Checkpoint blockade and BRAF/MEK therapy in the therapeutic setting improved the overall survival after sentinel node biopsy: A retrospective study comparing patients with primary care between 1998-2009 and 2010-2017.

Immunotherapies using checkpoint blockade and BRAF/MEK therapies have improved overall survival (OS) in patients with unresectable melanoma metastases. In this retrospective study, we aimed to demonstrate the resulting increase in melanoma-specific survival (MSS) and OS after the excision of primary melanomas (≥1 mm thick) and sentinel lymph node (SN) biopsy (SNB). Using Kaplan-Meier estimates and Cox models, we compared two consecutive cohorts. Patients in cohort 1 (N = 518) underwent SNB between 1998 and 2009, and patients in cohort 2 (N = 460) between 2010 and 2017, when checkpoint blockade and BRAF/(MEK) inhibition became available for the treatment of unresectable relapses. The median follow-up times were 120 and 73 months, respectively. While recurrence-free and distant metastasis-free survival rates remained very similar, MSS and OS increased in favor of cohort 2. The estimated 5-year OS rate of SN-positive patients increased by 14.3% (78.5% vs 64.2%, logrank test: P = .005). The MSS benefit was significant even with low SN tumor burden (metastasis diameter < 1 mm). On multivariate analyses, the risk-reduction in favor of cohort 2 was significant in the total population and in the SN-negative and SN-positive subgroups. In SN-positive patients, besides the availability of modern therapies, SN metastasis diameter and ulceration were independent factors of MSS and OS. Treatment of unresectable melanoma recurrences with modern drug therapies results in significantly higher survival rates in a population with SNB. The survival benefit measured from primary melanoma affects both the SN-positive and SN-negative subpopulations.

Left-sided excess in the laterality of cutaneous melanocytic nevi and melanomas.

BACKGROUND AND OBJECTIVES: Asymmetrical distribution of melanomas in favor of the left body half has been repeatedly described. PATIENTS AND METHODS: In a prospective cross-sectional study, we investigated the distribution of melanocytic nevi between the left and right halves of the body in 702 patients. In 2,004 consecutive cases with melanomas, we retrospectively determined left to right (L/R) ratios of primary melanomas, lymph node metastases, and melanocytic nevi in sentinel lymph nodes (SN). RESULTS: The L/R ratios for cutaneous nevi and melanomas were 1.23 (95 % confidence interval [CI] 1.12-1.36) and 1.6 (95 % CI 1.37-1.88), respectively. In both cutaneous nevi and melanomas, the left-sided excess was mainly found in intermittently light-exposed skin. Of the nevus patients, 92.4 % were right-handed. Breslow thickness and rates of ulceration did not differ significantly between the two body halves. CONCLUSIONS: Melanocytic nevi and melanomas are more frequently found on the left body half. We assume asymmetric solar radiation as the causative factor. The vast majority of right-handed people might unconsciously align their posture during outdoor activities so that the light falls in from the left. This avoids shadow cast by the dominant arm, shoulder, or head.

Linksüberhang in der Verteilung von melanozytären Nävi und Melanomen.

HINTERGRUND UND ZIELE: Eine asymmetrische Verteilung von Melanomen zugunsten der linken Körperhälfte wurde wiederholt beschrieben. PATIENTEN UND METHODIK: In einer prospektiven Querschnittstudie untersuchten wir bei 702 Patienten einer dermatologischen Klinik die Verteilung melanozytärer Nävi zwischen der linken und der rechten Körperhälfte. Außerdem bestimmten wir retrospektiv das Verhältnis von links zu rechts (L/R) von primären Melanomen, Lymphknotenmetastasen und Nävi in Sentinel-Lymphknoten (SN) bei 2004 konsekutiven Melanomfällen. ERGEBNISSE: Die L/R-Ratios für kutane Nävi und Melanome betrugen 1,23 (95 %-Konfidenzintervall [KI] 1,12-1,36) sowie 1,6 (95 %-KI 1,37-1,88). Sowohl bei kutanen Nävi als auch bei Melanomen wurde der Linksüberschuss hauptsächlich in intermittierend lichtexponierter Haut gefunden. In der Nävuspopulation waren 92,4 % Rechtshänder. Die Tumordicke nach Breslow und die Ulzerationsrate waren bei linksseitigen oder rechtsseitigen primären Melanomen ähnlich. SCHLUSSFOLGERUNGEN: Melanozytäre Nävi und Melanome sind numerisch häufiger auf der linken Körperhälfte zu finden. Wir nehmen asymmetrische Sonneneinstrahlung als ursächlich an. Die große Mehrheit der Rechtshänder könnte ihre Körperhaltung bei Aktivitäten im Freien unbewusst so ausrichteten, dass das Licht von links einfällt. Dadurch wird der Schattenwurf durch den dominanten Arm, die Schulter oder den Kopf vermieden.

