Late adverse effects after soft X-ray therapy of cutaneous malignancies: pruritus, burning, epiphora and insufficient occlusion of the mouth.

BACKGROUND: Pruritus, burning, epiphora and insufficient occlusion of the mouth have been less extensively studied than cosmetic changes in irradiated fields. OBJECTIVES: How frequent are these late adverse effects? Do they usually occur permanently? Are they influenced by treatment and tumour parameters, sex and age of the patients? METHODS: Patients were interviewed at least once later than 90 days after soft X-ray therapy. RESULTS: Pruritus has been reported in 18.5% of the interviews, burning in 7.7%, epiphora in 36.2% and insufficient occlusion of the mouth in 11.5%. Patients were usually not permanently troubled and irritated by these symptoms: pruritus more than once per week was reported in every interview for 0.6% of the fields, burning for 0.2%, epiphora for 6.4% and insufficient occlusion for 0%. Irritation by these symptoms has been stated in every interview for 5.1% of fields around the eye and for 1.4% of fields at other sites. Late pruritus, burning and epiphora were less frequently reported after irradiation with lower total doses, lower time-dose-fractionation factor (TDF) and by men. Patients older than 70 years of age experienced pruritus and burning less frequently. The largest diameter of the irradiated field influenced pruritus and the half value depth of the X-rays influenced burning and epiphora. CONCLUSIONS: Late pruritus, burning, epiphora and insufficient occlusion of the mouth do not considerably reduce the value of soft X-ray therapy because these adverse effects usually are not experienced permanently. Total dose and TDF should not be chosen higher than necessary.

Survival probabilities and hazard functions of malignant melanoma in Germany 1972-1996, an analysis of 10433 patients. Evolution of gender differences and malignancy.

The evaluation of the impact of prevention activities on the course of survival in conjunction with the individual hazard rate of dying is described using data from a follow-up study of 10433 melanoma patients during three observation periods (1972-1980, 1981-1988, 1989-1996). Kaplan-Meier survival curves combined with hazard functions were calculated. At all observation periods, survival of men was lower compared with women and their maximum dying risk was earlier (70 versus 100 months after removal of the primary tumour). In 1989-1996, differences in the survival rates were approximately halved compared with those for 1972-1980 or 1981-1988, respectively. This improvement was predominantly seen in young men. There was a lower survival rate of men compared with women with identical thickness categories. The maximum dying risk for those men with tumours >4 mm peaked at approximately 60 months, the other thickness categories showing a lower and later maximum; in women, the maximum dying risk for tumours >4 mm was also seen at approximately 60 months, but less pronounced. Over time, the influence of Breslow thickness on the survival rates remained constant in women; in men, with the exception of thick tumours, there was a trend towards a better survival. Melanoma awareness campaigns conducted in Germany since the late 1980s have resulted in a trend towards a remarkable increase of thin tumours in recent years, whereas the number of new cases with thick tumours has remained constant.

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.

The usefulness of single and combined clinical characteristics for the diagnosis of dysplastic naevi.

A total of 761 melanocytic lesions were studied to elucidate the usefulness of clinical features for the diagnosis of dysplastic naevi. Characteristics associated with high (irregular border, irregular pigmentation), intermediate (black coloured areas, largest diameter greater than 0.5 cm, change of size, change of colour) and low diagnostic efficiency could be defined. Combinations of criteria had high sensitivities: at least one of the following four criteria was positive in 96% of the dysplastic naevi and in all melanomas with less pronounced clinical characteristics: irregular border, irregular pigmentation, greatest diameter greater than 0.5 cm, black coloured areas. A lesion is therefore unlikely to be a dysplastic naevus or a melanoma if all these criteria are absent. When change of size and change of colour were analysed in addition to the features mentioned above a sensitivity of 0.96 was found for at least two of these six criteria. At least three of these six criteria were observed in all melanomas with less pronounced clinical characteristics. However, a rather low specificity (0.19 for at least one of four positive criteria, 0.20 for at least two of six positive criteria) indicated that dysplastic and non-dysplastic naevi cannot be clinically differentiated with acceptable certainty. With less stringent histological criteria approximately twice as high specificities were found. Specificities were about twice as high in a subgroup of patients with at least one proven dysplastic naevus besides the lesion under diagnostic consideration. This facilitates the identification of individuals at risk of developing a melanoma.

