Histopathology 2000, 37, 199±211

REVIEW

Bone marrow manifestations of infections and systemic

diseases observed in bone marrow trephine biopsy
J Diebold, T Molina, S Camilleri-BroeÈt, A le Tourneau & J Audouin
Service Central `Jacques-Delarue' d'Anatomie et de Cytologie Pathologiques, HoÃtel-Dieu, Paris, France

Diebold J, Molina T, Camilleri-BroeÈt S, le Tourneau A & Audouin J

(2000) Histopathology 37, 199±211
Bone marrow manifestations of infections and systemic diseases observed in bone marrow
trephine biopsy

Bone marrow modifications resulting from infections
and systemic diseases can be studied by analysis of
morphology and aetiology. Two types of lesions or
modifications can be observed, those occurring in the
connective tissue comprising inflammatory processes,
acute and chronic, as well as immune reactions, and
those involving the normal haematopoietic cell lines,
with possible hyperplastic or aplastic changes in one or
more cell lines. The main lesions are described
(oedema, haemorrhage, necrosis, suppuration, granu-
lomas, lymphoid nodules and hyperplasia, immuno-
Keywords: bone marrow biopsy, infection, granuloma, necrosis, HIV infection, lymphoid nodules, myelofibrosis,
iatrogenic disease, malignancies
blastic or plasmacytic hyperplasia), as well as the main
aetiologies. In association, the three main haemato-
poietic cell lines show hyperplasia, hypoplasia, aplasia of
one or all of the cell lines, sometimes with dysmyelopoi-
esis. The stroma and vessel reactions comprise myelofi-
brosis, gelatinous transformation or amyloid deposits.
The methods for identifying aetiological agents are
emphasized. It should also be stressed that malignant
neoplasias of different types involving the bone marrow
can be responsible for such inflammatory or immune
reactions.

Introduction disorders can be seen. One lesion is characterized by

Bone marrow changes in infectious and systemic
diseases can be studied by morphology. Morphologi-
cally, similar lesions can arise from different patholo-
gical agents and one disease can cause several different
lesions.
Aetiological agents can be detected by tissue sections
that have been specially stained, and/or by immuno-
histochemistry. Malignant diseases can be associated
with reactive changes and should always be considered.
Changes following bone marrow transplantation are
not covered in this review.
Two types of changes that result from the develop-
ment of an inflammatory response or immune
Address for correspondence: Professor J Diebold, Service Central
`Jacques-Delarue' d'Anatomie et de Cytologie Pathologiques, HoÃtel-
Dieu, Place du Parvis Notre-Dame, 75181 Paris, Cedex 04, France.
q 2000 Blackwell Science Limited.
stromal reactions in the connective tissue and micro-
vascular bed, the second by the response of haemato-
poietic stem cells to local or general stimulation.
Acute inflammation
Acute inflammation can be seen in a large number of
infections, particularly in septicaemia.1±3
E X U DAT I V E T Y P E
Interstitial oedema and small haemorrhages are
associated with arteriolo-capillary congestion. The
endothelial cells are often hypertrophic. Sometimes
stellate fibrin deposits are present between the haema-
topoietic cells. Intravascular coagulation may also be
200 J Diebold et al.
seen, particularly in severe infections, and this is often
associated with haemorrhage or necrosis.
Oedema should be distinguished from gelatinous
transformation of bone marrow. This lesion is char-
acterized by hyaline deposits between adipocytes in
areas without any haematopoietic cells. This substance
is faintly eosinophilic, PAS-positive and may show
metachromasia with Giemsa staining. Gelatinous
transformation is observed in patients with severe
malnutrition and protein loss. It can be observed in
HIV-positive patients.4±11
H A E M O R R H AG I C T Y P E
Large areas in which haemorrhages have occurred can
sometimes be seen. The haemorrhages are often
associated with hypoplasia of the haematopoietic cells.
Such alterations have been described in aplasia after
hepatitis B infection or in patients with severe
macrophage (histiocyte) activation syndrome. In a
few patients such haemorrhages are associated with a
malignant lymphoma, often of the T-cell type, which is
difficult to diagnose without immunohistochemistry.
N E C RO T I C T Y P E ( TA B L E 1 )
Small foci or large areas of haematopoietic and adipose
tissue are affected by ischaemic type necrosis (Figure
1a). Sometimes fibrin deposits with a stellate pattern
can also be seen (Figure 1b).
Such ischaemic necrosis during the acute phase of
inflammation is secondary to arteriolar thrombosis
and may be found in patients with septicaemia,
bacterial endocarditis, different bacterial, viral, fungal
or parasitic infections, Q fever, dysimmune disorders
Figure 1. Necrosis. a, Ischaemic necrosis. H & E. b, Necrosis with
fibrin deposits. H & E.
Table 1 Infections or inflammatory conditions responsible for
bone marrow necrosis
Endocarditis (with embolism)
Disseminated intravascular coagulation
Anti-phospholipid syndrome
Haemophagocytic histiocytosis (activated macrophage
syndrome)
Septicaemia due to:
Gram-positive bacteria (Streptococcus, Staphylococcus)
Gram-negative bacteria (Escherichia coli)
Typhoid fever
Diphtheria
Q fever
Tuberculosis
Fungal infection (histoplasmosis, candidosis, aspergillosis)
Parasitosis (toxoplasmosis)
such as disseminated erythematous lupus,12 or
hypersensitivity.
The progression of the necrosis is characterized by
either a total or partial restitution. In some cases,
collagenous fibrosis replaces the necrotic areas.
Necrosis of an inflammatory origin is not easily
distinguished from the bone marrow necrosis that
occurs in sickle cell anaemia13 or drug toxicity such as
that resulting from fludarabine,14 rapidly growing
leukaemia and lymphomas, including Hodgkin's dis-
ease or in carcinomatous metastasis.
A peculiar condition should also be mentioned: the
so-called antiphospholipid syndrome. This rare disease
with a poor prognosis is responsible for severe
pancytopenia resulting from extensive bone marrow
necrosis. This syndrome occurs in patients with severe
infections, but also with neoplastic disorders or sickle
cell anaemia.15,16 This antiphospholipid syndrome may
be more frequently involved in bone marrow necrosis
than it is currently believed.
Another rare type of necrosis is observed in
tuberculosis.1±3 In acute tuberculosis with haemato-
genous dissemination, areas of caseous necrosis can be
observed surrounded by only a few histiocytes without
epithelioid cells. Such caseous necrotic areas are
present along bone trabeculae or in the adipose tissue
that replaces haematopoietic cell clusters. Numerous
acid-fast bacilli are easily observed in these necrotic
areas by the use of Ziehl±Neelsen staining.
S U P P U R AT I V E T Y P E
Suppurative type lesions are only seen in acute osteo-
myelitis. Osteomyelitis results from the haematogenous
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 Bone marrow biopsies in infections and systemic diseases 201

