Lymphomas

Principles of diagnosis and management

Harry Gill, MBBS, MD, FRCP, FRCPath

 Principles of diagnosis,
investigations and
management of lymphomas
Introduction – a simplified definition

⎼ Lymphoma = neoplasm of the lymphoid system

(lymphoid organs/ cells of B-, T- or NK- origin)
⎼ In general, lymphoma usually refers to mature
lymphoid neoplasm
⎼ The accurate diagnosis of lymphoma requires
integration of clinical, morphologic,
immunophenotypic, and genetic features
Jeremy S. Abramson, David T. Yang, 2019, Non-
Hodgkin lymphomas, American Society of
Hematology Self-Assessment Program,
Seventh Edition
Jeremy S. Abramson, David T. Yang,
2019, Non-Hodgkin lymphomas,
American Society of Hematology Self-
Assessment Program, Seventh Edition
 A practical classification of lymphoma

Lymphoma

B-cell lymphomas NK/T cell

T-cell lymphomas Hodgkin lymphoma
and B-LPDs lymphomas

Low-grade B-cell
High-grade B-cell Nodular lymphocyte
lymphomas / B-
lymphomas Classical Hodgkin predominant
LPDs
e.g. DLBCL, Burkitt lymphoma Hodgkin lymphoma
e.g. FL, MZL, CLL,
lymphoma, MCL (very rare)
MCL, WM

Don’t attempt to recite the WHO classification – it is beyond your scope !

Risk factors in the development of lymphomas

Viral infections
o EBV, HTLV-1, HHV-8, HCV
Bacterial infection
o Helicobacter pylori
o Chalmydia psittaci
Impaired/altered immunity
o Congenital immunodeficiency
o Acquired immunodeficiency - HIV, organ or stem cell
transplantation, aging, chronic immunosuppressive drugs
o Autoimmune - RA, SLE, Sjögren syndrome, celiac disease
Environmental/occupational
Principles of diagnosis of lymphomas

⎼ Accurate history taking and physical examination

⎼ Proper tissue diagnosis
⎼ An adequate biopsy of the representative site is
essential for histologic, immunohistochemical and
genetic assessment
⎼ Simple cytological assessment (e.g. fine-needle
aspirations) are NOT acceptable
Investigations for lymphomas - aims

1. Accurate diagnosis
2. Staging
3. Detect complications of lymphoma
4. Determine prognosis
5. Determine suitability or fitness for treatment
6. Detecting complications of treatment
7. Assessing response to treatment
Investigations in lymphomas
⎼ Complete blood count
⎼ Liver and renal function tests
⎼ Serum electrolytes (Na, K, Ca, PO4)
⎼ LDH and urate levels
⎼ CXR (to look for disease-related complications, active or prior
infections)
⎼ ESR (prognostic marker for early stage cHL)
⎼ SPE
⎼ β2-microglobulin (prognostic marker for follicular lymphoma)
⎼ Bone marrow aspiration and trephine biopsy (for staging)
⎼ Whole body 18-FDG positron emission tomography- computerized
tomography (PET-CT) (for staging)
Staging of lymphomas – Ann Arbor Staging
Investigations
⎼ ECG and transthoracic echocardiogram (risk of
cardiotoxicity with anthracyclines)
⎼ Lung function studies (risk of pulmonary fibrosis with
bleomycin)
⎼ Hepatitis B and C serology (risk of reactivation upon
immunosuppression)
⎼ HIV serology (Lymphomas may be a presenting feature
of HIV AIDS)
⎼ G6PD assay (risk of oxidative hemolysis with
Co-trimoxazole)
Principles of management of lymphomas
⎼ Multi-agent cytotoxic chemotherapy +/- monoclonal antibodies (e.g. anti-
CD20 in CD20+ B-cell lymphomas)
⎼ Targeted therapy (BTK or BCL-2 inhibitors) in specific B-LPDs
⎼ Multiple cycles of chemotherapy with interim and end-of-treatment
assessment by imaging +/- biomarkers
⎼ The use of immuno-conjugates, checkpoint inhibitors, bi-specific antibodies
for certain subtypes of lymphoma
⎼ Supportive care with the prevention of tumour lysis syndrome and
management of disease/treatment complications
⎼ HSCT (autologous HSCT, in general) is reserved for selected relapsed
patients who are chemo-sensitive
⎼ Chimeric antigen receptor T (CART) cell therapy for specific subtypes of B
lymphomas (e.g. R/R DLBCL)
Monoclonal antibody against CD20