The sentinel node invasion level (SNIL) as a prognostic parameter in melanoma.

Sentinel lymph node (SN) tumor burden is becoming increasingly important and is likely to be included in future N classifications in melanoma. Our aim was to investigate the prognostic significance of melanoma infiltration of various anatomically defined lymph node substructures. This retrospective cohort study included 1250 consecutive patients with SN biopsy. The pathology protocol required description of metastatic infiltration of each of the following lymph node substructures: intracapsular lymph vessels, subcapsular and transverse sinuses, cortex, paracortex, medulla, and capsule. Within the SN with the highest tumor burden, the SN invasion level (SNIL) was defined as follows: SNIL 1 = melanoma cells confined to intracapsular lymph vessels, subcapsular or transverse sinuses; SNIL 2 = melanoma infiltrating the cortex or paracortex; SNIL 3 = melanoma infiltrating the medulla or capsule. We classified 338 SN-positive patients according to the non-metric SNIL. Using Kaplan-Meier estimates and Cox models, recurrence-free survival (RFS), melanoma-specific survival (MSS) and nodal basin recurrence rates were analyzed. The median follow-up time was 75 months. The SNIL divided the SN-positive population into three groups with significantly different RFS, MSS, and nodal basin recurrence probabilities. The MSS of patients with SNIL 1 was virtually identical to that of SN-negative patients, whereas outgrowth of the metastasis from the parenchyma into the fibrous capsule or the medulla of the lymph node indicated a very poor prognosis. Thus, the SNIL may help to better assess the benefit-risk ratio of adjuvant therapies in patients with different SN metastasis patterns.

AL-Amyloidoma of the Skin-A Rare Manifestation of Primary Cutaneous Marginal Zone Lymphoma.

AL-amyloidoma is considered to be a variant of primary cutaneous marginal zone lymphoma (pcMZL). A 51-year-old white man presented a 2 × 2-cm erythematous to brownish waxy plaque on the back of the scalp. The plaque was first noticed 16 years ago. It was asymptomatic, and the patient was otherwise healthy. The lesion was excised. Histological examination revealed dermal deposits of amyloid and a subtle perivascular infiltrate, predominately consisting of plasma cells. Infiltrating cells expressed CD79a, bcl2, and IgG and were negative for bcl6, CD56, and IgM. A monoclonal light-chain expression of lambda (lambda:kappa = 10:1) was demonstrated by in situ hybridization. The diagnosis of pcMZL, presenting as an AL-amyloidoma, was made because staging procedures excluded systemic manifestation of lymphoma, monoclonal gammopathy, and systemic amyloidosis. Cutaneous amyloid deposits with monoclonal plasma cell proliferation can occur as a result of monoclonal gammopathy/plasmocytoma or as a rare manifestation of pcMZL. Systemic B-cell lymphoma and systemic monoclonal plasma cell proliferations have to be excluded.

The impact of nodal tumour burden on lymphoscintigraphic imaging in patients with melanomas.