spread of bacteria which settle in the bone marrow.

During the acute phase, typical lesions are character-
ized by areas of suppurative necrosis containing
basophilic cellular debris and neutrophils, with a
variable number of macrophages. Necrosis destroys
adipose and haematopoietic tissue as well as bone
trabeculae. Hyperplasia of neutrophil granulocytes can
be observed in the bone marrow at a distance from the
abcesses. A reparative phase follows with fibrosis,
plasmacytosis and bone modifications with osteoblastic
growth.

Chronic inflammation and immune reactions

Stromal reactions also occur as a result of chronic
inflammation. The most frequent lesion is character-
ized by the development of granulomas.1,3,4,15,16,18±22
However, lymphoid hyperplasia and reactive plasmacyt-
osis are also often observed, mainly because of de-
regulated immune reactions.
Figure 2. Epithelioid and giant cell granuloma of unknown origin.
H & E.
should not be misdiagnosed as a follicular malignant
lymphoma. Tuberculosis in bone marrow is seen
mainly in HIV-positive patients.4±11,16,17,19

Sarcoidosis
G R A N U L O M AT O U S C H RO N I C I N F L A M M AT I O N
Only 15±30% of patients with sarcoidosis have
Granulomas are identified by an accumulation of epithelioid cell granulomas in the bone marrow.23
histiocytes or epithelioid cells organized in a nodular Fibrosis around and inside the granulomas is common.
pattern with sharp outlines. Giant cells may also be An increased activity of the osteoclasts may cause
present (Figure 2). The centres of the granulomas may increased bone resorption and hypercalcaemia.
be occupied by different types of necroses according to
the aetiology; for example, fibrinoid in hypersensitivity, Brucellosis
caseous in tuberculosis (Figure 3). The granulomas Large, well-circumscribed nodular epithelioid cells and
may be surrounded by a variable number of lympho- giant cell granulomas without necrosis are frequently
cytes, with a predominance of T-cells over B-cells. observed.
Collagenous fibrosis may also envelop the granulomas
or even penetrate between the cells. Granulomas may Rickettsiosis
be found in lacunar spaces or occasionally in close Bone marrow granulomas made of histiocytes and/or
contact with bone trabeculae (paratrabecular) (2±3 per epithelioid cells have been described in Q-fever.
tissue section).
Granulomas can be observed in hypo-, normo-or
hypercellular bone marrow. Plasma cells and eosino-
phils often accumulate nearby.
There are a large number of diseases (Table 2) that
cause chronic inflammatory responses. These cellular
immune reactions explain why granulomas can be seen
in bone marrow biopsies in patients with malignancies.

