Large B-Cell Lymphomas in the 5th Edition of the WHO-Classification of Haematolymphoid Neoplasms-Updated Classification and New Concepts.

The family/class of the large B-cell lymphomas (LBCL) in the 5th edition of the World Health Organization (WHO) classification of haematolymphoid tumors (WHO-HAEM5) features only a few major changes as compared to the 4th edition. In most entities, there are only subtle changes, many of them only representing some minor modifications in diagnostic terms. Major changes have been made in the diffuse large B-cell lymphomas (DLBCL)/high-grade B-cell lymphomas (HGBL) associated with MYC and BCL2 and/or BCL6 rearrangements. This category now consists of MYC and BCL2 rearranged cases exclusively, while the MYC/BCL6 double hit lymphomas now constitute genetic subtypes of DLBCL, not otherwise specified (NOS) or of HGBL, NOS. Other major changes are the conceptual merger of lymphomas arising in immune-privileged sites and the description of LBCL arising in the setting of immune dysregulation/deficiency. In addition, novel findings concerning underlying biological mechanisms in the pathogenesis of the different entities are provided.

Follicular Lymphoma in the 5th Edition of the WHO-Classification of Haematolymphoid Neoplasms-Updated Classification and New Biological Data.

The conceptual description of Follicular lymphoma (FL) in the 5th edition of the World Health Organization (WHO) classification of haematolymphoid tumors (WHO-HAEM5) has undergone significant revision. The vast majority of FL (85%) with a follicular growth pattern are composed of centrocytes and centroblasts, harbor the t(14;18)(q32;q21) translocation and are now termed classic FL (cFL). They are set apart from three related subtypes, FL with predominantly follicular growth pattern, FL with unusual cytological features (uFL) and follicular large B-cell lymphoma (FLBCL). In contrast to the revised 4th edition of the WHO classification of haematolymphoid tumors (WHO-HAEM4R), grading of cFL is no longer mandatory. FL with a predominantly diffuse growth pattern had been previously recognized in WHO-HAEM4R. It frequently occurs as a large tumor in the inguinal region and is associated with CD23 expression. An absence of the IGH::BCL2 fusion and frequent STAT6 mutations along with 1p36 deletion or TNFRSF14 mutation is typical. The newly introduced subtype of uFL includes two subsets that significantly diverge from cFL: one with "blastoid" and one with "large centrocyte" variant cytological features. uFL more frequently displays variant immunophenotypic and genotypic features. FLBCL is largely identical to WHO-HAEM4R FL grade 3B and renaming was done for reasons of consistency throughout the classification. In-situ follicular B-cell neoplasm, pediatric-type FL, duodenal-type FL and primary cutaneous follicle center lymphoma are categorized as discrete entities. In addition, novel findings concerning underlying biological mechanisms in the pathogenesis of early and systemic follicular lymphoma will be presented.

Case Report: Dynamic Interdependencies Between Complementary and Alternative Medicine (CAM) Practice, Urinary Interleukin-6 Levels, and Fatigue in a Breast Cancer Survivor.

Background: This study investigated the influence of complementary and alternative medicine (CAM) techniques (i.e., Jin Shin Jyutsu, music, physiotherapy, Tai Chi, and energy healing) on urinary interleukin-6 (IL-6) levels and fatigue in a 49-year-old breast cancer survivor suffering from cancer-related fatigue and depression. Data were sampled under conditions of "life as it is lived." Methods: For 28 days, a female breast cancer survivor collected her full urine output in 12-h intervals from about 8 a.m. to 8 p.m. and from about 8 p.m. to 8 a.m. These urine samples were used to determine urinary IL-6 levels through ELISA and creatinine concentrations via HPLC. In 12-h intervals (every morning and evening), the patient completed the DIARI, which included fatigue measurement and notes on incidents and activities such as CAM practice. In addition, the patient was interviewed weekly to identify meaningful everyday incidents. In this context, CAM practice was also discussed. Time series analysis consisted of ARIMA modeling and cross-correlational analyses (p < 0.05). Results: When each CAM technique was considered separately in time series analysis, CAM was consistently associated with increases in urinary IL-6 release and decreases in fatigue. Furthermore, when all CAM techniques experienced as positive were included in one time series, a biphasic urinary IL-6 response pattern was found in which CAM practice was first preceded by decreases in IL-6 by 12-0 h and then followed by increases in IL-6 after 108-120 h. Finally, cross-correlations between IL-6 and fatigue showed that increases in IL-6 were followed by decreases in fatigue intensity after 48-60 h and, conversely, that decreases in fatigue intensity were followed by decreases in IL-6 after 24-36 h and 48-60 h. Conclusion: IL-6 increases and fatigue decreases highlight potential health-promoting effects of CAM practice. Moreover, a cyclic IL-6 pattern in response to all CAM activities experienced as positive underscores that CAM was meaningful to the patient. Additionally, a negative feedback circuit between IL-6 and fatigue intensity was detected. Taken together, this study confirms the necessity of integrating subjective meaning and dynamic complexity into biopsychosocial research in order to understand human functioning under real-life conditions.

