Atlas
 

Bone marrow tumorus diseases



3  Bone Marrow Pathology

3.5  Bone marrow tumorus diseases

3.5.1  Myelodysplastic Syndrome (MDS)

Introduction:

A collection of clonal disorders affecting hematopoietic stem cells. It is characterised by dysplastic changes in one or more lineages and ineffective hematopoiesis.

Etiology:

De novo origin or following exposure to toxins (including certain chemotherapeutics), ionizing radiation or association with some hematological diseases (for example Fanconi anemia).

Clinical signs:

  • age: primarily elderly patients (median is 70 years of age)
  • incidence 3/100.000, 20/100.000 among 70-year olds
  • anemia — weakness, paleness, dyspnoea
  • neutropenia — opportune infections
  • thrombocytopenia — increased susceptibility to bleeding

Classification:

WHO 2008:

  • Refractory cytopenia with unilineage dysplasia (RCUD)
  • Refractory anemia with ringed sideroblasts (RARS)
  • Refractory cytopenia with multilineage dysplasia (RCMD)
  • Refractory anemia with excess blasts (RAEB)
  • MDS with isolated 5q deletion (5q-syndrome)
  • MDS unclassified (MDS-U)

Histology:

  • Structural features:
    • bone marrow is usually hypercellular
    • distorted architecture:
      • clusters of megakaryocytes
      • peritrabecular erythropoiesis
      • dispersed erythropoietic islands
      • ALIP (abnormal localisation of immature precursors) myelopoiesis phenomena
  • Cytological features:
    • megakaryocytes: hypolobated or hyperlobated nuclei, hyperchromia, micromegakaryocytes
    • erythropoiesis: megaloblastic changes, bizzare nuclear shapes, nuclear budding, internuclear bridges, polynucleated cells, cytoplasmic vacuolization, ringed sideroblasts
    • granulopoiesis: nuclear hypolobation (pseudo–Pelger-Huet anomaly), nuclear hypersegmentation, hypogranular cytoplasm
3.5.1.1  Refractory Cytopenia with Unilineage Dysplasia (RCUD)

Clinical signs:

  • unilineage dysplasia affecting erythropoiesis (refractory anemia  —  RA), granulopoiesis (refractory neutropenia  —  RN) or megakaryocytes (refractory thrombocytopenia  —  RT), at least 10% of a given lineage should be affected
  • all other causes of non-clonal dysplastic changes must be excluded
  • the number of myeloblasts in bone marrow is less than 5%
  • prognosis: approximately 6% of patients develop AML, median survival time is approx. 66 months

Histology:

The number of myeloblasts in bone marrow is less than 5%.

3.5.1.2  Refractory Anemia with Ringed Sideroblasts (RARS)

Clinical signs:

  • basic features are the same as in RA
  • prognosis: about 1 – 2% of patients develop AML, median survival time is approx. 6 years

Histology:

  • ringed sideroblasts constitute more than 15% of all erythroid precursors
  • ringed sideroblasts are erythroid precursors (normoblasts), siderotic granules are arranged in a ring around the nucleus

Pictures

Refractory anemia with ringed sideroblasts, iron stain:
Refractory anemia with ring sideroblasts, Prussian blue 100x (72496)

3.5.1.3  Refractory Cytopenia with Multilineage Dysplasia (RCMD)

Clinical signs:

  • dysplastic changes are present in more than 10% of cells from two or more lineages
  • prognosis: about 11% of patients develop AML, median survival time is approx. 33 months
  • there are fewer than 5% of myeloblasts in the bone marrow
  • bicytopenia or pancytopenia
  • the number of ringed sideroblasts may be increased (RCMD-RS)
3.5.1.4  Refractory Anemia with Excess Blats (RAEB)

Clinical signs:

  • dysplastic changes are present in at least 10% of cells from two or more lineages
  • prognosis: 25% of patients with RAEB-1 and 33% of patients with RAEB-2 develop AML, median survival time is 18 (RAEB-1) or 10 (RAEB-2) months

