Christina Mitteldorf

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.

Factors Predicting the Risk of In-Transit Recurrence After Sentinel Lymphonodectomy in Patients With Cutaneous Malignant Melanoma

BackgroundIn-transit metastasis is an important morbidity factor after sentinel lymphonodectomy (SLNE). So far, factors posing an increased risk after SLNE have not been adequately analyzed.MethodsUsing Kaplan-Meier estimations and the Cox proportional hazards model, we analyzed the risk of developing in-transit metastases after SLNE for 328 consecutive patients (median tumor thickness, 2.0 mm; median follow-up period, 40 months).ResultsThe 5-year probability of developing in-transit metastases as a first recurrence was 11.2%. After negative and positive SLNE, the probabilities were 6.3% and 24%, respectively. Patients in whom satellite metastases were excised concurrently with the primary tumor had a probability of recurrence with in-transit metastases of 41%. In sentinel lymph node (SLN)-negative patients with primary tumors having a thickness of more than 4 mm, the probability was 22.1%. Among the group of SLN-positive patients, significantly increased in-transit probabilities were observed in those with primary tumors that were thicker than 4 mm (41.8%), with tumors located on the distal extremities (42.1%), and with penetration of the nodal metastasis of >1 mm into the SLN (36%) and in patients with capsular breakthrough (63.3%). By using multifactorial analysis, the SLN status (P = .005), Breslow thickness (P = .0009), and extremity location of the primary melanoma (P = .005) significantly predicted the risk of in-transit recurrence. Satellite metastasis (P < .089), Clark level, and ulceration did not reach significance.ConclusionsSubgroups of patients can be identified who seem to have an increased risk of developing in-transit metastases as a first recurrence after SLNE. Individualized therapeutic strategies should be developed for these patients.

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.

Cutaneous lymphomas: an update. Part 2: B-cell lymphomas and related conditions.

Abstract:Primary cutaneous B-cell lymphomas (PCBCL) are the second most common form of primary cutaneous lymphomas and account for approximately 25%–30% of all primary cutaneous lymphomas. Both forms of low-grade malignant PCBCL, primary cutaneous follicle center lymphoma (PCFCL) and primary cutaneous marginal zone lymphoma of mucosa-associated lymphoid tissue-type (MALT lymphoma) (PCMZL) represent the vast majority of PCBCL and show an indolent slowly progressive course and an excellent prognosis despite a high recurrence rate. Genetic analysis indicates that PCMZL differ from other forms of extranodal MALT lymphomas. The more common class-switched and the non–class-switched form of PCMZL can be distinguished as two distinctive subsets that differ in the cellular composition, IgM expression, and biological behavior with extracutaneous involvement found in the non–class-switched form. Recently, unusual clinical and histological forms of PCMZL and PCFCL manifesting with miliary or agminated lesions have been described that are diagnostically challenging. In contrast to PCMZL and PCFCL, primary cutaneous diffuse large B-cell lymphoma, leg type, and other rare forms of large B-cell lymphomas such as intravascular large B-cell lymphoma have an unfavorable prognosis. There is an emerging group of Epstein–Barr virus (EBV)–driven B-cell lymphoproliferations including posttransplant lymphoproliferative disorders and mucocutaneous ulcer occurring in immunocompromised patients and EBV-associated diffuse large B-cell lymphoma of the elderly arising in the setting of senescence-linked immunodeficiency. This review reports on recent findings expanding the spectrum of clinicopathological features, differential diagnostic aspects, and the pathogenesis of PCBCL and discusses the group of EBV-associated B-cell lymphoproliferations involving the skin.

