Diseases of white blood cells, lymph nodes, spleen, and thymus

Diseases of White Blood Cells,
Lymph Nodes, Spleen, &
Thymus - 4
DR ROOPAM JAIN
PROFESSOR & HEAD, PATHOLOGY

MYELODYSPLASTIC SYNDROMES
• heterogeneous group of haematopoietic clonal stem cell disorders having
abnormal development of different marrow elements (i.e.
dysmyelopoiesis)
• characterised by cytopenias,
• associated with cellular marrow and ineffective blood cell formation.
• Also termed as preleukaemic syndromes or dysmyelopoietic syndromes.

FAB CLASSIFICATION
• Following 5 groups:
1. Refractory anaemia (RA) Blood blasts <1%, marrow blasts <5%.
2. Refractory anaemia with ringed sideroblasts (RARS) (primary acquired
sideroblastic anaemia) Blood blast <1%, marrow blasts <5%; ring
sideroblsts >15%.
3. Refractory anaemia with excess blasts (RAEB) Blood blasts 5%,
marrow blasts 5-20%.
4. Refractory anaemia with excess of blasts in transformation (RAEB-t)
Blood blasts 5%, marrow blasts 21-30%.
5. Chronic myelomonocytic leukaemia (CMML) Blood blasts, 5%,
monocytosis.

WHO classification of MDS consists of following 8 categories:
1. Refractory anaemia (RA) Same as FAB type 1 MDS. Incidence 5-10%;
characterised by anaemia without any blasts in blood; marrow may show
<5% blasts.
2. Refractory anaemia with ringed sideroblasts (RARS) Same as FAB
type 2 MDS. Incidence 10-12%.
3. Refractory cytopenia with multilineage dysplasia (RCMD) New
entity. Incidence 24%; blood shows cytopenia of 2 or 3 cell lineage and
monocytosis but no blasts; marrow shows <5% blasts. 4. RCMD with
ringed sideroblasts (RCMD-RS) New entity. Incidence 15%; all blood and
marrow findings similar to RCMD plus in addition >15% ringed
sideroblasts in marrow.

5. Refractory anaemia with excess blasts (RAEB-1) -In WHO
classification, RAEB of FAB category 3 has been divided into 2
subtypes with combined incidence of 40%. RAEB-1 has blood
cytopenia with <5% blasts and monocytosis; and marrow blast
count 5-9%.
6. RAEB-2 Findings of blood and marrow similar to RAEB-1 but
marrow blast count is 10-19%.
7. Myelodysplastic syndrome unclassified (MDS-U)- Blood
cytopenia without any blasts; marrow shows dysplasia of myeloid
and thrombocytic cell lineage and marrow blast count <5%.
8. MDS with isolated del (5q) -Anaemia in blood and blasts <5%;
marrow blasts <5%, normal or increased megakaryocytes which
may be hypolobated and characteristic isolated deletion of 5q.

Myelodysplastic Syndromes
WHO has thus divided MDS into 8 types:
• Refractory anaemia
• Refractory anaemia with ring sideroblasts
• Refractory cytopenia with multilineage dyspalsia (RCMD)
• RCMD with ring sideroblasts
• RAEB-1
• RAEB-2
• MDS unclassified
• MDS with isolated del (5q)

Pathophysiology
i) Primary MDS is idiopathic but factors implicated in etiology are radiation
exposure and benzene carcinogen.
ii) Secondary MDS
iii) Several cytogenetic abnormalities
iv) At molecular level, mutations are seen in N-RAS oncogene and p53 anti-
oncogene .

Clinical Features
• Found more frequently in older people
• past 6th decade of life,
• slight male preponderance.
• At presentation the patient may have following features:
1. Anaemia appreciated by pallor, fatigue and weakness.
2. Fever.
3. Weight loss.
4. Sweet syndrome having neutrophilic dermatosis
5. Splenomegaly seen in 20% cases of MDS.

Laboratory Findings
BLOOD FINDINGS
• There is cytopenia affecting two (bi-) or all the three blood cell
lines (pancytopenia):
1. Anaemia: Generally macrocytic or dimorphic.
2. TLC: Usually normal
3. DLC: Neutrophils are hyposegmented and hypogranulated.
4. Platelets: Thrombocytopenia with large agranular platelets.

• BONE MARROW FINDINGS :
1. Cellularity: Normal to hypercellular to hypocellular.
2. Erythroid series: Dyserythropoiesis as seen by abnormally appearing
nuclei & ring sideroblasts.
3. Myeloid series: Hypogranular and hyposegmented myeloid precursor
cells.
4. Megakaryocyte series: Reduced in number and having abnormal nuclei.

