Langerhans cell histiocytosis as differential diagnosis of a mediastinal tumor

We describe the case of a 55-year-old man who presented with parasternal swelling. The chest CT scan showed a large tumor of the chest wall infiltrating the subcutaneous tissue. To assume histologic diagnosis an open biopsy was performed. Between the myofibrils a coarse, white tumor with infiltrative growth was noted. Histopathologic examination revealed expanded atrophic skeletal muscle that was infiltrated by histiocytic cells. Numerous eosinophilic granulocytes and lymphocytes CD20 and CD3 positive could be detected and immunohistochemical staining was also positive for S-100 proteins and CD1a. Histologic findings were characteristic of Langerhans cell histiocytosis (LCH). To the best of our knowledge a LCH originating from the mediastinum in an adult as presented has not been previously described.

Treatment of mediastinal fibrosis with mycophenolate mofetil

We present the case of a 67-year-old male patient with mediastinal and retroperitoneal fibrosis. In Europe, this is a rare disease. Treatment was established to prevent complications due to strictures or compressions. Because of his diabetes, a therapy of low-dose prednisone combined with mycophenolate mofetil, known as steroid sparing agent, was applied. As a result, the radiological follow-up showed a marked decrease in the mediastinal and retroperitoneal masses.

Perioperative anaesthetic management of mediastinal mass in adults

Mediastinal mass syndrome remains an anaesthetic challenge that cannot be underestimated. Depending on the localization and the size of the mediastinal tumour, the clinical presentation is variable ranging from a complete lack of symptoms to severe cardiorespiratory problems. The administration of general anaesthesia can be associated with acute intraoperative or postoperative cardiorespiratory decompensation that may result in death due to tumour-related compression syndromes. The role of the anaesthesiologist, as a part of the interdisciplinary treatment team, is to ensure a safe perioperative period. However, there is still no structured protocol available for perioperative anaesthesiological procedure. The aim of this article is to summarize the genesis of and the diagnostic options for mediastinal mass syndrome and to provide a solid detailed methodology for its safe perioperative management based on a review of the latest literature and our own clinical experiences. Proper anaesthetic management of patients with mediastinal mass syndrome begins with an assessment of the preoperative status, directed foremost at establishing the localization of the tumour and on the basis of the clinical and radiological findings, discerning whether any vital mediastinal structures are affected. We have found it helpful to assign 'severity grade' (using a three-grade clinical classification scale: 'safe', 'uncertain', 'unsafe'), whereby each stage triggers appropriate action in terms of staffing and apparatus, such as the provision of alternatives for airway management, cardiopulmonary bypass and additional specialists. During the preoperative period, we are guided by a 12-point plan that also takes into account the special features of transportation into the operating theatre and patient monitoring. Tumour compression on the airways or the great vessels may create a critical respiratory and/or haemodynamic situation, and therefore the standard of intraoperative management includes induction of anaesthesia in the operating theatre on an adjustable surgical table, the use of short-acting anaesthetics, avoidance of muscle relaxants and maintenance of spontaneous respiration. In the case of severe clinical symptoms and large mediastinal tumours, we consider it absolutely essential to cannulate the femoral vessels preoperatively under local anaesthesia and to provide for the availability of cardiopulmonary bypass in the operating theatre, should extracorporeal circulation become necessary. The benefits of establishing vascular access under local anaesthesia clearly outweigh any associated degree of patient discomfort. In the case of patients classified as 'safe' or 'uncertain', a preoperative consensus with the surgeons should be reached as to the anaesthetic approach and the management of possible complications.