Tuberculosis
Epithelioid cell granulomas with Langhans-type giant
cells are seen in about 40% of patients with miliary
tuberculosis. Caseous necrosis may also be present
(Figure 3). Rarely Mycobacterium tuberculosis can be
observed, mainly in necrosis by using Ziehl±Neelsen
staining. The granulomas are often closely related to Figure 3. Tuberculous necrosis with early histiocytic and epithelioid
the bone trabeculae. Such juxta-trabecular granulomas cell granulomatous reaction in a HIV-positive patient. H & E.

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202 J Diebold et al.

Table 2. Conditions associated with bone marrow granulomas Histoplasma capsulatum in the USA,28,29 different
strains of leishmania (Figure 5), Toxoplasma gondii30
and Cryptococcus neoformans (Figure 6). At present,
Bacterial infections
such opportunistic agents are mainly observed in HIV-
Tuberculosis
Typhoid fever positive patients.4±11,30 In these patients, the agents
Brucellosis can be found in the extracellular space. Occasionally,
Leprosy they may also appear in the cytoplasm of megakar-
Syphilis yocytes as a result, not of phagocytosis, but rather a
Legionnaire's disease phenomenon called `emperipolesis'. Bone marrow
Viral infections biopsy plays a very important role in the identification
EBV infections of such agents in patients with unexplained fever and
Herpes zoster particularly in HIV-positive patients.7±10
HIV infections
Rickettsial infection
Q fever Autoimmune diseases causing granulomas
Parasitic infections Many autoimmune diseases cause granulomas in the
Leishmaniosis bone marrow. These include primary biliary cirrhosis,
Toxoplasmosis Crohn's disease,31 and rheumatoid arthritis.12 In asso-
Fungal infections ciation with this last disease, an interesting syndrome
Histoplasmosis has been described, characterized by bone marrow
Cryptococcosis
granulomas, interstitial nephritis and uveitis.32±33
Dysimmune disorders
Drug hypersensitivity also represents a common
Sarcoidosis
Drug hypersensitivity aetiology of granulomas. The list of drugs responsible
Malignant diseases (with/without tumourous bone involve- for the formation of granulomas is very long. Recently,
ment) granulomas have been observed in patients given 2-
Hodgkin's disease chlorodioxyadenosine for the treatment of hairy cell
Malignant lymphoma of T- or B-cells leukaemia,34 interleukin-2 for the treatment of acute
Multiple myeloma myeloblastic leukaemia,35 interferon alpha for the
Some carcinomas treatment of chronic myeloid leukaemia,36 or in
patients taking chlorpromazine,37 or tocanide.38

Viral diseases Malignant diseases

Histiocytic or epithelioid clusters or granulomas can In malignant diseases, histiocytic and/or epithelioid cell
occur in viral infections, i.e. in the bone marrow of granulomas can be observed. These granulomas have
patients with infectious mononucleosis.24,25 In this been described in different types of B- or T-cell
disease, the granulomas are smaller, less nodular and
not as well delimited as in tuberculosis, sarcoidosis or
brucellosis. Giant cells are absent in 30% of the cases.
In addition to granulomas, dispersed erythrophagocytic
histiocytes can be observed as well as small histiocytic
granulomas around the adipose cells.17 In cytomega-
lovirus infections, histiocytic or epithelioid cell granul-
omas have also been described, but viral nuclear
inclusions are seen only rarely. Epithelioid cell clusters
or granulomas are often present in HIV-positive
patients with or without opportunistic infections4±11,17

Opportunistic agents
Opportunistic agents can be associated with granul-
omas. They can be observed in the cytoplasm of
Figure 4. Atypical mycobacteria infection in a HIV-positive patient.
histiocytes or giant cells either directly or after special A, Accumulation of histiocytes realizing small granulomas. H & E.
staining.4±11 The most common are an atypical B, Presence of a high quantity of bacilli in the histiocytes. Ziehl±
Mycobacterium (avium intracellulare)26,27 (Figure 4), Neelsen

