S2k Guideline - Merkel cell carcinoma (MCC, neuroendocrine carcinoma of the skin) - Update 2022.

Merkel cell carcinoma (MCC, ICD-O M8247/3) is a rare, malignant, primary skin tumor with epithelial and neuroendocrine differentiation. The tumor cells share many morphologic, immunohistochemical, and ultrastructural features with cutaneous Merkel cells. Nevertheless, the cell of origin of MCC is unclear. MCC appears clinically as a reddish to purple spherical tumor with a smooth, shiny surface and a soft to turgid, elastic consistency, usually showing rapid growth. Spontaneous and often complete regressions of the tumor are observed. These likely immunologically-mediated regressions explain the cases in which only lymph node or distant metastases are found at the time of initial diagnosis and why the tumor responds very well to immunomodulatory therapies even at advanced stages. Due to its aggressiveness, the usually given indication for sentinel lymph node biopsy, the indication of adjuvant therapies to be evaluated, as well as the complexity of the necessary diagnostics, clinical management should already be determined by an interdisciplinary tumor board at the time of initial diagnosis.

Meningeal enhancement depicted by magnetic resonance imaging in tumor patients: neoplastic meningitis or therapy-related enhancement?

PURPOSE: To assess the prevalence of false-positive meningeal contrast enhancement in patients with solid tumors who were undergoing chemotherapy. METHODS: A total of 2572 magnetic resonance imaging (MRI) examinations of the brain were retrospectively evaluated by two readers for the presence of pathological meningeal contrast enhancement conspicuous for neoplastic meningitis. These patients either had malignant melanoma, breast or lung cancer, or lymphoma. The reference standards were cerebrospinal fluid cytology results and follow-up MRI. In cases with pathological contrast enhancement that decreased upon follow-up and non-malignant cytology, the enhancement pattern was further described as pial or dural, local or diffuse, or supra- or infra-tentorial. Moreover, the underlying therapy regimes were assessed. RESULTS: The final study cohort included 78 patients (51 females, median age 57 years), of which 11 patients (14.1%) had a repeated non-malignant cytology ('pseudomeningeosis'). In one case, this finding, a granular pleocytosis, was attributed to previous radiotherapy. Of the remaining patients, seven were receiving multimodal, immunotherapy-based therapy regimens. Patients with unsuspicious cytology had a predominantly supratentorial distribution pattern in comparison to patients with neoplastic meningitis. CONCLUSIONS: The overall prevalence of the presence of false-positive meningeal contrast enhancement is low (< 1%) and not associated with specific imaging patterns. We hypothesize that there is a possible relationship between immunotherapy and 'pseudomeningeosis'. Therefore, in all cases with suspected neoplastic meningitis, the cerebrospinal fluid should be analyzed to confirm the diagnosis, especially in patients undergoing immunotherapy.

S2k guidelines for Merkel cell carcinoma (MCC, neuroendocrine carcinoma of the skin) - update 2018.

Merkel cell carcinoma (MCC, ICD-O M8247 / 3) is a rare malignant primary skin tumor with epithelial and neuroendocrine differentiation. The neoplastic cells share many morphological, immunohistochemical and ultrastructural characteristics with Merkel cells of the skin. The diagnosis of MCC is rarely made on clinical grounds. Histological and immunohistochemical studies are usually required to confirm the clinical suspicion. Given the frequent occurrence of occult lymph node metastasis, sentinel lymph node biopsy should be performed once distant metastasis has been ruled out by cross-sectional imaging. Primary tumors without evidence of organ metastases are treated with complete surgical excision with appropriate surgical margins. Radiation therapy should be considered at all stages of the disease. For advanced MCC that is no longer amenable to curative treatment by surgery or radiation therapy, there is currently no established systemic therapy for which an improvement in recurrence-free survival or overall survival has been demonstrated in a prospective randomized trial. However, immunotherapy using PD-1/PD-L1 blockade seems to be superior to chemotherapy. Various factors warrant that further diagnostic and therapeutic interventions be determined by an interdisciplinary tumor board. These factors include the tumor's aggressiveness, the frequent indication for sentinel lymph node biopsy along with the frequent occurrence in the head and neck region, the potential indication for adjuvant radiation therapy as well as the complexity of the required diagnostic workup.

