The Lymphoproliferative

disorders
By
Dr. Esmail Husein Feyte,
MB,ChB (Yemen),
MRCP (UK),
MSc In Internal Medicine (Ain shams
University, Egypt),
Egyptian fellowship board in Hepato-
Gastroenterology.
 Definition of CLPDs
 Chronic Lymphoproliferative Disorders (CLPDS) are
a heterogeneous group of malignancies characterized by
the proliferation of mature B and rarely T lymphoid
cells in the peripheral blood, bone marrow and/or
lymph nodes/spleen and other lymphoid tissues.
 Mature B-, T-/NK neoplasms can be further segregated
into disorders likely to exhibit primary
manifestations in blood and bone marrow (ie, chronic
leukemias) compared with mature neoplasms that
predominate in extramedullary sites but may involve
blood or bone marrow more typically as a secondary
event (B-, T-/NK- lymphomas).
CLPDs
 Workup of LPDs
1. Clinical history with reference to B Other tests:
symptoms and family history Neck CT
2. Physical examination with particular Head CT or magnetic resonance
attention to node-bearing areas, imaging (MRI)
Waldeyer’s ring, and size of liver and PET scan
spleen
Coagulation screen
3. FBC, differential and film DAT
4. ESR Serum immunoglobulins/electrophoresis
5. LDH, urea and electrolyte, creatinine, Beta 2 microglobulin
albumin, aspartate transaminase (AST),
bilirubin, alkaline phosphatase, serum
CRP
calcium, uric acid Tissue transglutaminase test (tTG) to
exclude coeliac disease
6. LN (tissue) biopsy
EBV, HTLV serology
7. Chest and abdominopelvic computed
tomography (CT) FISH or PCR on involved
marrow/blood for specific lymphoma-
8. Bone marrow aspirate and trephine associated translocations and molecular
9. Immunophenotyping of marrow +/- markers
blood Echo and PFTs
10. Hepatitis B and C and HIV status Lumbar puncture
The Lympho-proliferative disorders

The Lympho-proliferative disorders include:

1) Chronic lymphocytic leukaemia (CLL)
2) Lymphoma
 Hodgkin’s lymphoma (HL)
 Non-Hodgkin’s lymphoma
 Chronic lymphocytic leukaemia (CLL)

 CLL is caused by a monoclonal proliferation of well-

differentiated lymphocytes which are almost always B-
cells (99%).
 CLL is the commonest leukaemia found in adults
(>25%; incidence: ~5/100 000/yr).
 M:F≈2:1.
 Generally, affects older populations (The median age at
diagnosis is 72 years)
 The hallmark is progressive accumulation of a malignant
clone of functionally incompetent B cells.
 CLL manifestations
Symptoms:
1) Often none.
2) Presenting as a surprise finding on a routine FBC.
3) Constitutional: Anorexia, weight loss & sweats
4) Patients may be bleeding, anaemic or infection-prone.
Signs:
1. Enlarged, rubbery, non-tender lymphadenopathy
more marked than CML.
2. Splenomegaly,
3. Hepatomegaly.
Bilateral cervical lymphadenopathy in CLL.
 Complications
1) Recurrent bacterial infections due to
hypogammaglobulinaemia (=↓IgG), especially encapsulated
organisms (bacterial Infections are the most frequent
complication causing death in patients with CLL).
2) Severe T cell immunosuppression with increased susceptibility
to viral (eg herpes zoster) and fungal infections.
3) Autoimmune complications are common with CLL:
 Warm autoimmune haemolytic anaemia in 10-15% of patients
{the combination of spherocytes with a raised bilirubin, LDH and
positive direct Coombs' test is consistent with an autoimmune
haemolysis}.
 Immune thrombocytopenia (ITP)
4) Marrow failure
5) Increased risk of secondary malignancies.
6) Risk of Transformation to high-grade lymphoma (Richter's
transformation)
 Investigations
1. CBC:
 Elevated Lymphocytes—may be marked.
 Later: autoimmune haemolysis,
 Marrow infiltration: low Hb, low neutrophils and low platelets.
2. Blood film:
 Smudge cells (also known as smear cells): smudge cells are the artifacts
produced by the lymphocytes damaged duringthe slide preparation
 ≥ 5000 monoclonal B lymphocytes/μl persisting for longer than
3 months.
3. Immuno-phenotyping:
 Peripheral blood flow cytometry is the most valuable test to
confirm a diagnosis of CLL.
 Will demonstrate the cells to be B-cells and T-cells.
 CLL cells co-express the T-cell antigen CD5 and B-cell surface
antigens CD19, CD20, and CD23.
 Investigations
4) Direct antiglobulin test in case of AIHA
5) Fluorescence in situ hybridization (FISH) to detect
del(11q); del(13q); del(17p)
6) Molecular analysis to detect immunoglobulin heavy
chain region (IgV H) mutation status
7) Determination of CD38 and ZAP-70 expression by flow
cytometry
8) Abdominal US
9) CT scans
10) Bone marrow aspirate
11) PET/CT only if transformation suspected
Staging and survival in CLL
 Treatment of CLL
1) Asymptomatic: Observation policy ‘watch and wait’ is usual
during the early stages of the disease.
2) If symptomatic: Consider drugs treatment:
 Fludarabine, cyclophosphamide and rituximab (FCR) has now
emerged as the initial treatment of choice for the majority of patients
(there is synergism).
 Ibrutinib (Bruton tyrosine kinase inhibitor)
monotherapy, venetoclax (BCL- 2 inhibitor) +
obinutuzumab, and BR (bendamustine +
rituximab).
 Steroids and IV immunoglobulin help autoimmune
haemolysis (seen after treatment with fludarabine).
3) Radiotherapy: Helps lymphadenopathy and splenomegaly.
4) Stem-cell transplantation may have a role in carefully selected
patients.
5) Supportive care: Transfusions, IV human immunoglobulin if
recurrent infection ± antimicrobial prophylaxis.
 Indications for treatment in CLL
1. Progressive marrow failure: The development or worsening
of anaemia and/or thrombocytopenia
2. Lymphocyte doubling time of less than 12 months
3. Massive (>10 cm) or progressive lymphadenopathy
4. Massive (>6 cm) or progressive splenomegaly
5. Progressive lymphocytosis: > 50% increase over 2 months or
lymphocyte doubling time < 6 months.
6. Immune complications, for example, ITP, autoimmune
haemolysis
7. Systemic symptoms: (Disabling B symptoms)
 Weight loss > 10% in previous 6 months,
 Fever >38 C for > 2 weeks,
 Extreme fatigue,
 Night sweats
 Natural history of CLL