A nine-gene signature predicting clinical outcome in cutaneous melanoma.

PURPOSE: Current histopathological staging of cutaneous melanoma is limited in predicting outcome, and complementary molecular markers are not available for prognostic assessment. The purpose of this study was to identify a quantitative gene expression score in primary melanoma and adjacent stroma that can be used in clinical routine to define, at the time of diagnosis, patient risk and need for therapy. METHODS: Expression of 92 candidate genes was quantified by RT-PCR in a training subset of 38 fresh-frozen melanomas. Correlation of gene expression with overall survival (OS) was evaluated using univariate regression analysis. Expression analysis of 11 prognostically significant genes in the complete training cohort of 91 melanomas yielded nine genes predicting outcome. Results were confirmed in a validation cohort of 44 melanomas. RESULTS: We identified a nine-gene signature associated with OS and distant metastasis-free survival. The signature comprised risk and protective genes and was applicable to melanoma samples across all AJCC stages in the presence of adjacent stroma. A signature-based risk score predicted OS in both the training cohort (multivariate regression analysis: p = 0.0004, hazard ratio 3.83) and the validation cohort, independently of AJCC staging. Consequently, when combining risk score and AJCC staging, patients in the AJCC intermediate-risk stages, IIA/B or IIIA, were re-classified either to low or high risk. CONCLUSIONS: Our gene score defines patient risk and need for therapy in melanoma. The score has the potential to be utilized in clinical routine, since it is quantitative, robust, simple, and independent of AJCC stage and sample purity.

Late side-effects with cosmetic relevance following soft X-ray therapy of cutaneous neoplasias.

BACKGROUND: Cosmetic changes are to be expected after radiotherapy for skin tumours. OBJECTIVES: This study aimed to answer the questions: How frequent are cosmetic changes after soft X-ray therapy? Do treatment parameters, tumour thickness, localization and size of the irradiated field have a major influence? Were patients irritated by the visual appearance of the irradiated field? METHODS: In total, 2474 examinations of 1149 irradiated fields were performed. RESULTS: Hypopigmentation was found in 64.7% of examinations more than 90 days after therapy, teleangiectases in 43.1%, erythema in 24.8%, and hyperpigmentation in 16.8%. The frequency of hypopigmentation, teleangiectases and hyperpigmentation increased with time from X-ray exposure; more than 4 years after therapy hypopigmentation was diagnosed in 91.8% and teleangiectases in 82.2% of examinations. Total dose, the time-dose-fractionation factor (TDF), field size and dose per fraction were significantly related to the frequency of cosmetic changes. Incidence rates of cosmetic changes differed by less than 15% if different treatment conditions were compared: thicker vs. thinner tumours, larger vs. smaller fields, higher vs. lower total doses, doses per fraction, and TDF. Frequencies of hypopigmentation, teleangiectases, erythema and hyperpigmentation differed by more than 15% between some localizations on the head. Women reported irritation by the visual appearance of the irradiated field in 12.6% of 1116 interviews, and men in 4.4% of 1284 interviews. CONCLUSIONS: Cosmetic changes after soft X-ray therapy are relatively frequent. Treatment parameters, tumour thickness and field size have only a minor influence. Few patients, but more women than men, were irritated by the visual appearance of the irradiated field.

[Not diagnosable malignant melanomas]. / Nichtdiagnostizierbare maligne Melanome.

Of the 3574 malignant melanomas treated in Hornheide between December 1981 and August 1990 (not including preinvasive cases) 97 were not immediately recognized. These tumours did not look like melanomas. In 72% they were smaller than 10 mm in diameter, and in 20%, smaller than 5 mm. Clark's so often quoted "pencil rule" should no longer be used as an aid to exclusion of invasive melanoma. Localization of the unrecognized melanomas was on the head and neck in 22% of cases. In 37%, the patients were under the age of 40 years. No less than 25% of the patients had multiple melanomas. Many of these melanomas. Many of these melanomas were thin tumours (less than 0.75 mm in 55% and less than 1.5 mm in 77%). This explains why more than 50% of the lesions are described as "macules". The most common incorrect diagnoses were dysplastic naevi (44%) and common (23%) naevi. The most important anamnestic criteria are the patients' own statements about changes in size, colour and shape. These "dynamic" elements must be more carefully observed and documented during process of the clinical diagnosis.