S2k Guidelines for Cutaneous Basal Cell Carcinoma - Part 1: Epidemiology, Genetics and Diagnosis.

Basal cell carcinoma is the most common malignant tumor among fair-skinned individuals, and its incidence has been rising steadily in the past decades. In order to maintain the highest quality of patient care possible, the German S2k guidelines were updated following a systematic literature search and with the participation of all professional societies and associations involved in the management of the disease. Part 1 highlights new developments in genetics in particular as well as aspects regarding epidemiology, diagnosis, and histology.

S2k Guidelines for Cutaneous Basal Cell Carcinoma - Part 2: Treatment, Prevention and Follow-up.

Basal cell carcinoma (BCC) is the most common malignant tumor among fair-skinned individuals, and its incidence had been steadily rising in the past decades. In order to maintain the highest quality of patient care possible, the German S2k guidelines were updated following a systematic literature search and with the participation of all professional societies and associations involved in the management of the disease. Part 2 addresses issues such as proper risk stratification, the various therapeutic approaches, and prevention as well as follow-up of patients with basal cell carcinoma.

Breast tomosynthesis for the clarification of mammographic BI-RADS 3 lesions can decrease follow-up examinations and enables immediate cancer diagnosis.

Background The limited sensitivity of mammography in case of a high breast density often produces unclear or false-positive findings, so-called BI-RADS 3 lesions, which have to be followed up to prove benignity. Digital breast tomosynthesis (DBT) was developed to reduce such summation effects. Purpose To evaluate the influence of an additional DBT on the management of mammographic BI-RADS 3 findings and whether DBT can decrease the time to definitive diagnosis or not. Material and Methods We analyzed 87 patients with a mammographic non-calcified BI-RADS 3 lesion who underwent an additional DBT of the affected breast. A follow-up two-dimensional (2D) examination or a histological result of the lesion had to be available. The images were analyzed especially for the BI-RADS category and incremental diagnostic accuracy. Moreover, the inter-reader reliability and the radiation dose were evaluated. Results The BI-RADS category has been changed by the addition of DBT: 57.1% were assessed as BI-RADS 1 or 2, 4.6% as BI-RADS 4, and only 38.3% remained as BI-RADS 3. The intraclass correlation coefficient for the three readers showed a good agreement for inter-reader reliability. No false-negative examination was found in the follow-ups. Nine lesions were biopsied (seven benign, two malignant). Both malignant lesions were suspicious in the DBT (BI-RADS 4). A significant higher glandular dose was necessary for the DBT. Conclusion DBT has the potential to reduce the recall-rate of BI-RADS 3 lesions and to find and diagnose malignant lesions earlier than 2D mammography alone.

Mid-term development of the right ventricle in competitive athletes.

BACKGROUND: Long-term intensive training induces physiological, morphological, and functional adaption of the athlete's heart. PURPOSE: To evaluate the development of athlete's heart during a mid-term follow-up of competitive athletes using cardiac magnetic resonance (CMR). MATERIAL AND METHODS: Eighteen competitive long-distance runners and triathletes (age 43 ± 13 years, 3 women) were prospectively examined in a longitudinal follow-up study 5.05 ± 0.6 years after baseline. CMR at 1.5-T was performed for functional and late gadolinium enhancement (LGE) imaging. Left ventricular (LV) and right ventricular (RV) end-diastolic volume (LVEDV, RVEDV) as well as ejection fraction (LVEF, RVEF), LV myocardial mass (LVMM), and atrial sizes were determined and compared to baseline in matched pairs statistics for paired difference. RESULTS: LVEDV (197 ± 38 mL vs. 196 ± 38 mL, paired difference -0.9 mL, P = 0.7) and LVEF (62 ± 7% vs. 62 ± 5%, paired difference 0.1%, P = 0.9) did not change during the follow-up period, whereas LVMM increased significantly (149 ± 31 g vs.164 ± 32 g, paired difference 14 g, P < 0.0001). RVEDV significantly increased from 221 ± 47 mL at baseline to 230 ± 52 mL (paired difference 10 mL, P = 0.0033). RVEF decreased from baseline 57 ± 8% to 53 ± 7% (paired difference -3%, P = 0.0234). Left atrial size showed no significant changes (24 ± 5 cm2 vs. 25 ± 6 cm2, paired difference 0.5 cm2, P = 0.17) and right atrial size increased significantly (30 ± 5 cm2 vs. 32 ± 4 cm2, paired difference 2 cm2, P = 0.0054). CONCLUSION: This study supports the theory of ongoing remodeling in an athlete's heart. Predominantly the right heart can further enlarge in a mid-term period. This response seems not linearly dependent on a steady, decreased, or increased training volume.

