Primary cutaneous melanoma. Identification of prognostic groups and estimation of individual prognosis for 5093 patients.

BACKGROUND: Numerous investigations have examined prognostic factors for patients with primary cutaneous melanoma. However, only a few studies have been published on the definition of prognostic groups. The first aim of the present study was to determine the relative importance of different prognostic factors in a large collective study. The second aim was to define prognostic groups of patients based on combinations of prognostic factors and to define a model that allows the estimation of individual survival probability. METHODS: Long term follow-up of 5264 patients with invasive primary cutaneous melanoma was performed from 1970 to 1988 at four German University Departments of Dermatology (Berlin-Steglitz, Münster-Hornheide, Tübingen, and Würzburg). The multivariate Cox model was used to analyze 5093 patients, and 4371 patients with complete information were included in a classification and regression tree analysis (CART). RESULTS: Tumor thickness, sex, anatomic location, and level of invasion were highly significant prognostic factors according to the multivariate analysis (P < 0.0001). However, histologic subtype and age influenced prognosis less significantly (P < 0.05). The CART analysis resulted in 12 groups defined mainly by tumor thickness, sex, and anatomic location, which were combined into five prognostic groups. The prognostic stratification defined by the five groups was superior compared with the standard TNM model. Ten-year survival rates of the five groups ranged from 97% to 14% (P < 0.0001), and an equation was used to calculate individual survival probabilities based on the significant factors of the Cox model. CONCLUSIONS: Consideration of all significant prognostic factors of patients with primary cutaneous melanoma investigated in the present study allows for the definition of prognostic groups with a more reliable estimation of prognosis than by previous staging systems and also enables calculation of individual survival probabilities.

Primary cutaneous melanoma. Prognostic classification of anatomic location.

BACKGROUND: Anatomic location has been identified by several investigators as a significant prognostic factor for patients with primary cutaneous melanoma (CM). However, the best determination of higher and lower risk sites is still controversial, and the biologic significance of tumor site in the course of primary CM is unknown. The aim of the present study was to identify higher and lower risk sites based on multivariate analysis. METHODS: A series of 5093 patients with invasive primary cutaneous melanoma followed from 1970 to 1988 at four university centers in Germany was investigated using the multivariate Cox proportional hazard model to analyze the importance of anatomic location for survival probability. RESULTS: The anatomic location was found to be a highly significant prognostic factor for patients with primary melanoma by multivariate analysis (P < 0.0001). An optimized classification into sites of higher and lower risk with respect to survival was evaluated by multivariate analysis controlling for the possible confounding effects of the other significant prognostic factors. Relative to the lower leg as the prognostically favorable baseline, the following locations were associated with a significantly higher risk of death caused by primary cutaneous melanoma: back and breast (thorax), upper arm, neck, and scalp (TANS regions). The lower trunk, thigh, lower leg, foot, lower arms, hands, and face were identified as lower risk sites. CONCLUSIONS: Anatomic location was confirmed as an independent prognostic factor for patients with primary cutaneous melanoma. The TANS regions were identified as high risk sites, and the lower trunk, thigh, lower leg, foot, lower arms, hands, and face were identified as intermediate sites.

Primary cutaneous melanoma. Optimized cutoff points of tumor thickness and importance of Clark's level for prognostic classification.

BACKGROUND: Maximum tumor thickness and level of invasion are known to be the most important prognostic factors for patients with primary cutaneous melanoma. However, the classification of tumor thickness and the question of whether the combination of tumor thickness and level of invasion provides a better prognostic classification than tumor thickness alone are still matters of debate. The present study examined the relationship between tumor thickness and survival probability to define cutoff points of tumor thickness. Secondly, it investigated the prognostic value of the combination of tumor thickness and level of invasion as proposed in the current TNM classification system. METHODS: A series of 5093 patients with invasive primary cutaneous melanoma followed from 1970 to 1988 at four University centers in Germany (Departments of Dermatology in Tübingen, Würzburg, Berlin-Steglitz, and at the Fachklinik) were analyzed by multivariate Cox models. RESULTS: The relationship between tumor thickness and relative risk of death caused by melanoma was found to be almost linear to a tumor thickness of 6 mm. For tumors greater than 6 mm, no further marked increase in relative risk was observed. The stratification of tumor thickness with endpoints at 1, 2, and 4 mm resulted in the best fit to the authors' data among all classifications with three endpoints, but differences were only slight. By multivariate analysis, the combination of tumor thickness and level of invasion as proposed by the current TNM classification were found to be prognostically less significant than tumor thickness alone. The prognostic influence of level of invasion was proved statistically only for tumor thickness less than or equal to 1 mm. CONCLUSIONS: The proposed stratification of tumor thickness with cutoff points at 1, 2, and 4 mm was supported by multivariate statistical analysis. The analysis of the current TNM staging system indicates the precedence of tumor thickness for the staging of patients with primary cutaneous melanoma in the case of discordance between tumor thickness and level of invasion.

