SPARC-positive macrophages are the superior prognostic factor in the microenvironment of diffuse large B-cell lymphoma and independent of MYC rearrangement and double-/triple-hit status.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with respect to outcome. Features of the tumor microenvironment (TME) are associated with prognosis when assessed by gene expression profiling. However, it is uncertain whether assessment of the microenvironment can add prognostic information to the most relevant and clinically well-established molecular subgroups when analyzed by immunohistochemistry (IHC). PATIENTS AND METHODS: We carried out a histopathologic analysis of biomarkers related to TME in a very large cohort (n = 455) of DLBCL treated in prospective trials and correlated with clinicopathologic and molecular data, including chromosomal rearrangements and gene expression profiles for cell-of-origin and TME. RESULTS: The content of PD1+, FoxP3+ and CD8+, as well as vessel density, was not associated with outcome. However, we found a low content of CD68+ macrophages to be associated with inferior progression-free survival (PFS) and overall survival (OS; P = 0.023 and 0.040, respectively) at both univariable and multivariable analyses, adjusted for the factors of the International Prognostic Index (IPI), MYC break and BCL2/MYC and BCL6/MYC double-hit status. The subgroup of PDL1+ macrophages was not associated with survival. Instead, secreted protein acidic and cysteine rich (SPARC)-positive macrophages were identified as the subtype of macrophages most associated with survival. SPARC-positive macrophages and stromal cells directly correlated with favorable PFS and OS (both, P[log rank] <0.001, P[trend] < 0.001). The association of SPARC with prognosis was independent of the factors of the IPI, MYC double-/triple-hit status, Bcl2/c-myc double expression, cell-of-origin subtype and a recently published gene expression signature [lymphoma-associated macrophage interaction signature (LAMIS)]. CONCLUSIONS: SPARC expression in the TME detected by a single IHC staining with fair-to-good interobserver reproducibility is a powerful prognostic parameter. Thus SPARC expression is a strong candidate for risk assessment in DLBCL in daily practice.

[Hematological neoplasias as differential diagnoses of soft tissue tumors]. / Hämatologische Neoplasien als Differenzialdiagnosen von Weichgewebstumoren.

BACKGROUND: Several hematological malignancies might morphologically present as differential diagnoses of sarcomas. OBJECTIVES: To illustrate entities of hematological malignancies that might cause difficulties in differentiation from sarcomas and to introduce immunohistochemical and molecular tests that facilitate the diagnosis. MATERIAL AND METHODS: Selective literature research ( http://www.ncbi.nlm.nih.gov ) was combined with the clinico-pathological experience of the authors. RESULTS: In particular, hematologic malignancies with small blue round cell cytology, as well as lymphomas with anaplastic or spindle cell morphology, may mimic sarcomas. Identification of the correct diagnosis is usually possible by applying immunohistochemical and molecular analyses. Lymphomas without expression of CD45 and hematological neoplasias with expression of markers characteristic of sarcomas may cause difficulties in differential diagnosis. CONCLUSION: Hematological malignancies should be kept in mind as differential diagnoses of sarcomas and should be excluded by immunohistochemical and molecular analyses according to morphology and the clinical picture.

[Recovery of paraffin blocks and central archiving : Experiences of the Kiel lymph node registry and the German study group for Hodgkin lymphoma]. / Rückforderung von Paraffinblöcken und zentrale Archivierung : Erfahrungen des Lymphknotenregisters Kiel und der Deutschen Studiengruppe für Hodgkin Lymphome.

BACKGROUND: Central collection of tissue blocks for pathological and translational research is particularly important in rare diseases. Transfer of tissue blocks from primary to central pathology is of crucial importance. OBJECTIVES: We aimed to answer the following questions: Has the transfer of tissue blocks sent for consultation or within clinical trials changed over the last 20 years? What are the reasons for reclaiming tissue blocks by the primary pathology and what actions would convince primary pathologists to leave the blocks in the reference pathology? MATERIAL AND METHODS: The first 100 biopsies of each year between 1995 and 2015 (n = 2100), as well as all tissue transfers within therapeutic studies (n = 1405, German Hodgkin Study Group, GHSG) between 1998 and 2015, were analyzed separately for block reclaims using the Department of Pathology database. A questionnaire evaluated the reasons for block reclaiming by the peripheral pathologists. RESULTS: There is a significant increase in block reclaims during the period analyzed among submissions for consultation as well as in clinical trials (linear regression, p = 0.0195 and p = 0.0107). The percentage of block reclaims does not differ between consultations and cases submitted upon request within clinical trials (p = 0.2404, t-test). A survey among pathologies that reclaim the block showed that their willingness to leave the block at the reference center would increase if the compatibility with accreditation guidelines (39.3%), a positive statement from professional associations (25%), or a formal confirmation of availability (53.6%) is provided. DISCUSSION: In particular, to improve research on rare diseases, it is desirable to point out the compatibility of central archiving in a designated center with accreditation guidelines.