[Metastatic melanoma of low Breslow thickness]. / Metastasierende Melanome geringer Breslow-Dicke.

We treated 8123 patients with invasive malignant melanoma were treated up to 1995. 2200 had invasive melanomas with less than 0.75 mm Breslow thickness; of these, 45 developed metastases. Three had second primary tumors with greater thickness. One case showed metastasis from another tumor. In two cases the metastases were not ascertained histologically. The remaining 39 cases showed some peculiarities: a greater proportion of late and of internal (as contrasted to regional) metastases. Most of these primary tumors had a Breslow thickness of more than 0.5 mm and were Clark level III or even IV. Male patients and primary tumor sites in the area of head and neck were significantly over-represented.

[First melanoma metastases after 10 years and more of remission]. / Melanomerstmetastasen nach 10 und mehr Jahren Erscheinungsfreiheit.

36 (3.5%) of 1015 patients who had ten or more years of follow-up after treatment of invasive malignant melanomas (stage I and II, UICC 1978) in Hornheide 1967-1984 developed late metastases. The mean disease-free interval was 12.5 years. These patients were younger (mean age of 45.8 years) compared to the age of all melanoma patients at the time of primary therapy. The rate of late relapses was 2.8% in women (20/705) and 5% in men (16/310). In melanomas located on the trunk or on the legs in male individuals, the relapse was twice as high as in females. The median tumor thickness in patients with late progression was 1.5 mm; in patients without relapse 1.2 mm. The well known association of tumor thickness with the risk of metastases disappeared after a 10 years disease-free interval. The frequency of metastases (3.5%) did not vary in different thickness classes from 0.76 mm to 3 mm or more. Melanomas with a Breslow thickness < 0.75 mm had a risk of only 1.4%. 23 patients (64%) developed distant, only 13 (36%) regional late metastases as first evidence of recurrent disease. The survival of these patients correlated neither to the duration of previous relapse-free follow up, nor to site of the primary lesion nor to sex. It correlated only to the site of metastases: 83% of all patients with distant late metastases had a remaining life time of 14 months or less, but patients with regional metastases survived more than 7 years in 69% of the cases. We have been unable to define risk factors for late metastases.

[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)

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.

[Mortality of invasive malignant cutaneous melanoma. A review with special consideration of gender distribution]. / Zur Sterblichkeit am kutanen invasiven malignen Melanom. Ubersicht unter besonderer Berücksichtigung der Geschlechterverteilung.

BACKGROUND AND OBJECTIVE: The final goals of malignant melanoma prevention are lowering incidence and mortality. We assessed the parameter "survival" for both men and women as the beginning point for future gender-directed prevention campaigns. We compared the periods 1972-1980, 1981-1988, 1989-1996, and determined the influence of age and of Breslow' tumor thickness on survival. PATIENTS/METHODS: We had sufficient follow-up on 10.433 patients. We calculated survival curves according to Kaplan-Meier and defined differences by the logrank test. RESULTS: At all periods of time, survival of women was higher compared with men, but with no impressive changes over time. This was especially true for younger men. The most important prognostic factor was the Breslow tumor thickness. Within all periods of time, its median was higher in men. A trend downwards for both genders could be observed with higher influence on survival in men. CONCLUSIONS: Our findings justify melanoma prevention campaigns addressed to men. Evaluation of such campaigns has to take into account an already existing upwards trend for male survival, which exceeds that of female survival.

Should adjuvant radiotherapy be recommended following resection of regional lymph node metastases of malignant melanomas?

BACKGROUND: Several authors have recommended adjuvant radiotherapy following resection of regional lymph node metastases in cutaneous malignant melanoma. There is, however, little evidence from controlled trials that patients benefit from this treatment. OBJECTIVES: To evaluate the usefulness of adjuvant radiotherapy following resection of lymph node metastases in cutaneous malignant melanoma. METHODS: We performed a retrospective study comparing 58 patients who underwent radiotherapy following resection of regional lymph node metastases with 58 controls from another centre who exclusively underwent regional lymphadenectomy. Patients and their controls were matched with respect to the number of tumour-bearing lymph nodes (1 vs. > 1) and to gender, although the proportion of thick tumours was greater in the irradiation group. RESULTS: The overall survival curves were almost identical in the two groups. There were nine disease recurrences in the study group and 12 in the control group (not significant). Regional recurrences in the irradiated patients were usually accompanied by metastases at other sites. CONCLUSIONS: The present study does not support the recommendation of adjuvant radiotherapy following resection of regional lymph node metastases in patients with malignant melanoma.