Histology:

  • the number of blasts in bone marrow is between 5 and 19%
  • RAEB-1: 5 – 9% myeloblasts
  • RAEB-2: 10 – 19% myeloblasts
3.5.1.5  MDS with Isolated 5q Deletion (5q-syndrome)

Clinical signs:

  • genetic definition: isolated deletion of the short arm of chromosome 5
  • less than 5% blasts in the bone marrow
  • middle-aged to elderly women
  • anemia, slight leukopenia, thrombocythemia
  • prognosis: relatively good

Histology:

Dysplastic changes and increased numbers of small megakaryocytes with dysplastic hypolobated nuclei.

Pictures

MDS with isolated 5q deletion:
5q-syndrome, HE 100x (72892)

3.5.1.6  Myelodysplastic Syndrome Unclassified (MDS NOS)

MDS which does not fall into any of the above mentioned categories.

3.5.2  Myeloproliferative neoplasms

Introduction:

A group of clonal disorders of the hematopoietic stem cells, which are characterised by proliferation of one or more hematopoietic lineages. Maturation is relatively normal  — effective hematopoiesis.

Etiology:

Most often unclear.

Clinical signs:

  • predominantly elderly people (50 – 60 years of age)
  • incidence 6 – 9/100.000
  • polyglobulia
  • leukocytosis
  • thrombocytosis
  • organomegaly

Classification:

WHO classifies MPNs into tho categories according to the presence of the BCR/ABL1 fusion gene:

  • BCR/ABL1 positive:
    • chronic myeloid leukemia (CML)
  • BCR/ABL1 negative:
    • polycythemia vera (PV)
    • essential thrombocythemia (ET)
    • primary myelofibrosis (PMF)
    • chronic neutrophilic leukemia (CNL)
    • chronic eosinophilic leukemia (CEL)
    • mastocytosis
    • MPN unclassifiable (MPN-U)

Grades of bone marrow fibrosis in myeloproliferative neoplasms:

  • MF-0: scattered linear reticulin with no intersections
  • MF-1: loose network of reticulin with many intersections, especially in perivascular areas
  • MF-2: Diffuse and dense reticulin network with extensive intersections, occasionally with focal bundles of collagen or focal osteosclerosis
  • MF-3: Diffuse dense reticulin network with extensive intersections and coarse bundles of collagen, often associated with significant osteosclerosis
3.5.2.1  Polycythemia Vera (PV)

Introduction:

  • characterised by an uncontrolled erythrocyte production
  • 3 stages:
    • prepolycytemic
    • polycytemic
    • spent phase (postpolycytemic myelofibrosis)
  • prognosis: with adequate therapy, median survival time is more than 10 years, approx. 20% of patients develop MDS or AML

Etiology:

More than 95% of patients carry the somatic JAK2 V617F mutation.

Clinical signs:

  • polyglobulia — plethora
  • headaches
  • tinnitus
  • vision problems
  • thrombosis
  • organomegaly

Histology:

  • pre-polycytemic and polycytemic stages: bone marrow is hypercellular, panmyelosis with a relative elevation of erythropoiesis (M:E is 1 – 2:1 or even less), clusters of polymorphopus megakaryocytes, no stromal iron, none or only slight fibrosis
  • postpolycytemic myelofibrosis (spent phase): extensive bone marrow fibrosis with residual hematopoiesis, clusters of dysplastic megakaryocytes, dilatated sinuses with hematopoetic cells, osteosclerosis, extramedular hematopoiesis
3.5.2.2  Essential Thrombocythemia (ET)

Clinical signs:

  • primarily affects the proliferation of megakaryocytes
  • thrombocytosis: abnormal hemorrhage, epistaxis, thrombosis
  • prognosis: indolent disorder, median survival time is 10 – 15 years, less than 5% of patients develop MDS or AML

Etiology:

Approx. 40 – 50% of patients carry the somatic JAK2 V617F mutation, qpprox. 1% carry the MPL W515K/L mutation.

