Pediatric Langerhans cell histiocytosis: the impact of mutational profile on clinical progression and late sequelae.

Langerhans cell histiocytosis (LCH) is a clonal histiocytic disorder with recurrent mutations of BRAF and MAP2K1, but data on the impact of genetic features on progression and long-term sequelae are sparse. Cases of pediatric LCH with long-term follow-up from our institution were analyzed for mutations in BRAFV600 and MAP2K1 exons 2 and 3 by immunostaining with mutation-specific VE1 antibody, as well as allele-specific PCR and sequencing, respectively. Clinical and follow-up data were obtained from our files and a questionnaire sent to all former patients. Sixteen of 37 (43%) evaluable cases showed BRAFV600E, one case a BRAFV600D and eleven (30%) a MAP2K1 mutation. Nine cases were unmutated for both genes. All cases with risk organ involvement showed either BRAFV600 or MAP2K1 mutation. Patients with BRAFV600 mutation excluding Hashimoto-Pritzker cases had a significantly higher risk for relapses (p = 0.02). Long-term sequelae were present in 19/46 (41%) patients (median follow-up 12.5 years, range 1.0 to 30.8) with a trend for higher rates in mutated cases (mutated = 9/17, 53% versus non-BRAFV600/MAP2K1 mutated = 2/7, 29%). In addition, 8/9 cases with skin involvement including all Hashimoto-Pritzker cases (n = 3) were positive for BRAFV600E. Infants below 2 years more frequently had BRAFV600 mutations (p = 0.013). Despite favorable prognosis, pediatric LCH shows a high frequency of relapses and long-term medical sequelae.

Diagnostic accuracy of a new ex vivo confocal laser scanning microscope compared to H&E-stained paraffin slides for micrographic surgery of basal cell carcinoma.

BACKGROUND: For safe excision of malignant skin tumours, complete negative surgical margins are mandatory. The gold standard for analysis is frozen sections or paraffin-embedded haematoxylin and eosin (H&E)-stained slides. The production of H&E-stained slides is time-consuming (>20 h) while wounds remain unclosed. An upcoming method is confocal laser scanning microscopy (CLSM), a technique that scans unfixed fresh tissue rapidly. OBJECTIVE: Evaluation of the process to generate and analyse CLSM images and assessment of the accuracy to detect basal cell carcinoma (BCC) tissue. METHODS: Digital microscopic images were generated by the Histolog Scanner v1 from 544 fresh specimens of 148 BCCs that had been stained with a 0.01% proflavine solution. CLSM images were compared to the histological diagnoses of the corresponding H&E-stained slides. RESULTS: A total of 525 images could be analysed. The sensitivity was 73% (95% CI = [65.27%; 80.47%]), and the specificity was 96% (95% CI = [93.40%; 97.60%]). Detection of BCCs in punch biopsies was certainly detected (sensitivity of 100%). The median total time to generate and evaluate a CLSM image was 5.17 min (maximum 20.17 min and minimum 2.05 min). The greatest challenge was flattening the specimen to assure complete representation of the surgical margins. CONCLUSION: Confocal laser scanning microscopy is a time-saving and very effective alternative to classical paraffin-embedded or frozen sections. Patient treatment could be improved due to shorter hospital stays or faster outpatient therapy due to reduced intervals between surgical stages. Diagnostic accuracy of the microscope used still must be improved.

Incidence and characteristics of thick second primary melanomas: a study of the German Central Malignant Melanoma Registry.

BACKGROUND: Fast-growing melanomas are thought to be responsible for the stable incidence of thick melanomas. It has been suggested that campaigns for early diagnosis are unlikely to have a major impact on prognosis as rapid vertical growth rather than diagnostic delay is the major determinant for thick melanomas. OBJECTIVE: We investigated the impact of follow-up examinations on the incidence of thick second primary melanomas (SPMs) and analysed their clinic-pathologic characteristics. METHODS: We analysed a single-centre cohort of 2253 patients of the German Central Malignant Melanoma Registry with prospectively documented follow-up examinations. RESULTS: Primary tumour and patient characteristics were well balanced between patients with and without SPMs except for age (median 61 years, interquartile range [IQR] 51-67 vs. 56 years, IQR 43-67; P = 0.005). Metachronous SPMs occurred in 107 patients (4.7% of total) were thinner than the respective first primary melanoma (FPM) (median Breslow thickness of invasive melanomas 0.40 mm, IQR 0.28-0.75 vs. 0.80 mm, IQR 0.50-2.00; P < 0.001) and less often ulcerated (0.9% vs. 15.0%; P < 0.001). Melanomas >2.00 mm occurred in 2.8% of SPMs as compared to 23.4% of FPMs (P < 0.001). Thick SPMs (>1.00 mm; 14.0%) despite close-meshed follow-up examinations were frequently associated with atypical clinical presentation and uncommon histopathologic subtypes. One-third (5/15) of thick SPMs were clinically misdiagnosed as non-melanocytic lesions, most of them as basal cell carcinomas (n = 4). CONCLUSIONS: Regular total body skin examinations enable a highly efficient detection of early-stage melanomas and reduction of thick melanomas as compared to first primary melanomas. Our data indicate that fast-growing melanomas without opportunity of early detection are rare and cannot explain the stable incidence of thick melanomas. This highlights the importance of close-meshed total body skin examinations in patient groups that are at high risk of first or multiple primary melanomas.

