Interdisciplinary management of EGFR-inhibitor-induced skin reactions: a German expert opinion.

BACKGROUND: Anti-epidermal growth factor receptor treatment strategies, i.e. monoclonal antibodies such as cetuximab and panitumumab, or epidermal growth factor receptor (EGFR) small molecule tyrosine kinase inhibitors, such as erlotinib and gefitinib, have expanded the treatment options for different tumor types. Dermatologic toxic effects are the most common side-effects of EGFR inhibitor therapy. They can profoundly affect the patient's quality of life. PURPOSE: The aim of this study was to provide interdisciplinary expert recommendations on how to treat patients with skin reactions undergoing anti-EGFR treatment. MATERIAL AND METHODS: An expert panel from Germany with expertise in medical oncology, dermatology or clinical pharmacology was convened to develop expert recommendations based on published peer-reviewed literature. RESULTS: The expert recommendations for the state-of-the-art treatment of skin reactions induced by EGFR inhibitor therapy include recommendations for diagnostics and grading as well as grade-specific and stage-adapted treatment approaches and preventive measures. It was concluded that EGFR-inhibitor-related dermatologic reactions should always be treated combining basic care of the skin and a specific therapy adapted to stage and grade of skin reaction. For grade 2 and above, specific treatment recommendations for early- and later-stage skin reactions induced by EGFR-inhibitor therapy were proposed. CONCLUSION: This paper presents a German national expert opinion for the treatment of skin reactions in patients receiving EGFR inhibitor therapy.

Quality of life in localised malignant melanoma.

BACKGROUND: The incidence of melanoma is still increasing in fair-skinned populations. At least 80% of patients have localised disease and expect a 5-year relative survival of >90%. PATIENTS AND METHODS: In 2003-2004, disease-free patients with localised melanoma were recruited from the Munich Cancer Registry to answer quality-of-life (QoL) questionnaires 2 years after treatment. RESULTS: A response rate of 72% was achieved from a total of 1085 distributed questionnaires. Hundred and seventeen questionnaires had to be excluded because of updated information about secondary tumour and progression events. Thus, questionnaires from 664 patients were evaluated. QoL scores in melanoma patients were essentially similar to those of a general population. Differences were detected between women and men concerning emotional and sexual functioning. Age and number of comorbidities were the strongest factors influencing most all aspects of QoL. Fifty percent of patients referred to deficits in communication with their doctors. CONCLUSIONS: Patients who overcome melanoma do not necessarily have a reduced QoL. Strategies used by these melanoma patients resulted in similar levels of coping as previous studies in comparable general populations. Nevertheless, doctor-patient communication was correlated with emotional and social functioning and should be emphasised in treatment and care of melanoma patients.

Distal and proximal interleukin (IL)-10 promoter polymorphisms associated with risk of cutaneous melanoma development: a case--control study.

Inherited promoter polymorphisms of the interleukin (IL)-10 gene resulting in altered IL-10 production may contribute to a genetic susceptibility for melanoma. We investigated the role of a haplotype from distal as well as proximal polymorphic sites [-7400InDel, -6752AT (rs6676671), -3538AT (rs1800890), -1087AG (rs1800896), -597AC (rs1800872)] of the IL-10 5'-flanking region in a hospital-based case-control study of 165 Caucasian patients with cutaneous melanoma from Germany in comparison with 162 healthy cancer-free Caucasian control participants from the same area matched by age. Using multivariate analysis for the number of nevi and skin type, the IL-10 'higher producing' haplotype ITAGC was found to be significantly associated with a reduced risk of developing melanoma (adjusted P=0.02). Although our findings need to be confirmed by independent and larger multicenter studies, we have described for the first time the association of distal gene variants of the IL-10 gene as an independent risk factor for melanoma.

Identification and characterization of 20 immunocompetent patients with simultaneous varicella zoster and herpes simplex virus infection.

BACKGROUND: It has been shown that varicella zoster virus (VZV) and herpes simplex virus (HSV) can co-localize to the same sensory ganglion. However, only a few case reports on VZV/HSV co-infections exist. Objective To identify and characterize patients with concurrent VZV and HSV infection at the same body site. SUBJECTS/METHODS: In 1718 patients, the presence of VZV and HSV in suspicious skin lesions was investigated by polymerase chain reaction analysis. Clinical characteristics of co-infected patients were compared with matched control patients infected with either VZV or HSV. The data are discussed in the context of an extensive review of the literature. RESULTS: Twenty (1.2%) of 1718 patients were infected with both VZV and HSV at the same body site. The mean age was 54 years (range, 2-83). The clinical diagnosis was zoster in 65%, herpes simplex in 20%, varicella in 10% and erythema multiforme in 5% of cases. The trigeminus region was affected in 60% and the trunk in 25%. Involvement of the head was most commonly associated with a severe course of disease and with older age. CONCLUSION: Simultaneous VZV/HSV infection is rare but can occur in immunocompetent patients, which is often overlooked. The majority of cases is localized to the trigeminus region and affects elderly people.

