Bernward Völker

The hand‐foot‐syndrome associated with medical tumor therapy – classification and management

The hand‐foot‐syndrome (HFS, palmoplantar erythrodysesthesia, chemotherapy‐associated acral erythema) is characterized by painful predominantly palmo‐plantar lesions. The association with different chemotherapeutic agents has been known for over 20 years. More recently, HFS has been reported in association with regimens using targeted agents, in particular the multikinase inhibitors (MKI) sorafenib and sunitinib. The HFS associated with MKI has a different distribution and clinical appearance than the traditional disorder. In this review, similarities and differences between chemotherapy‐ and MKI‐associated HFS are discussed and current recommendations for their prophylaxis and management are summarized.

Anal Mucosal Melanoma with KIT-Activating Mutation and Response to Imatinib Therapy – Case Report and Review of the Literature

Previously an increased frequency of KIT aberrations in mucosal melanomas was reported, whereas c-KIT in most types of cutaneous melanomas does not appear to be of pathogenetic importance. Imatinib has become the standard of care in other cancers with KIT mutations such as gastrointestinal stromal tumors. Recently 12 cases of metastatic melanoma and KIT-activating mutations have been published to be successfully treated with c-KIT blockers such as imatinib, sunitinib, dasatinib or sorafenib. We report here on one of our patients with KIT-activating mutation in metastatic anal mucosal melanoma, who showed a response to imatinib therapy and summarize the available literature regarding this new therapeutic option.

Sentinel lymph node status is the most important prognostic factor for thick (≥ 4 mm) melanomas

Background: The value of the status of the sentinel lymph node (SLN) in patients with thick melanomas (Breslow thickness ≥ 4 mm) is controversial.

Dynamic Changes in Nevi of a Patient With Melanoma Treated With Vemurafenib: Importance of Sequential Dermoscopy

BACKGROUND Therapy with vemurafenib, an inhibitor of mutated BRAF, yields a response rate of approximately 50% in patients with metastatic melanoma harboring a BRAF V600E mutation. As an adverse effect of vemurafenib, proliferative disorders of keratinocytes, including squamous cell carcinoma, have been described. Low concentration of vemurafenib as present in the epidermis were found to activate wild-type RAF, which, in combination with a preexisting RAS mutation, can promote keratinocyte proliferation. While activating BRAF mutations occur in approximately 50% of melanomas, they are even more frequently observed in melanocytic nevi. OBSERVATION We present the case of a patient with dynamic changes of melanocytic nevi well documented by sequential digital dermoscopy during vemurafenib therapy. A variety of dermoscopic changes were observed. First, nevi involuted, and all of these originally showed a centrally elevated papillomatous and predominant globular pattern. Second, preexisting nevi increased in size, and pigmentation that rendered them atypical. Such lesions were flat and showed a predominant reticular pattern at baseline. Third, multiple new nevi occurred. One example of each of the latter 2 categories was excised and showed wild-type BRAF. CONCLUSION Our findings of changing nevi in a patient treated with vemurafenib highlight the need for sequential skin examinations, including dermoscopy.

Prognostic significance of isolated HMB45 or melan a positive cells in melanoma sentinel lymph nodes

The detection of micrometastases (defined as groups of malignant cells) in the sentinel lymph node (SLN) is an important prognostic tool in melanoma. The use of immunohistochemistry with melanocytic markers such as HMB45 and Melan A increases the detection rate of micrometastases but there are also cases with isolated immunohistochemically positive cells (IPC). To determine the prognostic significance of isolated HMB45 and/or Melan A positive cells in melanoma SLN, we compared the clinical course of 47 patients with IPC to 308 patients with negative SLN and to 122 patients with micrometastases. The mean follow-up was 38.1 months. By Kaplan-Meier analyses, relapse free survival and overall survival of patients with IPC were similar to SLN negative patients, whereas patients with micrometastases had a significantly worse relapse free survival and overall survival. In the 47 patients with IPC, 6 relapses (12.8%) and 3 melanoma-related death (6.4%) occurred, in the SLN negative patients 36 relapses (11.7%) and 17 melanoma-related deaths (5.5%), in the patients with micrometastases 46 relapses (37.7%) and 29 melanoma-related deaths (23.8%). Prognosis of patients with IPC in SLN did not correlate with type of positive staining (HMB45, Melan A, or both), capsular involvement, number of cells, presence of cytologic atypias of IPC, or tumor penetrative depth. In conclusion, with short-term follow-up IPC in melanoma SLN are without prognostic significance.

Age as a key factor influencing metastasizing patterns and disease-specific survival after sentinel lymph node biopsy for cutaneous melanoma.

