Search

Contains fulltext : 249882.pdf (Publisher’s version ) (Closed access) ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in 3 infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-positive histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-positive histiocytosis to date, with detailed clinicopathologic data of 39 cases, including 37 cases with confirmed ALK rearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (7 and 12 from Groups 1B and 2, respectively). Histology included classic xanthogranuloma features in almost one-third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and often conferred strong expression of phosphorylated extracellular signal-regulated kinase, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, whereas CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK, and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, 10 with neurologic involvement. This study presents the existing clinicopathologic and molecular landscape of ALK-positive histiocytosis and provides guidance for the clinical management of this emerging histiocytic entity.

Patient: Male, 3-day-old Final Diagnosis: Neonatal leukemia Symptoms: Skin lesions Medication: — Clinical Procedure: Biopsy • stem cell transplant Specialty: Hematology • Pediatrics and Neonatology Objective: Rare disease Background: Neonatal acute leukemia is a rare condition. Little is known about its incidence and outcomes, and treatment options have not been standardized. Case Report: A 3-day old, apparently healthy male newborn was referred to the pediatric intensive care unit with multiple violaceous macules and a few papules on his face and upper trunk. After initial spontaneous regression, the lesions reappeared. Skin biopsy and bone marrow aspirate revealed a diagnosis of acute lymphoblastic leukemia (ALL). ALL induction therapy was initiated on day 24, resulting in morphological remission at the end of induction therapy. ALL chemotherapy was guided by sequential PCR-based monitoring of minimal residual disease (MRD). The patient received a transplant from an unrelated HLA high-resolution matched (10/10 loci) permissive donor. He was followed-up after transplant conducted by sequential PCR-based measurements of MRD in bone marrow. Conclusions: Neonatal leukemia often presents as congenital skin lesions known as blueberry muffin rash. ALL induction therapy was started at the end of the neonatal period. Treatment was well-tolerated and effective. Early donor search and PCR-MRD guided treatment surveillance can help to achieve and maintain molecular remission.

Seit 2011 wurde weltweit bei uber 100 Besuchern der Insel Tioman, Malaysia, die Verdachtsdiagnose einer muskularen Sarkozystose gemeldet, einer bislang nur sporadisch beobachteten parasitaren Erkrankung. Ursachlich ist vermutlich Sarcocystis nesbitti. Ausbruchsursache sowie Therapie sind unklar. Die Diagnosesicherung erfordert den mikroskopischen Zystennachweis im Muskelbiopsat. Studienziel war die systematische Beschreibung der diagnostisch wegweisenden Symptome, Laboruntersuchungen und des Therapieansprechens. Die 40 Falle aus 6 tropenmedizinischen/infektiologischen Zentren Deutschlands hatten zumeist einen Aufenthalt im Nordwesten der Insel Tioman und zeigen einen charakteristischen 2-phasigen Krankheitsverlauf mit initialem Fieber und spater prolongierten Myalgien, Eosinophilie und CK-Erhohung. Bei einer Schwangeren trat eine fetale Wachstumsretardierung auf. Eine Steroidstostherapie ist in der Spatphase rasch beschwerdelindernd. Bei moglichst fruhzeitiger Cotrimoxazoltherapie war die Beschwerdedauer kurzer (0,7 vs. 3,0 Monate; p = 0,03), moglicherweise kann damit die Muskelinvasion der Parasiten verhindert werden. Bei Fieber nach Malaysiaaufenthalt sollte die Sarkozystose differenzialdiagnostisch bedacht werden. Die Infektionsquelle erscheint konzentriert auf den Nordwesten Tiomans. Weitere Untersuchungen, inklusive zur Fruhdiagnostik und Therapie, sind notwendig.