Dynamic Effects of CAM Techniques on Inflammation and Emotional States: An Integrative Single-Case Study on a Breast Cancer Survivor.

BACKGROUND: This study on a breast cancer survivor investigated how episodic practice of various complementary and alternative medicine (CAM) techniques affected the dynamics of emotional states and urinary neopterin-an inflammation marker. METHODS: The 49-year-old female patient (diagnosis: ductal breast carcinoma 5 years before study start, suffering from chronic fatigue and depression) collected her entire urine in 12-hour intervals (from about 8 a.m. to 8 p.m. and from about 8 p.m. to 8 a.m.) for 28 days. The resulting 55 consecutive urine samples were analyzed for neopterin and creatinine levels using HPLC. Also in 12-hour intervals, the patient filled out questionnaires on emotional states and everyday routine, including CAM practice. Weekly, she was interviewed to identify emotionally meaningful everyday incidents, including use of CAM techniques. Time series analysis consisted of ARIMA modeling and cross-correlational analyses. RESULTS: Qualitative evaluation revealed that, with the exception of Tai Chi, all CAM techniques, that is, Jin Shin Jyutsu, music, physiotherapy and energy healing, were experienced as positive. Cross-correlational analyses showed that practice of such CAM techniques was followed first by significant (P < .05) increases in positive mood and mental activity on the same day (lag 0) and then by decreases in positive mood after a total of 72 to 84 hours (+lag 6) and in mental activity after a total of 84 to 96 hours (+lag 7). Negative mood, by contrast, first decreased on the day of CAM practice (lag 0) and then increased after a total of 84 to 96 hours (+lag 7) following CAM. Moreover, urinary neopterin levels first increased on the day of CAM practice (lag 0) and then decreased after a total of 36 to 48 hours (+lag 3). Similar biphasic effects were also detected for irritation in response to CAM, although only partly significant. CONCLUSION: Cyclic psychophysiological response patterns following CAM practice were attributable to biopsychosocial feedback mechanisms involving personally meaningful experiences. As lower neopterin levels following CAM point to a health-promoting effect, the patient of this study may have actively contributed to her healing process through episodic CAM practice.

Extraskeletal osteosarcoma of the breast in an adolescent girl.

Extraskeletal osteosarcoma (ESOS) is a rare malignancy, usually arising in older adults. We were unable to find reports of children or adolescents affected by an ESOS of the breast. Here, we present the case of a high-grade osteosarcoma arising in the breast of a 16-year-old girl. The tumor was treated with breast-conserving resections and adjuvant multiagent chemotherapy, based on a regimen of doxorubicin, high-dose methotrexate, cisplatin, and ifosfamide. At last follow-up, the patient was in first complete remission, 29 months after initial diagnosis.

The value of contrast enhanced ultrasound (CEUS) in the characterisation of patients with renal masses.

Renal masses are frequently incidentally found on ultrasound. Contrast enhanced computed tomography (CECT) is regarded as the method of choice. Contrast enhanced ultrasound (CEUS) has a high impact for characterisation of hepatic lesions. Its use in renal masses has been less comprehensively studied. Two hundred and one patients referred for surgical treatment of a renal mass, 143 patients fulfilling inclusion criteria (histology and reference method). Baseline ultrasound and CEUS with BR1, histology obtained by surgery (89%) or biopsy (11%). Eighty-eight percent of the patients had renal lesions which were malignant and 12% benign lesions. Eighty percent had renal cell carcinoma (RCC). Seven percent of the lesions were cystic. Two patients were upgraded by CEUS from CECT Bosniak II into CEUS Bosniak III resp. IV. CEUS could predict malignancy with a sensitivity, specificity, positive, negative predictive value and accuracy in 97%, 45%, 91%, 75%, and 90%. The correct staging was diagnosed by CEUS (CECT) in 83% (69%). CEUS was superior to CECT in the staging and characterisation of RCC, also in the subgroup of patients with cystic lesions. CEUS can replace CECT e.g. in patients with allergies or contraindications against CECT. Multicentre studies are necessary to confirm the findings.