Prognostic immunohistochemical markers of primary human melanomas.

BACKGROUND: Several clinical and histological factors of primary melanomas comprise a relatively large quantity of prognostic information. OBJECTIVE: To find immunohistochemical markers that can improve the prognostic accuracy achieved by factors that are available without extra laboratory work, i.e. mitotic rate, tumour thickness, ulceration, localization, gender and age. METHODS: Immunohistochemical markers were determined on frozen sections. Univariate and multivariate Cox regression analyses were performed after 5-10 years follow-up. RESULTS: Seven immunohistochemical markers were related to disease-free and overall survival in univariate Cox regression analysis: Ki-67, human leucocyte antigen (HLA) -DQ, HLA-DP, Muc 18, A-10-33, transferrin receptor, and H-2-8-10. Only Ki-67 (n = 399) and HLA-DQ (n = 452) retained prognostic significance when evaluated in multivariate analyses in several models together with tumour thickness alone and with tumour thickness, gender, mitotic rate, age, localization and ulceration. CONCLUSIONS: Ki-67 and HLA-DQ may be useful for risk assessments in primary melanomas.

Prognostic classification of malignant melanomas by combining clinical, histological, and immunohistochemical parameters.

In a retrospective study the prognostic relevance of clinical, histopathological, immunohistochemical, and flow-cytometric parameters in primary malignant melanomas was evaluated using both the receiver operating characteristic ROC procedure and the logistic regression model. The proteolytic enzymes collagenase IV, cathepsin B, and cathepsin D proved to be significant prognostic factors. Combining the results obtained with these enzymes with gender, anatomic site, tumour thickness, Clark's level, ulceration, pattern of invasive growth, and presence of large round cells resulted in greatly improved discrimination between metastasized and non-metastasized cases. It is anticipated that this method could allow for precise individual prognostic characterization and in particular for identification of high-risk patients for adjuvant therapy.

Can immunohistochemical markers and mitotic rate improve prognostic precision in patients with primary melanoma?

BACKGROUND: In addition to tumor thickness, several other prognostic parameters have been identified in primary human melanomas. Some are available readily (localization, gender, age, and ulceration). Others must be evaluated with a moderate or even substantial amount of work (mitoses and immunohistochemical markers). This study was undertaken to determine whether this extra effort is justified because it actually improves the precision of prognostic statements. METHODS: Immunohistologic markers were determined on frozen sections from 691 biopsies of human melanomas with the immunoperoxidase method. Univariate and multivariate Cox regression analyses were performed with metastases and with death as endpoints. RESULTS: Fifteen parameters were related to disease free survival in univariate Cox regression analysis: tumor thickness, ulceration, localization, gender, age, mitoses, and the immunohistochemical markers very late antigen (VLA)-2, human leukocyte antigen (HLA)-ABC, HLA-DR, NKI-beteb, Mel 14, intercellular adhesion molecule (ICAM-1), K-1-2, G-7-E2, and H-2-4-7. Three of the easily available parameters exhibited independent significance in multivariate Cox regression analysis: tumor thickness, ulceration, and localization. If mitotic rate was included in this model, then it had independent prognostic significance but ulceration was no longer significant. However, the model that included tumor thickness, localization, and ulceration had a slightly higher overall chi-square test score, indicating a better performance compared with thickness, localization, and mitoses. The model that included tumor thickness, localization, and mitoses could not be improved by any of the immunohistochemical markers in this study. CONCLUSIONS: Nine immunohistochemical markers with established prognostic significance for primary human melanoma were not found to improve a prognostic model that included tumor thickness, localization, and mitoses. If mitoses was replaced by ulceration, then the model performed slightly better, although ulceration was not significant in the presence of mitoses.

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.

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.

[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.