PURPOSE: To retrospectively study the influence of nodal tumour burden on lymphoscintigraphic imaging in 509 consecutive patients with melanomas. METHODS: Bidirectional lymphatic drainage, the clear depiction of an afferent lymphatic vessel, time to depiction of the first sentinel lymph node (SLN) and number of depicted and excised nodes were recorded. Nodal tumour load was classified as SLN-negative, SLN micrometastases or macrometastases. RESULTS: In the overall population, using multivariate regression analysis, a short SLN depiction time was significantly associated with the depiction of a greater number of radioactive nodes, a short distance between the primary tumour site and the nodal basin, younger age and lower nodal tumour burden. The proportion of patients with clear depiction of an afferent lymphatic vessel depended on the nodal tumour load (46% in SLN-negative patients, 57% in SLN positive patients, and 69% in patients with macrometastases; P = 0.009). Macrometastasis was significantly associated with delayed depiction of the first radioactive node and a greater number of depicted hotspots. In patients with clinically nonsuspicious nodes, i.e. the classical target group for SLN biopsy, clear depiction of an afferent vessel was significantly associated with a higher number of SLNs during dynamic acquisition, SLN micrometastasis and a higher overall number of metastatic lymph nodes after SLN biopsy plus completion lymphadenectomy. The excision of more than two SLNs did not increase the metastasis detection rate. In patients with bidirectional or tridirectional lymphatic drainage, the SLN positivity rates for the first, second and third basin were 25.4%, 11.7% and 0.0 %, respectively (P = 0.002). CONCLUSION: In patients with clinically nonsuspicious lymph nodes, clear depiction of an afferent lymph vessel may be a sign of micrometastasis. Macrometastasis is associated with prominent afferent vessels, delayed depiction of the first radioactive node and a higher number of depicted hotspots.

Repetitive injections of botulinum toxin A continuously increase the duration of efficacy in primary axillary hyperhidrosis: a retrospective analysis in 101 patients.

BACKGROUND AND OBJECTIVES: Botulinum toxin type A is an effective, well-tolerated, albeit temporary treatment for primary axillary hyperhidrosis. However, little is known about the influence of repetitive injections on the duration of efficacy. PATIENTS AND METHODS: 139 patients with primary axillary hyperhidrosis were injected with 50 units of botulinum toxin per axilla. In 101 patients, who received at least three treatments, the duration of efficacy after the first, second, and last treatment was evaluated. RESULTS: The median duration of efficacy was 4.0 months, 4.5 months, and 5.0 months after the first, second, and last injection, respectively. Overall, the duration of efficacy was significantly longer after the last injection compared to the duration of efficacy after the first injection (p = 0.0055, Wilcoxon matched-pairs signed-rank test). Likewise, the difference between the first and second injection (p = 0.0302) as well as the difference between the second and the last injection (p = 0.0381) were significant. In 25.7 % of patients, the duration of efficacy remained unchanged over the entire treatment period. CONCLUSIONS: Repetitive botulinum toxin treatments led to a significantly increased duration of efficacy in axillary hyperhidrosis. While the average duration of efficacy continued to increase with each treatment, there were considerable interindividual differences.

Sentinel node biopsy improves prognostic stratification in patients with thin (pT1) melanomas and an additional risk factor.

BACKGROUND: Sentinel lymph node (SLN) biopsy (SLNB) for pT1 melanomas is not generally recognized as a clinical standard. We studied the value of SLNB for pT1 melanoma patients having at least one additional risk factor. PATIENTS: Among 931 patients with SLNB, 210 had pT1 melanomas. All of the latter showed at least one of the following risk factors: ulceration (4 %) Clark level IV (44 %), nodular growth pattern (11 %), mitoses (59 %), regression (38 %) or age ≤ 40 years (27 %). RESULTS: In this selected pT1 population, we observed a surprisingly high SLN positivity rate of 18 %. The melanoma-specific overall survival significantly depended on SLN status. Compared with Clark IV, a lower invasion level (Clark II/III) was associated with a higher proportion of positive SLNs (25 vs. 10 %; p < 0.01). There was a trend towards a higher SLN positivity rate in younger patients (p = 0.06). Breslow, ulceration, mitoses, nodular growth pattern, and sex did not reach significance. Regression was significantly more frequently found in very thin melanomas (≤ 0.75 mm) and tended to be significant in this subgroup (p = 0.075). CONCLUSIONS: SLNB improves prognostic stratification in patients with thin melanomas having an additional risk factor. Clark level IV most likely does not belong to these risk factors. The impact of regression deserves further consideration. Our data suggest that SLNB should be offered to patients with thin melanomas, if ulceration, nodular growth pattern, mitoses, or regression are present, or if the patient is younger than 40 years of age.