Hintergrund: Seit 2011 wurde weltweit bei ca. 100 Besuchern der Insel Tioman, Malaysia, die Verdachtsdiagnose einer muskularen Sarkozystose gemeldet, einer bislang nur sporadisch beobachteten parasitaren Erkrankung. Ausbruchsursache sowie Therapie sind unklar. Die Diagnosesicherung erfordert den mikroskopischen Zysten-Nachweis im Muskelbiopsat. Studienziel war die systematische Beschreibung der diagnostisch wegweisenden Symptome, Laboruntersuchungen und des Therapieansprechens. Methodik: Systematische Fallserie. Ergebnisse: Die 26 Falle aus funf tropenmedizinischen Zentren Deutschlands zeigen einen charakteristischen zweiphasigen Krankheitsverlauf: zwei Wochen nach Urlaubsmitte (min. 7,5/ max. 22 Tage) tritt uncharakteristisches knapp einwochiges Fieber mit Kopfschmerz auf, nach zweiwochiger uberwiegender Beschwerdefreiheit folgen ca. 6 Wochen andauernde (min. 7/ max. 207 Tage), starke Myalgien (6,5, Skala 0–10), Fieber, Erhohung der Kreatinkinase (CK; bis 3,5-fach) und Eosinophilie (2,9-fach). Eine von zwei Muskelbiopsien zeigte eine Sarkozystose-typische Zyste, bei 6 von 7 untersuchten Patienten war mittels ELISA ein Anstieg Sarcocystis-spezifischer Antikorper nachweisbar. Behandlungsversuche mit systemischen Glukokortikoiden und Albendazol, oder Ivermectin erbrachten zumeist deutliche Beschwerdebesserungen. Bei einem Patienten entwickelte sich nach fruhzeitiger Cotrimoxazol-Therapie keine zweite Erkrankungsphase. Alle Patienten hatten Aufenthalte im Nordwesten der Insel Tioman. Folgerungen: Die Muskelsarkozystose verlauft zweiphasig mit initialem Fieber und spater prolongierten Myalgien, Eosinophilie und CK-Erhohung. Eine Steroidstostherapie ist in der Spatphase beschwerdelindernd. Fruhzeitige Cotrimoxazol-Gabe verhindert moglicherweise die parasitare Muskelinvasion. Bei Fieber nach Malaysia-Aufenthalt sollte Sarkozystose differenzialdiagnostisch bedacht werden. Die Infektionsquelle erscheint konzentriert auf den Nord-Westen Tiomans. Weitere Untersuchungen, inklusive zur Fruh-Diagnostik und Therapie sind notwendig.

Availability of statistically sufficient numbers of tumor samples and other biomaterials in high quality together with corresponding clinical data is crucial for biomedical research. Tumor repositories from individual scientists are mostly not sufficient to satisfy these criteria, especially since pediatric tumors are rare. In 2000 three centralized tumor repositories (neuroblastoma in Cologne, nephroblastoma in Wurzburg, hepatoblastoma, brain tumors in Bonn) have been established by the "German Competence Net Pediatric Oncology und Hematology". The aim was to collect biomaterial including tumor samples, normal tissue, and blood in high quality for research and diagnostic purposes at a central institution. Informed consent of the parents or patients is a prerequisite for scientific use of the samples and is requested by the therapy trial. The samples are collected according to accepted standards and shipped in the specially designed Tumorbox. The tumor repository organizes the distribution of the samples to the cooperating diagnostic laboratories. The number of collected tumor samples has increased over the years. In 2000, samples from 200 patients were collected while the patient number increased to 321 in 2005. Over the years the tumor repositories collected more than 7,150 samples (fresh frozen tumor, fresh frozen normal tissue, and blood). Through links with clinical trial databases the samples can be connected with clinical data. 12 of 14 applications for tumor material to be used in specific scientific projects have been approved by an independent supervisory board. The establishment of central tumor repositories represents a major step for biomedical research activities and quality control in pediatric oncology.

Immunocytological bone marrow assessment for contamination with neuroblastoma cells is based on their characteristic GD2 surface staining. Neuroblastoma without GD2 expression have been rarely and only after antibody therapy reported. Conventional cytology was performed using Pappenheim staining. For immunocytology, the APAAP method was utilized with the 14G2a anti-GD2 mouse monoclonal antibody. 7 x 10(5) cells on cytospin preparations were investigated. In 2003, 288 bone marrow samples from 191 neuroblastoma patients were investigated by cytology and immunocytology. Three cases demonstrated GD2 negativity on cytologically unambiguous neuroblastoma cells. Two female cases (94 and 37 months of age) with stage 4 neuroblastoma had GD2 expressing neuroblastoma cells in bone marrow at diagnosis. At 2nd relapse 25 and 23 months after diagnosis and 8 months and 12 months after anti-GD2 antibody treatment (ch14.18), the bone marrow infiltrating neuroblastoma cells lacked GD2 staining. The third patient, a 63-month-old girl with bone marrow replacement by neuroblastoma cells showed at diagnosis a mixture of GD2-unstained tumor clumps and very weakly stained neuroblastoma cells. Neuroblastoma cells may lack GD2 expression at diagnosis and at recurrence. This observation has diagnostic and therapeutic implications.

