Perivascular Plasmacytosis Research Articles

Consideration of exposure to pharmacological agents helps to avoid diagnostic pitfalls in bone marrow histopathology

Trephine bone marrow biopsy is a frequent routine investigation, particularly important in cases with an unsuccessful aspirate. In addition to a representative trephine biopsy length and quality, the patient's clinical history is of critical importance. Especially drug-induced bone marrow changes are often difficult to interpret without prior knowledge of exposure to respective agents. Since some of these changes mimic malignancies, this can lead to serious misinterpretations. Drugs in general can induce a wide spectrum of bone marrow reactions. Immunosuppressants such as Azathioprine and Methotrexate cause morphological bone marrow changes that can not be distinguished from myelodysplastic syndromes, while cytokines and growth factors induce an overall increase in cellularity and, in particular, a left shift of myelopoiesis with increased myeloblasts and monoblasts, mimicking acute myeloid leukaemia. Moreover, drugs with immuno-allergic- (such as Allopurinol, Carbimazole, Crabamazepine, Clozapine, non-steroidal anti-rheumatics, Phenytoin, Sulfonamides) or direct myelotoxic potential can lead either to T-cell-mediated bone marrow stem cell destruction with the morphological pattern of aplastic anaemia, to direct toxic or immunological burst- or colony-forming units' destruction with isolated erythro- or myelopoietic hypoplasias or to other changes such as eosinophilia, (haemo)phagocytosis, T-cell lymphocytosis (which can be very severe, resembling lymphoma/leukaemia), perivascular plasmacytosis, siderosis or stromal oedema. In summary, clinical information on drug exposure is at least as important as a good quality biopsy for comprehensive histology-based bone marrow diagnostics, helping to avoid not only misinterpretation but also expensive additional examinations.

Is it justified to perform a bone marrow biopsy examination in sustained erythrocytosis?

The diagnostic criteria of the Polycythemia Vera Study Group do not consider bone marrow histopathology, nor do they recognize the dynamics of polycythemia vera (PV). Precursor stages, when accompanied by an elevated platelet count, may clinically mimic essential thrombocythemia. Significantly extending former descriptions of bone marrow features, a trilineage myeloproliferation (panmyelosis) with a pleomorphous appearance (differences in size) of megakaryopoiesis is a characteristic histopathologic finding in PV. Differentiation from secondary polycythemia is accomplished by also considering the conspicuously expressed stromal changes (perivascular plasmacytosis, eosinophils, cell debris, and iron deposits). A clear-cut discrimination is possible, even in the initial (latent) stages of PV, which do not fulfill all the conventional diagnostic criteria. Advanced stages (spent phases) of PV show an increased left-shifted granulocytic proliferation accompanied by reduction of erythroid precursors and progressive myelofibrosis (postpolycythemic myeloid metaplasia). Finally, an increase in dysplastic changes and immaturity of cell lineages signals a transition into blastic crisis.

Bone marrow features of diagnostic impact in erythrocytosis

Controversy continues to persist about the role of histopathology regarding diagnosis of polycythemia vera (PV). For this reason, a clinicopathological study was performed on 334 patients presenting with a sustained borderline to marked erythrocytosis (hemoglobin >17 g/dl in men and >15 g/dl in women). The aim was to elucidate the discriminating impact of bone marrow biopsy examinations in an independent fashion from laboratory parameters. According to morphological findings based on a semiquantitative evaluation of standardized features, cellularity, megakaryocytes (quantity, size, pleomorphous aspect, clustering, nuclear lobulation), eosinophils, cellular debris, perivascular plasmacytosis and iron-laden macrophages exerted a distinctive value. Comparison with clinical data and follow-up revealed that in only 13 patients (4%), histopathology failed to differentiate clearly between PV (208 patients) and secondary polycythemias (113 patients). In conclusion, certain sets of morphological parameters allow a distinction between autonomous and reactive polycythemias and therefore enhance significantly diagnostic validity.

Acute panmyelosis with myelofibrosis: a clinicopathological study on 46 patients including histochemistry of bone marrow biopsies and follow-up.

