Metastatic glucagonoma: treatment with liver transplantation.

Glucagonoma is a rare pancreatic endocrine tumor that is often both well developed and malignant at detection. In the case of metastatic spread the patient has a poor long-term prognosis. We hope to familiarize dermatologists and other specialists with this rare and potentially fatal disorder because early recognition of necrolytic migratory erythema, a clinical feature that may appear in patients with glucagonoma, can lead to possible cure, whereas delayed identification of the disease is associated with metastatic disease and a poor prognosis. We report the case of a 57-year-old patient with a metastatic glucagon-producing tumor; necrolytic migratory erythema was diagnosed and was successfully treated by a multimodal intervention including liver transplantation. Currently, 72 months after transplantation, our patient is in complete remission, which has been verified by somatostatin receptor scintigraphy monitoring, computed tomographic scanning and glucagon serum control. Increased awareness of the clinical symptoms and visible polymorphic mucocutaneous and nonspecific histopathologic features of glucagonoma syndrome is needed to avoid unnecessary delay in the diagnosis of this syndrome.

Immunomagnetic enrichment, genomic characterization, and prognostic impact of circulating melanoma cells.

PURPOSE: The finding of melanoma cells in the peripheral blood, thus far mainly inferred from the PCR-based demonstration of tyrosinase mRNA, has been associated with metastatic melanoma. Neither the malignant nature nor the prognostic significance of circulating cells could be established. To address this question, we analyzed immunomagnetically isolated circulating melanoma cells for chromosomal aberrations and performed a clinical follow-up study of the enrolled patients. EXPERIMENTAL DESIGN: In a prospective study, blood samples were taken from 164 melanoma patients and 50 donors without malignant disease. Circulating melanoma cells were enriched by immunomagnetic cell sorting using a murine monoclonal antibody against the melanoma-associated chondroitin sulfate proteoglycan. To prove the malignant origin of the positive cells and to define their chromosomal aberrations, we analyzed the genomes of 15 individually isolated cells from seven patients by single-cell comparative genomic hybridization (SCOMP). RESULTS: Absolute and relative frequencies of circulating melanoma cells were associated with stage and with the presence or absence of detectable tumor. The detection of two or more cells correlated significantly with a reduced survival of patients with metastatic melanoma. All of the cells that were analyzed by SCOMP displayed multiple chromosomal changes and carried aberrations typical for melanoma. CONCLUSIONS: Immunomagnetic enrichment enables isolation and genomic characterization of circulating melanoma cells. The prognostic impact on survival of metastatic patients apparently reflects the aggressiveness of an ongoing tumor spread. Direct genomic analysis of the enriched and isolated cells will help to clarify the molecular-genetic basis of the establishment of generalized melanoma.

Ulcerated epithelioid hemangioendothelioma of the foot in childhood.

Epithelioid hemangioendothelioma is an uncommon malignant vascular tumor usually involving soft tissue and, in rare cases, the skin. Histologically and biologically it is considered to be a borderline neoplasm between an angiolymphoid hyperplasia with eosinophilia and an epithelioid angiosarcoma. Here we describe an 11-year-old girl with a 1-year history of an isolated, spontaneously appearing, painful ulceration on the instep of the right foot. The histopathologic examination of a wedge biopsy specimen revealed epithelioid eosinophilic cells with intracytoplasmic vacuoles containing erythrocytes. Immunohistochemical staining was positive for the endothelial markers CD31, CD34, and factor VIII. On the basis of these findings the diagnosis of epithelioid hemangioendothelioma was made. Two weeks after complete excision of the tumor, a lymph node metastasis in the right groin was excised. Because of another inoperable lymph node metastasis on the proximal right femur, polychemotherapy was started. As our case report shows, in the event of a nonhealing cutaneous ulceration the possibility of a malignant tumor such as epithelioid hemangioendothelioma should be considered, even in children.

Fibroblast growth factor-2 but not Mel-CAM and/or beta3 integrin promotes progression of melanocytes to melanoma.