Bullous Sweet Syndrome in a Patient With t(9;22)(q34;q11)-Positive Chronic Myeloid Leukemia Treated With the Tyrosine Kinase Inhibitor Nilotinib: Interphase Cytogenetic Detection of BCR-ABL– Positive Lesional Cells

BACKGROUND An association of Sweet syndrome with chronic myeloid leukemia (CML) has been recently observed in patients treated with tyrosine kinase inhibitors. OBSERVATIONS We describe a 67-year-old patient with a 6-year history of Philadelphia chromosome translocation t(9;22)(q34;q11)-positive CML. The tyrosine kinase inhibitor AMN107 (nilotinib) kept the patient in chronic phase. After 10 months of taking nilotinib, he developed pneumonia with septic features. Seven days later, bullous skin infiltrations on the upper arms and a large, painful bullous swelling of the right neck occurred without any evidence of a viral, bacterial, or fungal blood infection. Findings from histologic examination showed massive infiltrations of the whole dermis with neutrophil granulocytes as well as with monocytoid histiocytic cells. Fluorescence in situ hybridization analysis of paraffin-embedded tissue revealed a BCR-ABL fusion, indicating the presence of t(9;22)(q34;q11). The addition of oral prednisolone to an adequate antibiotic treatment led to rapid resolution of the cutaneous infiltrations. CONCLUSIONS Skin infiltrations consistent with Sweet syndrome can occur in patients with septic CML during the treatment with tyrosine kinase inhibitors, including nilotinib. Skin infiltrations can include specific CML cells.

High frequency of primary cutaneous lymphomas associated with lymphoproliferative disorders of different lineage

In patients suffering from primary cutaneous lymphomas, secondary malignancies of various origin may develop. However, the frequency of a second neoplasm deriving from another lymphoid lineage is still unclear and may be underestimated. We screened all our patients with primary cutaneous lymphomas from a 4-year recruitment period for a coexisting secondary lymphoproliferative disorder. The cohort comprised of a total of 82 patients with primary cutaneous lymphomas, 62 with primary cutaneous T-cell lymphoma (CTCL), 18 with primary cutaneous B-cell lymphomas, and two with CD4+/CD56+ hematodermic neoplasm/blastic lymphomas. Seven patients (8.5%) were identified with a coexisting lymphoma of a different lymphoid lineage. Four patients with Sézary syndrome (SS) suffered from systemic B-cell lymphoma. Two of these developed SS after chemotherapy of their B-cell lymphoma. The other three patients with various types of skin lymphomas (SS, Mycosis fungoides [MF], primary cutaneous marginal zone lymphoma) developed Hodgkin’s disease (hairy cell leukemia). Our data indicate that patients with primary cutaneous lymphomas have an elevated risk for the development of a secondary lymphoproliferative disorder even without previous chemotherapy. Possible explanations for this association include a genetic predisposition, alterations in early progenitor cells, underlying viral infections, and/or stimulation of a B-cell clone by the malignant helper T cells of the primary CTCL and vice versa.

Detection of Merkel cell polyomavirus and human papillomaviruses in Merkel cell carcinoma combined with squamous cell carcinoma in immunocompetent European patients.

Background: About 10% of patients with Merkel cell carcinoma (MCC) suffer from an associated squamous cell carcinoma (SCC). In European patients, Merkel cell polyomavirus (MCPyV) is detectable in 60%–88% of the MCC tumors. In combined lesions, MCPyV was not detectable so far. Methods: We investigated 2 combined tumors of MCC and SCC for the presence of MCPyV and human papillomavirus (HPV) by polymerase chain reaction and immunohistochemistry. Results: In both lesions, MCPyV DNA was found, and in 1 case, HPV DNA was also detected. This is the first report of a coinfection with HPV and MCPyV in combined MCC–SCC tumors. Conclusions: The results underline the hypothesis of cocancerogenesis of 2 oncogenic viruses in nonmelanoma skin cancer. Technical reasons and a low viral copy number of MCPyV hampering immunohistochemical detection may be responsible for the negative results in the literature.