A rare case of a large spinal meningioma with mediastinal extension and malignant behavior classified histologically as benign

AIM To report a rare case of a spinal WHO grade I meningioma extending through intervertebral foramina C7 to D4 with an extensive mediastinal mass and infiltration of the vertebrae, and to discuss the malignant behavior of a tumor classified as benign. METHODS (Clinical Presentation, Histology, and Imaging): A 54-year-old man suffered from increasing lower back pain with gait difficulties, weakness and numbness of the lower extremities, as well as urge incontinence. CT scan of the thorax and MRI scan of the spine revealed a large prevertebral tumor, which extended to the spinal canal and caused compression of the spinal cord at the levels of C7 to D4 leading to myelopathy with hyperintense signal alteration on T2-weighted MRI images. The signal constellation (T1 with and without contrast, T2, TIR) was highly suspicious for infiltration of vertebrae C7 to D5. Somatostatin receptor SPECT/CT with (111)In-DTPA-D: -Phe-1-octreotide detected a somatostatin receptor-positive mediastinal tumor with infiltration of multiple vertebrae, dura, and intervertebral foramina C7-D4, partially with Krenning score >2. Percutaneous biopsies of the mediastinal mass led to histopathological findings of WHO grade I meningioma of meningothelial subtype. RESULTS (Therapy): C7 to D4 laminoplasty was performed, and the intraspinal, extradural part of the tumor was microsurgically removed. Postoperative stereotactic radiation therapy was done using the volumetric modulated arc therapy (VMAT) technique (RapidArc). No PRRNT with (90)Y-DOTA-TOC was done. CONCLUSIONS Due to the rare incidence and complex presentation of this disease not amenable to complete surgical resection, an individualized treatment approach should be worked out interdisciplinarily. The treatment approach should be based not only on histology but also on clinical and imaging findings. Close clinical and radiological follow-up may be mandatory even for benign tumors.

Intraductal papillary neoplasms of the bile duct: stepwise progression to carcinoma involves common molecular pathways

Intraductal papillary neoplasms of the bile duct are still poorly characterized regarding (1) their molecular alterations during the development to invasive carcinomas, (2) their subtype stratification and (3) their biological behavior. We performed a multicenter study that analyzed these issues in a large European cohort. Intraductal papillary neoplasms of the bile duct from 45 patients were graded and subtyped using mucin markers and CDX2. In addition, tumors were analyzed for common oncogenic pathways, and the findings were correlated with subtype and grade. Data were compared with those from 22 extra- and intrahepatic cholangiocarcinomas. Intraductal papillary neoplasms showed a development from preinvasive low- to high-grade intraepithelial neoplasia to invasive carcinoma. Molecular and immunohistochemical analysis revealed mutated KRAS, overexpression of TP53 and loss of p16 in low-grade intraepithelial neoplasia, whereas loss of SMAD4 was found in late phases of tumor development. Alterations of HER2, EGFR, β-catenin and GNAS were rare events. Among the subtypes, pancreato-biliary (36%) and intestinal (29%) were the most common, followed by gastric (18%) and oncocytic (13%) subtypes. Patients with intraductal papillary neoplasm of the bile duct showed a slightly better overall survival than patients with cholangiocarcinoma (hazard ratio (cholangiocarcinoma versus intraductal papillary neoplasm of the bile duct): 1.40; 95% confidence interval: 0.46-4.30; P=0.552). The development of biliary intraductal papillary neoplasms of the bile duct follows an adenoma-carcinoma sequence that correlates with the stepwise activation of common oncogenic pathways. Further large trials are needed to investigate and verify the finding of a better prognosis of intraductal papillary neoplasms compared with conventional cholangiocarcinoma.

ISL1 expression is not restricted to pancreatic well-differentiated neuroendocrine neoplasms, but is also commonly found in well and poorly differentiated neuroendocrine neoplasms of extrapancreatic origin