Combined treatment with ipilimumab and intratumoral interleukin-2 in pretreated patients with stage IV melanoma-safety and efficacy in a phase II study.

Treatment of advanced melanoma patients with ipilimumab results in improved survival. However, only about 20% of treated patients experience long-term benefit. Combining treatment of ipilimumab with other drugs may improve immune activation and potentially enhance clinical efficacy. The aims of the phase II clinical trial reported here were to investigate tolerability and efficacy of a combined immunotherapeutic strategy comprising standard systemic ipilimumab at 3 mg/kg four times at 3-week intervals and intratumorally injected IL-2 at 9 MIU daily twice weekly for four weeks in pretreated melanoma patients with distant metastasis. The primary endpoint was the disease control rate according to immune-related response criteria at week 12; tolerability according to Common Terminology Criteria for Adverse Events criteria was secondary endpoint. No objective responses were observed in the 15 enrolled patients. Three patients had stable disease 12 weeks after starting treatment, yielding a disease control rate of 20%. Tolerability of this combination treatment was acceptable. Observed adverse events were those expected from the respective monotherapies. Autoimmune colitis was observed in two patients. Grade III/IV adverse events were observed in 40% of patients, and no treatment-related deaths occurred. Thus, this combined immunotherapy is associated with adverse events similar to those associated with the respective monotherapies. However, this study does not provide any evidence of improved efficacy of the combination over ipilimumab alone.

Imaging of gastrointestinal melanoma metastases: Correlation with surgery and histopathology of resected specimen.

OBJECTIVE: To assess the appearance of gastrointestinal melanoma metastases on CT and PET/CT and evaluate the diagnostic value of CT and PET/CT compared with surgery and histopathology. METHODS: We retrospectively included 41 consecutive patients (aged 56.1 ± 13.5 years) with gastrointestinal melanoma metastases who underwent preoperative imaging (CT: all, PET/CT: n = 24) and metastasectomy. Two blinded radiologists assessed CT and PET/CT for gastrointestinal metastases and complications. Diagnostic accuracy and differences regarding lesion detectability and complications were assessed, using surgical findings and histopathology as standard of reference. RESULTS: Fifty-three gastrointestinal melanoma metastases (5.0 ± 3.8 cm) were confirmed by surgery and histopathology. Lesions were located in the small bowel (81.1 %), colon (15.1 %) and stomach (3.8 %), and described as infiltrating (30.2 %), polypoid (28.3 %), cavitary (24.5 %) and exoenteric (17.0 %). Fifteen patients (37 %) had gastrointestinal complications. Higher complication rates were associated with large and polypoid lesions (p ≤ .012). Diagnostic accuracy was high for CT and PET/CT (AUC ≥ .802). For reader B (less experienced), CT yielded lower diagnostic accuracy than PET/CT (p = .044). CONCLUSION: Most gastrointestinal melanoma metastases were located in the small bowel. Large and polypoid metastases were associated with higher complication rates. PET/CT was superior for detection of gastrointestinal melanoma metastases and should be considered in patients with limited disease undergoing surgery. KEY POINTS: • Gastrointestinal melanoma metastases (GI-MM) are rare but often cause serious gastrointestinal complications. • Early detection of GI-MM is important to prevent complications and guide surgery. • PET/CT is superior to CT for detection of GI-MMs. • PET/CT should be considered for patients with limited disease before surgical resection.