Controversy continues whether acute panmyelosis with myelofibrosis (APMF) exists as a well-defined clinicopathological entity. Following exclusion of overt acute myeloid leukemia (AML), especially the megakaryoblastic subtype, a retrospective study was performed on 46 patients with clinical and morphological features suggesting the diagnosis of APMF. All patients had a bone marrow (BM) biopsy performed at onset, and 13 had follow-up examinations. Enzyme histochemical and immunohistochemical techniques were applied and BM features evaluated by a semiquantitative scoring system. Clinical findings consisted of pancytopenia associated with a left-shifted differential count of the peripheral blood (less than 5% blasts) and no or minor splenomegaly. During follow-up (median survival 9 months) 35 patients developed severe BM insufficiency and 10 transformed into overt AML. Although myelofibrosis was a characteristic finding, other BM features proved to be heterogeneous. Cellularity was reduced in 13 and increased in 25 specimens. Most prominent was a left-shifted, often macrocytic erythropoiesis and a maturation defect of the neutrophil series. In 15 patients an increase (less than 20%) in CD34+ progenitors, immature myelomonocytic cells, and megakaryoblasts was noted. Abnormalities of megakaryocytes (atypical microforms, clustering, dysplasia) were regularly present. The stroma showed an inflammatory reaction (perivascular plasmacytosis, lymphoid nodules, many macrophages, iron deposits) in about 50% of the samples. Sequential BM biopsies revealed an accumulation of lysozyme-expressing myelomonocytic and CD34+ progenitor cells suggesting an increase in blasts. In conclusion, APMF may not be a distinct entity, but includes hyperfibrotic myelodysplastic syndromes (MDS) either primary or secondary, a rare form of initial AML with fibrosis, and even cases of toxic myelopathy.

Acute Panmyelosis with Myelofibrosis

Acute panmyelosis with myelofibrosis (APMF) is an ill-defined disorder that may either evolve as a clonal hematopoietic condition or as a sequel of toxic exposure to the bone marrow (BM). Therefore, controversy and discussion continues as to whether APMF may be considered as a hyperfibrotic (de novo) myelodysplastic syndrome (MDS), as acute myeloid leukemia (AML) or as a severe toxic myelopathy with accompanying myelofibrosis. In this context scant knowledge exists about BM findings, but especially evolution of this disorder according to sequential examinations. Clinically patients present with pancytopenia, a very few blasts in the peripheral blood and no or little splenomegaly. Initially BM histopathology is characterized by different degrees of reticulin-collagen fibrosis and wide ranges of cellularity with a prominent left-shifted and often macrocytic erythropoiesis associated with a reduction and maturation defects of the neutrophil series. Most conspicuous are abnormalities of the megakaryocytes including loose clustering, dislocation towards the endosteal border and appearance of atypical microforms with compact nuclei. Moreover, besides myelofibrosis in a number of patients the interstitial compartment displays a remarkable inflammatory reaction with lymphoid nodules, abundant iron-laden macrophages, perivascular plasmacytosis and increase in microvessels. Repeatedly performed BM biopsies reveal an accumulation of dispersed or clustered CD34+ and lysozyme-expressing blasts in keeping with the insidious transformation into acute leukemia. Prognosis is unfavorable with a median survival of less than 1 year. In conclusion, APMF has to be regarded as a condition that shows considerable overlappings with primary hyperfibrotic MDS, AML and toxic myelopathy (secondary MDS) with accompanying myelofibrosis and therefore can not be considered as a definite clinical entity.

Perivascular Plasmacytosis: A Light-Microscopic and Immunohistochemical Study of 93 Bone Marrow Biopsies

In bone marrow biopsies from 13 hematologically normal persons and from 80 patients with a variety of disorders, we found perivascular plasmacytosis. In all instances except the one case of multiple myeloma, plasma cells were polyclonal and normal in morphology. This was especially pronounced in patients with HIV infection, and in individuals following chemotherapy. In the same patients, sinusoids were also prominent, and appeared dilated. In biopsy sections, small endothelial-lined vessels appeared to arise from attenuation of the sinusoidal lumen. After a short segment of only endothelial-lined vessels, perivascular plasmacytosis appeared. When smooth muscle cells began to line the endothelium, plasma cells virtually disappeared. The biological significance of this finding is unknown. Possibly, the close proximity of plasma cells to endothelial cells early in the development of blood vessels could facilitate entry of immunoglobulins into the blood.

Polyglobuly versus polycythemia vera

Differentiation of an elevated hemoglobin/hematocrit level warrants not only the determination of relevant laboratory values, including erythropoietin, but also an elaborate evaluation of bone marrow histopathology. Particularly in the initial stages of polycythemia vera (PV), when not all stringent clinical criteria are completely fulfilled, a more refined analysis of morphological features helps to distinguish autonomous (PV) from spurious or secondary erythrocytosis - polyglobuly (PG). PV is characterized by a panmyelosis, i.e., a trilinear proliferation of all cell lineages, whereas in PG erythropoiesis predominates. Megakaryopoiesis exerts a significant impact on differentiation, because in PV there is a conspicuous grouping associated with a strikingly expressed pleomorphous appearance. This peculiar feature implicates assemblies of small- to medium-sized megakaryocytes lying adjacent to giant cells with extensively lobulated, staghorn-like nuclei. A further discriminating parameter is presented by the interstitial lesions frequently occurring in PG. These, according to the usually underlying inflammatory cause (chronic bronchitis-recurrent bronchopneumonias), include iron-laden macrophages, a prominent perivascular plasmacytosis, phagocytosis of cell debris by histiocytic reticular cells and often an in- crease in the number of eosinophils. Comparable findings are not, or only to a minor ex-tent, detectable in PV. In conclusion, by regarding hematopoiesis and the myeloid stroma initial stages of PV may be definitively distinguished from PG.