[Differential diagnostic specific skin infiltrates in chronic myelomonocytic leukemia]. / Differenzialdiagnose spezifischer Hautinfiltrate bei chronischer myelomonozytärer Leukämie.

A 72-year-old male patient presented with multiple erythematous plaques on the lower arms, lower legs and feet. The patient suffered from rheumatoid arthritis and accompanying interstitial granulomatous dermatitis under treatment with tocilizumab. Several months prior to presentation a chronic myelomonocytic leukemia (CMML) had been diagnosed. The skin biopsy showed a perivascular infiltration of medium-sized cells with positivity for CD123, CD303 and CD4 with a low proliferation activity so that a diagnosis of a CMML-associated proliferation of plasmacytoid dendritic cells was made. The differential diagnosis of specific cutaneous infiltrates in CMML is discussed.

PRIMARY MALIGNANT AMELANOTIC MELANOMA ARISING FROM A VITILIGO PATCH OF AN AFRICAN TANZANIAN: CASE REPORT.

Skin cancer is rare in people of African origin while vitiligo occurs worldwide. The occurrence of primary malignant melanoma and vitiligo together is very rare. We present a rare case of primary malignant amelanotic melanoma arising from a depigmented patch of a patient with vitiligo. It was completely excised and followed for one year. No recurrence or metastases was noted during the follow up period.

[Chronic actinic dermatitis. Therapy with systemic PUVA and mycophenolate mofetil]. / Chronisch aktinische Dermatitis. Therapie mit systemischer PUVA und Mycophenolatmofetil.

A 66-year-old man was diagnosed with psoriasis in 2001 and treated accordingly; in 2007, the diagnosis was switched to atopic dermatitis and the therapy modified. Initially he improved with fumarates and methotrexate, but then experienced recurrent exacerbations with erythroderma and severe superinfection requiring hospitalization. Based on the modified clinical picture with striking accentuation on the head and back of the hands, we diagnosed chronic actinic dermatitis. In September 2008 immunosuppressive therapy with mycophenolate mophetil (2×500 mg/d) was started. Since the response was modest, photo-hardening with systemic photochemotherapy (PUVA) was added, producing close to complete recovery within 6 months.

A meningioma of the scalp that might have developed from a rudimentary meningocele.

Meningiomas of the skin are extremely rare. In this case of a congenital meningioma of the scalp, magnetic resonance imaging showed no communication to the meninges. The histological examination discovered a small group of meningioma cells in the periosteum, supporting the assumption that primary cutaneous meningiomas may develop from rudimentary meningoceles.

Clinical course and prognostic factors of Merkel cell carcinoma of the skin.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare neuroendocrine malignancy of the skin first described by Toker as 'trabecular carcinoma of the skin' in 1972. To date, the origin of the tumour cells still remains unclear. OBJECTIVES: The present study analyses prognostic factors of MCC. PATIENTS AND METHODS: The medical records of 57 patients with MCC treated between 1988 and 2006 at the Department of Dermatology in Tübingen were reviewed. RESULTS: We identified 26 (45.6%) male and 31 (54.4%) female patients with MCC; the age at diagnosis ranged from 26 to 97 years (median 71 years). Primary tumours were located mainly on the head and neck areas (27 cases, 47.4%) and upper extremities (14 cases, 24.6%); 11 tumours were found on the lower extremities (19.3%) and four lesions on the chest (7%); one patient had an unknown primary location. Forty-five (78.9%) patients were diagnosed at stage I of the disease, 11 (19.3%) at stage II, and one patient (1.8%) at stage III at initial presentation. Stage of the disease and age at initial presentation were statistically significant with regard to overall (P < 0.0001; P = 0.0327) and tumour-specific survival (P < 0.0001; P = 0.0156). Use of the Cox regression model revealed initial stage of the disease as the only significant factor in the multivariate analysis. Radiotherapy applied promptly after excision of the primary tumour extended the time to progression significantly (P = 0.0376) but did not prolong overall or tumour-specific survival. Other parameters such as sex, site of tumour, sentinel node biopsy, excision margins, skin and noncutaneous malignancies were found to be not significant. CONCLUSIONS: Currently, early recognition of the disease seems to be the only method of ensuring overall survival. However, evidence-based treatment modalities are still urgently needed.