Signal decay mapping of myocardial edema using dual-contrast fast spin-echo MRI.

PURPOSE: To introduce a dual-contrast fast spin-echo (dcFSE) sequence for signal decay mapping of myocardial edema. MATERIALS AND METHODS: After consultation with the Institutional Review Board, 22 acute myocardial infarction (MI) patients were examined with magnetic resonance imaging (MRI) at 1.5T 2 days after revascularization. Edema was evaluated in 16 myocardial segments with an exponential fit for signal decay time (SDT) in dcFSE mapping and T2 signal intensity ratio for single-contrast FSE. Myocardial viability was evaluated in late gadolinium enhancement (LGE). A control group of 10 volunteers was examined for edema imaging. SDT was compared in segment groups: 1) with LGE in MI, 2) penumbra, 3) remote from LGE, 4) controls. Groups 1/3 and 3/4 were tested on difference. Three phantoms providing similar T2 but different T1 relaxation times (low, intermediate, high) were examined with dcFSE and multicontrast spin echo sequence as a reference. RESULTS: The SDT/T2 ratio for segment groups was 1) 82msec/1.7 in segments with LGE; 2) 65msec/1.6 for penumbra, 3) 62msec/1.7 for remote segments, and 4) 50msec/1.6 in controls. In dcFSE group 1/3 (P < 0.0001) and in group 3/4 (P = 0.0002) SDT was significantly different. In single-contrast FSE the T2 ratio was not significantly different for both tests: 1/3 P = 0.1889; 3/4 P = 0.8879. T2 -overestimation of dcFSE was 23% in low, 29% in intermediate, and 35% in highly T1 contaminated phantoms. CONCLUSION: dcFSE signal decay edema mapping is feasible in volunteers and patients. DcFSE SDT is superior to T2 ratio for detection of high-grade and diffuse myocardial edema. J. Magn. Reson. Imaging 2016;44:186-193.

Metastatic patterns and metastatic sites in mucosal melanoma: a retrospective study.

OBJECTIVES: Melanomas arising from mucosa are rare and associated with a poor prognosis. This study aims to provide an analysis of metastatic pathways, time intervals, factors influencing metastatic spread and organs for distant metastases. METHODS: A total of 116 patients with mucosal melanomas of different sites were included. The mean follow-up interval was 47 ± 52 months. Patients were assigned to two different metastatic pathways, either presenting loco-regional lymph node metastases as first spread or direct distant metastases. The distribution of distant metastases was assessed. RESULTS: Twenty-six patients presented with a pre-existing metastatic spread and were not assigned to pathways. Of the included patients, 44 developed metastases after treatment of the primary tumour; 25 patients directly developed distant metastases; 16 patients developed regional lymph node metastases prior to distant metastases. Location of the primary tumour in the upper airway or GI tract and advanced T stage were significant risk factors of direct distant metastases. Distant metastases are mainly located in the lung, the liver and non-regional lymph nodes. CONCLUSIONS: Mucosal melanomas show a high rate of direct distant metastases rather than regional lymph node metastases. Thus the follow-up should always include a whole-body cross-sectional imaging in high-risk tumours. KEY POINTS: • Mucosal melanomas show a high rate of direct distant metastases. • T stage and primary location are predictors for direct distant metastases. • Distant metastases were mainly found in lung, liver and lymph nodes. • Follow-up of a high-risk mucosal melanoma should include whole-body imaging.

Cardiovascular magnetic resonance patterns of biopsy proven cardiac involvement in systemic sclerosis.