General Principles of Treatment and Prognosis
• MDS is difficult to treat and may not respond to cytotoxic
chemotherapy.
• Stem cell transplantation
• Patients generally either succumb to infections or
develop into acute myeloid leukaemia.

LYMPHOID NEOPLASMS
• Lymphoid malignancies can be formed by malignant
transformation of each of these cell lines.
• Malignancies of lymphoid cells in blood have been
termed as lymphatic leukaemias and those of
lymphoid tissues as lymphomas.
• Classified on the basis of survival and biologic course
 chronic and acute (CLL and ALL)
• Cinicopathologically distinct groups of lymphomas are :
 Hodgkin’s lymphoma or Hodgkin’s disease (HD)
 Non-Hodgkin’s lymphomas (NHL)

New classification schemes of lymphoid
malignancies:
I. HISTORICAL CLASSIFICATIONS:
• Morphologic classification
• Rappaport classification (1966)
• Rappaport divided NHL into two major subtypes:
1. Nodular or follicular lymphomas
2. Diffuse lymphomas

NHL was further classified according to the degree of
differentiation of neoplastic cells into:
• Well -differentiated
• Poorly -differentiated
• Histiocytic (large cells) types of both nodular and diffuse
lymphomas

• Immunologic classifications Lukes-Collins
classification (1974) was proposed to correlate the
type of NHL with the immune system because the
identification of T and B-cells
• Its subsequent modification was Kiel classification
(1981).
• Both these classifications employed immunologic
markers for tumour cells, and divided all malignant
lymphomas into either B-cell or T-cell origin, and rarely
of macrophages.
• The FCC in the germinal centre undergo transformation
to become large immunoblasts and pass through the
four stages—small cleaved cells and large cleaved cells,
small noncleaved cells and large non-cleaved cells.

II. OLD CLINICOPATHOLOGIC CLASSIFICATIONS :
• FAB classification of lymphoid leukaemia
• Although old FAB classification for lymphoid leukaemia
based on morphology and cytochemistry divided ALL into
3 types (L1 to L3), but it was subsequently revised to
include cytogenetic and immunologic features as well.
• FAB classification is still followed in many centres where
both pathologists and clinicians stick to labelling
lymphoid leukaemia separate from lymphomas.

Classification of NHL-working formulations for
clinical usage (1982)

REAL classification (1994)
• International Lymphoma Study Group (Harris et al)
proposed another classification called revised European-
American classification of lymphoid neoplasms
abbreviated as REAL classification.
• Based on the hypothesis that all forms of lymphoid
malignancies represent malignant counterparts of normal
population of immune cells present in the lymph node
and bone marrow.
• Lymphoid malignancies arise due to arrest at the various
differentiation stages of B and T-cells since tumours of
histiocytic origin are quite uncommon.

• REAL classification divides all lymphoid malignancies into
two broad groups, each having further subtypes:
”
. Leukaemias and lymphomas of B-cell origin: B-cell
derivation comprises 80% cases of lymphoid leukaemias
and 90% cases of NHLs.
”
. Leukaemias and lymphomas of T-cell origin: T-cell
malignancies comprise the remainder 20% cases of
lymphoid leukaemia and 10% cases of NHLs.
REAL classification subsequently merged into WHO
classification.

III. WHO CLASSIFICATION OF LYMPHOID
NEOPLASMS(2008)
• REAL classification, evolved a consensus international
classification of all lymphoid neoplasms together as a
unified group (lymphoid leukaemias-lymphomas) under
the aegis of the WHO.
• WHO classification takes into account morphology,
clinical features, immunophenotyping, and cytogenetic of
the tumour cells.

• As per current WHO classification, all lymphoid
neoplasms fall into following 5 categories:
I. Hodgkin’s disease
II. B-cell malignancies: Precursor (or immature), and
peripheral (or mature)
III. T-cell/NK cell malignancies: Precursor (or immature),
and peripheral (or mature)
IV. Histiocytic and dendritic cell neoplasms
V. Post-transplant lymphoproliferative disorders (PTLDs)

Various immunophenotypes of B and T-cell
malignancies are correlated with normal immunophenotypic
differentiation/maturation stages of B and T-cells in the bone
marrow, lymphoid tissue, peripheral blood and thymus.