[Prognostic advantage for defined risk groups by lymphocyte dissection. Long-term study of 3,616 melanoma patients]. / Prognosevorteil für definierte Risikogruppen durch die Lymphknotendissektion. Langzeitstudie an 3616 Melanompatienten.

Nine medical centres with different practices in elective lymph node dissection (ELND) but comparable standards regarding diagnosis, excision of the primary tumour, classification, and follow-up, have collected their data on 3616 patients with primary melanoma of the skin (tumour category pT 2 to pT 4a, N 0, M 0 [UICC 1987] with the aim of producing an unbiased analysis of the prognostic benefit of ELND. The multivariate risk analysis (Cox's proportional hazard model) revealed tumour thickness (Breslow or alternative pT categories), sex, anatomic site of the primary tumour, and ELND therapy ("yes" or "no") as independent prognostic factors. Observed survival curves (Kaplan-Meier) show a significant difference of prognosis with regard to ELND therapy in the following risk groups: women with melanomas over 2.5 to 4 mm thick on head, neck, thorax, and in acral locations; men with melanomas over 1.5 to 4 mm thick on head, neck, thorax, and in acral locations; and finally men with melanomas over 2.5 to 4 mm thick on abdomen and extremities. Further investigations and the discovery of additional prognostic factors would help in more precisely formulation of guidelines for ELND.

[Is acrolentiginous melanoma (ALM) more malignant than superficially spreading melanoma (SSM) at a high-risk site? A matched-pair comparison between 113 ALM and SSM within the scope of a multicenter study]. / Ist das akrolentiginöse Melanom (ALM) maligner als das superfiziell spreitende Melanom (SSM) in einer High-risk-Lokalisation? Ein matched- pair-Vergleich zwischen je 113 ALM und SSM im Rahmen einer multizentrischen Studie.

Even today, the prognosis of acrallentiginous melanoma (ALM) remains a controversial topic. We present a large case study including all known factors relevant for prognosis. 113 ALMs in 3616 melanoma patients were paired as precisely as possible with their twins, i.e. with 113 superficial spreading melanomas (SSM) from a group of 619 SSMs with high-risk location. The ALMs and SSMs were equivalent in tumor thickness, patient gender and mode of treatment. The follow-up period was for at least 5 years. The 5-year Kaplan-Meier survival curve in both groups are identical. The poor prognosis often ascribed to ALM results from the prognostic factor location. ALM should therefore be regarded as acral localized melanoma.

Benefit of elective lymph node dissection in subgroups of melanoma patients. Results of a multicenter study of 3616 patients.

BACKGROUND: The benefit of elective lymph node dissection (ELND) for the treatment of the nonmetastasized malignant melanoma has been assessed differently until today. METHODS: Nine medical centers with a different ELND practice but comparable standards regarding diagnosis, excision of the primary tumors, classification, and follow-up, have collected their data (primarily ascertained prospectively) of 3616 patients of the tumor categories pT2 to pT4N0M0 to produce an unbiased analysis of the prognostic benefit of ELND, and to find the indications for its application. The data are based on patients 70 years of age and younger with a primary melanoma of the skin, who have been followed for at least 4 years (median, 9.6 years). The stratification (according to pT category [alternatively, tumor thickness], sex, anatomic site) was in accordance with the results of the multivariate risk analysis (Cox hazard model). Imbalances of other criteria such as ulceration, type, and age were excluded by chi-square tests of the individual strata. The results are based on the observed survival rates according to Kaplan-Meier analysis of the different strata. RESULTS: A prognostic benefit of the ELND group (improvement of the 5-year survival rate of about 20%) can be claimed for male patients with axial and acral melanomas (excluding lentigo maligna melanoma [LMM] and ulcerated tumors) of the categories pT3a up to pT4a (tumor thickness of > 1.5-4.5 mm, respectively) (P < 0.001). As to the rest of the nonulcerated tumors of male patients, only those of the categories pT3b and 4a benefited from ELND (P < 0.01). A benefit from ELND for women was statistically verified (improvement of the 5-year survival rate of about 5%-10%) only for the subgroup with a tumor thickness > 2.5-5 mm, excluding LMM) (P = 0.016). CONCLUSIONS: This retrospective study strongly suggests the efficacy of ELND in subgroups of melanoma patients.