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 Bone marrow biopsies in infections and systemic diseases
Figure 5. Parasitic infections in HIV-positive patients. A, Leishmania
in the cytoplasm of histiocytes. H & E. B, Toxoplasma gondii in the
interstitium surrounded by the cytoplasm of megakaryocytes
(emperipolesis). H & E.
lymphomas, in leukaemia,39±41 in Hodgkin's lymph-
omas,42±43 and in acute myeloid leukaemias or chronic
myeloproliferative syndromes.36 As mentioned pre-
viously, granulomas may appear after treatment has
begun.18,34,35 They can also be observed in the absence
of bone marrow involvement in patients with B- or T-
cell lymphomas or with Hodgkin's lymphomas.
Such granulomas may develop in patients with bone
marrow abnormalities that occur as a result of a
carcinoma, for example an infiltrating breast carci-
noma. Cytokeratin should be used as an immunohis-
tochemical marker to identify small clusters of
carcinomatous cells near the granulomas.44
In many patients, no aetiology can be easily detected.
R E A C T I V E LY M P H O I D L E S I O N S
Lymphoid cell hyperplasia has been described in
Figure 6. Histiocytic granuloma in a HIV-positive patient.
Cryptococcus neoformans are recognized in the histiocytes and in the
intercellular spaces. A, Alcian blue. B, Grocott
q 2000 Blackwell Science Ltd, Histopathology, 37, 199±211.
203
numerous different diseases but with a highly variable
frequency from one publication to another. Brunning
and MacKenna45 in a survey of the literature, reported
a frequency of 18±47% in trephine bone marrow
biopsies.
Lesions are more frequently seen in patients older
than 50 years of age and in women. Thus there is not a
clear distinction between lymphoid cell hyperplasia as a
pathological or a physiological phenomenon. In
younger patients, such lymphoid hyperplasias seem to
be more often associated with various chronic inflam-
matory diseases or immune disorders.
Different types of reactive lymphoid lesions
Histopathology and immunohistochemistry allow three
different types of reactive lymphoid lesions45 to be
distinguished:
Reactive lymphocyte aggregates1,45,46,47
These aggregates are composed of small clusters of
lymphoid cells (Figure 7a). They are roundish, well-
circumscribed, and well-demarcated from the sur-
rounding haematopoietic cells. The lymphocytes are
small or medium-sized (Figure 8). Early aggregates can
be very small.
Immunohistochemistry demonstrates that the lym-
phoid cells express a B- or T-cell phenotype in variable
proportions. No follicular dendritic network can be
seen.
A few scattered histiocytes are present as well as a
small number of mature polytypic plasma cells and
mast cells. The number of eosinophils may be slightly
increased around the aggregates.
The aggregates are often organized in close contact
with capillaries, venous sinuses or arterioles, but they
develop at a distance from the bone trabeculae. Their
number varies greatly in each bone marrow section,
from one to five nodules can be observed. Silver
impregnation studies show a dense framework around
and sometimes in the nodules, but without true
myelofibrosis. Their significance is unknown. As
mentioned previously they can occur naturally in
older patients. Their frequency increases with age.
However they can also be associated with chronic
inflammatory and dysimmune diseases, i.e. auto-
immune haemolytic anaemia, connective tissue dis-
eases, i.e. rheumatoid polyarthritis, scleroderma, etc.,4
malignant lymphomas including Hodgkin's disease, or
with chronic myeloproliferative diseases.48,49
Lymphoid follicles with germinal centres1,45,50
Lymphoid follicles are also seen at a distance from the
bone trabeculae. They are often closely connected to
204 J Diebold et al.
Figure 7. Reactive lymphoid nodule. A. Reactive lymphocyte
aggregate. H & E. B. Lymphoma follicle with germinal centre.
Giemsa.
vessels. The latter are less common than the reactive
lymphocyte aggregates. Only 1±2 nodules can be
observed in each bone marrow section.
These well-circumscribed nodules have a typical
reactive germinal centre with macrophages containing
tingible bodies and a typical mantle zone (Figure 7b).
Mitotic figures as well as large centrofollicular cells are
commonly found in the germinal centres. Occasionally,
the reactive centres are small and can only be observed
in some sections.
The majority of the lymphoid cells express CD20. The
centrofollicular cells are CD10-positive and the mantle
cells express IgD. A normal follicular dendritic cell
network is easily demonstrated. A few scattered T-cells