Frequently, treatment of patients with non-small cell lung cancer with tyrosine kinase inhibitors is stopped because of new or progressive bone metastases. Osteoblastic response is considered a healing reaction during effective systemic therapy, defined by osteoblastic demarcation of preexisting or “new” bone lesions, whereas disease response can be identified in other tumor locations. 1 In this study, we describe three patients with non-small cell lung cancer harboring sensitizing epidermal growth factor receptor (EGFR) mutations with osteoblastic responses during disease control by tyrosine kinase inhibitor treatment. PATIENT 1 This 47-year-old woman, former smoker, was diagnosed with stage IV adenocarcinoma (EGFR exon19 del) of the lung with pulmonary, hepatic, and osseous metastases. After five cycles of platinum-containing chemotherapy plus radiotherapy (right shoulder, thoracic spine, and both femurs), progressive hepatic and osseous metastasis occurred. Gefitinib was started, and 8 weeks later, computed tomography (CT) confirmed a partial response in lung and liver. Simultaneously, progressive demarcation of a preexisting osteoblastic lesion in the left iliac bone could be identified as possible sign of response (Figures 1A, B). Six months later, when progressive disease was diagnosed in lung, liver, and axillary lymph nodes, the lesion in the left iliac bone showed less sclerosis and more lytic areas (Figures 1B, C).

A 31-year-old woman with a history of infection with human papilloma virus was found to have an elevated human chorionic gonadotropin level (beta-HCG) of more than 9000 IU/L in January 2006. The patient reported an irregular menstrual cycle. Extensive clinical work-up including gynecologic examinations with laparoscopy, hysteroscopy, and curettage were performed but no pathologic explanation of this elevated beta-HCG could be found. In the initial computed tomography (CT) of the abdomen and the thorax, a tumor could not be detected. Based on a clinical decision, chemotherapy with methotrexate in a dose of 1 mg/kg body weight was started. Four months after beginning of the chemotherapy the beta-HCG level dropped to 3048 IU/L. At this time a first F-18 FDG PET was performed and the findings were negative. After completion of 7 cycles of chemotherapy the beta-HCG level rose again. In a second F-18 FDG PET in August 2006 focal, intense and pathologic F-18 FDG accumulation with a SUV max. of 5.4 was seen in the mediastinum in the region of the thymus. At this time the beta-HCG level was 7000 IU/L. In a subsequent CT of the chest a retrosternal mass of 4 x 1.7 cm was detected with contrast enhancement. Resection of the tumor and thymus gland demonstrated a choriocarcinoma in part adjacent to the thymus and in part in the thymus. Postoperative beta-HCG levels dropped to 105 IU/L.

Purpose The excellent prognosis of localized neuroblastoma in infants, the overdiagnosis observed in neuroblastoma screening studies, and several case reports of regression of localized neuroblastoma prompted us to initiate a prospective cooperative trial on observation of localized neuroblastoma without cytotoxic treatment. Patients and Methods For infants with localized neuroblastoma without MYCN amplification, chemotherapy was scheduled only in cases with threatening symptoms; otherwise, the tumor was either resected or observed by ultrasound and magnetic resonance imaging (MRI). Results Of 340 eligible participants, 190 underwent resection, 57 were treated with chemotherapy, and 93 were observed with gross residual tumor. Of those 93 patients with unresected tumors, spontaneous regression was seen in 44, local progression in 28, progression to stage 4S in seven, and progression to stage 4 in four. Time to regression was quite variable, with first signs of regression noted 1 to 18 months after diagnosis and in 15 of 44 patients even after the first year of life. So far, complete regression was observed in 17 of 44 patients 4 to 20 months after diagnosis. Known clinical risk factors were not able to differentiate between patients with regression and regional or metastatic progression. Overall survival (OS; 3-year OS, 0.99 ± 0.01) and metastases-free survival (rate at 3 years, 0.94 ± 0.03) for patients with unresected tumors was excellent and was not different from patients treated with surgery or chemotherapy. Conclusion Spontaneous regression is regularly seen in infants with localized neuroblastoma and is not limited to the first year of life. A wait-and-see strategy is justified in those patients.

