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CHAPTER 15
Haematopoietic Neoplasms
There are no benign neoplasms of haematopoietic derivation in
the skeleton. The malignant tumours can be divided broadly into
two groups  myeloma and lymphoma.
Myeloma is the most common neoplasm of bone.The majority is
diagnosed with a bone marrow aspirate, rather than a bone
biopsy. Most patients have disseminated disease, associated
with a poor prognosis. Some have solitary myeloma with a more
favourable clinical course but eventually, most become multi-
focal. A small percentage of patients have sclerotic bone
lesions, which may be associated with paraneoplastic syn-
dromes, especially peripheral neuropathy.
Lymphoma of bone may be primary or secondary to systemic
disease. Most are diffuse large B-cell type lymphomas.
Leukaemic infiltrates such as with granulocytic leukaemia have
to be differentiated from lymphomas with the aid of immunohis-
tochemistry.
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F.J. Martinez-Tello
Plasma cell myeloma
M. Calvo Asensio
J.C. Lorenzo-Roldan
Definition at diagnosis is 68 years in males and 70 (Bence-Jones protein) is found in the
Plasma cell myeloma is a monoclonal in females. Both sexes are equally affect- serum in 75% of the patients {1850}.
neoplastic proliferation of plasma cells of ed {512}. Renal failure is the result of tubular
bone-marrow derivation, usually multi- lesions due to monoclonal light chain
centric, that eventually infiltrates various Sites of involvement
organs but rarely produces plasma cell The bones that contain haematologic
Table 15.01
leukaemia. It is characterized by osteo- marrow in adults are the most frequently
Diagnostic criteria for plasma cell myeloma.
lytic lesions, bone pain, hypercalcemia, involved: vertebrae, ribs, skull, pelvis,
Major criteria:
a monoclonal gammopathy, and disor- femur, clavicle and scapula {843,1850}.
ders due to depositon of abnormal
> Plasmacytoma on biopsy
immunoglobulin chains (amyloid) in vari- Clinical features / Imaging
> Marrow plasmacytosis (>30%)
ous tissues, including kidney. The extensive osteolytic skeletal lesions
> M component:
cause bone pain, pathological fractures,
Serum IgG>3.5g/dl, IgA>2g/dl
ICD-O code 9732/3 hypercalcemia and anaemia. The lumbar
Urine ->Ig/24 hr or kappa or lambda
or thoracic spinal regions are most often
(Bence Jones protein) without amyloidosis
Synonyms and variants affected by pain. Frequently a pathologi-
Myeloma, multiple myeloma. cal fracture is the first symptom. Most
Minor criteria:
The following variants of plasma cell fractures affect the spine. Neurologic
myeloma have been described {844}: symptoms due to spinal cord or nerve
> Marrow plasmacytosis (10-30%)
non-secretory myeloma, indolent myelo- roots lesions, secondary to extraosseous
> M component present but less than listed
ma , smoldering myeloma, plasma cell extension of the tumour or pathological
above
leukaemia (PCL), in addition to extra- fracture, are frequently observed.
> Lytic bone lesions
medullary plasmacytoma, and solitary Peripheral neuropathy is increasingly
> Reduced normal levels of immunoglobulins
plasmacytoma of bone. The exact dis- observed with the osteosclerotic variant
(<50% normal: IgG <600mg/dl, IgA<100 mg/dl,
tinction is based on clinical and radi- of multiple myeloma but it is rare with
IgM<50mg/dl)
ographic features. classic plasma cell myeloma {2155}.
Anaemia is a consequence of marrow
The diagnosis of myeloma requires a minimum
Epidemiology destruction and renal damage with
of one major and one minor criterion or three
Plasma cell myeloma is the most fre- resultant loss of erythropoetin {122}. An
minor criteria, which must include the first
quent tumour that occurs primarily in M-component is found in the serum or
two. These criteria must be present in a clini-
bone and the most common lymphoid urine in 99% of the patients. The mono-
cal setting of symptomatic and progressive
neoplasm in Blacks and the second clonal proteins are in 50% of the cases of
disease.
most common in Whites. It is rare in indi- the IgG class, 25-20% of the IgA class,
viduals younger than 40 years (less than and, rarely, of the IgM, IgD or IgE class-
_______________________
10%). Most patients are in the sixth and es. Biclonal gammopathies are found in
From references {843,1850}.
seven decades of life. The median age 1% and a monoclonal light chain
A B C
Fig. 15.01 Plasma cell myeloma. A Plain radiograph of the lumbo-sacral region of the spine shows a very light radiolucency of the right wing of the sacrum. B CT
scan of the same patient, at the level of S2, shows loss of the cancellous bone of the right wing of the sacrum, of a large area of the vertebral body, and small scal-
loping of the endosteal surface of the cortical bone. C Patient with POEMS syndrome with multiple lesions in the skeleton. CT scan of L1 with extensive radiodense
areas, and points of disruption in the anterior cortex.