expressing CD3 are dispersed in the follicles. The
majority are CD4-positive, and a few are CD8-positive.
Some CD57-positive cells are also scattered in the
germinal centres. The oncoprotein bcl-2 is only
Figure 8. Reactive lymphoid aggregate. Same as Figure 7a. At
higher magnification small and medium sized lymphocytes can be
recognized. H & E.
expressed by mantle cells and T-cells, and not by the
cells in the germinal centres. Occasionally, due to the
presence of a large number of T-cells in the small
germinal centre, bcl-2 can be difficult to interpret. Such
reactive lymphoid nodules can be observed in the same
diseases as the lymphocyte reactive aggregates.
Reactive lymphohistiocytic infiltrates7,45
This type of reactive lymphoid infiltrate doesn't have a
germinal centre. The infiltrates are larger than the
reactive lymphoid aggregates, with poorly defined
margins, and occasionally, can occupy an entire
medullary space (Figure 9). They are also often more
numerous and can be found in multiple medullary
spaces.
The lymphoid population is more pleomorphic,
consisting of small lymphocytes with round regular or
irregular nuclei, activated lymphoid cells with a larger
cytoplasm, a paler nucleus, and a more open chroma-
tin. Immunoblasts and mature plasma cells are often
associated.
In addition, other cell types are present, including
histiocytes, which are often activated with an abundant
cytoplasm and a large clear nucleus, mast cells,
eosinophils, and epithelioid cells that are isolated or
in small clusters.
Inside the lymphohistiocytic infiltrates, the reticulum
framework is dense but without myelofibrosis. Capil-
laries are often present that have hypertrophic
endothelial cells.
Immunohistochemistry demonstrates that the lym-
phoid cell population consists of a mixture of B- and T-
cells. Plasma cells are polytypic. No follicular dendritic
network can be observed. In some aetiologies, for
example in HIV-positive patients, T-cells represent more
than 60% of the total lymphoid cell population, and the
majority of these cells express CD8 and contain the
`cytotoxic granules' associated protein TiA-1.
Reactive lymphohistiocytic infiltrates are never seen
in normal patients, even in the aged population. They
are, however, present in patients with viral diseases or
more often dysimmune disorders. HIV infection,4±10,51
particularly during the initial period, represents one of
the most common aetiologies.
Differential diagnosis
The most important differential diagnosis is represented
by bone marrow involvement in malignant lymph-
omas.
Reactive lymphoid aggregates should not be confused
with early infiltrates of small B- or T-cell ML (B-CLL,
lymphoplasmacytic ML, splenic marginal zone
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 Bone marrow biopsies in infections and systemic diseases
Figure 9. Reactive lymphocytic infiltrate in a HIV-positive patient.
Giemsa.
lymphoma, mantle cell lymphoma, T prolymphocytic
leukaemia, etc.).
Follicular centroblastic-centrocytic ML represents the
most frequently observed ML in bone marrow. In the
majority of cases, the centroblastic-centrocytic infil-
trates are situated either in close contact to bone
marrow trabeculae or along their length. This localiza-
tion, and the presence of myelofibrosis in the areas
infiltrated by the centrofollicular cells, are the two most
important criteria for the differential diagnosis of
reactive lymphoid aggregates and follicles with reactive
germinal centres. It should be stressed that a reactive
germinal centre can be observed in bone marrow
localization of primary splenic marginal zone lym-
phoma.
The large reactive lymphohistiocytic infiltrates often
mimic a ML extension, particularly a T-cell ML, due to
the predominance of CD3, and often CD8-positive
lymphocytes. Clinical data, immunohistochemistry,
flow cytometry and molecular biology are useful for
eliminating an involvement of the bone marrow in a
ML. Such large reactive lymphohistiocytic infiltrates
are frequently observed in HIV-positive patients. But
small B-cell ML and T-cell ML are very exceptional in
HIV-positive patients.
Differential diagnosis is often very difficult, particu-
larly when multiple or extensive reactive lymphoid
lesions are present in the bone marrow. Another
difficulty is the fact that reactive lymphocyte aggre-
gates and even follicles with germinal centres can be
found in patients with ML and/or Hodgkin's disease,
even in the absence of lymphomatous involvement.
Furthermore cases have been observed in which
reactive lymphoid lesions have developed into a true