A variety of melanoma-associated antigens have been identified that mediate adhesion, growth, proteolysis, and modulation of immune response. However, the mechanisms by which human normal melanocytes become malignant are not clearly understood. Among the most consistent observations is the up-regulation of fibroblast growth factor-2 (FGF-2) and of the adhesion molecules beta3 integrin and Mel-CAM during melanoma progression. To evaluate the potential role of FGF-2, beta3 integrin and Mel-CAM in melanoma development we overexpressed FGF-2, beta3 integrin and Mel-CAM in normal human melanocytes using replication-deficient adenoviruses as a gene delivery vehicle. Fibroblast growth factor-2 overexpressing melanocytes in monolayer culture displayed cytological atypia. Furthermore, in human skin reconstructs where the physiological milieu is recreated in vitro, FGF-2-overexpressing melanocytes exhibited marked proliferation, upwards migration, cluster formation and type IV collagen expression within the epidermal compartment, simulating early radial growth phase melanoma. In contrast, overexpression of beta3 integrin and/or Mel-CAM in melanocytes did not affect their biological behaviour in human skin reconstructs. The described results of the current and previous studies emphasise the key role of FGF-2 in melanoma development and progression, underscoring the promise of FGF-2 as a target for therapy.

[Psychosocial burden and subjective experience of melanoma patients in the ambulant follow-up]. / Psychosoziale Belastung und subjektives Erleben von Melanompatienten in der ambulanten Nachsorge.

INTRODUCTION: The ambulant follow-up is established for early detection of metastases thus improving the survival probability of tumor patients. In spite of the safety aimed at, follow-up also puts a burden on tumor patients and has effects on their quality of life. AIM: To investigate within the scope of follow-up, to collect data on the psychosocial burden on melanoma patients in relation to the predictors (medical factors, psychological variables, sociodemographic data) in order to define a "burden-risk patient". METHOD: From June to December 1997, 615 ambulant melanoma patients were questioned with the aid of the Hornheide questionnaire and the German version of the Hospital Anxiety and Depression Scale (HADS-D). RESULTS: The leading predictors for a psychosocial burden were found to be fear and depression, as well as tumor thickness, metastases, year of operation, sex, age, and marital status/household. With the aid of these results, a burden-risk patient could be defined: female sex, age between 40 and 59 years, divorced or widowed, separately living, with a tumor thickness of more than 4 mm, first diagnosis less than 3 years ago and prevailing metastases. This risk patient had also a high probability of having significant fear and depression values. CONCLUSION: The use of the Hornheide questionnaire for identifying the psychosocial burden is suitable to collect the individual burdens of the patients in particular and within a short period. In the same way, the needs of the patients can be met in particular, and thus his/her quality of life can be increased.

Modified ABC-point list of dermoscopy: A simplified and highly accurate dermoscopic algorithm for the diagnosis of cutaneous melanocytic lesions.

BACKGROUND: The use of dermoscopy (epiluminescence microscopy, surface microscopy, dermatoscopy) improves clinical diagnostic sensitivity by 10% to 27%, particularly achieved by different algorithms or scores. OBJECTIVE: We sought to develop a simplified and highly accurate dermoscopic-point list for cutaneous melanocytic lesions. METHOD: We studied consecutive patients with suspicious melanocytic lesions, which were excised and histopathologically examined at our institution. On the basis of the ABCD rule of Stolz, Menzies score, and the modified ABCD rule of Kittler, a simplified ABC-point list was developed. Simple points were given for the following: asymmetry of outer shape (A) or differential structures inside the lesion in at least 1 axis ((A)); the abrupt cutoff of network at the border in at least one quarter of circumference (B); 3 or more colors (C); 3 or more differential structures (D); or noticed change (evolution) in the last 3 months (E). Using 20-fold magnification of computer dermoscopy, the sensitivity, specificity, and diagnostic accuracy were examined in 269 cutaneous melanocytic lesions. Of these, 84 (31.2%) were cutaneous melanomas. Also, the sensitivity, specificity, and diagnostic accuracy were investigated with a 7-point checklist and the 7 features for melanoma. RESULTS: With the ABC-point list for the diagnosis of cutaneous melanoma, sensitivity was 90.5%, specificity was 87%, and diagnostic accuracy was 88.1%, confirmed by cross-validation. The ABCD rule resulted in 90.5%, 72.4%, and 78.1%; Menzies score in 95.2%, 77.8%, and 83.3%; 7-point checklist in 90.5%, 87%, and 88.1%; and 7 features for melanoma in 94%, 74.6%, and 80.7%, respectively, CONCLUSIONS: The ABC-point list is simpler than the already established algorithms. Despite its simplicity, a high sensitivity, specificity, and diagnostic accuracy was achieved. This simplified approach in dermoscopic diagnostics may contribute to further spread and enable to learn and use this method more easily.