In our study, we investigated the impact of the constitutional factor age on the clinical courses of melanoma patients with sentinel lymph node (SLN) biopsy. Descriptive statistics, Kaplan‐Meier estimates, logistic regression analysis and the Cox proportional hazards model were used to study a population of 2,268 consecutive patients from three German melanoma centers. Younger age was significantly related to less advanced primary tumors. Nevertheless, patients younger than 40 years of age had a twofold risk of being SLN‐positive (p < 0.000001). Of the young patients with primary melanomas with a thickness of 0.76 mm to 1.0 mm, 19.7% were SLN‐positive. Using multivariate analysis, younger age, increasing Breslow thickness, ulceration and male sex were significantly related to a higher probability of SLN‐metastasis. During follow‐up, older patients displayed a significantly increased risk of in‐transit recurrences (p = 0.000002) and lymph node recurrences (p = 0.0004). With respect to melanoma specific overall survival the patients age was highly significant in the multivariate analysis. The unfavorable effect of being older was significant in the subgroups with positive and negative SLNs. Age remained also significant for the survival after the onset of distant metastases (p = 0.002). In conclusion, the patients age is a strong and independent predictor of melanoma‐specific survival in patients with localized melanomas, in patients with positive SLNs and after the onset of distant metastases. Younger patients have a better prognosis despite their higher probability of SLN metastasis. Older patients are less frequently SLN‐positive but have a higher risk of loco‐regional recurrence.

Comparison of classification systems in melanoma sentinel lymph nodes--an analysis of 697 patients from a single center.

In melanoma, different classification systems have been proposed that predict overall survival (OS) and recurrence‐free survival (RFS) based on findings in the sentinel lymph node (SLN). The authors of this report compared the RFS and OS of 697 melanoma patients as predicted by various classification systems.

Tumoral melanosis involving the sentinel lymph nodes: a case report

Abstract:  Tumoral or nodular melanosis is characterized by a clinical lesion suspicious for malignant melanoma, the histopathological correlate is a nodular accumulation of melanophages in the dermis. We present a patient with nodular melanosis involving also the sentinel lymph nodes and discuss possible differential diagnoses as well as prognostic and therapeutic implications.

Erythema nodosum in a patient undergoing vemurafenib therapy for metastatic melanoma

ejd.2012.1915 Auteur(s) : Annette Degen1 Degen.Annette@mh-hannover.de, Bernward Volker2, Alexander Kapp1, Ralf Gutzmer1 1 Department of Dermatology and Allergy, Skin Cancer Center Hannover, Ricklinger Str. 5 D- 30449 Hannover, Germany 2 Department of Pathology, Klinikum Nordstadt, Hannover, Germany Inhibitors of mutated BRAF such as vemurafenib and dabrafenib achieve objective response rates in approximately 50% of metastasizing melanomas harbouring a BRAF mutation [1], but they are also associated [...]

Allele frequencies of BRAFV600 mutations in primary melanomas and matched metastases and their relevance for BRAF inhibitor therapy in metastatic melanoma.

Background The detection of BRAFV600 mutations in patients with metastatic melanoma is important because of the availability of BRAF inhibitor therapy. However, the clinical relevance of the frequency of BRAFV600 mutant alleles is unclear. Patients and Methods Allele frequencies of BRAFV600 mutations were analyzed by ultra-deep next-generation sequencing in formalin-fixed, paraffin-embedded melanoma tissue (75 primary melanomas and 88 matched metastases). In a second study, pretreatment specimens from 76 patients who received BRAF inhibitors were retrospectively analyzed, and BRAFV600 allele frequencies were correlated with therapeutic results. Results Thirty-five patients had concordantly BRAF-positive and 36 (48%) patients had concordantly BRAF-negative primary melanomas and matched metastases, and four patients had discordant samples with low allele frequencies (3.4–5.2%). Twenty-six of 35 patients with concordant samples had BRAFV600E mutations, three of whom had additional mutations (V600K in two patients and V600R in one) and nine patients had exclusively non-V600E mutations (V600K in eight patients and V600E -c.1799_1800TG > AA- in one patient). The frequency of mutated BRAFV600 alleles was similar in the primary melanoma and matched metastasis in 27/35 patients, but differed by >3-fold in 8/35 of samples. BRAFV600E allele frequencies in pretreatment tumor specimens were not significantly correlated with treatment outcomes in 76 patients with metastatic melanoma who were treated with BRAF inhibitors. Conclusions BRAFV600 mutation status and allele frequency is consistent in the majority of primary melanomas and matched metastases. A small subgroup of patients has double mutations. BRAFV600 allele frequencies are not correlated with the response to BRAF inhibitors.