Search

Besides histopathological findings, there are no indicators of increased risk for fibrotic progression in myeloproliferative neoplasms (MPNs). Age-related clonal hematopoiesis (ARCH) or clonal hematopoiesis of indetermined potential (CHIP) are frequent findings in the elderly and combinations with MPN driver mutations (JAK2, MPL, and CALR) have been described. To determine the impact of ARCH/CHIP-related mutations for the development of fibrosis in primary myelofibrosis (PMF), the mutational status of cases with fibrotic progression from grade 0 to grade 2/3 (n = 77) as evidenced by follow-up bone marrow biopsies (median 6.2 years) was compared to prefibrotic PMF samples without the development of fibrosis (n = 27; median follow-up 7.3 years). Frequent ARCH/CHIP-associated mutations (TET2, ASXL1, DNMT3A) demonstrable at presentation were not connected with fibrotic progression. However, mutations that are rarely found in ARCH/CHIP (SRSF2, U2AF1, SF3B1, IDH1/2, and EZH2) were present in 24.7% of cases with later development of fibrosis and not detectable in cases staying free from fibrosis (P = 0.0028). Determination of tumor mutational burden (TMB) in a subgroup of cases (n = 32) did not show significant differences (7.68 mutations/MB vs. 6.85 mutations/MB). We conclude that mutations rarely found in ARCH/CHIP provide an independent risk factor for rapid fibrotic progression (median 2.0 years) when already manifest at first presentation.

Since its first description at the Institute of Pathology in Kiel more than 34 years ago, the immunohistochemical proliferation marker Ki67 has been shown to be of prognostic significance in a huge number of retrospective and even some prospective trials on malignant tumours of various tissue derivation. Lack of standardization in the evaluation provides potential sources of variance in assessment. Tumour area to be assessed, minimum number of cells to be analyzed, tedious counting cell by cell or semiquantitative eyeballing, choice of immunohistochemical techniques represent nonstandardized issues that potentially lead to considerable assay heterogeneity. In addition, interpretation is not homogeneous, in particular with regard to thresholds between high and low proliferative activity. Due to these numerous potential methodological limitations, for a long time Ki67 was not generally accepted as a prognostic marker, in particular outside Germany and by nonpathologists. However, in recent years a shift has taken place. Despite the challenge that biological heterogeneity may be hidden by differences in assay performance, Ki67 now plays an important auxiliary role in grading of malignant neoplasms such as breast cancer, neuroendocrine tumours and malignant lymphomas. In this context it is applied in clinical diagnostics as well as in clinical trials for the purpose of stratification. Because of its widespread use, it is of utmost importance to raise awareness of the potential methodological limitations in order to use Ki67 in a meaningful way.

Intravascular B‑cell lymphomas (IVL) are rare neoplasms that can manifest at any age (mean age ~62-63 years). About half of the cases are associated with Epstein-Barr virus. The most common sites of manifestation are the brain, skin, and bone marrow. The diagnosis is difficult due to unspecific clinical presentation and laboratory changes. FACS (fluorescence-activated cell sorting) and clonality analysis from peripheral blood and radiological findings are often not diagnostic. The most sensitive and most specific diagnostic method is the histopathological and immunohistochemical evaluation of a tissue biopsy. Because of the rarity of this disease, little is known about therapy and prognosis, whereby therapy is mainly similar to non-IVL lymphomas. The prognosis is poor; median survival after diagnosis is approximately one year.

Background: Bone marrow carcinosis is a sign of advanced tumor stage with nonspecific clinical and hematological symptoms. Diagnosis is based on bone marrow biopsy and histopathology, but biopsies are not part of the standard work-up in oncological diseases and data on the correlation between clinical presentation and pathological findings are sparse., Material and Methods: In a retrospective single-center study, data from 20 tumor patients with bone marrow carcinosis were analyzed. Bone marrow biopsies were re-evaluated regarding quantity of tumor cells, fibrosis/necrosis, and bone changes. Immunohistochemistry of potential therapy-relevant receptors and PD-L1 was performed., Results: The median age in these 20 patients (13 women, 7 men) was 65 years. The most frequent diagnoses were breast (n = 8) and lung cancer (n = 5). Anemia (94% of patients), thrombocytopenia (72%), and elevated LDH (83%) were frequent findings. The degree of bone marrow infiltration was highly variable and accounted for between 1 and 95% of biopsy space. Significant bone remodeling was present in 14/20 biopsies. No correlation could be found between histological and radiological findings. Treated patients showed some clinical and biochemical improvement, but the overall survival was poor (median 4.5 months, range < 0.5 to 21.5 months)., Discussion: Anemia and thrombocytopenia are frequently associated with bone marrow carcinosis, but are nonspecific. The extent of tumor cell infiltration and osteolytic/osteoblastic changes did not correlate with radiological findings. Therapy-relevant target factors should be evaluated, but therapeutic options are often limited and the prognosis is bad.