The prognosis of patients with stage III melanoma. Prospective long-term study of 286 patients of the Fachklinik Hornheide.

BACKGROUND: Prognostic factors for patients with stage III melanoma are still controversial. METHODS: Two hundred eighty-six patients with solitary cutaneous malignant melanoma of the skin in Stage III (International Union Against Cancer [UICC]) were followed up for as long as 11 years. RESULTS: Patients in risk group pT 4a, pN O (primary tumor thickness of more than 4 mm or invasion of subcutis and absence of regional lymph node metastasis in elective lymph node specimen) have a 5-year survival rate of 72.8%. If regional metastases are excluded clinically (pT 4a, NO), the 5-year survival rate is 62.8%. Patients with regional lymph node metastases have an average 5-year survival rate of 39%, depending mainly on the number of involved lymph nodes and the depth infiltration of the primary tumor. The number of involved lymph nodes reflects the grade of dissemination. It shows a stronger correlation with the prognosis than does the size of metastases. CONCLUSIONS: The authors recommend that revisions of the UICC classification should distinguish Stage IIIA and IIIB based on the presence or absence of regional metastases and that a clearer distinction should be made between regional cutaneous or subcutaneous metastases and regional lymph node metastases.

DNA flow cytometry in the prognosis of primary malignant melanoma.

DNA flow cytometry was carried out on 804 primary melanomas. The data were analyzed with a follow-up of 24-96 months. 57% of the cases were diploid, 32% had one abnormal cell population, and 11% were multiclonal. In 8% of the aneuploid tumors there were cell lines in the hypertetraploid range. A reliable S phase determination was possible in 524 cases. Among these 11% had an S phase exceeding 15%. Using an increased tumor thickness, relapse rate and mortality as criteria of tumor progression, aneuploidy and multiclonality, the occurrence of hypertetraploid cell lines and a high S phase (greater than 15%) proved to be correlated with a poor prognosis.

Sequential DNA flow cytometry in metastatic malignant melanoma.

Sequential flow cytometry was performed on 73 metastatic malignant melanomas, derived from 804 primary tumors. Tumor thickness was confirmed an excellent prognostic parameter in primary melanoma, but did not allow reliable predictions in metastatic disease. Also, aneuploidy and genetic heterogeneity, both common in metastatic melanoma, were equally distributed among patients differing in survival time. However, a remarkable acceleration was observed in the generation of abnormal cell lines in patients dying early of metastatic disease.

[Problems in surgery of the sole of the foot]. / Probleme der Chirurgie an der Fusssohle.

The structure of the weight-bearing plantar skin and the subcutaneous cushion is adapted to mechanical loads of 3-10 kp/cm2 under walking conditions. Such loads, however, are only tolerated when compensated by constant alternation of loaded points. If the surgical therapy with free skin grafts or pedicled flaps does not take into account the vascular and neural architecture of the plantar skin, healing without problems may result--but only for a short time. As a rule, such grafting is later followed by painful keratotic lesions or non-healing "trophic" ulcers, which are caused by loss of sensitive innervation, changing of loaded points as well as the specific subcutaneous architecture. Therefore, reconstructive surgery of loaded plantar skin often requires innervated musculo-cutaneous flaps. Plantar warts or other benign lesions with possible regression are not indications for grafting at all.

[Malignant melanomas of the head and neck area]. / Das maligne Melanom im Kopf-Hals-Bereich. Ergebnisse aus klinischen Studien.