Purpose To develop a gene expression–based classifier for neuroblastoma patients that reliably predicts courses of the disease. Patients and Methods Two hundred fifty-one neuroblastoma specimens were analyzed using a customized oligonucleotide microarray comprising 10,163 probes for transcripts with differential expression in clinical subgroups of the disease. Subsequently, the prediction analysis for microarrays (PAM) was applied to a first set of patients with maximally divergent clinical courses (n = 77). The classification accuracy was estimated by a complete 10-times-repeated 10-fold cross validation, and a 144-gene predictor was constructed from this set. This classifier's predictive power was evaluated in an independent second set (n = 174) by comparing results of the gene expression–based classification with those of risk stratification systems of current trials from Germany, Japan, and the United States. Results The first set of patients was accurately predicted by PAM (cross-validated accuracy, 99%). Within the second set, the PAM classifier significantly separated cohorts with distinct courses (3-year event-free survival [EFS] 0.86 ± 0.03 [favorable; n = 115] v 0.52 ± 0.07 [unfavorable; n = 59] and 3-year overall survival 0.99 ± 0.01 v 0.84 ± 0.05; both P < .0001) and separated risk groups of current neuroblastoma trials into subgroups with divergent outcome (NB2004: low-risk 3-year EFS 0.86 ± 0.04 v 0.25 ± 0.15, P < .0001; intermediate-risk 1.00 v 0.57 ± 0.19, P = .018; high-risk 0.81 ± 0.10 v 0.56 ± 0.08, P = .06). In a multivariate Cox regression model, the PAM predictor classified patients of the second set more accurately than risk stratification of current trials from Germany, Japan, and the United States (P < .001; hazard ratio, 4.756 [95% CI, 2.544 to 8.893]). Conclusion Integration of gene expression–based class prediction of neuroblastoma patients may improve risk estimation of current neuroblastoma trials.

This study was undertaken to analyze the differentiation profiles assessed by immunophenotyping in AIDS-related B-cell lymphoma (ARL) and their relation to the clinical course. Paraffin-embedded sections of 89 ARL cases during 1989 to 2004 were stained immunohistochemically with antibodies to CD3, CD10, CD20, CD38, CD138/Syndecan-1 (Syn-1), multiple myeloma-1/interferon regulatory factor-4 (MUM1/IRF4), B-cell lymphoma protein-2 (BCL-2), BCL-6, latent membrane protein-1 (LMP-1), and Ki-67. Expression of CD10 and CD20 were associated with better overall survival (OS; P = .009 and P = .04, respectively). Expression of CD20 was associated with longer disease-free survival (DFS; P = .03), whereas expression of CD138/Syn-1 was associated with shorter DFS (P = .03). OS and DFS were worse in patients with immunophenotypic profiles related to post-germinal center (GC) differentiation (BCL-6 and CD10 negative, MUM1/IRF4 and/or CD138/Syn-1 positive) when compared with GC differentiation (P = .01). When controlled for age-adjusted International Prognostic Index (IPI), prior AIDS-defining illness (ADI), and year of ARL diagnosis, a post-GC differentiation remained significantly associated with poor OS and DFS. Expression of CD10 was associated with a preserved immunocompetence, whereas CD20 was less frequent in patients developing ARL while on highly active antiretroviral therapy (P = .04). In summary, lack of CD20 or CD10 expression and a post-germinal center signature are associated with a worse prognosis in ARL.

Recently, Geosentinel has been notified of patients with acute muscular Sarcocystis-like infections related to travel to Tioman Island, peninsular Malaysia ([1][1]). The outbreak started in the summer of 2011, and the initial patients were seen in Wurzburg, Germany ([2][2]). The epidemic is

6579 Background: In HIV-1 infected patients, AIDS-related lymphoma (ARL) remains one of the most frequent AIDS-defining illnesses (ADI). Little is known about the differentiation profiles in ARL an...

The recent World Health Organization (WHO) classification of hematopoietic and lymphoid tissue tumors represents the first worldwide consensus classification of these malignancies. However, the applicability of this classification to a representative number of hepatic lymphomas in liver biopsy specimens has not yet been investigated. The frequency and infiltration pattern of a series of 205 liver biopsies with lymphoma manifestations was analyzed with the aid of immunohistochemical and molecular pathological analyses. Diffuse large B-cell lymphoma (DLBCL) was by far the most frequent entity, comprising 45% of the cases analyzed. Using a previously published immunohistochemical algorithm, 35% of 80 DLBCL were assigned to a germinal center B-cell-like (GCB) and 65% to a non-GCB group. Most B-cell lymphoma entities involving the liver revealed a characteristic infiltration pattern. Diagnostically challenging entities were T-cell-rich B-cell lymphomas, anaplastic large cell lymphomas and peripheral T-cell lymphomas, which frequently required additional molecular clonality assessment. Overall, the percentage of T-cell lymphomas in the liver (12%) was higher as compared to other extranodal sites except for the skin and the small intestine. This study provides relevant data on the distribution of hepatic lymphomas and demonstrates the applicability of the WHO classification proposing a diagnostic algorithm for liver biopsies.