Bone Marrow Histopathological Changes in Visceral Leishmaniasis

Over a period of two years (June 1989-May 1991), bone marrow trephine biopsies from 16 patients with visceral leishmaniasis were examined histologically to assess the correlation between the peripheral blood counts and bone marrow status. Only 25% of patients had normal peripheral blood counts. Of the remainder, 25% and anemia alone, 25% had anemia with thrombocytopenia, and 25% had pancytopenia. The anemia was microcytic/hypochromic in 88.7% of cases and normocytic in 12.3% of cases. Thrombocytopenia was a notable feature, with mean platelet count of 115 +/- 72.47 x 10(9)/L, and eight patients having thrombocytopenia below 120 x 10(9)/L. There was diffuse bone marrow hypercellularity in 13 cases and focal hypocellularity in three. The increased cellularity was attributable to trilineage hyperplasisa, with a predominance of erythroid activity in most cases. Increase in the histiocytic population was a prominent feature in all the cases. In 10 cases, most of the histiocytes were found to be full of LD bodies, while in the six, the parasite load was much less. Megakaryocytes were abundant in number, forming aggregates in most cases. Other notable features included erythrophagocytosis (nine cases) and moderate perivascular plasmacytosis (13 cases).

Histopathology of the bone marrow in toxic myelopathy. A study of drug induced lesions in 57 patients.

Following the introduction of numerous highly effective drugs in recent decades, haematologists are confronted with a panmyelopathy or "toxic myelopathy" originating from the exhibition of certain therapeutic regimens. Among 16,711 trephines referred to us in the last 5 1/2 years, 57 cases or 0.34 percent were found to have clear evidence of lesions caused by the ingestion of potentially toxic agents. The evaluation of the histopathology shows two groups of alterations which concern the haematopoietic parenchyma as well as the mesenchyme of the bone marrow. Different degrees of cellularity ranging from aplasia to regenerative hyperplasia and a pronounced mesenchymal reaction with proteinaceous oedema, perivascular plasmacytosis and frequent necrobiosis of neutrophilic granulocytes or cellular debris are the most conspicuous features. However, the histopathology of the bone marrow described gives no indication of the specific drug responsible and no specific suggestion of any group of drugs. Generally the histopathology allows the recognition of lesions which are induced by the toxicity of these agents. Therefore a bone marrow biopsy should be included in the diagnostic procedures whenever a toxic lesion is suspected of causing haematological disorders, particularly in all cases of uncertain pancytopenia.

Myeloid dysplasia (MD): a hematological disorder preceding acute and chronic myeloid leukemia. A morphological study on sequential core biopsies of the bone marrow in 27 patients.

Light- and electron microscopic appearances of core biopsies of the bone marrow in 27 selected patients out of about 195 cases with a clinically suspected preleukemic syndrome. The correct diagnosis of “ preleukemia” was established retrospectively by sequential biopsies of the iliac crest or autopsy in those patients who developed overt leukemia in periods ranging from 2 to 36 months. As a final diagnosis chronic myelogenous leukemia (CML) was established in 10, with accompanying blast crisis in 6 and acute non-lymphocytic leukemia (ANLL) in 11 cases. Histomorphology of the resin embedded cores of bone marrow showed hypercellularity in 21 specimens, a hypocellular marrow in 5 and a normal bone marrow in 1 case. There was also a conspicuous macrocytic or megaloblastoid maturation of erythropoiesis with frequent sideroblasts. Ultrastructural abnormalities included atypical nuclear clefts, dense iron deposits in the mitochondrial matrix and an increase of ferritin uptake. Neutrophilic granulopoiesis showed a shift to the left and often a remarkable aberration of nuclear segmentation consistent with a pseudo-Pelger-Huet anomaly. Electron microscopy displayed atypias of granulogenesis in comparison with maturation and segmentation of the nuclei, abnormal nuclear loops and blebs and very conspicuous nuclear fibrillar appendages (so called Nebenkerne). There was also an increase in eosinophilic granulocytes, monocytic elements, edema and a remarkable perivascular plasmacytosis of the myeloid stroma. Our results suggest that characteristic morphological features of the bone marrow exist before onset of overt, acute and chronic leukemia. These alterations are identical in CML and ANLL and are the morphological substrate of a maturation defect of hematopoiesis which precedes the establishment of the leukemic clone. The clinical term preleukemia should be replaced by myeloid dysplasia (MD), thus indicating transformation into overt leukemia in only a certain proportion of patients (only 27 of 195 clinically suspected patients who displayed an identical histopathology of MD in the bone marrow in 93 cases to date) and has to include ANLL as well as CML.