Factors associated with a high tumour thickness in patients with melanoma.

BACKGROUND: Prognosis of patients with melanoma is strongly associated with tumour thickness at time of diagnosis. Therefore, knowledge of patient characteristics and behaviour associated with a high tumour thickness is essential for the development and improvement of melanoma prevention campaigns. OBJECTIVES: The present study aimed to identify sociodemographic, clinical and behavioural factors associated with high tumour thickness according to Breslow. METHODS: The study population consisted of 217 patients with histologically proven primary invasive cutaneous melanomas seen at the Department of Dermatology and Allergology at the Ludwig-Maximilian-University Munich, Germany, between January 1999 and January 2001. Personal interviews were conducted by two physicians to obtain information on sociodemographic characteristics and on patients' knowledge of melanoma symptoms, sun behaviour, delay in diagnosis and related factors. Multivariate linear and logistic regression analysis with stepwise variable selection was used to identify risk groups with a high tumour thickness. To assess possible effect modifications, interaction terms were included in the regression analysis. RESULTS: The median tumour thickness was 0.8 mm (interquartile range 0.5-1.6). Fifty-seven patients (26%) had tumour thickness >1.5 mm. In a multivariate linear regression analysis, patients living alone and patients with a low educational level showed a significantly greater tumour thickness. The relation of melanoma knowledge to tumour thickness was modified by the melanoma subtype: whereas lack of melanoma knowledge led to an increased tumour thickness for the subtypes superficial spreading melanoma, lentigo maligna melanoma and unspecified malignant melanoma, no significant effect was estimated for the subtypes nodular melanoma (NM) and acrolentiginous melanoma (ALM). Sex, age, self-detection of melanoma, patient delay and professional delay were not significantly associated with the tumour thickness in multivariate linear regression. Similar results were found in multivariate logistic regression. CONCLUSIONS: An increased tumour thickness was found in subjects living alone and having a low educational level. These subjects should be targeted in future prevention campaigns in a more focused way. Further efforts are necessary to improve knowledge and earlier detection of melanoma subtypes NM and ALM.

Malignant melanoma of the anal region.

Malignant melanoma (MM) of the anal region is an uncommon disease. In many cases, the disease is undetected or mistaken for a benign polyp or haemorrhoids until it reaches an advanced state. Owing to delayed diagnosis and early metastases, the prognosis is often poor. In contrast to melanomas of the skin, a history of sun exposure does not seem to have an impact in development of MM in this region. Anorectal melanomas (AM) are most common in the rectum, followed by the anal canal and anal verge. Ras mutations, especially in codon 61 of the N-ras oncogene, are common in CM and rare in melanomas of the vulva and anorectum. The diagnosis of an AM is usually made using a biopsy. Histopathological examinations show spindle-shaped and pleomorphic cells. Adjuvant immunohistological markers are the calcium-binding protein S-100, the melanoma antigen HMB-45, the melanoma-expressed protein Melan A, and microphthalmia-associated transcription factor (MiTF). To date, there are few published guidelines for the correct management of AM, and surgery remains the mainstay of treatment. We report on a 39-year old man who presented with a 5-week history of recurrent prolapse of an anal tumour. The tumour was histologically confirmed to be malignant melanoma.

Protein expression of melanocyte growth factors (bFGF, SCF) and their receptors (FGFR-1, c-kit) in nevi and melanoma.