Individualized surgery: gamma-probe-guided lymphadenectomy in patients with clinically enlarged lymph node metastases from melanomas.

BACKGROUND: The value of a preoperative lymphoscintigraphy in melanoma patients with clinically evident regional lymph node metastases has not been studied. Therapeutic lymph node dissection (TLND) is regarded as the clinical standard, but the appropriate extent of TLND is controversial in all lymphatic basins. PATIENTS AND METHODS: Of the 115 consecutive patients with surgery on palpable lymph node metastases, 34 received a pre-operative lymphoscintigraphy. Lymphatic drainage to a second nodal basin outside the clinically involved basin was found in 15 cases. In 13 patients, the ectopic tumor-draining lymph nodes were excised as in a sentinel node biopsy. The lymph nodes from the TLND specimens were postoperatively separated and classified as either radioactive or non-radioactive. RESULTS: A total of 493 lymph nodes were examined pathologically. The largest macrometastasis maintained the ability to take up radiotracer in 77% of cases. Radioactively labeled lymph nodes carried a higher risk of being involved with metastasis. The proportions of tumor involvement for radioactive and non-radioactive lymph nodes were 44.5 and 16.9%, respectively (P=0.00002). Of the 13 ectopic nodal basins surgically explored, six harbored clinically occult metastases. CONCLUSION: In patients undergoing TLND for palpable metastases, tumor-draining lymph nodes in a second, ectopic nodal basin should be excised, because they could be affected by occult metastasis. With respect to radioactive lymph nodes situated within the nodal basin of the macrometastasis but beyond the borders of a less-radical lymphadenectomy, further studies are needed.

Leg swelling after inguinal sentinel lymph node biopsy and primary melanoma excision with a safety margin.

BACKGROUND: Risk-factors for leg swelling following primary melanoma excision and inguinal sentinel lymphadenectomy (SLNE) have not been sufficiently investigated. PATIENTS AND METHODS: We prospectively studied three parameters in 105 subjects: 1) subjectively perceived swelling, 2) clinically diagnosed swelling and 3) photo-optical measurement of volume differences between both legs. RESULTS: Perceived swelling, clinically diagnosed swelling, and manifest edema occurred in 31%, 15%, and 7% of patients respectively. Following inguinal SLNE, there was a mean volume increase of 1.5% in the operated leg. Both the lower leg and the thigh increased in volume. Obesity, primary melanoma location on the lower leg, and inguinal seromas were identified as significant risk factors for postoperative swelling. Wider excision margins around a primary melanoma on the thigh were also associated with a significant increase in volume. Age, sex, the number of sentinel lymph nodes, the drainage fluid volume, and the time since SLNE were non-significant. CONCLUSIONS: Both inguinal SLNE and primary melanoma excision may contribute to minimal fluid accumulation in the leg. More than two-thirds of patients did not have any swelling. Obesity, location of the primary melanoma at a distal site on the leg, a wide safety margin, and seromas are associated with postoperative leg swelling.

Melanocytic nevi in sentinel lymph nodes: association with cutaneous nevi and clinical relevance in patients with cutaneous melanomas.