 ⅓ never progress (or even regress),

 ⅓ progress slowly,
 ⅓ progress actively.
 CD23 and B-2 microglobulin correlate with bulk of
disease and rates of progression.
 CD38 expression positive and deletions of part of the
short arm of chromosome 17 (del 17p) are poor
prognostic factors.
 Death is often due to infection or transformation to
aggressive lymphoma (Richter’s syndrome).
 Lymphomas
Lymphomas are disorders caused by malignant
proliferations of lymphocytes.
These accumulate in the lymph nodes causing
lymphadenopathy, but may also be found in peripheral
blood or infiltrate organs.
 Lymphomas are histologically divided into
Hodgkin’s and non- Hodgkin’s types.
 Hodgkin's lymphoma (HL)
 Hodgkin's lymphoma is a malignant proliferation of
lymphocytes.
 In Hodgkin’s lymphoma, characteristic cells with mirror-
image nuclei are found, called Reed–Sternberg cells.
 Haematological malignancy arising from mature B cells.
 Lymphadenopathy, typically painless and most commonly
involving the cervical and/or supraclavicular nodal chain, is
the most common presenting symptom of HL.
 Hodgkin's lymphoma (HL)

Incidence: Two peaks: young adults (HL is the

commonest malignancy in 15–24yr olds) and elderly.
M:F ≈ 2:1.
Risk factors
1. History of EBV infection
2. Family history of Hodgkin's lymphoma
3. Young adults from higher socio-economic class
4. Immunodeficiency: e.g., organ or cell transplantation,
immunosuppressants, HIV infection , chemotherapy
5. Autoimmune diseases (e.g., rheumatoid arthritis,
sarcoidosis, SLE)
 Features of HL
1) Painless lymphadenopathy: Often presents with enlarged, non-
tender, ‘rubbery’ superficial lymph nodes (60– 70% cervical, also
axillary or inguinal).
2) Mediastinal lymph node involvement can cause mass effect, eg bronchial or
SVC obstruction, or direct extension, eg causing pleural e!usions.
3) Splenomegaly or hepatomegaly may occur if the spleen or liver are
involved.
4) Constitutional B symptoms (25%).
 Night sweats,
 Weight loss > 10% in the past 6 months,
 Fever > 38°C (100.4°F)
 Lethargy.
5) Pel-Ebstein fever: Intermittent fever with periods of high temperature for 1–2
weeks, followed by afebrile periods for 1–2 weeks. Relatively rare but very specific
for HL.
6) There may be alcohol- induced lymph node pain.
7) Pruritus (focal or generalized)
8) Emergency presentations Infection; SVC obstruction— Raised JVP,
sensation of fullness in the head, dyspnoea, blackouts, facial oedema.
 Investigations of HL