Histology:

Normocellular bone marrow, increased numbers of clusters formed by huge megakaryocytes, which have hyperlobated stag-horn and cloudy nuclei, M : E ratio is normal (2 – 3 : 1), no or only slight fibrosis.

Pictures

Essential thrombocythemia, bone marrow:
Essential thrombocytopenia, bone marrow, HE 100x (72624)

3.5.2.3  Primary Myelofibrosis (PMF)

Clinical signs:

  • proliferation, especially of the magakaryocytic and granulocytic lineages, associated with fibrosis
  • 2 stages:
    • pre-fibrotic/cellular
    • fibrotic
  • early symptoms are non-secific, in later stages symptoms include anemia, organomegaly, subfebrile temperatures, fatigue, weight loss
  • prognosis: median survival time is approx. 3 – 7 years for patients diagnosed in the fibrotic stage and approx. 10 – 15 years for patients diagnosed during the early pre-fibrotic stage, 5 – 30% of patients develop AML

Histology:

  • pre-fibrotic stage: hypercellular bone marrow, clusters of increased numbers of large megakaryocytes with hyperlobated nuclei, dysplastic megakaryocytes, a relative increase in granulopoiesis (M : E ratio is approx. 5 : 1), none or only slight fibrosis (MF-0 or MF-1)
  • fibrotic stage: extensive fibrosis of the bone marrow (MF-2 nebo MF-3) with residual hematopoiesis, clusters of dysplastic megakaryocytes, dilatated sinuses with hematopoietic cells, osteosclerosis, extramedullar hematopoiesis
3.5.2.4  Chronic Myeloid Leukemia (CML)

Introduction:

  • genetic hallmark is the presence of the BCR/ABL1 fusion gene
  • 3 phases:
    • chronic
    • accelerated
    • blast crisis
  • prognosis: median survival time is approx. 5 – 7 years

Clinical signs:

  • at first asymptomatic
  • anemia
  • leukocytosis
  • sometimes thrombocytosis
  • later severe anemia, thrombocytopenia and splenomegaly (up to 10 kg)

Etiology:

Caused by the BCR-ABL1 fusion gene, which in approximately  90 – 95% of all cases comes from reciprocal translocation t(9,22)(q34,q11.2)  —  Ph chromosome.

Histology:

  • chronic phase: significantly hypercellular bone marrow (usually 95 – 100%), severe myeloid hyperplasia (markedly inreased myelopoiesis) (M : E ration is 10 : 1 or more), predominantly myelocytes and segment neutrophils, myeloblasts up to 10%, increased numbers of small megakaryocytes with hypolobated nuclei, residual erythropoiesis, varying grades of fibrosis
  • accelerated phase: myeloblasts 10 – 19%, increased numbers of megakaryocytes organized in clusters, expressive fibrosis
  • blast crisis (acute leukemia): myeloblasts exceed 20% (AML), sometimes transformation into acute lymphoblastic leukemia (ALL) or biphenotypic/bilinear leukemia
3.5.2.5  Chronic Neutrophilic Leukemia (CNL)

Introduction:

A rare disorder characterised by neutrophilia in peripheral blood and expansion of neutrophilic granulopoiesis. The BCR-ABL1 fusion gene is absent as well as other reactive causes and MPNs.

Etiology:

90% of all cases show a normal genetic prophile, BCR-ABL1 is absent, however JAK 2 mutation may occasionally occure.

Clinical signs:

  • splenomegaly, which may be symptomatic
  • usually hepatomegaly
  • asi ve 25 – 30% cutaneous and mucous haemorrhage, especially in the GIT
  • prognosis: survival time varies from 6 months to 20 years, sometimes transformation into AML

Histology:

Hypercellular bone marrow with predominant neutrophilic granulopoiesis (M:E is 20:1 or more), the number of myeloblasts and promyelocytes is not increased, myelocytes and mature neutrophils predominate. Erythroid and megakaryocytic preliferation may occur. Significant dysplastic changes are absent.