From a historical perspective, histological grading was the earliest cell-based method for assessing tumor biology and the prognosis of breast cancer. This review article provides detailed and practical instructions for grading of breast cancer in routine diagnostics. Furthermore, the increasing relevance of precise histological grading in the era of molecular pathology is discussed.

Molecular pathology has been an integral part of the diagnostics of tumors of the hematopoietic system substantially longer than for solid neoplasms. In contrast to solid tumors, the primary objective of molecular pathology in hematopoietic neoplasms is not the prediction of drug efficacy but the diagnosis itself by excluding reactive proliferation and by using molecular features for tumor classification. In the case of malignant lymphomas, the most commonly applied molecular tests are those for gene rearrangements for immunoglobulin heavy chains and T-cell receptors. However, this article puts the focus on new and diagnostically relevant assays in hematopathology. Among these are mutations of MYD88 codon 265 in lymphoplasmacytic lymphomas, B-raf V600E in hairy cell leukemia and Stat3 exon 21 in indolent T-cell lymphomas. In myeloproliferative neoplasms, MPL W515, calreticulin exon 9 and the BCR-ABL and JAK2 V617F junctions are the most frequently analyzed differentiation series. In myelodysplastic and myeloproliferative neoplasms, SRSF2, SETBP1 and CSF3R mutations provide important differential diagnostic information. Genes mutated in myelodysplastic syndromes (MDS) are particularly diverse but their analysis significantly improves the differential diagnostics between reactive conditions and MDS. The most frequent changes in MDS include mutations of TET2 and various genes encoding splicing factors.

Optimal management of breast cancer patients is based on efficient multidisciplinary cooperation. The role of pathologists is to survey those parameters that are crucial for the individually adopted therapy. Thereby, distinct quality criteria have to be considered concerning the handling of the tissue samples, including preparation and examination, as well as the analytical methods used. The interdisciplinary S3 guideline "Diagnosis, therapy and follow-up of breast cancer" includes recommendations concerning these aspects based on current evidence. Its third edition was published in July 2012. In this article an overview of the topics relevant for pathologists that have been modified in the latest edition is provided.

Myeloproliferative neoplasms (chronic myeloproliferative disorders according to former nomenclature) comprise chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, primary myelofibrosis, chronic eosinophilic leukemia, chronic neutrophilic leukemia and systemic mastocytosis. All disorders have excessive proliferation of one or more hematopoietic lineages in common and progress with different probability to blast crisis or fibrosis. A further common feature is provided by the activating mutation of tyrosin kinases and associated pathways of signal transduction (BCR-ABL, JAK2(V617F), MPL(W515L/K), KIT(D816V) and FIP1L1-PDGFRA) causative for the abnormal proliferation. With regard to diagnosis and therapy these mutations are of utmost importance because they enable the exclusion of reactive processes, contribute with varying specificity to subtyping of MPN and are at least partly sensitive to targeted therapy. The molecular mechanisms of blastic and fibrotic progression are not yet understood.

In breast surgery intraoperative frozen sections for the diagnosis of malignancy has lost impact and has largely been replaced by preoperative core needle biopsies. Nevertheless, there is still need for immediate pathological investigation of native breast tissue during surgery due to three reasons: (1) macroscopic and microscopic evaluation of resection margins, (2) the histological analysis of sentinel lymph nodes in order to circumvent secondary axillary surgery and (3) the preparation of native tissue for tumor banking or measurement of biomarkers. Because histology provides only a facultative component of immediate pathological examination of breast specimens during surgery, the term frozen section does not seem to be appropriate anymore. Intraoperative evaluation of resection specimens by pathologists provides surgically relevant information immediately, guarantees standardized preparation and fixation of specimens and enables tissue banking of native tissue for assessment of biological markers.

In pulmonary hypertension there is a discrepancy between the dramatic but unspecific clinical presentation and the remodeling of mostly only limited segments of the vascular compartment of pulmonary parenchyma. Clinical diagnosis relies for the most part on invasive procedures, such as right heart catheterization. Therefore, morphology can provide a reliable etiopathogenetic classification only in close cooperation with the clinical partner disciplines involved. Moreover, the histopathological approach requires intimate knowledge of the vascular anatomy of the lungs and assessment of the parenchyma to be able to diagnose pulmonary hypertension and differentiate between the various types.

Graft-versus-host disease (GvHD) occurs as a major complication in 35%-50% of all patients undergoing allogeneic stem cell transplantation. A distinction is made between acute and chronic GvHD depending on the time of onset, type of clinical symptoms and histology. Both forms preferably show manifestations in the skin, mucosal membranes, gastrointestinal tract, liver and (less often) lung. As the clinical presentation is rather unspecific, particularly for the diagnosis of acute GvHD, histology is important to exclude infectious diseases or drug reactions. This review covers the diagnostic morphological criteria and differential diagnoses of GvHD in the skin, gastrointestinal tract and the liver.