Acral lentiginous melanoma: conventional histology vs. three-dimensional histology.

BACKGROUND: Patients with acral lentiginous melanoma (ALM) seem to have a poor prognosis. ALMs represent 4-10% of cutaneous melanomas in white populations. Surgery is mostly based on conventional histological evaluation. With micrographic surgery, continuously spreading tumours can be excised with smaller excision margins for better cosmesis and function. OBJECTIVES: Clinical parameters and surgical strategies influencing the prognosis of patients with ALM were evaluated. METHODS: Two hundred and forty-one patients (44% male, 56% female) with stage I/II ALM were recorded during 1980-2006. One hundred and thirty-three patients underwent complete histology of three-dimensional excision margins (3D histology) using the paraffin technique. Risk factors for disease-specific and recurrence-free survival were estimated. RESULTS: Patients were aged 26-87 years (median 63) with median tumour thickness of 2.0 mm. The median follow-up was 41 months. Multivariate analysis identified ulceration, conventional histology and tumour thickness as risk factors for recurrence-free and disease-specific survival. Using 3D histology, excision margins were significantly smaller (median 7 vs. 20 mm) without an increased risk of local recurrences. Patients with 3D histology had a 5-year survival of 81% compared with 63% with conventional histology. Retrospective analysis with immunohistological methods (anti-Melan-A) could improve the diagnostic specificity in detecting further melanocytic cell nests. CONCLUSIONS: Clinical and surgical risk factors seem to have different influences on the outcome of ALM. 3D histology allows reduction of excision margins by two-thirds without an increased risk of local recurrences and with better prognosis. 3D immunohistology could be a valuable diagnostic tool to reduce the rate of local recurrences.

[The consequences of subcutaneous India ink injection to produce factitial disease. Bilateral mastectomy, lymph node dissection, irradiation, and continued suspicion of neoplasia]. / Folgen von subkutaner Tuscheinjektion bei artifizieller Störung. Mastektomie, Lymphknotenausräumung, Radiatio und fortdauernder Malignomverdacht.

A 68-year-old woman with insulin-dependent diabetes mellitus presented with blue nodules on the ventral aspect of the thorax. According to the past history, these lesions had developed repeatedly. She had already had bilateral mastectomies and lymph node dissection. The histologic diagnosis was always mastitis with plasma cells and no neoplasia. Yet another biopsy was taken; the subcutis was stained blue-black. Histology revealed exogenous black pigment and mastitis. With Raman spectroscopy the pigment was identified as carbon black, which is a component of India ink. These findings together with the unusual course of the disease suggested the diagnosis of an artificial disorder. The likely conclusion is that our patient, over years, used her own (insulin) syringe to inject India ink into her skin and subcutaneous tissue; the damaging effect and tissue reaction was probably caused by preservatives such as phenol.

Correlation with digital dermoscopic images can help dermatopathologists to diagnose equivocal skin tumours.

BACKGROUND: A variety of pigmented skin tumours can lead to diagnostic difficulties in dermatopathology. OBJECTIVES: To investigate whether the interobserver agreement between histopathological diagnoses of equivocal pigmented tumours made by two referral centres can be improved by additional use of dermoscopic images. MATERIAL AND METHODS: Retrospective study using 160 tumours excised in the pigmented skin lesions clinic in Graz and 141 from Tübingen. Tumours were diagnosed in the referring centres using clinical data, histopathology and, if required, immunohistochemistry. The tumours were initially diagnosed as 74 melanomas, 218 melanocytic naevi and nine nonmelanocytic tumours. Haematoxylin and eosin sections, patients' age and sex, tumour localization and digital dermoscopic images were then exchanged between the participating centres. Then, diagnoses were made initially based solely on dermatopathology and clinical information. After a washout phase, the same sections were reevaluated with the additional use of dermoscopic images. The main outcome measures were the Cohen's kappa-coefficients of the initial diagnoses of the centre submitting the cases and the diagnoses of the other centre without and with dermoscopy. RESULTS: The kappa-coefficient between the initial diagnoses with those made by the second centre without dermoscopy was 0.90 in Graz, 0.73 in Tübingen, and 0.81 overall. With the additional use of dermoscopy the kappa-value was invariably high with 0.89 in Graz, and improved to 0.87 in Tübingen, and to 0.88 overall. CONCLUSIONS: The additional use of digital dermoscopic images further improved the overall very good agreement of histopathological diagnoses between two referral centres.