302 Haematopoietic neoplasms
bb5_23.qxd 13.9.2006 13:24 Page 303
Erosions of the cortex are commonly
observed but prominent periosteal new
bone formation is not. Expansion of the
affected bone may occur in bones with a
small diameter, such as the ribs. The ear-
liest and more severe changes are seen
in the skull, vertebrae, ribs and pelvis.
About 12-25% of patients have no
detectable foci of bone destruction at
presentation but may show generalised
osteoporosis {2155}. Solitary myeloma
lesions are also typically lytic and may
also expand the bone. Infrequently the
lesions in plasma cell myeloma may be
sclerotic, which are typical for the very
rare POEMS syndrome (polyneuropathy,
organomegaly, endocrinopathy, mono-
clonal gammopathy, skin changes) {122,
871}. CT and MRI studies may discover a
very subtle small lesion not visible on
plain radiographs. The features of MRI
are variable, because plasma cell myelo-
ma does not involve the marrow in a
homogeneous fashion and because the
Fig. 15.02 Plasma cell myeloma. Patient with POEMS Fig. 15.03 Plasma cell myeloma. Photographs of
syndrome with multiple lesions in the skeleton. X-ray extent of fatty marrow replacement which gross autopsy specimens. The normal bone struc-
of the dorso-lumbar region of the spine showing ture and bone marrow of the vertebral bodies are
varies with age. For differential diagnosis
marked radiodensity with a less radiodense central replaced by a gelatinous haemorrhagic tissue.
metastatic carcinoma, malignant lym-
area. The discal space L1-L2 is typically diminished.
phoma, and hyperparathyroidism have to
be considered. The lesions of metastatic
proteinuria. The patients have often carcinoma and malignant lymphoma are ers), and exposure to asbestos, pesti-
recurrent bacterial infections, partially usually positive on bone scan, whereas cides, petroleum products, rubber, plas-
because a decreased normal immuno- those of myeloma are usually not {538}. tic and wood products {1851}. Some
globulin production due to displacement cases of POEMS syndrome have been
by the neoplastic clone. Aetiology associated with Kaposi sarcoma / human
The myelomatous bone lesions are lytic, The aetiology is largely unknown. herpesvirus 8 infection {154,1467}.
sharply demarcated lesions, being the Possible, but unproven, aetiologic fac-
consequence of replacement of bone tors include long standing chronic infec- Macroscopy
trabeculae by tumour tissue, are not sur- tions (chronic osteomyelitis, rheumatoid Biopsy or curettage samples show frag-
rounded by a sclerotic zone and may arthritis, etc.), exposure to low level radi- ments of tan-grey soft tissue. At autopsy,
reach 5 cm in its greatest diameter. ation (radiologists, nuclear plant work- soft pink or grey friable masses are the
A B
Fig. 15.04 Plasma cell myeloma. A High power view shows cells with eccentric round or oval nuclei, with a speckled chromatin and abundant cytoplasm, that in the tis-
sue section stains pink. B Poorly differentiated plasma cell myeloma, showing cellular pleomorphism with frequent multinucleated cells and atypical mito-tic features,
consistent with the term "anaplastic myeloma".
Plasma cell myeloma 303
bb5_23.qxd 13.9.2006 13:24 Page 304
clear zone that correspond ultrastruc-
turally to a well developed RER and a
prominent Golgi centre, respectively.
The tumour cells may accumulate
immuno-globulins in the cytoplasm and
show a morular appearance or "Mott
cells". Extracellular globules of poly-
merized immunoglobulines, called
Russell bodies, may be also observed.
The cells of less differentiated tumours
show nuclei with less clumping of the
chromatin and enlarged nucleoli, and
the cytoplasmic membrane becomes
indistinct. The poorly differentiated
plasma cell myeloma may show atypi-
cal cells, with occasional double nuclei,
brisk mitotic activity and atypical mitot-
ic figures making difficult to recognize
the plasma cell nature of the cells.