ML.52 Table 3 shows the most important criteria for
differential diagnosis but as stressed by Brunning and
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205
MacKenna `exceptions to these criteria are relatively
common'.45
IMMUNOBLASTIC HYPERPLASIA
This is a very rare condition, never seen in isolation. In
viral diseases, particularly in infectious mononucleosis,
a small number of immunoblasts can be observed
associated with reactive lymphoid lesions, mainly with
reactive lymphohistiocytic infiltrates. They can be of
the B-cell and/or T-cell type.
PLASMACYTOSIS
Plasma cell hyperplasia is a common finding in patients
with chronic inflammatory diseases, in dysimmune
disorders such as Castleman disease,53 in septicaemia,
and in HIV infection.
Plasma cells of the mature Marschalko type are
present along the capillaries. Sometimes small clusters
are dispersed in the centre of the lacunar spaces but
rarely in close contact with bone trabeculae (Figure
10). Differential diagnosis with early myeloma is based
on the absence of atypical or giant plasma cells.
Immunohistochemistry is also very important, as it
demonstrates the polytypy of the plasma cell population
(Figure 10). The presence of such a plasmacytosis is
very helpful for the diagnosis of reactive diseases. For
example, the presence of this type of plasmacytosis
associated with peripheral blood abnormalities mimick-
ing a chronic myeloproliferative disorder, is consistent
with a diagnosis of benign leukaemoid hyperplasia.
Table 4 summarizes the most important aetiologies.
HISTIOCYTIC HYPERPLASIA
Histiocytosis with haemosiderin
In inflammatory diseases, mainly those that are
chronic, an increase in the number of dispersed
histiocytes laden with brown Perls' positive granules
is often seen.
Disseminated histiocytosis
This represents a very peculiar type of inflammatory
disorder. Histiocytes are increased in number and
dispersed between the haematopoietic cells but are
not organized into granulomas.54,55
Histiocytosis with haemophagocytic syndrome51,55257
In trephine bone marrow biopsies, the number of
histiocytes is increased. The histiocytes are dissemi-
nated individually throughout the bone marrow or
present as small clusters of macrophages. A few can be
206 J Diebold et al.
Table 3. Criteria for benign lymphoid lesions and malignant lymphomas including Hodgkin's disease45
Benign lymphoid lesions
No paratrabecular localization
Often are well-circumscribed, roundish
No interstitial infiltrate between the lesions
Polymorphic cell population
Organized around a vessel
No myelofibrosis
Sometimes presence of a reactive germinal centre
No large cells in the lesions or in the sinuses
Absence of lymphoma cells on sternal puncture smears
seen in the lumen of the sinuses. The most important
feature is the presence of erythrocytes (2±5 or more) in
the cytoplasm of large histiocytes (Figure 11). Occa-
sionally, the lymphoid cells, granulocytes or erythro-
blasts are also phagocytosed.
Reactive lymphoid aggregates, polymorphic lym-
phoid lesions or follicles with germinal centres may
be associated.
At the beginning of the disease, the bone marrow is
Figure 10. Reactive plasmacytosis mimicking a myeloma in a
patient with a localized Castleman disease. On the left, Marschalko-
type plasma cells, some binucleated. Giemsa. On the right,
immunohistochemistry demonstrates the polyclonality of the
plasma cell population: kappa and lambda light chain expression.
ABC technique, immunoperoxidase.
Malignant lymphomas
Frequent paratrabecular localization
Often have diffuse borders, irregular shape
Frequent infiltration into the adjacent marrow
Monomorphic cell population
No vessel or vascular hyperplasia
Often myelofibrosis in the lymphoma infiltrate
No reactive germinal centre
Presence of large B- or T-cells, of lymphoid cells in the sinuses,
of Reed±Sternberg cells
Presence of lymphoma cells on sternal puncture smears
often hypercellular and the erythrophagocytic histiocytes
are rare and scattered throughout the bone marrow.
In more advanced stages, the bone marrow is
hypocellular, with reduced erythroblastosis and gran-
ulopoiesis. The number of megakaryocytes can be
normal or increased. Often the hyperplastic or normal
areas alternate with the hypocellular or acellular areas.
Areas of bone marrow destruction that result from
focal extensive oedema, haemorrhage and necrosis
with depletion of haematopoietic cells can be observed.
Systemic myelofibrosis can develop, particularly in the
necrotic areas. Macrophages with haemosiderin may