3.5.2.6  Chronic Eosinophilic Leukemia (CEL)

Clinical signs:

  • fever
  • fatigue
  • cough
  • angioedema
  • myalgia
  • pruritus, diarrhoea
  • sometimes neurological, pulmonar an rheumatic symptoms

Etiology:

The BCR-ABL1 gene or the PDGFRA, PDGFRB rebuild is absent. JAK2 mutation is occasionally present.

Histology:

Hypercellular bone marrow with predominatnt eosinophilic proliferation, the number of myeloblasts may be increased between 5 – 19%, Charcot-Leyden crystals are often present. Erythropoiesis and megakaryocytes are usually normal. Fibrosis may sometimes be found.

3.5.2.7  Mastocytosis

Introduction:

Clonal neoplastic mast cell proliferation. Mast cells accummulate in one or more organs. Mastocytosis is characterized by multifocal cohesive aggregates or infiltrates formed by abnormal mast cells.

Classification:

  • Cutaneous mastocytosis (CM)
  • Indolent systemic mastocytosis (ISM)
  • Systemic mastocytosis with associated clonal haematological non-mast cell lineage diseases (SM-AHNMD)
  • Aggressive systemic mastocytosis (ASM)
  • Mast cell leukemia (MCL)
  • Mast cell sarcoma (MCS)
  • Extracutaneous mastocytoma
3.5.2.8  MPN unclassifiable (MPN-U)

This category comprises of all cases, which show clinical, laboratory and morphological features of MPN, however do not meet the diagnostic criteria of the above described MPNs.

3.5.3  Myelodysplastic-myeloproliferative diseases (MDS/MPD)

Introduction:

Clonal hematopoietic disorders, which show both myeolodysplastic and myeloprliferative features.

Clinical signs:

  • most often elderly patients (60 years of age or more)
  • incidence 3/100.000

Classification:

WHO 2008:

  • Chronic myelomonocytic leukemia (CMML)
  • Atypical chronic myeloid leukemia (ACML)
  • Juvenile myelomonocytic leukemia (JMML)
  • Myelodysplastic-Myeloproliferative diseases unclassifiable (MDS/MPD NOS)
3.5.3.1  Chronic Myelomonocytic Leukemia (CMML)

Introduction:

Clonal disease of the hematopoietic stem cell, defined by persistent monocytosis (at least 3 months).

Clinical signs:

Approximately 40% of cases show a RAS gene mutation, are BRC-ABL1 negative, and the PDGFRA and PDGFRB transformations are absent.

Clinical signs:

  • weight loss
  • fever
  • night sweats
  • infections
  • hemorrhage
    • monocytosis in peripheral blood more than 1×109/l
    • splenomegaly
    • BCR/ABL1 negative
    • less than 20% blasts in peripheral blood or bone marrow
    • dysplastic changes in at least one hematopoietic lineage
      • CMML-1: less than 10% blasts
      • CMML-2: 10 – 19% blasts
    • prognosis: median survival time is 20 – 40 months, 15 – 30%
    • of patients develop AML
3.5.3.2  Atypical Chronic Myeloid Leukemia (aCML)

Introduction:

Leukemia with both myelodysplastic and myeloproliferative features with predominant affection of the granulocytic lineage, BCR-ABL1 negative.

Clinical signs:

BCR-ABL1 gene and PDGFRA and PDGFRB transformation are absent, mutation JAK2 V617F is sometimes present, 30% of cases show NRAS or KRAS mutation.