[Histiocytic diseases in childhood and adolescence]. / Histiozytäre Erkrankung des Kindes- und Jugendalters.

Histiocytic diseases are generally rare with a variable clinical course and variable morphology which often have a peak frequency of occurrence in childhood and adolescence. Histiocytoses are subdivided into Langerhans cell histiocytosis and the so-called non-Langerhans cell histiocytosis, such as juvenile xanthogranuloma, Erdheim-Chester disease and Rosai-Dorfman disease. The most common forms of histiocytosis in childhood are Langerhans cell histiocytosis and juvenile xanthogranuloma. In contrast, forms of histiocytosis which occur more frequently in adulthood, such as Erdheim-Chester disease and Rosai-Dorfman disease are rare in childhood. Some forms of histiocytosis harbor BRAFv600E mutations. In Langerhans cell histiocytosis they have been found in 50-55 % of the cases examined and in Erdheim-Chester disease in up to 100 % of cases. In the remaining forms of histiocytosis (especially juvenile xanthogranuloma and Rosai-Dorfman disease) BRAF mutations could not be detected. A prognostic relevance could not be shown so far; however, in individual cases a mutation analysis of BRAF could provide help in the differential diagnostic considerations or the option of a therapy approach with BRAF inhibitors.

[Malignant lymphomas in children and adolescents. Practical knowledge for diagnosis]. / Maligne Lymphome im Kindes- und Jugendalter : Praktisches Wissen für den diagnostischen Alltag.

Malignant lymphomas are very rare in childhood. Therefore in Germany and Europe-wide the diagnosis and treatment of these diseases and research into them are carried out in multicenter-study groups and registries that provide central clinical consulting as well as histopathological, genetic, and molecular diagnoses. Despite these central structures, the diagnosis of these aggressive lymphomas is usually made initially outside these specialized centers. Therefore, in clinical situations that are often quite critical, every pathologist may be required to make the initial diagnosis and decide on the initial therapy regimen. Specific features related to the incidence, biology, and clinical presentation of pediatric lymphomas strongly influence the diagnostic workup and require a different diagnostic procedure from that employed in adults. In this paper, we will try to provide the most important information required for a tissue-saving initial diagnosis of the most common pediatric lymphomas. The proposed procedures allow reliable differentiation into the main lymphoma categories and, thus, provide the necessary information for the first therapeutic regimens, although the final subtyping will remain the responsibility of specialists. The most relevant histopathological features, appropriate immunohistochemical stains, and diagnostic pitfalls are demonstrated. As examples of the most common entities, special attention is paid to Burkitt lymphoma, diffuse large B-cell lymphoma, precursor T- and B-cell lymphoma, and anaplastic large-cell lymphoma.

[Primary Hodgkin's lymphoma of the colon]. / Primäres Hodgkin-Lymphom des Kolons.

Primary Hodgkin's lymphoma of the colon is exceedingly rare. We report on the case of a 74-year-old female patient presenting with weight loss and hematochezia. Proctocolonoscopy revealed a bleeding tumor localized in the right colonic flexure. Histological examination of initial mucosal biopsies could not verify malignancy; however, explorative surgery was decided in an interdisciplinary conference setting and right-sided hemicolectomy was performed. Macroscopically, a tumor measuring 5.5 cm in maximum diameter was found. By means of histology and immunohistochemistry the diagnosis of classic Hodgkin's lymphoma was made. Mesenteric lymph nodes were not affected and postoperative staging revealed no systemic spread. Therefore, the tumor fulfilled the criteria of a primary colonic Hodgkin's lymphoma. Diagnosis of primary colonic lymphoma can be difficult as clinical symptoms are typically unspecific and, as shown in this case, even primary biopsy histology can be falsely negative.

[Mycosis fungoides or inflammatory dermatitis: differential diagnosis between early lymphoma and inflammation in skin biopsies]. / Mycosis fungoides oder entzündliche Dermatose: Differenzialdiagnostik zwischen frühem Lymphom und Entzündung an der Hautbiopsie.