BACKGROUND: Basic fibroblast growth factor (bFGF) and stem cell factor (SCF) are essential growth factors for melanocytes which carry the receptors FGFR-1 for bFGF and c-kit for SCF. Because both factors may be involved in melanoma development, the expression of bFGF/FGFR-1 and SCF/c-kit was investigated in melanocytic tumors of different progression stages. METHODS: Fifty primary melanomas and 44 melanocytic nevi were analyzed for the expression of SCF, c-kit, bFGF, and FGFR-1 by immunohistochemistry. RESULTS: In melanoma, SCF and c-kit were expressed in 76 and 84%, respectively, and coexpressed in 66%. bFGF and FGFR-1 were expressed in 45 and 86%, respectively, and coexpressed in 46%. In melanocytic nevi, SCF was expressed in 23% and c-kit in 70% while coexpression was more common in dysplastic (39%) than non-dysplastic subtypes (8%). bFGF and FGFR-1 were expressed in 55 and 67%, respectively, while coexpression was found in 47% but varied considerably between different histological subtypes. CONCLUSIONS: SCF and c-kit were frequently expressed by melanomas and dysplastic nevi suggesting an autocrine growth mechanism as described for bFGF. In both nevi and melanoma, c-kit was almost exclusively found in the epidermis while bFGF was more common in the dermis. Thus the growth factor/receptor expression seems to depend on the cutaneous localization of the melanocytic tumors.

Disease progression in patients with thin cutaneous melanomas (tumour thickness < or = 0.75 mm): clinical and epidemiological data from the Tumour Center Munich 1977-98.

BACKGROUND: Although survival in patients with thin melanomas (tumour thickness < or = 0.75 mm) is usually excellent, thin melanomas have the potential to metastasize. OBJECTIVES: To determine risk factors for the development of disease progression in patients with thin cutaneous melanomas. METHODS: A retrospective study was performed between 1977 and 1998 to identify risk factors for the development of disease progression in 2302 patients with cutaneous melanoma with tumour thickness < or = 0.75 mm, diagnosed and treated at the Department of Dermatology and Allergology, Ludwig-Maximilians University, Munich, Germany. The Kaplan-Meier method was used to estimate the influence of different clinical characteristics for the occurrence of first progression during 10 years of follow-up. RESULTS: An analysis of the data from 6298 patients with cutaneous melanoma identified 2302 patients (37%) who presented with cutaneous melanoma with a tumour thickness < or = 0.75 mm, without clinical signs of metastasis at initial diagnosis (clinical stage Ia). A small subgroup of our patients (77 of 2302) developed metastatic disease during the follow-up period. The estimated rate of occurrence of metastasis after 10 years of follow-up was 4.7%. The mean follow-up time was 62 months (median 46). Of these 77 patients, 16 experienced progression at the primary tumour site and 32 presented with regional lymph node metastases. Twenty-eight patients primarily developed systemic metastases (seven patients with and 20 without regional lymph node metastases, one patient with regional lymph node metastases and local recurrence). In one patient the primary site of metastatic disease was not reported. Clinical characteristics included age, sex of the patient and different subtypes of cutaneous melanoma: superficial spreading melanoma, nodular melanoma, acrolentiginous melanoma (ALM) and lentigo maligna melanoma (LMM). Male patients and patients with LMM or ALM were significantly over-represented (P = 0.02 and P = 0.002). In the group of 77 patients with thin melanomas (< or = 0.75 mm), local recurrence was over-represented as compared with those with melanomas > 0.75 mm. No difference in group was found for overall survival after the occurrence of lymph node metastasis as the first manifestation of disease progression. CONCLUSIONS: Thorough follow-up and skin examination is recommended for a subgroup of patients with thin tumours, which consists of male patients with LMM or ALM located in the head and neck region.

Lymphadenopathy detected by ultrasound examination as first diagnostic hint of chronic lymphocytic leukaemia in a patient with melanoma.

Recent reports indicate that patients with malignant melanoma might be at higher risk for developing a non-cutaneous unrelated second malignancy. We describe the case of a 46-year-old woman who had a malignant melanoma on her right shoulder that was treated in 1998 by surgical excision combined with axillary lymph node dissection. In 1999, ultrasound examination of peripheral lymph nodes revealed one suspicious echopoor structure in the woman's right axilla that was not palpable. Diagnostic excision and histopathological examination revealed a small B-cell lymphocytic lymphoma, and further investigations led to a diagnosis of chronic lymphocytic B-cell leukaemia (B-CLL). We would like to point out the value of high-resolution ultrasound examination in the follow-up of patients with malignant melanoma; this examination can detect early metastasis as well as other unrelated malignancies.

Delay in the diagnosis of cutaneous melanoma: an analysis of 233 patients.