A benign tumour of the liver mimicking malignant liver disease--cholangiocellular adenoma.

OBJECTIVE: To describe three patients with liver lesions mimicking malignant tumours diagnosed finally, using contrast-enhanced ultrasound, as cholangiocellular adenoma (bile duct adenoma). MATERIAL AND METHODS: Focal liver lesions found incidentally in three patients. Contrast-enhanced ultrasound was with use of Siemens or Esaote equipment, low MI technique, after an intravenous bolus of 2.4 ml Sonovue (Bracco, Italy). RESULTS: Lesions were 9 mm, 15 mm and 20 mm in diameter and all were enhanced in the arterial phase and hypo-enhanced in the portal venous and late phases, suggesting their malignant nature. In two patients, no primary liver tumour was found, and in the third patient, previously resected for breast cancer, a tissue specimen was considered useful for characterizing tumour receptors for more targeted chemotherapy, the lesion being assumed metastatic in nature. Transcutaneous core biopsies were performed in all three patients. Pathological analysis (including the reference pathology) revealed cholangiocellular adenoma in all of them. CONCLUSION: Cholangiocellular adenoma is a rare entity and can be a reason for possible false malignant diagnosis using contrast-enhanced ultrasound. Follow-up examinations are recommended.

Improved differentiation of pancreatic tumors using contrast-enhanced endoscopic ultrasound.

BACKGROUND & AIMS: Endoscopic ultrasound is a widely accepted imaging method for staging of ductal adenocarcinoma and the localization of neuroendocrine tumors of the pancreas. We prospectively evaluated conventional color Doppler imaging and contrast-enhanced endoscopic Doppler ultrasound (CE-EDUS) as a new imaging technique for further characterization and differentiation of solid pancreatic tumors. METHODS: From 300 patients with pancreatic lesions investigated using contrast-enhanced endoscopic ultrasound we could finally include 93 patients with an undetermined, solitary, predominantly solid, lesion 40 mm or less, and a definite histologically proven diagnosis. After bolus injection of the contrast agent SHU 508A 4 g (400 mg/dL) the vascular pattern of the lesion during the arterial phase was compared with the vascularity of the residual pancreatic parenchyma. RESULTS: Color Doppler imaging did not reveal vascularity of the pancreatic parenchyma in any of the patients, and therefore tumor hypovascularity could not be determined in contrast to all CE-EDUS-examined patients revealing at least some degree of parenchymal vascularity. Fifty-seven of 62 patients with ductal adenocarcinoma of the pancreas showed a hypovascularity of the tumor using CE-EDUS. All other pancreatic lesions revealed an isovascular or hypervascular pattern using contrast-enhanced endoscopic ultrasound (20 neuroendocrine tumors, 10 serous microcystic adenomas, and 1 teratoma). Hypovascularity as a sign of malignancy in contrast-enhanced endoscopic ultrasound obtained 92% (82%-97%) sensitivity and 100% specificity (89%-100%). CONCLUSIONS: Contrast-enhanced endoscopic ultrasound is effective in differentiating small solid pancreatic tumors of different origin in most cases. Hypovascularity indicates malignancy of pancreatic tumors.

Contrast-enhanced ultrasound of histologically proven liver hemangiomas.