Clinical signs:

  • leukocytosis more than 13×109/l, splenomegaly, BCR/ABL1 negativity, less than 20% blasts in peripheral blood or bone marrow, dysplastic changes in all three hematopoietic lineages, M:E ratio is usually higher than 10:1
  • prognosis: bad, median survival time is 14 – 29 months, 15 – 40%
  • of patients develop AML
  • symptomes resulting from anemia, sometimes thrombocytopenia, splenomegaly
3.5.3.3  Juvenile Myelomonocytic Leukemia (JMML)

Introduction:

Clonal hematopoietic disorder which affects children. It is characterised by granulocytic and monocytic proliferation.

Etiology:

25% monosomy 7, 35% mutation of PTPN11, 20% mutation of NRAS, KRAS2 and NF1, BCR-ABL1 is absent.

Clinical signs:

  • frequent infections
  • hepatosplenomegaly
  • lymphadenopathy or tonsil swelling in approximately 50% of cases
  • leukocytosis in peripheral blood usually 20 – 30×109/l with monocytosis, BCR/ABL negative, less than 20% blasts in peripheral blood or bone marrow, predominant granulopoietic proliferation in bone marrow, less significant increase of the monocyte count, dysplastic changes are often only minimal
  • prognosis: without allogeneic stem cell transplantation, the median survival time is approximately 1 year, progression into AML is rare
3.5.3.4  Myelodysplastic-Myeloproliferative Diseases Unclassifiable

This category includes all cases, which show clinical, laboratory and morphological features of MDS/MPN, however do not meet the diagnostic criteria of the above described MDS/MPNs.

3.5.4  Acute Myeloid Leukemia (AML)

Introduction:

Clonal expansion of myeloid blasts in bone marrow, peripheral blood or other organs.

Etiology:

  • viral infections
  • ionizing radiation
  • cytotoxic chemotherapy
  • benzene
  • and other

Clinical signs:

  • most often elderly patients (median is 60 years)
  • incidence 10/100.00
  • anemia
  • thrombocytopenia
  • leukocytosis with neutropenia (or leukopenia)
  • infections
  • and other

Classification:

  • FAB 1982 — purely morphological classification
  • WHO 2008 — takes cytogenetic abnormalities and prognosis into account (besides morphology)

FAB classification:

  • M0 — Minimally differentiated myeloblastic leukemia
  • M1 — Myeloblastic leukemia without maturation
  • M2 — Myeloblastic leukemia with maturation
  • M3 — Promyelocytic leukemia
  • M4 — Myelomonocytic leukemia
  • M5a — Monoblastic leukemia
  • M5b — Monocytic leukemia
  • M6 — Erythroid leukemia
  • M7 — Megakaryoblastic leukemia

WHO classification:

  • AML with recurrent genetic abnormalities (usually balanced translocations, relatively favourable prognosis, high complete remission rate)
  • AML with multilineage dysplasia (worse prognosis)
  • therapy-related AML (cytotoxic chemotherapy or radation therapy, refractory to antileukemic therapy, short median survival time)
  • AML not otherwise categorized (morphologic clasification similar to the FAB system)
  • AL with double differentiation (bilinear, biphenotypic)

Histology:

Bone marrow is markedly hypercellular, sometimes hypocellular (especially therapy-related AML), myelopoiesis is usually markedly increased with a differentiation arrest and increased myeloblast (monoblast) levels above 20%. Megakaryocytes and erythropiesis are residual (except M6 and M7), M7 leukemia causes significant fibrosis.

Most common sites of infiltration are the spleen, liver, lymph nodes and other, however significant organomegaly is uncommon. Sometimes tumoriform lesions (myelosarcoma) may be found.

Secondary symptoms: bleeding, infections, anemia.