"Functional" surgery in subungual melanoma.

BACKGROUND: Subungual melanomas represent approximately 2% to 3% of cutaneous melanomas in White populations. Complete or partial amputation proximal to the distal interphalangeal joint of the digits has been suggested. Recently, we introduced for acral melanomas, similar to lentigo maligna melanoma, limited excision and complete histology of excisional margins (three-dimensional histology). OBJECTIVE: To evaluate the prognostic relevance of clinical parameters and different surgical management in patients with subungual melanoma. STUDY DESIGN: From 1980 to 1999, subungual melanoma was diagnosed in 62 of 3,960 stage I and II melanoma patients (1.6%) of the melanoma registry of the Department of Dermatology (University of Tuebingen). A retrospective comparative analysis of two treatment groups was performed: Thirty-one patients had an amputation in or proximal to the distal interphalangeal joint (median follow-up of 55 months), and 31 patients had "functional" surgery with local excision of the tumor and only partial resection of the distal phalanx (median follow-up of 54 months). RESULTS: In the univariate analysis, the level of invasion (P=0.0059), ulceration (P=0.0024), and tumor thickness (P=0.0004) were significant prognostic factors for recurrence-free survival but not for survival. In a multivariate analysis, only lower tumor thickness and a reduced level of amputation were independent significant prognostic parameters for recurrence-free survival (P=0.035 and P=0.0069). Patients with an amputation in or proximal to the distal interphalangeal joint did not fare better than patients with less radical "functional" surgery. CONCLUSION: Limited excision with partial resection of the distal phalanx only and three-dimensional histology to assure tumor-free resection margins give better cosmetic and functional results and do not negatively affect the prognosis of patients with subungual melanoma.

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

BACKGROUND: Cutaneous melanoma is the most aggressive form of skin carcinoma in humans, frequently with a rapid progression of disease. To detect early developing metastasis, laboratory tests to determine levels of lactate dehydrogenase (LDH) and alkaline phosphatase (AP) form part of the regular follow-up, but often cannot discover recurrent disease at a sufficiently early stage. METHODS: To evaluate the diagnostic accuracy of protein S-100beta (S-100beta), melanoma-inhibitory activity (MIA), LDH, AP, and tyrosinase/MART-1 reverse transcription-polymerase chain reaction (RT-PCR), the authors included 296 consecutive AJCC Stage II or III clinically disease-free melanoma patients. Follow-up examinations were performed every 3 months and blood samples were drawn to determine the levels of these tumor markers. RESULTS: Metastasis occurred in 41 of the 296 patients during a median follow-up period of 19 months (range, 1-33 months). The sensitivity to detect new metastases was 29% for protein S-100beta, 22% for MIA, 2% for LDH, 17% for AP, and 24% for RT-PCR. The diagnostic accuracy was best for MIA (86%) and S-100beta (84%), whereas AP (79%), LDH (77%), and RT-PCR (72%) demonstrated lower values. Elevated values of S-100beta and MIA during follow-up examinations were associated with decreased survival rates in the further course of the disease, but pathologic findings of the other tumor markers showed no prognostic impact. CONCLUSIONS: To the authors' knowledge, the current study is the first comparison of the diagnostic accuracy of currently available tumor markers in the follow-up of high-risk melanoma patients. Protein S-100beta and MIA demonstrated a higher sensitivity, specificity, and diagnostic accuracy in the diagnosis of newly occurring metastasis compared with to the tumor markers AP, LDH, and RT-PCR diagnostics. Therefore, the tumor markers S-100beta and MIA may be useful in the follow-up of disease-free Stage II and III melanoma patients.