COMMON TO ALL LYMPHOID
MALIGNANCIES
1. Overall frequency Five major forms of lymphoid
malignancies and their relative frequency are as under:
i) NHL= 62%, most common lymphoma
ii) HD= 8%
iii) Plasma cell disorders = 16%
iv) CLL= 9%, most common lymphoid leukaemia
v) ALL= 4%

2. Incidence of B, T, NK cell malignancies
• Majority of lymphoid malignancies are of B cell origin (75% of
lymphoid leukaemias and 90% of lymphomas) while remaining are
T cell malignancies; NK-cell lymphomas-leukaemias are rare.
• Relative frequency of subtypes within various common NHLs :
i) Diffuse large B cell lymphoma = 31%
ii) Follicular lymphoma = 22%
iii) MALT lymphoma = 8%
iv) Mature T cell lymphoma = 8%
v) Small lymphocytic lymphoma (SLL) = 7%
vi) Mantle cell lymphoma = 6%
vii) Mediastinal large B cell lymphoma = 2.5%
viii) Anaplastic large cell lymphoma (ALCL) = 2.5%
ix) Burkitt’s lymphoma = 2.5%
x) Others = ~10%
COMMON TO ALL LYMPHOID MALIGNANCIES

3. Diagnosis
• The diagnosis of lymphoma (both Hodgkin’s and non-
Hodgkin’s) can only be reliably made on examination of
lymph node biopsy.
• While the initial diagnosis of ALL and CLL can be made
on CBC examination, bone marrow biopsy is done for
genetic and immunologic studies.
• Subsequently, clinical chemistry, electrophoresis and
tests for organ involvement including CSF examination if
CNS involvement is suspected, need to be carried out.
4. Staging --In both HD and NHL, Ann Arbor staging is
done for proper evaluation and planning treatment.
MALIGNANCIES

5. Ancillary studies CT scan, PET scan and gallium
scan are additional imaging modalities which can be
used in staging HD and NHL cases.
6. Immune abnormalities
• Lymphoid neoplasms arise from immune cells of the
body, immune derangements pertaining to the cell of
origin may accompany these cancers.
• Particularly so in B-cell malignancies and include
occurrence of autoimmune haemolytic anaemia,
autoimmune thrombocytopenia and
hypogammaglobulinaemia.
MALIGNANCIES

HODGKIN’S DISEASE
• Primarily arises within the lymph nodes and involves the extranodal
sites secondarily.
• This group comprises about 8% of all cases of lymphoid neoplasms.
• Incidence of the disease has bimodal peaks—one in young adults
between the age of 15 and 35 years and the other peak after 5th
decade of life.
• The HD is more prevalent in young adult males than females.
• Classical diagnostic feature is the presence of Reed-Sternberg (RS)
cell (or Dorothy-Reed- Sternberg cell) .

CLASSIFICATION
• Diagnosis of HD requires accurate microscopic diagnosis by
biopsy, usually from lymph node.
• universally accepted classification of HD i.e. Rye classification
adopted since 1966.
• Rye classification divides HD into the following 4 subtypes:
1. Lymphocyte-predominance type
2. Nodular-sclerosis type
3. Mixed-cellularity type
4. Lymphocyte-depletion type

WHO classification of lymphoid neoplasms
divides HD into 2 main groups:
I. Nodular lymphocyte-predominant HD (a new type).
II. Classic HD (includes all the 4 above subtypes in the Rye
classification).
• Central to the diagnosis of HD is the essential
identification of Reed-Sternberg cell though this is not
the sole criteria.

Modified WHO classification of Hodgkin’s disease

REED-STERNBERG CELL
1. Classic RS cell
• Large cell which has characteristically a bilobed nucleus
appearing as mirror image of each other.
• owl-eye appearance.
• The cytoplasm of cell is abundant and amphophilic.
2. Lacunar type RS cell
• It is smaller, which is due to artefactual shrinkage of the
cell cytoplasm.
• characteristically found in nodular sclerosis variety of HD

REED-STERNBERG CELL
3. Polyploid type (or popcorn or lymphocytic-
histiocytic i.e. L and H) RS cells
• These are seen in lymphocyte predominance type of HD.
• This type of RS cell is larger with lobulated nucleus in the
shape of popcorn.
4. Pleomorphic RS cells
• These are a feature of lymphocyte depletion type.
• These cells have pleomorphic and atypical nuclei.

Microscopic features of 4 forms of Hodgkin’s disease of lymph node.
The inset on right side of each type shows the morphologic variant
of RS cell seen more often in particular histologic type

MORPHOLOGIC FEATURES
Grossly
• Any lymph node group may be involved but most commonly affected
are the cervical, supraclavicular and axillary groups.
• discrete tumour or diffuse enlargement of the affected organ.
• Lymph nodes or extranodal organ involved appears grey-white and
fishflesh-like.
• Nodular sclerosis type HD may show formation of nodules due to
scarring while mixed cellularity and lymphocyte depletion types HD
may show abundance of necrosis.
• Lymphomatous involvement of the liver, spleen and other organs may
be diffuse or may form spherical masses similar to metastatic
carcinoma.