Today's treatment methods have less effect on the prognosis of malignant melanomas in the primary tumor stage, irrespective of their localization, than certain prognostically important factors related to the tumor and the tumor patient. In a validation study the dominating prognostic value of tumor thickness after Breslow (1975) and the patient's gender as two independent factors is confirmed. The retrospective comparative treatment studies on the effects of elective lymph node dissection (ELND) and the extent of excision on prognosis are based on the separate evaluation of male and female patients grouped according to tumor thickness classes (0.76 to 1.5, 1.51 to 3.0 and greater than 3.0 mm). The results confirm what was to be expected according to more recent views on the pathology of melanomas (Balch et al. 1987), i.e. that regionally preventive radical measures, particularly elective lymph node dissection, have a positive effect only in a limited intermediate stage of development. Thus, it was only in a small patient group of men with melanomas of the tumor thickness class 1.5 to 3.0 mm that there was, both in relation to the total number of patients (n = 123) and to the group of head and neck melanomas (n = 30), a prognostic difference of 26% or, respectively, 44% to the favor of lymph node dissection. All other male patients as well as the female patient group exhibited better survival rates after removal of the primary tumor without subsequent elective lymph node dissection. Based on own studies and the critical consideration of published treatment studies, a number of recommendations for differentiated treatment according to acknowledged prognostic criteria (stage-specific therapy!) are given.(ABSTRACT TRUNCATED AT 250 WORDS)

Should elective lymph node dissection be used for treatment of primary melanoma?

A bicenter study compared survival probability in patients with malignant melanoma clinical stage I, treated by wide excision only or wide excision with elective lymph node dissection (ELND). ELND improved the survival only in men with primary tumors of 1.51-3.0 mm thickness. In female patients those without ELND showed a better survival. Thus, the total group of patients did not benefit from ELND, i.e. its value for the improvement of survival from malignant melanoma stage I could not be statistically proven.

[Experience of their environment and disease by facially disfigured patients--recognition of the handicap as a prerequisite for rehabilitation]. / Umwelterfahrung und Krankheitserleben gesichtsversehrter Patienten--Erkennen der Behinderung als Voraussetzung zur Rehabilitation.

In an investigation of psychosocial strain in persons having a facial or skin impairment, a total of 25 patients of Fachklinik Hornheide (a special clinic for the treatment of tumors, tuberculosis, and for facial and skin reconstruction) had participated in in-depth interviewing. It was found with unexpected clarity that these clients are exposed to a high measure of negative environmental reaction. In addition to having to cope with stressful disease consequences, often entailing a "loss of face" with the major problems of self-worth this involves, these negative experiences in many instances lead to behavioural problems, withdrawal reaction, occupational repercussions, or severe emotional crisis in those concerned. The degree to which these patients can overcome their problems is to a large extent dependent on how parents, spouse, colleagues, and important others respond. Early enough involvement of significant others, possibly already at the time of medical information, as well as support during emotional crisis are capable of considerably alleviating the coping process. The psychosocial problems confronting persons with disfiguring facial conditions have to be taken into account during therapy in order to successfully enhance the purpose of integration into the social environment.

[Clinical aspects and therapy of lymphangiomas, hemangiomas and nevi in the area of the head and neck]. / Klinik und Therapie der Lymphangiome, Haemangiome und Naevi im Kopf- und Halsbereich.

The superficial angiomas and nevi arise from the endothelial cells, the pigment-cell-system or the epidermal cells. Hemangiomas are benign tumours of the endothelial cells appearing predominantly in female newborn infants. Depending on localisation, growth and proliferation there is a tendency for spontaneous involution. For irreversible dysfunction or anatomical deformities surgical resection during the growth phase of the hemangioma is indicated. Surgery may be necessary to improve the functional and esthetic appearance after spontaneous involution causing loose residual skin. Radiotherapy of the lesion is rarely indicated. Systemic steroid therapy in cooperation with the pediatrician should be reserved only for desperate cases such as Kasabach-Merrit-Syndrome. Port wine nevi without scars can be covered with skin tanning cosmetics. Argon-Laser-Therapy is not yet so selective that healing can be achieved with certainty and without scars. Clinical progression requires surgery, especially for racemose angiectasia. Arterial embolization should only be used under special conditions, and then only as pretreatment. Lymphangiomas are mostly angiectatic processes, especially of lymphatic vascular tissue and vessels. Even large cystic lymphangiomas can be treated quite well by surgery, but operations on large diffuse invasive lymphangiomas often cause lymphedema and infection similar to erysipelas leading to pseudorecurrence. The benign malformations of the pigment cell system require clear differentiation from malignant melanoma and its precursors. Malignant melanoma develops more frequently from congenital nevi of the deep type than from other pigmented lesions. Malignant melanomas arising from giant nevi are usually diagnosed too late so that almost all patients die. Removal of giant nevi as early as possible is recommended. The epidermal malformations, too, need accurate diagnosis. Multisymptomatic syndromes such as the Basal-Cell-Nevus-Syndrome, and vascular and pigment cell abnormalities require special care.