Transplantation of solid organs and haematopoietic stem cells requires immunosuppressive drug therapy in order to prevent rejection or graft-versus-host disease. Depending on dosage and type of drug, the risk of developing an Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disease (PTLD) is increased. The lesion spectrum ranges from hyperplastic lesions to manifest lymphomas, the latter being classified as monomorphic PTLD. Hyperplastic changes, which are not distinguishable from viral reactions, comprise early or mononucleosis-like lesions. Those with effaced lymph node architecture or extranodal manifestation without a lymphoma-like phenotype are designated polymorphic PTLD. Monomorphic PTLD are either high grade B cell lymphomas, plasma cell neoplasms or Hodgkin lymphomas and only very rarely T cell lymphomas. Low grade B cell lymphomas do not occur. In a subfraction of cases, including even monomorphic PTLD, reduction of immunosuppression alone is sufficient to induce remission of the pathological process.

The grading of invasive breast cancers according to Bloom and Richardson (Nottingham modification) provides one of the most important prognostic factors in addition to size and the status of the lymph nodes. Diagnostic reproducibility has been problematic in daily practice as the required criteria for selection and extent of the grading area are frequently not present in the punch biopsies.A total of 346 cases were retrospectively used to compare routine grading from surgical preparations with an equivalently small sample from punch biopsies. In addition, a modified grading of these small samples was developed with Ki-67 immunochemistry and the measurement of core size. In the case of modified grading, 1-3 points were given for Ki-67 and average maximum core diameter. Tubule development was evaluated with 1 or 2 points. A comparison for recurrence free survival and total survival showed significant prognostic differences between 3-5 points (low risk) and 6-8 points (high risk) in uni- and multivariate analyses. The evaluation criteria for Nottingham-Bloom-Richardson grading in a small tissue sample, such as that from a punch biopsy, can hardly be fulfilled. In our series, prognostic value was only found for nodal negative cases. After modification using objective parameters such as nuclear size measurement and Ki-67 proliferation index, a small tissue sample can prove to be of significant prognostic value for nodal negative as well as nodal positive cases.

In contrast to hepatocellular carcinoma (HCC), very few molecular pathological studies have been carried out on hepatocellular adenoma (HCA). Particularly from the surgical point of view, based on views passed on verbally and in the literature of the 1970s and 1980s, a possible degeneration of the HCA provides grounds for operating. Published cases of transitions from HCA into HCC were evaluated on the basis of today's morphological standards. A comparison was made between the patterns of new molecular pathological studies of HCA, above all the work of our own groups, and those of HCC. The results speak against the suggestion that a typical solitary HCA in pre-menopausal women is a precursor lesion of HCC. After a critical review of the literature, only one casuistic case of a transition of HCA to HCC under a hormone therapy, which is no longer practiced today, remained. A limitation of particular HCA in genetic and metabolic diseases, children, adult males, adenomatosis, and HCA-like tumors with known risk factors of HCC would seem pragmatically meaningful. With classic HCA, however, the oncological indication for surgery does not apply. A prerequisite is a histological clarification, if necessary with the support of molecular pathological methods.

Overt myelofibrosis in bone marrow biopsies as a diagnostic postulate in cIMF has been discarded only recently by the WHO. Therefore, only a few studies have been performed on the evolution of myelofibrosis in "prefibrotic" cIMF by means of sequential bone marrow biopsies. We carried out this study on 38 patients, split up into two groups, A and B according to treatment modalities, to evaluate the dynamics and frequency of myelofibrosis in both groups. Our results indicate a step-wise development of myelofibrosis from a "prefibrotic" to a "classical" cIMF, as 75-80% of the respective patients in both groups progressed to myelofibrosis. However, this evolution seems to be heterogeneous and unpredictable in individual patients, since myelofibrosis could be seen as early as less than 2 years after diagnosis in 12/38 (31.6%) patients, whereas 3 patients remained "prefibrotic" even after up to 6 years of follow-up.

Staging biopsies of the bone marrow in lymphoma patients are among the most important indications and therefore of substantial practical importance. Occasionally it is the only organ infiltrated, and therefore a bone marrow biopsy is the prime diagnostic choice in cases of leukemic lymphomas. A synoptical diagnostic approach relying on immunophenotypic as well as on molecular biological criteria aside from histomorphology (cytomorphology), is of utmost importance for the subtyping of malignant lymphomas. This too can be done reliably on bone marrow biopsies, as comparative studies have yielded a concordance rate of more than 90% with lymphoma typing on corresponding lymph nodes. Cytology and the pattern of infiltrates, (i.e. diffuse, interstitial, nodular peritrabecular and intrasinusoidal), in combination with immunological phenotyping are the mainstays for subtyping, giving clear-cut decisions in most cases of small B-cell lymphoma, mantle zone as well as marginal cell and follicular lymphomas and hairy cell leukemia. Among the blastic variants the most important are the lymphoblastic lymphomas of either B- or T-cell type which have to be discerned from AML and the so-called blastoid mantle cell lymphomas. T-cell lymphomas are rare compared to B-cell lymphomas. Among the rarely seen T-cell neoplasias the lymphoma of large granular lymphocytes is the dominating lymphoma, which in most cases can only be diagnosed reliably by molecular biological means, followed by T-CLL, Sezary's syndrome and hepatosplenic chi delta lymphoma.