Immunophenotype
Fig. 15.05 Plasma cell myeloma. Low power appearance shows a rich vascular pattern. The tumour cells sur-
round the vascular channels, simulating a haemangiopericytomatous pattern. Myeloma cells have the same features
as normal plasma cells and express
their own distinct antigen [plasma cell
typical appearance. Diffuse involve- associated antigen (PCA, CD38)]
ment of bone marrow and discrete nod- {1270}. Plasma cell myeloma character-
ules are also common. Some plasma istically expreses monotypic cytoplas-
cell myelomas may simulate a lym- mic Ig and lacks surface Ig. In about
phoma showing a fish-flesh appear- 85% both heavy and light chains
ance. It is quite common to see expan- are produced, but in the remaining
sion of the affected bone and extraos- cases light chain only is expressed
sous extension, collapse of one or sev- (Bence Jones myeloma) {1178}. The
eral vertebral bodies and pathological monotypic expression of kappa or
A
fractures. Very infrequently the tumour lambda immunoglobulin by the tumour
masses have a grey, waxy appearance cells establishes the diagnosis of malig-
due to extensive amyloid deposition. nancy {2169}. Myeloma cells frequently
Unusual cases have a combination of express the natural killer antigen
lytic and sclerotic changes. CD56/58 which is not expressed in
reactive plasma cells {405}. The ma-
Histopathology jority of myelomas lack the pan-B
Plasma cell myeloma is a neoplasm of antigens CD19 and CD20, while CD38
round or oval cells of the plasma cell and the Ig-associated antigen CD79a
B
lineage showing a spectrum of variable are expressed in most cases {1270},
features of cellular maturity that have and CD138 {498} is a reliable marker for
prognostic significance. Well differenti- identifying and quantifying normal and
ated tumours show sheets of closely tumoural plasma cells in paraffin sec-
packed cells, that resemble normal tions. Myeloma cells may be positive for
plasma cells, with little intercellular EMA {841}. Few cases may express
matrix. In the histological sections these CD10 {842} and occasionally plasma
cells have abundant, dense eosino- cell myeloma may show aberrant
philic cytoplasm and show distinct cell expression of myelomonocytic antigen
outlines. The nucleus is eccentric, with {123}.
C
the chromatin clustered at the periph-
Fig. 15.06 Plasma cell myeloma. A A so called "Mott
ery, often showing a cartwheel appear- Prognostic factors
cell" is shown in the centre of the picture, with grape-
ance and a prominent nucleolus. Mitotic Multiple myeloma is generally an incur-
like cytoplasmic inclusions. The cell is surrounded by
figures are rare in well differentiated able disease (median survival 3 years;
numerous Russell bodies. B Plasma cell myeloma
plasma cell myeloma The cytological 10% survival at 10 years {560,1850}. A
containing amyloid. Deposition of pale, waxy amor-
features are better observed in Giemsa shorter survival time is associated with
phous proteinaceous material in between neoplastic
stained preparations in which the cyto- a higher stage {133,561}, renal insuffi-
plasma cells (Congo red stain). C Immunoexpression
of CD 138 in almost all neoplastic cells. plasm is basophilic with a perinuclear ciency {133,561}, degree of marrow
304 Haematopoietic neoplasms
bb5_23.qxd 13.9.2006 13:24 Page 305
Table 15.02
replacement by tumour cells {1154},
Diagnostic criteria of solitary myeloma (plasmacytoma of bone).
cellular immaturity and atypia {1851},
high Ki-67 proliferation antigen levels
Diagnostic criteria
{842} and chromosome deletion of
> A single tumour in the bone marrow showing identical macroscopic, microscopic, immunophenotype
13q14 and 17p13 {1682}. The lack or
and genetic features to those of plasma cell myeloma
weak expression of CD56 delineates a
> Solitary osteolytic lesion on radiological studies
special subset of plasma cell myeloma
> Absence of other lesions on complete skeletal radiographs
at diagnosis with a lower osteolytic
> No evidence of plasmacytosis in the bone marrow away of the solitary lesion
potential and a trend to develop a PCL
_______________________________________
{138}. The prognosis is better in solitary
From references {137,719,834,1194,1260,1391}.
lesions.
