. Excision after 1 1/2 years showed a lymph node metastasis. The second case presented 9 years after the excision of a superficial spreading melanoma with 0.76 mm tumor thickness with a suspicious lymph node in the right axilla which similarly grew very slowly. The subsequent excision showed likewise a melanoma metastasis. A protracted growth may occur in thin malignant melanomas with late development of ultrasound features of malignancy. In doubtful cases an early biopsy is recommended.

Pharmacodynamics of recombinant IFN-beta during long-term treatment of malignant melanoma.

The pharmacodynamics and biologic activities of recombinant human interferon-beta (rHuIFN-beta) derived from chinese hamster ovary (CHO) cells were examined during long-term therapy in 7 melanoma patients. The CHO-derived rHuIFN-beta was given s.c. in a dose of 3 x 10(6) U three times per week for 24 weeks. Serum levels of IFN could not be detected before and 48 h after the s.c. injections. 2'-5'-Oligoadenylate synthetase (2-5 OAS), beta 2-microglobulin, and neopterin levels increased significantly 48 h after application, with a maximum after 96 h. Subsequently, the values decreased and remained only slightly elevated during the long-term therapy. Natural killer (NK) cell activity increased in the first 96 h significantly and fell below pretreatment values after 4 weeks. The decrease of biologic response could not be attributed to the occurrence of anti-IFN-beta antibodies because only 2 of the 7 patients developed neutralizing antibodies after 16 and 24 weeks of treatment, respectively. This trial confirms the biologic potency of CHO-derived rHuIFN-beta. However, the selected parameters demonstrate that immunostimulation is only possible over a short treatment period.

[Intralesional therapy of melanoma metastases with recombinant interferon-beta]. / Intraläsionale Therapie von Melanommetastasen mit rekombinantem Interferon-beta.

In ten patients with metastasizing melanomas, discontinuous intratumoral treatment with recombinant interferon beta (rIFN-beta) was administered into 19 cutaneous or palpable subcutaneous metastases. Among the 16 metastases treated with 5 x 10(6) IU per injection, 8 showed partial or complete remission. No recurrence was observed during the 4-9-month follow-up period. There was no regression in 3 metastases treated with 3 x 10(6) IU rINF-beta per injection. No systemic antineoplastic effects were observed in any of the cases. The IFN-beta serum levels were measurably increased following intratumoral application. Local treatment led to a significant increase in (2'-5')oligoadenylate synthetase in the mononuclear blood cells and in the serum. Side-effects of the treatment were moderate; there was a temporary increase in transaminases, a decrease in thrombocytes and influenza-like symptoms. The results show that IFN-beta has a dose-dependent antitumour effect on malignant melanomas.

Ultrasonographic diagnosis of melanoma metastases in liver, gallbladder, and spleen.

Ultrasonographic findings in the liver, gallbladder, and spleen of 42 patients with metastatic melanoma of the skin are described in a retrospective study stressing sonomorphologic results. Liver metastases were detected in 27 (64%) of the patients. Clinically asymptomatic melanoma metastases were found in the gallbladder of three patients and in the spleen of three others. The liver metastases were still in the initial stages in 10 patients, whose survival times averaged 8.4 months. The significance of upper abdominal ultrasonography in assessing the spread of metastasizing malignant melanoma during follow-up is emphasized.