be numerous in the fibrotic areas.
It is necessary to look for signs of infection, for
example viral inclusions after such lesions are
observed. ML must also be looked for. Lymphomatous
infiltration can occur but often the infiltration is sparse
and difficult to recognize. Lymphoma cells should also
be looked for in the lumen of the sinuses. In some cases,
serial sections, immunohistochemistry and molecular
biology are required for an accurate diagnosis to be
made.
Sternal puncture smears can show the presence of
typical erythrophagocytic macrophages. Dyserythro-
poiesis may be involved. In cases of ML, lymphomatous
cells are present.
Erythro(haemo)phagocytic histiocytosis often has
the same symptoms as macrophage (histiocyte) activa-
tion syndrome.
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 Bone marrow biopsies in infections and systemic diseases
Table 4. Reactive plasma cell hyperplasia in bone marrow
Infectious diseases
Bacterial*
Viral (EBV, HIV, etc.)
Dysimmune disorders
Castleman's disease
Haemolytic anaemia
Thrombocytopenic purpura
Systemic connective tissue disease
Hypersensitivity
Monoclonal gammopathy of uncertain significance
Immune amyloidosis
Malignant disease (even in the absence of bone marrow
involvement by these malignacies)
Hodgkin's disease
Malignant lymphoma (B or T)
Chronic granulocytic leukaemia
Various diseases (metabolic)
Iron deficiency anaemia
Megaloblastic anaemia
Cirrhosis
Hypoplasia or aplasia
*Chronic osteomyelitis foci (Brodie's abcesses) are character-
ized by sheets of pure plasma cells that infiltrate the fibrosis.
Clinical data, particularly from bone X-rays, and immunohis-
tochemistry demonstrating that the plasma cells are poly-
clonal and can be used to distinguish the lesion from the
myeloma.
This syndrome causes fever, general malaise, anor-
exia, weight loss, night sweats and subicterus. Physical
examination reveals hepato-splenomegaly and some-
times small polyadenopathies. Peripheral blood cell
cytopenia (anaemia, leucopenia, thrombopenia), occa-
sionally pancytopenia are observed. Hypofibrinogen-
emia and hypertriglyceridaemia can be associated. The
evolution of the syndrome can be severe due to hepatic
or renal insufficiency, combined with haemorrhagic
syndrome and cardio-respiratory insufficiency. Sponta-
neous resolution can be seen. Treatment of the
aetiology often cures the patient.
The cause of this syndrome can be classified into two
main groups (Table 5):
X Infections due to different types of bacteria (often
Gram-negative), viruses (EBV, CMV, HIV, etc.),4±10,51,56
fungi or parasites.
X Malignant diseases particularly T-cell lymphoma,
anaplastic large T-cell lymphoma or Hodgkin's lym-
phoma.
This syndrome occurs often in patients with immune
deficiencies, either acquired, i.e. due to viral diseases,
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207
Figure 11. Haemophagocytic histiocytosis in a patient with T-cell
malignant lymphoma involvement of the bone marrow. On the left,
histiocytes containing many erythrocytes. H & E. On the right,
CD68 expression underlines the erythrophagocytosis. ABC,
immunoperoxidase.
polychemotherapy, organ transplantation, or congeni-
tal, i.e. Farquhar's disease, Chediak±Higashi disease,
etc. (Table 5).
The symptoms of the syndrome are probably due to a
hyperproduction of cytokines by the T-cells and
monokines by the histiomonocytes.
Histiocytosis with phagocytosis of infectious agents
In some cases, histiocytes do not exhibit haemophago-
cytosis. Aetiological agents can be recognized in the
cytoplasm of these histiocytes either morphologically
(Leishmania, Histoplasma)7,28,29 or by the use of special
stains (atypical Mycobacteria).4,6±11,26,27,30 Often this
type of disseminated histiocytosis is associated with
immune deficiency, particularly HIV infection (Fig-
ures 4±5 and 6).
C H RO N I C I N F L A M M AT I O N W I T H F I B RO S I S
Collagen bands can develop around vessels and/or
granulomas. Areas of fibrosis can also replace previous
necrosis. Interstitial oedema with a variable number of
plasma and lymphoid cells may be associated.
A fibro-histiocytic lesion with eosinophils, which
occurs in the centre of the lacunar spaces of bone
marrow has been described by Rywlin et al.46 Giemsa
staining reveals a high number of eosinophils and mast
cells, which are sometimes degranulated. Lymphoid
nodules of variable size develop in contact with the
fibrosis. Nests of plasma cells are also observed. This
lesion is now considered an early lesion of systemic
mastocytosis and not an inflammatory lesion.
208 J Diebold et al.