Plasma cell myeloma 305
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K.K. Unni
Malignant lymphoma
P.C.W. Hogendoorn
Definition Sites of involvement visceral sites or multiple lymph node at
Malignant lymphoma is a neoplasm com- Lymphoma affects portions of bone with multiple sites;
posed of malignant lymphoid cells, pro- persistent red marrow. The femur is the 4) the patient has a known lymphoma
ducing a tumefactive lesion within bone. most commonly involved single site. The and a bone biopsy is done to rule out
spine and the pelvic bones are other involvement of bone.
ICD-O code 9590/3 common sites. It is extremely unusual to Groups 1 and 2 are considered primary
see malignant lymphoma involving the lymphoma of bone.
Synonyms small bones of the hands and feet. When The roentgenographic features are quite
Reticulum cell sarcoma, primary non- malignant lymphoma presents in the variable and somewhat non-specific. In
Hodgkin lymphoma of bone, Hodgkin spine or in the maxillary antrum, it is often the long bones, the diaphysis tends to be
lymphoma. difficult to know whether the process is preferentially involved. The tumour tends
primary in bone or in soft tissues. to involve a large portion of the bone; it is
Epidemiology not unusual to see destruction of up to half
Malignant lymphoma involving bone is Clinical features / Imaging of the bone. Occasionally, the entire bone
unusual, accounting for approximate- The majority of patients with lymphoma is destroyed. The process is poorly
ly 7% of all bone malignancies. Lym- present with bone pain. Some patients demarcated with a wide area of transition
phomas involving bone account for present with a palpable mass. Neurolog- from normal bone. There may be variable
about 5% of extranodal lymphoma. ical symptoms are common with involve- sclerosis; rarely, the tumour is very scle-
Radiographic studies {249} show that ment of the spine. Patients with primary rotic or entirely lytic. More commonly,
16% of patients with lymphoma have evi- lymphoma of bone rarely present with however, it is a mixture of lysis and sclero-
dence of bone involvement. Patients may systemic or B symptoms, such as fever sis. The cortex is frequently destroyed
be of any age group but there is a ten- or night sweats. Occasionally, symptoms and there is a large soft tissue mass. In a
dency to involve adults, especially older associated with hypercalcemia, such as flat bone, such as the pelvis, large areas
adults. There is a male predominance constipation, lethargy and somnolence of destruction with soft tissue extension on
{943}. may be present {1512}. Lymphoma either side suggest a diagnosis of lym-
involving bone can be separated into phoma. Periosteal new bone formation is
four groups: unusual. A purely sclerotic lesion may be
1) a single skeletal site, with or without mistaken for Paget disease. If the cortex is
regional lymph node involvement; not involved, the marrow destruction may
2) multiple bones are involved, but there not be obvious on plain roentgenograms.
is no visceral or lymph node involvement; Radionuclide bone scan is almost always
3) patients present with a bone tumour positive. Magnetic resonance images
but work up shows involvement of other show signal abnormalities in the marrow,
A B
Fig. 15.08 Malignant lymphoma in a 15-year-old boy. A Plain roentgenogram does not reveal the lesion.
Fig. 15.07 Malignant lymphoma of femur and tibia.
B MRI of the same case shows multifocal involvement of bone with signal changes.
Note extensive lytic and sclerotic lesions.
306 Haematopoietic neoplasms
bb5_23.qxd 13.9.2006 13:24 Page 307
whereas the plain roentgenograms may bone tumour. Similarly, chronic lympho- be prominent. The cytoplasm is not abun-
be completely normal. cytic leukaemia rarely presents as a dant but may be amphophilic. Fine retic-
tumefactive process. Consequently, most ulin fibres are present between individual
Macroscopy skeletal lymphomas are diffuse large cell tumour cells. Occasionally, this gives rise
It is unusual to see gross specimens of type. It has a very characteristic growth to thick, fibrous bands. Rarely a lym-
malignant lymphoma involving bone, pattern similar to involvement elsewhere, phoma will have so much fibrosis that the
because the treatment is usually with and tends to leave behind normal struc- tumour cells may spindle, even showing
radiation and/or chemotherapy, following tures, such as medullary bone and mar- a storiform pattern, leading to an erro-
diagnoses made with needle biopsies. row fat cells and permeate between neous diagnosis of a sarcoma. Another
However, a portion of bone may be these structures. The bony trabeculae common finding is associated infiltrate of
resected if the patient presents with a may appear normal or may appear thick- non-neoplastic small lymphocytes. One
pathological fracture. Grossly, a large ened or irregular, even pagetoid. 92% of problem with the diagnosis of lymphoma
portion of bone is involved, with cortical primary non-Hodgkin lymphoma of bone in bone is that the cells tend to get
destruction. The lesion has the soft fish- was found to be of the large B cell type crushed. One may not be able to identify
flesh appearance of lymphoma else- and only 3% diffuse follicle centre cell, individual tumour cells but see complete
where in the body. 3% anaplastic large cell and 2% immuno- replacement of the marrow with DNA
cytoma {943}. The cytological features of smears. This may be associated with a
Histopathology the large B-cell type show quite a bit of very fine fibrosis. If a bone biopsy shows
The majority of lymphomas involving the variation including marked multilobation such crush artefact, a diagnosis of malig-
skeleton show a diffuse growth pattern. {1703}. The nuclei tend to be large and nant lymphoma should be suspected.