Treating advanced melanoma: current insights and opportunities

Whereas thin melanomas have an excellent prognosis after sufficient surgical treatment, melanoma disease in advanced stages is still a therapeutic challenge. After decades of frustrating studies, new therapeutic strategies have come up in the past few years. On the one hand, increasing insights into the molecular aberrations in melanoma have led to specific “targeted” therapies to affect only the mutated tumor cells, as in many other types of cancers. Today there are few “targeted” substances which are already approved and successfully used for single or combination therapy, but many others are under development. While on the other hand, nonpersonalized strategy substances have been developed successfully inducing an immunologic tumor response. Both kinds of therapy have been found to result in an improvement not only of the response rate, but also of the overall survival in metastatic disease, which represents a milestone in melanoma therapy. However, using these therapies there is still much to learn regarding the effects, the side effects, and the limitations of these promising substances.

Paediatric cutaneous lymphomas: a review and comparison with adult counterparts.

Primary cutaneous lymphomas (CL) in children is rare. Only a few studies focused specifically on paediatric CL and therefore little is known whether primary CL in children are similar to or different from their adult counterparts with respect to the clinicopathological presentation, behaviour and prognosis. An extensive literature search using PubMed/MEDLINE from January 1995 through July 2014 was undertaken for articles reporting cases of paediatric CL. In addition, we identified 31 children with CL in our institutions. Mycosis fungoides and lymphomatoid papulosis are the two most prevalent lymphoma forms in children. A few entities of cutaneous lymphomas such as cutaneous diffuse large B‐cell lymphoma leg type, and Sézary syndrome have not been reported so far in children. Other lymphoma entities such as hydroa vacciniforme‐like lymphoma are mostly seen in certain geographic areas (Asia, Central and South America). In the paediatric population, low‐malignant indolent forms such as primary cutaneous marginal zone lymphoma and primary cutaneous follicle centre lymphoma are very rare, whereas the more aggressive forms of B‐cell lymphomas, precursor lymphoblastic lymphomas, and blastic plasmacytoid dendritic cell neoplasm are the most common forms in children, mostly involving the skin secondarily. Most paediatric lymphomas have similar clinicopathological features and course as their adults counterparts, particularly in the group of cutaneous T‐cell lymphomas. The spectrum of cutaneous B‐cell lymphomas in children significantly differs from the one in adults. Diagnostic work‐up and treatment of paediatric patients with lymphomas are best achieved in close collaboration with paediatric haematopathologists and oncologists.

Cutting a sentinel lymph node into slices is the optimal first step for examination of sentinel lymph nodes in melanoma patients

The optimal processing for the pathology of sentinel lymph nodes of patients with melanoma is still a matter of debate. We compared two protocols of sentinel lymph node processing, which were consecutively applied. For the first protocol, the sentinel lymph nodes were cut into 1–2 mm thick slices. From each slice, 12 microtome sections were stained (multiple slices protocol). For the second protocol, which is a modification of the recent European Organisation for Research and Treatment of Cancer protocol, the sentinel lymph nodes were bivalved. Five consecutive series of microtome sections, with gaps of 50 μm between them, were prepared from each cut surface (bivalving protocol). H&E and immunohistochemical staining were integral elements of both protocols. A total of 584 sentinel lymph nodes (1.8±0.9 per patient) were examined. The percentages of micrometastases (29 versus 27%) and of capsular naevi (13 versus 15%) detected were very similar for both protocols. As shown by multivariate logistic regression, Breslow thickness (P=0.003) and younger age (P=0.01) correlated with nodal metastasis. The type of histological preparation, ulceration and sex were not significant. The multiple slices protocol produced, on average, 4 paraffin blocks and 46 microtome sections per node. The bivalving protocol constantly produced 2 paraffin blocks and 42 microtome sections. For technical processing, the multiple slices protocol required, on average, 38 min per sentinel lymph node, whereas the bivalving protocol required 55 min. Both protocols yielded excellent detection rates with a similar amount of work being required on the part of the pathologist. Compared with the bivalving protocol, the multiple slices protocol was less labor intensive for the technical staff.