Knowledge of factors associated with the detection of cutaneous malignant melanomas and reasons for delay in diagnosis are essential for the improvement of secondary prevention of cutaneous melanoma. For this reason, the extent and consequence of patient and professional delay in diagnosis and treatment was investigated in 233 patients with histologically proven primary cutaneous melanomas seen at the Department of Dermatology and Allergology at the Ludwig-Maximilians-University, Munich, Germany, between January 1999 and January 2001. Personal interviews were conducted by two physicians to obtain information on patients' knowledge of melanoma symptoms, sun behaviour, delay in seeking medical attention, professional delay and related factors. The main component of delay was patient related. Nearly one-third (29.2%) of all patients reported a delay interval of more than 12 months from the onset of an observed change in a pigmented lesion or first detection of a pigmented lesion to the first visit to a physician. The delay interval from the first visit to a physician to surgical treatment was shorter (< 1 month) in most of our patients (74.7%). The predominant symptoms of melanoma detected by patients were a change in colour and an increase in size or elevation. Most patients had obtained knowledge about cutaneous melanomas from television and magazines. A delay in diagnosis and a history of many sunburns and outdoor leisure time activities were not associated with a greater tumour thickness. However, fairer skin types, lower education levels and lack of knowledge about cutaneous melanoma were associated with a greater tumour thickness. Further efforts are necessary to improve public and medical education about early detection and prompt surgical treatment, which is known to be the most effective treatment modality for cutaneous melanomas.

Prognostic index for cutaneous melanoma: an analysis after follow-up of 2715 patients.

In 2715 of 4524 patients with cutaneous melanoma treated surgically between 1968 and 1992 prognostic parameters were analysed for their value in predicting the occurrence of first progression. All of the 2715 patients developed only one invasive cutaneous melanoma during the follow-up period. Data concerning tumour thickness and mitotic index (maximum number of mitoses per square millimetre) of the cutaneous melanomas were determined. Between the characteristics age, tumour thickness, mitotic index, prognostic index (PI), sex, site of tumour, melanoma subtype and Clark level, the value of the mitotic index, as a prognostic parameter independent of tumour thickness, and the combination of mitotic index and tumour thickness were evaluated. The development of the first metastases was documented during a mean follow-up of 7.5 years. The majority of first recurrences occurred at regional lymph nodes and attempts have been made to identify those patients at risk of developing metastatic disease. The most effective parameters proved to be tumour thickness and mitotic index. For both parameters an independent prognostic influence was shown. The prognostic index, defined as the product of tumour thickness and number of mitoses per square millimetre, was re-evaluated and confirmed. A new modified prognostic index, defined as the product of square tumour thickness and mitotic index, proved to be even more useful for defining a subgroup of patients who are at risk of developing metastases and, therefore, might benefit from adjuvant therapy.

Loss of tuberin, the tuberous-sclerosis-complex-2 gene product is associated with angiogenesis.

BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominantly inherited disorder associated with an alteration of the TSC2 tumor suppressor gene which encodes for the protein product tuberin. The disease is characterized by the development of hamartomas, e.g. cutaneous angiofibromas which consist of vascular cells, interstitial cells, and normal components of the skin. The Eker rat model, an animal model of inherited cancer, has been shown to carry a mutation of TSC2. METHODS: Immunohistochemical analyses of human angiofibromas were performed using antibodies directed against tuberin and angiogenic growth factors. Proliferation of human dermal microvascular endothelial cells (HDMEC) was determined after incubation with the supernatants of TSC2 (+/+) and TSC2 (-/-) rat embryonic fibroblasts (REF) that were derived from the Eker strain. RESULTS: Loss of the expression of tuberin was observed in the interstitial cells of 13 of 39 angiofibromas. The expression of tuberin was retained in the vascular cells. In all analyzed angiofibromas, the angiogenic factors bFGF, PD-ECGF, VEGF and angiogenin were detected in the interstitial cells and/or vascular cells. Expression of PDGF-B and TGF-beta1 was weak. Tissue culture supernatants from TSC2 (-/-) REF stimulated the growth of HDMEC significantly more than supernatants from TSC2 (+/+) REF. CONCLUSION: A functional loss of tuberin may stimulate vascular growth.

Interlaboratory evaluation of a new reverse transcriptase polymerase chain reaction-based enzyme-linked immunosorbent assay for the detection of circulating melanoma cells: a multicenter study of the Dermatologic Cooperative Oncology Group.