Mycosis fungoides is a cutaneous T-cell lymphoma with protracted clinical course and progression in different stages with increasing aggressiveness. The clinical picture as well as the histopathology of mycosis fungoides within the early patch and plaque phase is difficult to delineate from some inflammatory skin diseases. Thus, the diagnosis of these early stages of the lymphoma is only possible when clinical, histopathological, and molecular features are integrated into the diagnosis, especially as none of the individual disease criteria is specific. Important clues towards the diagnosis of mycosis fungoides are cytologically abnormal epidermotropic CD4-positive T-cells causing only minor epidermal alterations, the formation of Pautrier-abscesses and basal alignment of the epidermotropic T-cells. The findings of an aberrant T-cell immunophenotype of the intraepidermal lymphoid component as well as the molecular proof of T-cell clonality are important further features. In the differential diagnosis between early stage mycosis fungoides and parapsoriasis, there remains nevertheless a diagnostic and maybe also a true biological grey zone.

[Specifics of histopathological and genetical diagnosis and classification of lymphomas in children and adolescents]. / Besonderheiten der histopathologisch-genetischen Diagnose und Klassifikation von Lymphomen im Kindes- und Jugendalter.

Malignant lymphoma along with leukemias account for nearly half of all malignancies arising in childhood and adolescence. The correct tissue-based histopathological diagnosis of lymphomas results from a close interdisciplinary exchange between pediatric oncologists and hematopathologists. We describe here relevant features of lymphoma subtypes arising in the young age group, Burkitt lymphoma, precursor/lymphoblastic lymphomas, anaplastic large cell lymphoma and diffuse large B-cell lymphoma as well as primary mediastinal B-cell lymphoma and the rare pediatric follicular lymphomas. Special focus is put on specific diagnostic difficulties as well as new insights into biological features of pediatric lymphomas in comparison with their adult counterpart. In addition the relevance of newly defined lymphoma entities of the WHO-classification 2008, e.g. greyzone lymphomas, will be discussed for the young age group.

Nodal anaplastic large-cell lymphoma ALK-1- with CD30+ cutaneous lymphoproliferation treated with mistletoe: spontaneous remission or treatment response?

A 12-year old girl presented with general weakness and weight loss, a localised cervical lymph node enlargement and cutaneous lesions compatible with lymphomatoid papulosis (LyP). Biopsies from lymph node and skin revealed a histological diagnosis of nodal large cell ALK-1- anaplastic lymphoma (ALCL) with a synchronous CD30+ cutaneous lymphoproliferation consistent with lymphomatoid papulosis (LyP). The girl was treated with mistletoe (MT) as monotherapy. Within 1 week after initiation of MT-treatment the skin lesions and lymph node enlargement improved. Under continuing MT-therapy 30 months after diagnosis the patient is still in complete remission. It is not possible to know whether this was a rare case of spontaneous remission of the nodal and skin-manifestations of this CD30+ T-cell lymphoproliferation or whether the observed effect was a specific therapeutic response to MT-treatment.

Non-Hodgkin's lymphoma in adolescents: experiences in 378 adolescent NHL patients treated according to pediatric NHL-BFM protocols.

Age-related differences in the distribution, biology and treatment response of non-Hodgkin's lymphoma (NHL) in adolescents remain to be elucidated. The current analyses present clinical parameters and outcomes of adolescents treated in pediatric NHL-BFM trials. Patients were stratified by histological subtype: lymphoblastic lymphoma (LBL); mature B-NHL, including Burkitt's lymphoma/leukemia (BL/B-AL), diffuse B-cell lymphoma (DLBCL-CB) and mediastinal B-cell lymphoma (PMLBL); and anaplastic large cell lymphoma (ALCL). Between October 1986 and December 2007, 2915 patients were registered, including 378 (13%) adolescents (15-18 years) with BL/B-AL (n=101), ALCL (n=74), DLBCL-CB (n=55), T-LBL (n=45), PMLBL (n=24), pB-LBL (n=13) and rare or not-specified NHL subtypes (n=66). The 5-year event-free survival (EFS) was 79±2% for adolescents compared with 85±1% for patients aged <15 years (P=0.014). EFS was 83±7% for adolescents with T-LBL, 82±4% with BL/B-AL, 85±5% with DLBCL-CB, 57±10% with PMLBL and 70±6% with ALCL. According to sex, the 5-year EFS in females versus males, respectively, was 70±5 versus 83±2% overall (P=0.004), 57±17 versus 92±6% (P=0.0036) for T-LBL patients and 71±9 versus 97±3% (P=0.0067) for DLBCL-CB patients. Adolescents with NHL treated according to pediatric NHL-BFM protocols had an EFS of 79±2%, which is marginally inferior to that of children. In adolescents with T-LBL and DLBCL-CB, female sex was associated with a worse prognosis.