BACKGROUND: To determine morphological and functional cardiovascular magnetic resonance (CMR) patterns in histopathologically confirmed myocardial involvement in patients with systemic sclerosis (SSc). METHODS: Twenty patients (6 females; mean age 41 ± 11 years) with histopathologically proven cardiac involvement in SSc in the years 2008-2016 were retrospectively evaluated. Morphological, functional and late gadolinium enhancement (LGE) images were acquired in standard angulations at 1.5 T CMR. Pathologies were categorized: 1) Pericardial effusion; 2) pathologic left (LV) or right ventricular (RV) contractility (hypokinesia, dyssynchrony, and diastolic restriction); 3) reduced left (LV-EF) and right ventricular ejection fraction (RV-EF); 4) fibrosis and/or inflammation (positive LGE); 5) RV dilatation. 95 % confidence intervals (CI) were calculated for appearance of pathologic EF and RV dilatation. RESULTS: Seven patients (35 %) had positive CMR findings in three categories, 9 patients (45 %) in four categories and 4 patients (20 %) in five categories. The distribution of pathologic findings was: minimal pericardial effusion in 7 patients (35 %), moderate pericardial effusion >5 mm in nine patients (45 %); abnormal LV or RV contractility in 19 patients (95 %), reduced LV or RV function in 14 patients (70 %; 95 % CI: 51-88 %), pathologic LGE in all patients, RV dilatation in 6 patients (30 %; 95 % CI: 15-54 %). CONCLUSIONS: CMR diagnosis of myocardial involvement in SSc requires increased attention to subtle findings. Pathologic findings in at least three of five categories indicate myocardial involvement in SSc.

Anorectal malignant melanoma: curative abdominoperineal resection: patient selection with 18F-FDG-PET/CT.

BACKGROUND: Anorectal malignant melanomas (ARMM) are rare tumors, characterized by an early lymphatic spread and distant metastasis, resulting in an extremely poor overall survival. The objective of this study was to determine the pattern of regional lymph node metastasis (LNM) by computed tomography (CT) and 18F-FDG-PET/CT in patients undergoing abdominoperineal resection (APR) and its impact on oncologic outcome. METHODS: A retrospective analysis of six consecutive patients who underwent APR due to primary ARMM was performed. Patients were staged by CT and PET/CT. RESULTS: Four out of six patients had preoperative LNM involvement (two patients inguinal and perirectal, one iliacal, one perirectal), with two of them presenting with distant metastases additionally. Inguinal/iliacal LNM in two patients as well as liver metastasis in one patient was seen in PET/CT and missed by CT. The three patients with initial inguinal/iliacal LNM died during the observation period (overall survival: 10 (6-18) months). The three patients without inguinal/iliacal LNM involvement are currently alive, one patient showing a slowly progressive disease since 5 years, and two patients are tumor-free since 8.5 and 1.5 years (the patients had initial perirectal LNM). CONCLUSIONS: In ARMM, PET/CT is superior to CT in detection of LNM and distant metastasis. APR is possibly a curative approach if the PET/CT shows exclusively perirectal LNM despite locally advanced tumor growth.

Is the diagnostic yield of myocardial stress perfusion MRI impaired by three-vessel coronary artery disease?

BACKGROUND: Three-vessel coronary artery disease (CAD) comes along with globally reduced myocardial perfusion potentially restricting the demarcation of regional hypoperfusion in stress perfusion cardiac magnetic resonance imaging (MRI). PURPOSE: To evaluate whether stress perfusion cardiac MRI is capable of detecting myocardial hypoperfusion in patients with 3-vessel CAD reliably. MATERIAL AND METHODS: Two hundred and five patients with symptoms of CAD were included. The examination protocol comprised imaging of myocardial perfusion at stress (0.14 mg/kg/min adenosine for 4 min) using a 2D saturation recovery gradient echo sequence after administration of gadobutrol (0.1 mmol/kg body weight). Perfusion sequences were assessed qualitatively by two experienced observers. Coronary angiography served as standard of reference. RESULTS: Sensitivity and specificity for hemodynamically relevant stenoses in patients with 0-, 1-, 2-, 3-vessel coronary artery disease were 100%/91%, 91%/73%, 90%/71%, 92%/64%; positive/negative predictive value, 67%/100%, 91%/73%, 83%/81%, 93%/58%; diagnostic accuracy, 93%/87%/83%/87%, respectively. The negative predictive value in patients with 3-vessel CAD was lower than in patients with 0- and 2-vessel CAD and the specificity lower than in patients with no CAD whereas the positive predictive value was higher than in patients with no CAD. The other proportions did not differ significantly between the groups. CONCLUSION: The diagnostic value of stress perfusion cardiac MRI in patients with 3-vessel CAD is comparable to results in patients with 1- or 2-vessel CAD. In the rare event that stress perfusion images do not depict regional hypoperfusion in patients with severe 3-vessel CAD, myocardial ischemia could be identified by reduced semi-quantitative perfusion parameters.