PURPOSE: Reverse transcription-polymerase chain reaction (RT-PCR)-based detection of tyrosinase mRNA is the most frequently used laboratory method for the detection of circulating tumor cells in melanoma patients. However, previously published results showed considerable variability in the PCR positivity rates. MATERIALS AND METHODS: We designed a collaborative study to assess the sensitivity, specificity, and clinical relevance of a new standardized RT-PCR-based enzyme-linked immunosorbent assay (ELISA) for the detection of circulating melanoma cells. Blood samples of healthy donors mixed with cells of a melanoma cell line were prepared in a blinded fashion, and aliquots were sent to seven participating laboratories experienced in RT-PCR. RESULTS: The results demonstrate a high sensitivity (1 melanoma cell/mL blood) and specificity (no false-negatives and 7.4% [2 of 28] false-positives) of the assay and a satisfactory rate of interlaboratory reproducibility. The analysis of aliquots of blinded samples derived from 60 melanoma patients identified tyrosinase mRNA in 17 of 60 (28.3%): three (20%) of 15 stage I patients, two (13.3%) of 15 stage II patients, five (35.7%) of 14 stage III patients, and seven (43.8%) of 16 stage IV patients. The interlaboratory reproducibility of positive samples, however, was extremely low and indicates the presence of low amounts of target mRNA. CONCLUSION: Reverse transcriptase-PCR ELISA has a high sensitivity and specificity for the detection of tyrosinase mRNA in peripheral blood cells. The low interlaboratory reproducibility for the detection of tumor cells in blood samples of melanoma patients, however, raises the question of relevance of this assay for clinical use.

Risk of second primary malignancies in patients with cutaneous melanoma.

BACKGROUND: In several studies an increased risk for development of breast cancer, malignant lymphoma and neoplasms of the kidney as second primary cancers in patients with cutaneous melanomas was discussed. OBJECTIVES: To determine the risk for development of second primary neoplasms in patients with cutaneous melanomas. METHODS: A prospective study was performed between 1977 and 1992 to evaluate the occurrence of second primary malignancies in 4597 patients (2083 men, 2514 women) with invasive cutaneous melanomas, diagnosed and treated at the Department of Dermatology and Allergology, Ludwig-Maximilians-University, Munich, Germany. RESULTS: During a median follow-up of 7.2 years, 296 of 4597 patients (6.4%) developed one or more neoplasms at the time of or subsequent to the diagnosis of the first cutaneous melanoma. More than half of these patients developed one or more further melanomas (152, 3.3%). Cancers of the breast, prostate, colon, rectum and kidney occurred less frequently. Statistical calculations revealed a 33.8-fold increased risk for the development of a second melanoma in the entire group [relative risk 38.5 for men (95% CI, 30.4-48.1), 29.0 for women (95% CI, 22.0-37.5)]. Moreover, a significantly increased risk for the development of kidney carcinoma in men was found [relative risk 3.5 (95%, CI, 1.4-7.2)]. CONCLUSIONS: Thorough follow-up and skin examination in patients with cutaneous melanomas is recommended for early detection of other primary melanomas. Furthermore, ultrasound examinations routinely performed in melanoma patients for the detection of melanoma metastases may also be of value for early detection of kidney carcinomas in male patients.

[Metastases in malignant melanoma despite histologically negative sentinel lymph node: should the concept be changed?]. / Metastasierung beim malignen Melanom trotz histologisch negativem Sentinel Lymph Node: Muss das Konzept in Frage gestellt werden?

AIM: The Sentinel Lymph Node (SLN) is of considerable prognostic relevance, because extended lymph node dissection may not be performed in patients presenting with histologically negative SLN. The aim of the present study was to prove the prognostic value of the SLN-concept in these patients. METHODS: So far the clinical follow-up of 162 patients with histologically proven malignant melanoma and metastatically uninvolved (negative) SLN was investigated. Histological examination included standard methods (HE-Test) and special histochemical techniques (S-100, HMB-45). All patients underwent clinical examination, ultrasonic diagnosis of the regional lymph nodes, and x-ray of the chest every 3 months. RESULTS: Despite of negative SLN-findings in 8/162 patients metastases of the malignant melanoma were found after a time period of 5-27 months. Three patients presented with recurrence in the previously mapped (negative) SLN-basin. In another case the scintigraphically visualized SLN could not be identified intraoperatively by means of the hand-held gamma probe. One patient showed intransit-metastases or skin-metastases, respectively; another patient recurred in the scar area. One patient showed hematogenic dissemination (liver) which is not detectable by lymphoscintigraphy; in another patient metastases were found outside the primary lymphatic basin (cervical). CONCLUSION: In our patient group 4.9% presented with metastases despite negative SLN while published data report up to 11% (observation period 35 months), among them only 3 patients (1.9%) being real concept failures. Our results underline that there is no evidence to change this concept in patients with clinically early stage.