The human insulin gene enhancer-binding protein islet-1 (ISL1) is a transcription factor involved in the differentiation of the neuroendocrine pancreatic cells. Recent studies identified ISL1 as a marker for pancreatic well-differentiated neuroendocrine neoplasms. However, little is known about ISL1 expression in pancreatic poorly differentiated and in extrapancreatic well and poorly differentiated neuroendocrine neoplasms. We studied the immunohistochemical expression of ISL1 in 124 neuroendocrine neoplasms. Among pancreatic neuroendocrine neoplasms, 12/13 with poor differentiation were negative, whereas 5/7 with good differentiation but a Ki67 >20% were positive. In extrapancreatic neuroendocrine neoplasms, strong positivity was found in Merkel cell carcinomas (25/25), pulmonary small cell neuroendocrine carcinomas (21/23), medullary thyroid carcinomas (9/9), paragangliomas/pheochromocytomas (6/6), adrenal neuroblastomas (8/8) and head and neck neuroendocrine carcinomas (4/5), whereas no or only weak staining was recorded in pulmonary carcinoids (3/15), olfactory neuroblastomas (1/4) and basaloid head and neck squamous cell carcinomas (0/15). ISL1 stained the neuroendocrine carcinoma component of 5/8 composite carcinomas and also normal neuroendocrine cells in the thyroid, adrenal medulla, stomach and colorectum. Poorly differentiated neuroendocrine neoplasms, regardless of their ISL1 expression, were usually TP53 positive. Our results show the almost ubiquitous expression of ISL1 in extrapancreatic poorly differentiated neuroendocrine neoplasms and neuroblastic malignancies and its common loss in pancreatic poorly differentiated neuroendocrine neoplasms. These findings modify the role of ISL1 as a marker for pancreatic neuroendocrine neoplasms and suggest that ISL1 has a broader involvement in differentiation and growth of neuroendocrine neoplasms than has so far been assumed.

Establishing optimal quantitative-polymerase chain reaction assays for routine diagnosis and tracking of minimal residual disease in JAK2-V617F-associated myeloproliferative neoplasms: a joint European LeukemiaNet/MPN&MPNr-EuroNet (COST action BM0902) study.

Reliable detection of JAK2-V617F is critical for accurate diagnosis of myeloproliferative neoplasms (MPNs); in addition, sensitive mutation-specific assays can be applied to monitor disease response. However, there has been no consistent approach to JAK2-V617F detection, with assays varying markedly in performance, affecting clinical utility. Therefore, we established a network of 12 laboratories from seven countries to systematically evaluate nine different DNA-based quantitative PCR (qPCR) assays, including those in widespread clinical use. Seven quality control rounds involving over 21,500 qPCR reactions were undertaken using centrally distributed cell line dilutions and plasmid controls. The two best-performing assays were tested on normal blood samples (n=100) to evaluate assay specificity, followed by analysis of serial samples from 28 patients transplanted for JAK2-V617F-positive disease. The most sensitive assay, which performed consistently across a range of qPCR platforms, predicted outcome following transplant, with the mutant allele detected a median of 22 weeks (range 6-85 weeks) before relapse. Four of seven patients achieved molecular remission following donor lymphocyte infusion, indicative of a graft vs MPN effect. This study has established a robust, reliable assay for sensitive JAK2-V617F detection, suitable for assessing response in clinical trials, predicting outcome and guiding management of patients undergoing allogeneic transplant.

Novel radiotherapy techniques for involved-field and involved-node treatment of mediastinal Hodgkin lymphoma: when should they be considered and which questions remain open?

PURPOSE Hodgkin lymphoma (HL) is a highly curable disease. Reducing late complications and second malignancies has become increasingly important. Radiotherapy target paradigms are currently changing and radiotherapy techniques are evolving rapidly. DESIGN This overview reports to what extent target volume reduction in involved-node (IN) and advanced radiotherapy techniques, such as intensity-modulated radiotherapy (IMRT) and proton therapy-compared with involved-field (IF) and 3D radiotherapy (3D-RT)- can reduce high doses to organs at risk (OAR) and examines the issues that still remain open. RESULTS Although no comparison of all available techniques on identical patient datasets exists, clear patterns emerge. Advanced dose-calculation algorithms (e.g., convolution-superposition/Monte Carlo) should be used in mediastinal HL. INRT consistently reduces treated volumes when compared with IFRT with the exact amount depending on the INRT definition. The number of patients that might significantly benefit from highly conformal techniques such as IMRT over 3D-RT regarding high-dose exposure to organs at risk (OAR) is smaller with INRT. The impact of larger volumes treated with low doses in advanced techniques is unclear. The type of IMRT used (static/rotational) is of minor importance. All advanced photon techniques result in similar potential benefits and disadvantages, therefore only the degree-of-modulation should be chosen based on individual treatment goals. Treatment in deep inspiration breath hold is being evaluated. Protons theoretically provide both excellent high-dose conformality and reduced integral dose. CONCLUSION Further reduction of treated volumes most effectively reduces OAR dose, most likely without disadvantages if the excellent control rates achieved currently are maintained. For both IFRT and INRT, the benefits of advanced radiotherapy techniques depend on the individual patient/target geometry. Their use should therefore be decided case by case with comparative treatment planning.