Although bone marrow involvement is not irregular with a cleaved appearance. Hodgkin lymphoma may involve the
uncommon in follicular small cleaved cell There frequently is a mixture of small, skeleton as a manifestation of wide-
lymphoma, it is unusual to have this type medium and large cells, giving rise to a spread disease and produce a tumour
of lymphoma present as a destructive polymorphic appearance. Nucleoli may mass but primary manifestations are
A B
C D
Fig. 15.09 Malignant lymphoma. A In this low power appearance, the bony trabeculae are thickened and tumour cells fill up the marrow spaces. B Medium power appear-
ance of the neoplastic infiltrate. C In some cases lymphoma cells may cluster as shown in this photomicrograph. D Although nuclei are round and small there is more
variation in size and shape of nuclei than is seen in Ewing sarcoma.
Malignant lymphoma 307
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with chronic or acute myelogenous Prognostic factors
leukaemia may present with destructive Although the prognosis of lymphoma
lesions of bone or granulocytic sarcoma has been reportedly associated with cell
{1390}. The clinical course may be indo- type {544} the most important prognostic
lent {2247}. Histological features of the indicator is the stage of the disease.
infiltrating cells recapitulate the features Patients with the first two stages do
of the systemic disease. remarkably well, whereas patients with
stage 3 and stage 4 disease fare poorly
Immunophenotype {1626}. Recent data on primary non-
Immunoperoxidase stains have become Hodgkin lymphoma of bone show a
indispensable in the recognition and 5-year overall survival of 61%, and 46%
Fig. 15.10 Malignant lymphoma. Crush artefact is fre-
subclassification of malignant lym- of patients progression free at 5 years,
quently present.
phoma. Lymphomas involving bone are notwithstanding heterogeneous treat-
rare. Classical Reed-Sternberg cells with usually worked up in the same way as ment in that series {943}. Patients at
bi-lobed nuclei and prominent nucleoli lymph node counterparts. Almost all pri- presentation older than 60 years have a
are present but may be difficult to find. mary lymphomas involving bone are B- worse overall survival and a worse pro-
More commonly, one finds variants, such cell neoplasms and hence stain with gression-free period. Patients with the
as large cells with large nuclei and CD20 {943}. T-cell lymphomas and immunoblastic subtype have a worse
prominent nucleoli. Variation in size and anaplastic large lymphomas are vanish- survival than the centroblastic mono /
shape of the cells, especially the pres- ingly rare. CD15 and CD30 stains recog- polymorphic subtype or the centroblas-
ence of plasma cells and eosinophils nize Reed-Sternberg cells of Hodgkin tic multilobated subtype. Tumour local-
should alert one to the possibility of disease and myeloperoxidase reactions ization is not found to be a significant
Hodgkin lymphoma. Areas of necrosis help support a diagnosis of granulocytic prognostic factor. According to the Ann
may be also prominent. Nodular scleros- sarcoma. Arbor classification there is no dif-
ing Hodgkin lymphoma and mixed cellu- ference in survival between stage I and
larity are the usual types {1623}. Genetics stage II tumours and just a trend towards
Leukaemic infiltrates may produce a Specific studies on primary lymphomas worse prognosis in stage IV tumours
tumour mass centred in bone. Patients of bone are lacking. {943}.
308 Haematopoietic neoplasms