Microscopically:
I. CLASSIC HD:
1. Lymphocyte-predominance type -is characterised by
proliferation of small lymphocytes admixed with a
varying number of histiocytes forming nodular or
diffuse pattern.
2. Nodular-sclerosis type –
• seen more commonly in women than in men.
• Two essential features :
i) Bands of collagen
ii) Lacunar type RS cells

3. Mixed-cellularity type
• This form of HD generally replaces the entire affected
lymph nodes by heterogeneous mixture of various types of
apparently normal cells.
• These include proliferating lymphocytes, histiocytes,
eosinophils, neutrophils and plasma cells.
4. Lymphocyte-depletion type
• Two variants of lymphocyte-depletion HD:
i) Diffuse fibrotic variant is hypocellular and the entire lymph
node is replaced by diffuse fibrosis
ii) Reticular variant is much more cellular and consists of large
number of atypical pleomorphic histiocytes, scanty
lymphocytes and a few typical RS cells.

Hodgkin’s disease. A, Nodular sclerosis type. There are bands of
collagen forming nodules and characteristic lacunar RS cells
B, Mixed cellularity type. There is admixture of mature
lymphocytes, plasma cells, neutrophils and eosinophils and
classic RS cells in the centre of the field

CLINICAL FEATURES
• Hodgkin’s disease is particularly frequent among young
and middle-aged adults.
• All histologic subtypes of HD, except the nodular
sclerosis variety, are more common in males.
1. Most commonly, patients present with painless,
movable and firm lymphadenopathy. The cervical and
mediastinal lymph nodes are involved most frequently.
2. Approximately half the patients develop
splenomegaly. Liver enlargement too may occur.
3. Constitutional symptoms (type B symptoms) are
present in 25-40% of patients. The most common is low-
grade fever with night sweats and weight loss.
• Other symptoms include fatigue, malaise, weakness and
pruritus.

OTHER LABORATORY FINDINGS
Haematologic abnormalities
1. A moderate, normocytic and normochromic anaemia is often
present.
2. Serum iron and TIBC are low but marrow iron stores are normal or
increased.
3. Marrow infiltration by the disease may produce marrow failure with
leucoerythroblastic reaction.
4. Routine blood counts reveal moderate leukaemoid reaction.
5 Platelet count is normal or increased.
6. ESR is invariably elevated.
Immunologic abnormalities
1. There is progressive fall in immunocompetent T-cells with defective
cellular immunity. There is reversal of CD4: CD8 ratio and anergy to
routine skin tests.
2. Humoral antibody production is normal in untreated patients until
late in the disease.

STAGING
• Extent of involvement of the disease (i.e. staging) is studied
in order to select proper treatment and assess the
prognosis.
• Ann Arbor staging classification takes into account both
clinical andpathologic stage of the disease.
• The suffix A or B are added to the above stages depending
upon whether the three constitutional symptoms (fever,
night sweats and unexplained weight loss exceeding 10% of
normal) are absent (A) or present (B).
• The suffix E or S are used for extranodal involvement and
splenomegaly respectively.

Ann Arbor staging classification of
Hodgkin’s disease

For complete staging, a number of other essential diagnostic
studies are recommended. These are as under:
1. Detailed physical examination including sites of nodal
involvement and splenomegaly.
2. Chest radiograph to exclude mediastinal, pleural and lung
parenchymal involvement.
3. CT scan of abdomen and pelvis.
4. Documentation of constitutional symptoms (B symptoms).
5. Laboratory evaluation of complete blood counts, liver and
kidney function tests.
6. Bilateral bone marrow biopsy.
7. Finally, histopathologic documentation of the type of
Hodgkin’s disease.
More invasive investigations include lymphangiography of
lower extremities and staging laparotomy.

PROGNOSIS
• With use of aggressive radiotherapy and chemotherapy, the
outlook for Hodgkin’s disease has improved significantly.
”
. Patients with lymphocyte-predominance type of HD tend to
have localised form of the disease and have excellent
prognosis.
”
. Nodular sclerosis variety too has very good prognosis but
those patients with larger mediastinal mass respond poorly
to both chemotherapy and radiotherapy.
”
. Mixed cellularity type occupies intermediate clinical position
but patients with disseminated disease and systemic
manifestations do poorly.
”
. Lymphocyte-depletion type is usually disseminated at the
time of diagnosis and is associated with constitutional
symptoms. These patients usually have the most
aggressive form of the disease.

NON-HODGKIN’S LYMPHOMAS-LEUKAEMIAS
• Non-Hodgkin’s lymphomas (NHLs) and
lymphoid leukaemias comprise a large group
of heterogeneous of neoplasms of lymphoid
tissues and blood.
• NHLs have several types and are far more
common (62%) than HD (8%).

Contrasting features of Hodgkin’s disease and non-
Hodgkin’s lymphoma

Diseases of white blood cells, lymph nodes, spleen, and thymus

Diseases of white blood cells, lymph nodes, spleen, and thymus

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