PURPOSE: Melanocytic nevi in lymph nodes (NNs) are an important histological differential diagnosis of initial sentinel lymph node (SN) metastasis in melanoma. Our aim was to associate NN in SNs with clinicopathologic features and survival rates in 1, 250 patients with SN biopsy for melanoma. METHODS: To compare patients with present and absent NN, we used Fisher's exact test, Mann-Whitney U test, and multivariate logistic regression models in this retrospective observational study based on a prospectively maintained institutional database. RESULTS: NN prevalence in axillary, cervical, and groin SNs was 16.5%, 19.4%, and 9.8%, respectively. NN were observed in combination with all growth patterns of melanoma, but more frequently when the primary was histologically associated with a cutaneous nevus. We observed a decreasing NN prevalence with increasing SN metastasis diameter. Multiple logistic regression determined a significantly increased NN probability for SNs of the neck or axilla, for individuals with ≥ 50 cutaneous nevi, midline primary melanomas, and for individuals who reported non-cutaneous malignancies in their parents. Cancer in parents was also significantly more frequently reported by melanoma patients who had more than 50 cutaneous nevi. In SN-negative patients, NN indicated a tendency for slightly lower melanoma-specific survival. CONCLUSIONS: We found a highly significant association between NN diagnosis and multiple cutaneous nevi and provided circumstantial evidence that cutaneous nevi in the drainage area of lymph nodes are particularly important. The trend toward lower melanoma-specific survival in SN-negative patients with NN suggests that careful differentiation of SN metastases is important.

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 patient's 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 patient's 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.

Increased Lipoprotein (a) concentrations in patients with chronic venous leg ulcers: a study on patients with or without postthrombotic syndrome.

Chronic venous leg ulcers are common and cause considerable burden of disease for affected patients with significant costs for health care systems worldwide. The complex pathophysiology of chronic venous leg ulcers is still not entirely understood. In addition, reliable pathogenic and/or prognostic parameters are not known. Published data suggest that patients with chronic venous leg ulcers reveal congenital or acquired thrombophilia. We examined the serum Lipoprotein (a) [Lp(a)] level, a proatherogenic and prothrombotic risk factor, in patients with chronic venous leg ulcers (n=210, stratified into patients with postthrombotic syndrome or without) and in a healthy control group (n=341). Forty-two percent of all patients, compared with 20% of healthy controls, revealed significantly increased Lp(a) serum concentrations above 0.3 g/L. Furthermore, 49% without postthrombotic syndrome but only 35% with postthrombotic syndrome showed increased Lp(a) levels. The increase of Lp(a) level was significantly different between all three groups (p<0.001). There was no correlation of Lp(a) levels and CRP values in all groups. Based on these data, it is conceivable that Lp(a) plasma level is a novel pathogenic parameter for chronic venous leg ulcers. Elevated concentrations may contribute to the pathogenesis through induction of thrombogenic microcirculatory dysregulations, impaired extravascular fibrinolysis, or other mechanisms like proinflammatory effects.

The popliteal fossa - a problem zone for sentinel lymphonodectomy.

BACKGROUND: The impact of lymphatic drainage to popliteal sentinel lymph nodes (SLNs) has yet to be explored in detail. PATIENTS AND METHODS: We performed lymphoscintigraphy on 663 patients with cutaneous melanomas. The following day sentinel lymphonodectomy was performed. SLNs were studied on serial sections with both histology and immunohistochemistry. RESULTS: 166 patients had a melanoma located on the foot, the lower leg or the knee, i. e., the potential of lymphatic drainage to the popliteal lymph nodes. On lymphoscintigraphy, only 16 patients (9.6 %) showed popliteal SLNs. A popliteal SLN was surgically identified in only 6 of the 16 patients. The reason for the poor identification rate was exhausted radioactivity in the small popliteal nodes the day after lymphoscintigraphy. In 3 cases, popliteal SLN metastasis was diagnosed. All but one patient had an additional drainage to the inguinal lymph nodes; inguinal SLN metastasis was diagnosed in 7 patients. Even all 16 patients showed lymphatic drainage to iliac lymph nodes, metastasis in the pelvis was diagnosed in 4 patients. CONCLUSIONS: Popliteal SLNs are observed in less than 10 % of the patients with melanomas of the distal leg. In the case of suspected popliteal drainage, lymphoscintigraphy should be performed on the day of sentinel lymphonodectomy because the radioactivity of the small and deeply situated popliteal nodes diminishes rapidly. With respect to complete lymphadenectomy, decision-making is difficult since three nodal basins (popliteal, inguinal and iliac) may harbor metastases.