Table 5. Aetiologies associated with haemophagocytic syndrome

Infectious diseases

Viruses
Herpes viruses (simplex homini, herpes zoster, cytomegalovirus, EBV)
Adenovirus
Measles virus
Parainfluenza virus
Vaccinia virus
Rubella virus
HIV
Bacteria
Salmonella typhi
Escherichia coli
Other Gram-negative bacteria
Brucella
Mycobacterium tuberculosis
Legionella
Rickettsia
Fungi
Histoplasma
Protozoal infection
Toxoplasma
Leishmania
Malaria
Malignant diseases
Malignant lymphoma ± particularly anaplastic large cell lymphoma (null or T-type)(former malignant histiocytosis); T-cell
lymphoma, angioimmunoblastic type; myeloma
Hodgkin's disease
Disseminated carcinoma
Immune deficiency
Acquired: viral diseases, corticoid and polychemotherapy, organ transplantation
Congenital
Farquhar's disease (familial erythrophagocytic lymphohistiocytosis)
Chediak±Higashi disease
Other

C H RO N I C D I S E A S E S W I T H A M Y L O I D O S I S A C U T E I N F L A M M AT I O N

Amyloid deposits may occur in chronic inflammations
or in dysimmune diseases. The deposits are mainly
present on the vessel walls or in the interstitium. Congo
red staining and thioflavin-T-test are very useful.
Polytypic plasmacytosis is often found around the
vessels or around the interstitial amyloid deposits.
Haematopoietic cell line modifications
These modifications are probably secondary to the
production of various cytokines which either block or
stimulate the proliferation of haematopoietic stem cells
(growth factors) and their differentiation.2
In acute inflammation, an increase in the number of
cells of the granulocytic series is often observed. In
some cases, hyperplasia is associated with an accumu-
lation of mature neutrophil granulocytes in the centre
of the medullary spaces around the venous sinuses. In
other cases, due to the rapid delivery of mature
granulocytes to the peripheral blood through the
venous sinuses, the majority of the cells of the
granulocytic series are immature. In very severe
infections (septicaemia), an absence of mature granu-
locytes is associated with a proliferation of myelocytes
and promyelocytes, mimicking the process of acute or
chronic leukaemia (leukaemoid reaction). An increase
in megakaryocytes has been seen during infection,
q 2000 Blackwell Science Ltd, Histopathology, 37, 199±211.
 Bone marrow biopsies in infections and systemic diseases
Figure 12. Hyperplastic reactions of haematopoietic cells. A,
Hyperplasia of erythroblasts, granulocytes and megacaryocytes in a
patient with Hodgkin's lymphoma without bone marrow
involvement. Giemsa. B, Myelocyte and granulocyte hyperplasia
mimicking a myeloproliferative disorder (leukaemoid reaction) in a
patient with septicaemia. H & E.
particularly in cases of disseminated intravascular
coagulation. In different inflammatory diseases, anae-
mia is common and is responsible for an erythroblastic
hyperplasia. In cases of severe anaemia, the accumula-
tion of large basophilic erythroblasts may mimic
myelodysplasia.
In septicaemia, modifications of the three main cell
lines can occur and may be responsible for false
diagnosis of acute or chronic leukaemia or myelodys-
plasia.
In severe infection, hypoplasia or even aplasia can be
observed, as well as oedema, haemorrhage, fibrin
deposits, necrosis or even fibrotic organization.
C H RO N I C I N F L A M M AT I O N
Similar to the acute phase of inflammation, stimulation
of stem cells leads to hyperplasia of one, two or all of the
bone marrow haematopoietic normal cell lines (Figure
12a). In some cases hyperplasia predominates among
cells of the granulocytic series, with numerous
promyelocytes and myelocytes along the bone trabecu-
lae and mature neutrophil granulocytes in the centre of
the medullary spaces. The number of eosinophil
granulocytes can also be increased, particularly in
cases of drug hypersensitivity, allergy, collagen diseases,
inflammation due to parasites or Hodgkin and T-cell
ML. In eosinophilic hyperplasia, macrophages may
contain Charcot±Leyden crystals.
A leukaemoid pattern can be seen which generally
mimics a chronic myeloid leukaemia (Figure 12b). The
association with plasmacytosis or with granulomas
argues for a reactive hyperplasia. In contrast, the
q 2000 Blackwell Science Ltd, Histopathology, 37, 199±211.
209
presence of reactive lymphoid nodules is of no use for
the differential diagnosis, as a lymphoid hyperplasia
may develop in chronic myeloproliferative diseases.
Such a leukaemoid pattern can be observed in patients
with Hodgkin's lymphoma or T-cell ML, i.e. AILD-type,
even in the absence of lymphoma involvement.
Erythroblastic hyperplasia can be observed during
infection with Parvovirus B19.58,59 Giant erythroblasts
and multinucleated erythroblasts are dispersed in the
bone marrow. Viral inclusions can be seen in the nuclei
of erythroblasts. The other cell lines are normal. This
viral infection of the erythroblasts can cause a severe
anaemia or an anaplastic crisis.13 This infection occurs
frequently in immunosuppressed patients, particularly
after bone marrow or organ transplantation, or in
patients with myelodysplasia.58 A haemophagocytic
syndrome can be associated.59 The diagnosis is
confirmed by three techniques: serum assay for specific
anti-HPV 19 antibodies (IgM, IgD), demonstration in
the blood of the presence of HPV-19 DNA by PCR
technique, demonstration by in-situ hybridization in
tissue sections of HPV-19 DNA or RNA in giant
proerythroblasts or in normal erythroblasts. In normal
patients, the infection is resolved when specific
antibodies neutralize the activity of the virus. In
immunosuppressed patients, there is a lack of adequate
humoral immunity responses, without production of
neutralizing specific antibodies, responsible of persis-
tance of an active viral disease causing chronic severe
anaemia.
Identification of aetiological agents
Trephine bone marrow biopsy allows the identification
of some, but not all, aetiological agents. Marrowculture
and direct examination of smears can be used to
identify bacteria and parasites.
Common staining procedures (H & E, Giemsa, PAS)
may be very helpful in the diagnosis of viral inclusions,
some parasites (Leishmania, Toxoplasma) and fungi
(Histoplasma, Cryptococcus).
Special staining should always be performed when
an infection is suspected or when granulomas and/or
disseminated histiocytosis are present. Ziehl±Neelsen,
Gram and Grocott staining should be done routinely.
Immunohistochemistry can be useful for the demon-
stration and characterization of viral, parasites and
fungal agents.
Special stains and immunohistochemistry should be
done automatically in patients with a clinical presenta-
tion of infectious disease and/or a known immune
deficiency. Under these conditions, such as with
patients AIDS, intracellular (as Mycobacterium avium)
210 J Diebold et al.
or extracellular agents can be discovered. Toxoplasma,
Leishmania and Histoplasma have been discovered,
between haematopoietic cells in trephine bone marrow
biopsies. Occasionally, parasites seem to be located in
the cytoplasm of megakaryocytes due to a phenomenon
called `emperipolesis'.7,28,30 Bone marrow cultures can
also be very helpful.
Conclusion
Numerous inflammatory and dysimmune diseases are
responsible for various types of stromal reactions and
for modifications of normal bone marrow cell lines.
Trephine bone marrow biopsies may be helpful for the
diagnosis and for the identification of aetiological
agents. It play an important role for the diagnosis in
patients with fever of unknown origin.
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