Prognostic and predictive roles of MGMT protein expression and promoter methylation in sporadic pancreatic neuroendocrine neoplasms.

BACKGROUND/AIMS O(6)-methylguanine-methyltransferase (MGMT) is an important enzyme of DNA repair. MGMT promoter methylation is detectable in a subset of pancreatic neuroendocrine neoplasms (pNEN). A subset of pNEN responds to the alkylating agent temozolomide (TMZ). We wanted to correlate MGMT promoter methylation with MGMT protein loss in pNEN, correlate the findings with clinico-pathological data and determine the role of MGMT to predict response to TMZ chemotherapy. METHODS We analysed a well-characterized collective of 141 resected pNEN with median follow-up of 83 months for MGMT protein expression and promoter methylation using methylation-specific PCR (MSP). A second collective of 10 metastasized, pretreated and progressive patients receiving TMZ was used to examine the predictive role of MGMT by determining protein expression and promoter methylation using primer extension-based quantitative PCR. RESULTS In both collectives there was no correlation between MGMT protein expression and promoter methylation. Loss of MGMT protein was associated with an adverse outcome, this prognostic value, however, was not independent from grade and stage in multivariate analysis. Promoter hypermethylation was significantly associated with response to TMZ. CONCLUSION Loss of MGMT protein expression is associated with adverse outcome in a surgical series of pNET. MGMT promoter methylation could be a predictive marker for TMZ chemotherapy in pNEN, but further, favourably prospective studies will be needed to confirm this result and before this observation can influence clinical routine.

[Neuroendocrine neoplasms of the distal jejunum and ileum].

Neuroendocrine neoplasms (NEN) of the distal jejunum and ileum derive from serotonin-producing enterochromaffin (EC) cells. Due to their low proliferation rate and their infiltrative growth, they are often discovered at an advanced disease stage when metastasis has already occurred. The biology of these tumours is different from other NEN of the digestive tract. In order to standardise and improve diagnosis and therapy, the guidelines for the diagnosis and clinical management of jejuno-ileal NEN as well as for the management of patients with liver and other distant metastases from NEN were revised by the European Neuroendocrine Tumour Society (ENETS) in 2012. This review focuses on aspects relevant for surgical pathology.

Anaesthesiological management of mediastinal tumors

The perioperative management of patients with mediastinal masses is a special clinical challenge in our field. Even though regional anaesthesia is normally the first choice, in some cases it is not feasible due to the method of operation. In these cases general anaesthesia is the second option but can lead to respiratory and haemodynamic decompensation due to tumor-associated compression syndrome (mediastinal mass syndrome). The appropriate treatment begins with the preoperative risk classification on the basis of clinical and radiological findings. In addition to anamnesis, chest radiograph, and CT, dynamical methods (e.g. pneumotachography and echocardiography) should be applied to verify possible intraoperative compression syndromes. The induction of general anaesthesia is to be realized in awake-fiberoptic intubation with introduction of the tube via nasal route while maintaining the spontaneous breathing of the patient. The anaesthesia continues with short effective agents applied inhalative or iv. If possible from the point of operation, agents of muscle relaxation are not to be applied. If the anaesthesia risk is classified as uncertain or unsafe, depending on the location of tumor compression (tracheobronchial tree, pulmonary artery, superior vena cava), alternative techniques of securing the respiratory tract (different tubes, rigid bronchoscope) and cardiopulmonary bypass with extracorporal oxygen supply are prepared. For patients with severe clinical symptoms and extensive mediastinal mass, the preoperative cannulation of femoral vessels is also recommended. In addition to fulfilling technical and personnel requirements, an interdisciplinary cooperation of participating fields is the most important prerequisite for the optimal treatment of patients.