UNLABELLED: Differentiation of small and atypical hemangiomas from other hepatic masses using imaging methods can be difficult, especially in patients with underlying malignant disease. Therefore, contrast-enhanced ultrasound was assessed in patients with histologically confirmed hemangiomas with respect to contrast-enhancing kinetics and tumor characteristics. In 58 patients with indeterminate hepatic lesions demonstrated with at least 2 imaging methods (ultrasound/computed tomography/magnetic resonance imaging), ultrasound-guided liver biopsy revealed hemangioma. In all patients a hepatic neoplasm had been suspected because of underlying malignant disease (n=41), liver cirrhosis (n=15), or growth of the lesion (n=2). All patients underwent nonlinear, low mechanical index real-time contrast-enhanced ultrasound scanning with bolus injections of SonoVue. Peripheral nodular arterial enhancement was detected in 43 patients (74%), whereas the typical metastatic peripheral rim-like enhancement was not observed at all. Strong homogenous arterial enhancement was found in 9 of 58 (16%) patients. In 6 patients (10%), the arterial contrast enhancement pattern could not be determined because of the very small size of the lesions or fibrotic nodules. Forty-five (78%) of the hemangiomas showed homogenous centripetal filling within 180 seconds. CONCLUSION: Contrast-enhanced ultrasound demonstrates typical hemangioma imaging characteristics, that is, peripheral nodular contrast enhancement and iris-diaphragm sign in a high percentage of patients with undetermined lesions. This technique may therefore improve noninvasive functional characterization and differentiation of hemangiomas.

Analysis of neuroendocrine tumour metastases in the liver using contrast enhanced ultrasonography.

BACKGROUND: Imaging of liver tumours might be improved by contrast-enhanced ultrasonography, which allows much better demonstration of the microvascular system. The aim of this study was to assess the sonographic morphology and vascularity of neuroendocrine liver metastases. METHODS: Forty-eight patients with histologically proven neuroendocrine tumours (NET) and suspected liver metastases--as well as 50 consecutive patients with liver metastases of other origins--were included in a prospective study to evaluate tumour characteristics using B-mode, colour Doppler (CDI) and contrast-enhanced ultrasound (CEUS). RESULTS: In 4/48 patients with NET, liver biopsy revealed hemangiomas. The typical B-mode appearance was that of both echo-rich and echo-poor combined, also inhomogeneous depending on the size, and often centrally cystic. With CDI, neuroendocrine metastases appeared hypervascular (66%) or isovascular (34%). Metastases of another origin were hypovascular in 82%. With CEUS, neuroendocrine metastases showed increased arterial enhancement in 38 patients and hypoechoic appearance in the portalvenous phase in 39 patients. In liver metastases of another origin, the sensitivity for malignancy due to a hypoechoic appearance during the portalvenous phase was 100%. In liver metastases of NET origin the sensitivity for malignancy was 39/48 (82%). CONCLUSIONS: Neuroendocrine tumour metastases might show characteristics which are similar to hemangiomas. In patients with liver cirrhosis and severe fatty liver disease the identification of NET with CEUS as a malignant lesion is more difficult. The sensitivity of CEUS in identifying malignancy based on the lack of portalvenous enhancement is higher for metastases of other origin.

CARMA1 and chromosomal translocations in extranodal marginal zone B-cell lymphomas of MALT type or diffuse large B-cell lymphomas.

We analyzed the configuration of the CARMA1 gene, encoding a protein that closely interacts with BCL10 and MALT1, in a series of 120 extranodal marginal zone B-cell lymphomas of MALT-type and 35 diffuse large B-cell lymphomas. Our study suggests that CARMA1 is not targeted by chromosomal translocations in these lymphoma entities.

Epstein-Barr virus-associated B-cell lymphoproliferative disorders in angloimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, unspecified.

Various patterns of Epstein-Barr virus (EBV)-associated B-cell lymphoproliferation occur in patients with immunodeficiency. We studied 17 cases of T-cell lymphoma displaying extensive EBV-driven B-cell lymphoproliferation or simultaneous/subsequent EBV-associated B-cell lymphoma. In 10 cases of angioimmunoblastic T-cell lymphoma, an uncommonly prominent population of EBV+ atypical, activated, focally confluent large transformed B cells was found in the background of T-cell lymphoma. In 4 cases, an EBV-associated B-cell neoplasm (3 diffuse large B-cell lymphomas, 1 plasmacytoma) occurred in patients with T-cell lymphoma. Three cases were composite lymphomas of a peripheral T-cell lymphoma, unspecified, combined with EBV-associated diffuse large B-cell lymphoma. The transformed B-cell population displayed EBV latency types 2 and 3. Monoclonal and oligoclonal B-cell populations were detected in 5 and 6 cases, respectively. Similar to other states of immunodeficiency, disease-related and therapy-induced immunosuppression in T-cell lymphoma may lead to a prominent EBV-associated B-cell lymphoproliferation and to EBV+ B-cell neoplasms.