1. Tissue diagnosis: Lymph node excision biopsy if

possible (supraclavicular > cervical/axillary >
inguinal; send for pathology, immunohistochemisty/
flow cytometry). Image-guided needle biopsy,
laparotomy, or mediastinoscopy may be needed.
2. Bloods: FBC, blood film, ESR, LFT, LDH, urate,
Ca2+. High ESR or low Hb indicate a worse
prognosis.
3. Imaging: CXR, CT/PET of thorax, abdo, and pelvis.
Chest x ray showing a left-sided anterior–
superior mediastinal mass
CT/PET of thorax
WHO pathological classification of Hodgkin
lymphoma (HL)
Histological classification of HL
 Staging of HL
Ann-Arbor staging of Hodgkin's lymphoma:
Influences treatment and prognosis.
I: Involvement confined to single lymph node region
II: Involvement of 2 or more lymph nodes/regions on same
side of diaphragm.
 III: Involvement of lymph nodes on both sides of the
diaphragm (Spleen is regarded as a Lymph Node region,
So lymphoma with splenomegaly → Stage III).
IV: Spread beyond the lymph nodes, eg liver or bone
marrow.
Each stage may be subdivided into A or B
 A = no systemic symptoms other than pruritus
 B = weight loss > 10% in last 6 months, fever > 38c, night
sweats (poor prognosis).
Clinical stages of Hodgkin lymphoma (Ann
Arbor classification)
 Management of HL:
1. Radiotherapy + short courses of chemotherapy for stages I-A or
II-A with ≤3 areas involved.
2. Longer courses of chemotherapy for II- A with >3 areas involved
through to IV- B.
3. Large mass in chest regardless of stage: Radiotherapy and
chemotherapy.
 Chemotherapy includes: ABVD: Adriamycin (also known as
Doxorubicin), Bleomycin, Vincristine, Dacarbazine cures ~80% of
patients.
 More intensive chemotherapy regimens are used if poor prognosis or
advanced disease Eg BEACOPP (bleomycin/ etoposide/ doxorubicin/
cyclophosphamide/ vincristine/ procarbazine/ prednisone).
4. In relapsed Hodgkin lymphoma: Salvage chemotherapy (High-
dose chemotherapy) followed by autologous stem cell
transplantation.
5. Brentuximab vedotin + doxorubicin, vinblastine, and dacarbazine
(BV + AVD) is a promising new combination chemotherapy.
 Complications of treatment:
1. Radiotherapy may increase risk of second
malignancies—Solid tumours (especially lung and
breast, also melanoma, sarcoma, stomach and
thyroid cancers), ischaemic heart disease,
hypothyroidism, and lung fibrosis due to the
radiation field.
2. Chemotherapy SE include myelosuppression,
nausea, alopecia, infection.
3. AML , non-Hodgkin’s lymphoma, and infertility
may be due to both chemo- and radiotherapy.
 Poor prognosis
1) Weight loss > 10% in last 6 months
2) Fever > 38 C
3) Night sweats
4) Other factors associated with a poor prognosis identified in a
1998 NEJM paper included:
1. Age > 45 years
2. Stage IV disease
3. Haemoglobin < 10.5 g/dl
4. Lymphocyte count < 600/l or < 8%
5. Male
6. Albumin < 40 g/l
7. White blood count > 15,000/l
8. A mass of >10 cm in size
 Non-Hodgkin's lymphoma (NHL)

 Non-Hodgkin lymphoma (NHL) represents a monoclonal

proliferation of lymphoid cells of B-cell (90%) or T-cell (10%)
origin.
 This includes all lymphomas without Reed–Sternberg cells
(except Hodgkin’s lymphomas).
 Subtypes of non-Hodgkin's lymphoma (NHL):
Diffuse large B-cell lymphoma is commonest
Burkitt lymphoma.
 Not all centre on nodes (extranodal tissues generating
lymphoma include mucosa-associated lymphoid tissue, eg
gastric MALT).
 Causes of NHL
1. Immunodeficiency drugs;
2. HIV (usually high-grade lymphoma from EBV
transformed cells);
3. HTLV-1,
4. H. pylori ;
5. Toxins;
6. Congenital.
 Signs and symptoms
1) Superficial lymphadenopathy (75% at presentation).
2) Extranodal disease (50%):
 Gut (commonest):
1. Gastric MALT is caused by H. pylori, and may regress with its eradication.
Symptoms: as for gastric Ca, with systemic features . MALT usually involves the
antrum, is multifocal, and metastasizes late.
2. Non-MALT gastric lymphomas (60%) are usually diffuse large-cell B
lymphomas—high-grade and not responding well to H. pylori eradication.
3. Small-bowel lymphomas eg IPSID (immunoproliferative small intestine
disease), or EATCL (enteropathy/coeliac-associated intra-epithelial T-cell
lymphoma)— presents with diarrhoea, vomiting, abdominal pain, and weight
loss. Poor prognosis.
 Skin: (2nd commonest) Eg clonal T cells in mycosis fungoides (accounts
for ~50%).
 Oropharynx: Waldeyer’s ring lymphoma causes sore throat/obstructed
breathing.
 Other possible sites: Bone, CNS, and lung.
3) Systemic features—fever, night sweats, weight loss (less common than in
Hodgkin’s lymphoma, and indicates disseminated disease).
4) Pancytopenia from marrow involvement—anaemia, infection, bleeding
(low platelets).
Generally Non-Hodgkin lymphomas are Classified as:

1. Low-grade lymphomas are indolent, often incurable and

widely disseminated.
 Low-grade lymphomas Includes: Follicular lymphoma
(2nd most common NHL— 20%), marginal zone
lymphoma/MALT, lymphocytic lymphoma (closely related
to CLL and treated similarly), lymphoplasmacytoid
lymphoma (produces IgM = Waldenström’s
macroglobulinaemia).
2. High-grade lymphomas are more aggressive, but often
curable. There is often rapidly enlarging
lymphadenopathy with systemic symptoms.
 High-grade lymphomas Includes: Burkitt’s lymphoma
(childhood disease with characteristic jaw lymphadenopathy),
lymphoblastic lymphomas (like ALL), diffuse large B-cell
lymphoma (most common subtype NHL— 25%).
 Investigations
1) Blood: FBC, U&E, LFT. High LDH ≈ worse prognosis, reflecting increased
cell turnover.
2) Bone marrow aspiration and trephine to identify bone marrow involvement.
3) Lymph biopsy: Excision biopsy, if not surgically feasible → needle core
biopsy procedure
4) Immunophenotyping of surface antigens to distinguish T-cell from B-cell
tumours. This may be done on blood, marrow or nodal material.
5) Cytogenetic analysis to detect chromosomal translocations.
6) Immunoglobulin determination (Some lymphomas are associated with IgG
or IgM paraproteins, which serve as markers for treatment response).
7) Measurement of urate levels (Some very aggressive high-grade NHLs are
associated with very high urate levels, which can precipitate renal failure when
treatment is started as a consequence of tumour lysis syndrome).
8) HIV testing (HIV is a risk factor for some lymphomas and affects treatment
decisions).
9) Hepatitis B and C testing (should be done prior to therapy with rituximab).
10) Staging: Ann Arbor system —CT ± PET of chest, abdomen, pelvis.
 Treatment of NHL
1) Low grade:
Asymptomatic patients may not require therapy and are managed
by ‘watching and waiting’.
Radiotherapy may be curative in localized disease.
Chlorambucil is used in diffuse disease.
Remission may be maintained by using interferon alfa or
rituximab.
Bendamustine is effective both with rituximab and as a
monotherapy in rituximab- refractory patients.
2) High grade: (eg large B-cell lymphoma, DLBCL), ‘R-CHOP’
regimen: Rituximab, Cyclophosphamide, Hydroxy daunorubicin,
vincristine (Oncovin®) and Prednisolone.
3) Granulocyte colony-stimulating factors (G-CSFs) help
neutropenia—eg filgrastim or lenograstim.
Haematological malignancies: infections
1. Viruses
I. EBV: Hodgkin's and Burkitt's lymphoma,
nasopharyngeal carcinoma
II. HTLV-1: Adult T-cell leukaemia/lymphoma
III. HIV-1: High-grade B-cell lymphoma
2. Bacteria
 Helicobacter pylori: Gastric lymphoma (MALT)
3. Protozoa
 Malaria: Burkitt's lymphoma
 Haematological malignancies: genetics
 Below is a brief summary of the common translocations associated
with haematological malignancies:
1) t(9;22) - Philadelphia chromosome
 Present in > 95% of patients with CML
 Poor prognostic indicator in ALL
2) t(15;17)
 Seen in acute promyelocytic leukaemia (M3)
 Fusion of PML and RAR-alpha genes
3) t(1:14): This translocation is associated with MALT (mucosa-associated
lymphoid tissue) lymphoma and deregulates BCL10
4) t(8;14)
 Seen in Burkitt's lymphoma
 MYC oncogene is translocated to an immunoglobulin gene
5) t(11;14)
 Mantle cell lymphoma
 Deregulation of the cyclin D1 (BCL-1) gene
6) t(11; 18): This translocation is associated with MALT (mucosa-associated
lymphoid tissue) lymphoma and deregulates MALT1
7) t(14;18): This translocation is associated with follicular lymphoma
Thank you