Microcystic adnexal carcinoma: an often misdiagnosed, locally aggressive growing skin tumor.

Microcystic adnexal carcinoma (MAC) belongs to the spectrum of locally aggressive adnexal carcinomas and most commonly occurs in the head and neck region. Recently it has been proposed that MAC is an apocrine tumor. It is characterized by slow, but locally aggressive growth with infiltration of subcutaneous fat tissue, muscles, perichondrium, periosteum, or perineurium. As a result, surgical treatment often leads to ablation defects, which are many times the size of the clinical lesion. In 1982, Goldstein and colleagues first reported MAC to be a distinct histologic entity characterized by a combination of keratinous cysts in the upper dermis, islands and strands of small basaloid, benign-appearing keratinocytes or squamous cells in the deeper dermis within a dense desmoplastic stroma, and areas of ductular differentiation. The authors report the case of a 78-year-old woman in whom a diagnosis of MAC was made when a tumor on the right cheek recurred for the second time. Previous histopathologic diagnoses were squamous cell carcinoma and desmoplastic trichoepithelioma. Local recurrences of the tumor occurred, despite histographic surgery because in hematoxylin and eosin stains, small islands of the deceptively benign-appearing small basaloid cells of MAC were not recognized as tumor cells. The reported case demonstrates the difficulties in diagnosing MAC and indicates that MAC should always be considered in the differential diagnosis of slowly growing tumors in the head and neck region. If MAC is diagnosed too late, it can be inoperable because of its infiltrative growth.

[Relapsing, therapy refractory episcleritis, paraproteinemia and cutaneous-subcutaneous nodules on arm and hip: manifestations of a necrobiotic xanthogranuloma (NXG)]. / Rezidivierende, therapierefraktäre Episkleritis, Paraproteinämie und kutan-subkutane Knoten an Arm und Hüfte: Manifestationen eines nekrobiotischen Xanthogranuloms (NXG).

BACKGROUND: Necrobiotic xanthogranuloma is a rare granulomatous disease featuring nodular, sometimes ulcerating, skin lesions in association with paraproteinemia and variable organ disease. Eye involvement manifests itself often as periorbital plaque-like infiltrates but also as chronic episcleritis, conjunctivitis, keratitis and scleritis. CASE REPORT: A 49-year-old female patient presented to our hospital with a seven-year history of relapsing bilateral episcleritis refractory to treatment. Her past medical history included an IgG paraproteinemia and C4-deficiency of unknown etiology. A year prior to presentation the patient had undergone biopsy of a skin nodule on her arm which histologically was suspected to be an infectious granuloma. A recurrence of the lesion at the site of biopsy together with a new nodule on the hip prompted us to perform further histological analyses. RESULTS: The histological specimen displayed numerous giant cells of the foreign body and Touton type, some xanthomatous foam cells with cholesterol clefts and collagen necrosis, leading to the diagnosis of NXG. As part of the disease, serology showed an IgG lambda paraproteinemia, elevated cANCA values, a C4 deficiency and a negative rheumatoid factor. No other immunological dysfunction was detected. CONCLUSIONS: NXG is a severe multi-system disorder that may cause various chronic inflammatory conditions of the eye's anterior segment. Its early diagnosis is mandatory as potentially fatal organ complications may arise and the association with lymphoproliferative diseases has been described. Due to the relative rarity of the disease no binding therapeutic regimen exists. Options include alkylating agents in combination with corticosteroids, plasmapheresis and subcutaneous interferon alfa-2 b.

[Correlation between dermoscopy and histopathology in pigmented and non-pigmented skin tumours]. / Korrelation von Dermascopie und Histopathologie bei melanozytären und nichtmelanozytären Hauttumoren.

Dermoscopy (dermatoscopy, epiluminescence microscopy, surface microscopy) is a non-invasive method in dermatology. With this method pigmented and non-pigmented skin tumours can be diagnosed with a clear higher sensitivity and specificity compared to clinical examination. Malignant skin tumours are detected earlier and unnecessary excisions of benign skin tumours can be avoided. The knowledge about the correlation between dermoscopy and histopathology is hereby an essential condition. In this continuing medical education article the correlation of both examination techniques is presented for the dermoscopic differential diagnoses.