Prospective evaluation of a follow-up schedule in cutaneous melanoma patients: recommendations for an effective follow-up strategy.

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

[An unusual case of pyoderma gangrenosum with necrotizing granulomatous dermatitis]. / Ein ungewöhnlicher Fall eines Pyoderma gangraenosum mit nekrotisierender granulomatöser Dermatitis.

Four distinctive clinical and histological variants of pyoderma gangrenosum have been proposed: (1) ulcerative, (2) pustular, (3) bullous, and (4) vegetative. The rate of progression and associated systemic diseases, as well as the histopathologic changes, can vary considerably between these clinical variants. A 64-year-old man presented with ulcerative pyoderma gangrenosum associated with renal cell carcinoma and IgA paraproteinemia; he responded to oral thalidomide. Histopathology revealed unusual findings with signs of leukocytoclastic vasculitis, basophilic degeneration of collagen and zones of suppuration with a palisaded histiocytic and epithelioid granulomatous infiltration throughout the dermis.

Molecular diagnostics facilitate distinction between lethal and non-lethal subtypes of junctional epidermolysis bullosa: a case report and review of the literature.

UNLABELLED: The term epidermolysis bullosa (EB) encompasses a heterogeneous group of genodermatoses, characterised by fragility and blistering of the skin, often associated with extracutaneous manifestations. The clinical picture comprises severe subtypes with lethal outcome in the first years of life as well as milder subtypes with localised blistering or minimal symptoms confined exclusively to nail or teeth abnormalities. We present the case of a male infant, who was born with a few bullae and rapidly developed extensive blistering of the skin. The disease was complicated by painful erosions of the oral mucosa, refused ingestion, and recurrent infections. The child died at the age of 4 months because of cardiac failure due to severe sepsis. Antigen mapping of a skin biopsy showed a split within the lamina lucida of the epidermal basement membrane zone and junctional epidermolysis bullosa (JEB) was diagnosed within the first 3 weeks of life. Markedly reduced staining for laminin 5 indicated the Herlitz type of JEB (OMIM 226700), which could be confirmed by mutation analysis in the LAMB3 gene, showing homozygous nonsense mutations. CONCLUSION: early antigen mapping using antibodies against the proteins affected in epidermolysis bullosa, is a useful tool providing early mutation analysis and valuable prognostic information needed for adequate therapeutic strategies. The recently published literature on current diagnostic procedures and the revised classification system for inherited epidermolysis bullosa aim towards a better understanding of the disease.

Intravenous regional anesthesia (Bier's block) for botulinum toxin therapy of palmar hyperhidrosis is safe and effective.

BACKGROUND: Botulinum toxin type A (BTX-A) has been shown to be highly effective in reducing palmar hyperhidrosis. Since palmar injections is a painful procedure, the use of an anesthesia method is recommended. OBJECTIVE: To assess the efficacy of intravenous regional anesthesia (IVRA) for painless treatment of palmar hyperhidrosis with BTX-A compared to topical application of a local anesthetic agent. METHODS: Thirty patients with palmar hyperhidrosis were treated with BTX-A injections, using a total dose of 100 U BTX-A for each hand. One palm was pretreated with a topical application of local anesthetizing cream (EMLA cream), while the other palm was anesthetized with IVRA. Sweat secretion was visualized with Minor's test and quantified by corneometer analysis before and after BTX-A therapy. RESULTS: BTX-A therapy was significantly less painful in palms anesthetized with IVRA than in palms pretreated with EMLA cream (P < 0.0001, paired Wilcoxon rank test). Two weeks after the BTX-A injections, corneometer measurements showed that spontaneous sweat production had declined significantly, from 115 +/- 16.25 (left hand) and 114 +/- 17.58 (right hand) before therapy to 81.5 +/- 27.33 (left hand) and 74 +/- 28.08 (right hand) after therapy (P < 0.001, paired t test). CONCLUSION: IVRA safely and effectively alleviates the pain associated with BTX-A treatment for palmar hyperhidrosis. Quantitative analysis with the corneometer showed that BTX-A significantly reduces sweat production. We conclude that IVRA is a suitable method for providing pain relief in the treatment of patients with palmar hyperhidrosis.