Pictures

Acute myeloid leukemia, hypoplastic, bone marrow:
Hypoplastic acute myeloic leukemia, HE 100x (73112)

Hypoplastic acute myeloic leukemia, PAS 100x (73113)

Acute meyloid leukemia, kidney, infiltration into the glomerulus:
Kidney in acute myeloic leukemia, HE 100x (72796)

3.5.5  Lymphoproliferative Disorders

Introduction:

There are two basic categories of lymphoproliferative disorders:

  1. lymphomas — lymphoid tissue tumours
  2. leukemias — affect bone marrow, cancer cells are released into the peripheral blood

Lymphomas and leukemias often overlap, because lymphomas may undergo leukemisation and vice versa. For example small lymphocytic lymphoma/chronic lymphocytic leukemia or precursor lymphoblastic lymphoma/acute lymphoblastic leukemia: they are the same disorders with different manifestation.

Lymphomas are detailed in the chapter Pathology of the lymphatic nodes. This chapter will focus on lymphoproliferative disorders of the bone marrow.

Histology:

Types of tumorous bone marrow infiltration:

  • intersticial: the tumour infiltration respects the original architecture of the marrow and spreads through the intersticium
  • nodular: the tumour infiltration forms vague, loosely defined nodules, which are localized in the peritrabecular or non-peritrabecular spaces
  • diffuse, concentrated (packed marrow): a massive bone marrow affection, with an almost 100% cellularity, malignant population is predominant, hematopoiesis is only residual

Types of malignant bone marrow infiltration:

  • intersticial: the tumour infiltration respects the original architecture of the marrow and spreads through the intersticium
  • nodular: the tumour infiltration forms vague, loosely defined nodules, which are localized in the peritrabecular or non-peritrabecular spaces
  • diffuse, concentrated (packed marrow): a massive bone marrow affection with an almost 100% cellularity, malignant population dominates, hematopoiesis is only residual
3.5.5.1  Acute Lymphoblastic Leukemia (ALL)

Pathogenesis:

Caused by lymphoid precursors — lymphoblasts.

Clinical signs:

  • age: most common in children, less common in adults
  • anemia
  • thrombocytopenia
  • leukopenia or leukocytosis
  • hepatosplenomegaly
  • lymphadenopathy
  • skin infiltration and other symptoms
  • prognosis: a very aggressive disease, which however has high cure rates, especially in children (70 – 80% of cases achieve complete remission)

Histology:

Same as precursor lymphoblastic lymphoma —  small to middle-sized cells with round nuclei and finely dispersed chromatin, without prominent nucleoli, with a narrow rim of basophilic cytoplasm.

Imunophenotype: T lineage (CD3+) or B lineage (CD20+ a CD79a+), null type — both T and B markers are negative, CD10 (CALLA)+, TdT+.

3.5.5.2  Chronic Lymphocytic Leukemia (CLL)

Pathogenesis:

The offending cells are mature naive B lymphocytes.

Clinical signs:

  • age: affects mostly elderly patients (median is approx. 65 years of age)
  • at first asymptomatic
  • anemia
  • thrombocytopenia
  • leukocytosis with lymphocytosis
  • hepatosplenomegaly
  • lymphadenopathy and other
  • prognosis:
    • low malignant disease
    • indolent progression
    • incurable
    • median survival time is 7 let
    • may transform into an agressive malignant lymphoma (Richter's syndrome)

Histology:

Same as small lymphocytic lymphoma — small cells with the appearance of mature lymphocytes, with round nuclei, dense chromatin, and inconspicuous nucleoli, a narrow rim of basophilic cytoplasm. Proliferation centres also contain prolymphocytes and paraimunoblasts.

Imunophenotype: B lineage (CD20+ a CD79a+), CD5+, CD23+.

3.5.5.3  Prolymphocytic Leukemia (PLL)

Pathogenesis:

The offending cell line is either the peripheral B (postgerminal) or T (post-thymic) cell (?).

Clinical signs:

  • very rare disease, affecting mostly elderly patients (60 – 70 years old)
  • splenomegaly without lymphadenopathy
  • leukocytosis and lymphocytosis
  • anemia
  • thrombocytopenia
  • prognosis: not good, the disease often does not respond to therapy, median survival time is short (less than 1 year).