Baseline metastatic growth rate is an independent prognostic marker in patients with advanced BRAF V600 mutated melanoma receiving targeted therapy.

BACKGROUND: Targeted therapy (TT) of BRAF V600 mutated unresectable melanoma with inhibitors of the MAPK pathway achieves response rates of up to 76%, but most patients develop secondary resistance. Albeit TT is strikingly efficacious during the first days of treatment, even in advanced cases, long-term survival is highly unlikely, especially in patients with unfavorable baseline characteristics like elevated lactate dehydrogenase (LDH). In patients treated with anti-PD-1 immune checkpoint inhibitors, elevated baseline metastatic growth rate (MGR) was the most important prognostic factor. Here, we aimed at investigating the prognostic impact of MGR in patients with unresectable melanoma receiving TT. METHODS: Clinical records of 242 patients with at least one measurable target lesion (TL) receiving TT at seven skin cancer centers were reviewed. Baseline MGR was determined measuring the largest TL at baseline and at one earlier timepoint. RESULTS: Overall survival (OS) and progression-free survival (PFS) were significantly impaired in patients with an MGR > 3.9 mm/month (median OS: 11.4 vs. 35.5 months, P < 0.0001; median PFS: 4.8 vs. 9.2 months, P < 0.0001). Multivariable analysis of OS and PFS revealed that the prognostic impact of elevated MGR was independent of LDH, presence of brain and liver metastases, tumor burden, and line of treatment. The prognostic significance of elevated MGR was highest in patients with normal LDH. CONCLUSIONS: Baseline MGR is an important independent prognostic marker for OS and PFS in melanoma patients treated with TT. Its implementation in clinical routine is easy and could facilitate the prognostic stratification.

Preoperative assessment of peritoneal carcinomatosis: intraindividual comparison of 18F-FDG PET/CT and MRI.

OBJECTIVE: Exact determination of localization and extent of peritoneal carcinomatosis (PC) before peritonectomy and hyperthermic intraperitoneal chemotherapy (HIPEC) is crucial for the clinical outcome. Our study compares dynamic contrast enhanced 3D MRI (T1wDCE) and 18F-FDG PET/CT regarding diagnostic accuracy in correlation with surgical exploration (SE) and histological (HI) results. MATERIALS AND METHODS: 15 patients with PC were examined on a 1.5T MRI and 16 slice PET/CT. MRI: coronal T1wDCE covering the complete abdomen (0.15 mmol Gd-chelate/kg BW, 2000 mL mannitol solution p.o., 40 mg buscopan i.v.). PET-CT: contrast enhanced 16slice CT (120 mL ultravist 370 i.v., 1000 mL mannitol solution p.o., 40 mg buscopan i.v.), PET: 350 MBq 18-FDG i.v., 3 min acquisition time/bed, 60 min after tracer injektion). Assessment by two independent, experienced observers in correlation with results of SE and HI for each abdominal segment based on the peritoneal cancer index (PCI) proposed by Sugarbaker and co-authors. RESULTS: MRI and PET/CT provided reliable detection of PC. One patient had to be excluded from statistical analysis. In summary, 182 segments were assessed (13/patient, 14 patients, one patient excluded from statistical analysis). PC was found in 118 by MRI, 124 by PET/CT. 4 segments were classified false positive for MRI, 2 for PET/CT. False negative segments (MRI: 17, PET/CT: 9) did not result in irresectability. Positive predictive value for PC/segment was 97/98%, negative predictive value 73/84%, sensitivity 87/93%, specificity 92/96%, and diagnostic accuracy 88/94% (MRI/PET/CT). CONCLUSION: With high diagnostic accuracy for PC of both, MRI and PET/CT, PET/CT provides better diagnostic accuracy and especially better NPV.