Histology:

Prolymphocytes — middle-sized cells with round nuclei, dispersed chromatin, prominent nucleoli and a narrow rim of slightly basophilic cytoplasm.

Imunophenotype: B lineage (CD20 a CD79a+) nebo T lineage (CD3+), CD23-

3.5.5.4  Hairy cell leukemia (HCL)

Pathogenesis:

Arises from postgerminal cells (?).

Clinical signs:

  • age: usually affects middle-aged and older adults (median is approx. 55 years of age)
  • splenomegaly
  • bicytopenia or pancytopenia
  • prognosis: good, log-term remissions following chemotherapy or splenectomy

Histology:

Intersticial infitration of the bone marrow, middle-sized cells with round or kidney-shaped nuclei with diffuse chromatin without nucleoli, abundant pale cytoplams with thin hair-like projections.

Imunophenotype: B lineage (CD20 a CD79a+), DBA44+, CD103+, TRAP+

3.5.5.5  Plasma Cell Neoplasms

Introduction:

Immunosecretive tumorous disorders caused by expansion of a particular clone of differentiated B cells, which produce a single type of immunoglobulin. Previously called plasma cell dyscrasias.

Classification:

  • plasma cell (multiple) myeloma (MM)
  • solitary plasmacytomas: localized tumors which arise in bones or soft tissues. They contain cells morphologically identical to the cells of plasma cell myeloma. This myeloma develops in about 55% of cases of solitary plasmocytoma.
  • monoclonal gammapathy of undetermined significance (MGUS)
3.5.5.5.1  Plasma Cell (Multiple) Myeloma

Introduction:

Systemic bone marrow disease, with an occasional formation of osteolytic lesions.

Clinical signs:

  • pathological bone fractures
  • anemia
  • hypercalcemia
  • monoclonal gammopathy (AL amyloidosis)
  • prognosis: bad, an incurable disease, median survival time is 3 years

Complex diagnostic criteria  — Durie-Salmon staging system.

Histology:

The marrow is infiltrated with monoclonal plasma cells at various stages of differentiation (mature plasma cells, immature plasma cells, plasmablasts), with an occassional formation of osteolytic lesions.

Imunophenotype: CD138+, monoclonality according to the light chains of imunoglobulins kappa and lambda.

3.5.5.5.2  Solitary Plasmocytoma

Introduction:

Localized tumours which arise in bones or soft tissues. They contain cells morphologically identical to the cells of plasma cell myeloma. This myeloma develops in about 55% of cases.

3.5.5.5.3  Monoclonal Gammapathy of Undetermined Significance (MGUS)

Monoclonal gammopathies which do not meet the criteria of plasma cell myeloma, plasmocytoma or B-Cell lymphoma with plasmacytic differentiation. Monoclonal immunoglobulin serum levels are lower than 30 g/l, the marrow contains less than 10% of monocloal plasma cells with no signs of organ affection (no hypercalcemia, renal insufficiency, anemia or osteolytic lesions).

3.5.5.6  Other Lymphoproliferative Diseases

Bone marrow may be affected by all types of lymphomas. A bone marrow sample is always obtained in order to establish the stage of the disease and decide on adequate therapy.

Reasons for performing a trephine biopsy: quantification of the infiltrate, post-treatment moitoring, restaging (in case of a relapse).

3.5.6  Histiocytoses

Introduction:

Histiocytoses are a heterogenous group of disorders characterised by excessive proliferation of the histiocyte lineage. Some are reactive processes (for example cutaneous histiocytoma), some are malignant and others are very rare and therefore difficult to classify. This group of disorders also contains dendritic cell proliferations, while a relatively common malignant fibrous histiocytoma is classified among soft tissue tumors (because its histiocytic origin is not unequivocal).

3.5.6.1  Histiocytosis X (Langerhans Cell Histiocytosis)

Introduction:

Histiocytosis X is a clonal proliferation of cutaneous dendritic (Langerhans) cells, with their characteristic CD1a antigen expression and typical Birbeck granules, which may be observed ultramicroscopically. Tumorous forms of Langerhans cells can be found at various locations (bones, parenchymal organs), which is probably caused by presence of abnormal chemokine receptors that attract the cells into these organs. chemokinových receptorů, které je atrahují do příslušných orgánů.

Normally, dendritic cells are distributed in the epidermis. After antigen stimulation they change and lose the CD1 antigen as well as the Birbeck granules. Then they migrate into the lymph nodes, where they present the antigen to the T4 lymphocytes.

Classification:

Histiocytosis X is divided into:

  • multifocal multisystem form with generalizastion (Letterrer-Siwe)
  • monosystemic form
    • multifocal (Hand Schüller Christian)
    • unifocal (eosinophilic granuloma)

Apart from histiocytosis X, there are other (usually cutaneous) disorders, which originate in temporary forms of dendritic cells (which for example express the CD1a antigen, but do not contain Birbeck granules). Prognosis is usually good (self limiting histiocytosis of the head in children, undetermined cell histiocytosis and others).

3.5.6.1.1  Letterer-Siwe Histiocytosis

Clinical signs:

  • a rare disorder
  • age: children less than 2 years old
  • multiple cutaneous infiltrations with a fast progression
  • leukemic form with multiple-organ infiltration: liver, spleen, lymphatic nodes, bone marrow, lungs
  • anemia, thrombocytopenia, secondary infections
  • prognosis:
    • untreated patients die quickly
    • about 50% of patients who undergo aggresive chemotherapy survive the disease
3.5.6.1.2  Hand-Schüller-Christian Histiocytosis

Clinical signs:

  • rare disorder
  • affects children
  • multiple bone lesions with erosions
  • affction of the neurohypophysis causes diabetes insipidus
  • sometimes exophtalmus may be seen
  • prognosis is good:
    • one half of all cases regress without treatment
    • others respond to chemotherapy
3.5.6.1.3  Eosinophilic Granuloma

Clinical signs:

  • relatively uncommon disease
  • age: children and adults
  • isolated bone lesions with osteolysis (different bones: ribs, femur heads etc.)
  • spontaneous bone pain in in the lesion location
  • brightened X-ray
  • pathological fractures may occur
  • prognosis is very good (following surgical scraping or radiation therapy sometimes even regress spontaneously)

Histology:

The accumulation of Langerhans´s cells, eosinophils and additional plasma cells and neutrofils.

Immunophenotype: S100 protein, specifically CD1a; Birbeck´s granules may be observed using electron microscopy.

3.5.6.2  Histiocytic Sarcoma

Clinical signs:

  • very rare disease
  • affects older adults
  • organ infiltrations, multiple cutaneous lesions
  • prognosis is not good

Histology:

Polymorphous infiltration by histiocytes with wide cytoplasm and kidney-shaped nuclei.

Immunophenotype: in pure form only histiocytic markers are positive (CD68, MAC).

3.5.7  Metastatic Infiltration of the Bone Marrow

Introduction:

Metastatic infiltration of the bone marrow with solid tumours is relatively frequent (28 – 85%). Sarcomas most often infiltrate the marrow of children and adolescents (Ewing´s sarcoma, rhabdomyosarcoma, osteosarcoma) and neuroblastoma, while adult bone marrow is most often infiltrated with carcinomas (breast, prostate, lung, etc.).

Trephine biopsy indications in oncology: suspected metastatic cancer, staging, post-treatment monitoring.

Histology:

Histological image matches the primary tumour but metastasis may me less differentiated. It is possible (with certain probability) to determine the primary tumour by the appearance and immunohistological characteristics of the metastases.

The determination of the primary tumour may not be reliable and is nearly always expensive. Therefore it is usually better to determine tumour origin using different methods (clinical examination, screening methods).



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