Maloney DG. N Engl J Med 2012; 366;21: 2009-2016

Anti-CD30 immunoconjugate
Immune check-points and their inhibition

Nishino M el al. Nat Rev Clin Oncol 2017; 14: 655-668

PD-L1 and PD-1 inhibition
Important subtypes of
lymphomas and
lymphoproliferative
disorders
Hodgkin Lymphoma
• 10% of all lymphoma cases
• bimodal age distribution with one peak in the early 20s and
the second in the mid-70s.
• Slight male predominance
• Usually presents with painless lymphadenopathy involving
the neck and chest.
• Systemic symptoms of fevers, night sweats, and
unexplained weight loss may occur in patients with
advanced-stage disease
• majority of patients cured with combination chemotherapy
with or without radiation
Hodgkin lymphoma - pathology
• Monoclonal lymphoid neoplasm derived from B cells
• Two distinct entities, classical Hodgkin lymphoma (cHL) (95% of
cases) and nodular lymphocyte-predominant Hodgkin lymphoma
(NLPHL)
• Within classical cHL, there are four histologic subtypes: nodular
sclerosis (NS), mixed cellularity (MC), lymphocyte rich (LR), and
lymphocyte depleted (LD).
• Hallmark of cHL =Hodgkin Reed-Sternberg (HRS) cell
• NS cHL: 70% of cases; M/F equally affected; Typical age of
presentation of NS cHL=15-35
• Mediastinal involvement, which may be bulky, is more common in
NS cHL
Diffuse large B-cell lymphoma (DLBCL)
• DLBCL is composed of large B cells with a diffuse
growth pattern
• Subclassification – molecular (GCB / ABC);
pathologic; defined disease entities (e.g. primary
CNS DLBCL, primary mediastinal large B-cell
lymphoma)
• 30% of all NHLs
• present with nodal (more common) or extranodal
disease.
• BM involvement <10% of cases
DLBCL con’t
• In general, approximately two-thirds of patients are
cured
• Prognostic factors – clinical (IPI), biologic (genetic
subtype, MYC rearrangement)
• Backbone of treatment is R-CHOP
• Novel approaches for adverse biologic subtypes
(MYC and BCL2 and/or BCL6)
• Auto-HSCT for chemosensitive relapse
• Allogeneic HSCT not routinely done
• CAR T-cell therapy for R/R CD19+ DLBCL
Burkitt lymphoma (BL)
• Most aggressive of all human malignancies
• Rapid doubling time, acute onset and progressive
• Deregulated high-level expression of cMYC arising from
reciprocal translocation with immunoglobulin-heavy t(8;14)
or variant light-chain gene loci t(2;8) or t(8;22)
• Frequently present with a bulky abdominal mass, B-
symptoms and extranodal disease, including BM
involvement (up to 70%).
• Leptomeningeal involvement, may be present at diagnosis
in up to 30% of patients
Burkitt lymphoma

• Urgent treatment required

• Prevention of tumour lysis syndrome
• Rituximab + multi-agent chemotherapy
• Good prognosis with cure in > 80%
Follicular lymphoma

• Prototypical and most common indolent

lymphoma
• Limited-stage (Ann Arbor I or II) FL is relatively
uncommon
• Most patients diagnosed at advanced stage
• Prognosis favourable with anti-CD20 + purine
analogue/alkylating agent based therapy
Chronic lymphocytic leukaemia / small lymphocytic lymphoma

• CLL/SLL is the most prevalent lymphoid malignancy in North America and

Europe and is less common among people of African or Asian origin
• Median age 72 years
• M:F = 2:1
• CLL, including the SLL variant, is usually diagnosed on evaluation of an
incidental finding of asymptomatic
• Leukocytosis/lymphocytosis or lymphadenopathy/splenomegaly.
• Only ~20% of patients have symptomatic disease at diagnosis.
• CLL can present with symptomatic anemia, bleeding due to
thrombocytopenia, symptomatic adenopathy or splenomegaly (abdominal
distention or early satiety), or constitutional symptoms.
• Binet staging / Rai Staging
Extranodal NK/T cell lymphoma
NK/T-cell lymphomas
⎼ Geographical predilection for Asian and South American populations and
rare in other countries
⎼ Commonly a locally invasive disease destroying nasal and midline facial
structures
⎼ Other non-nasal sites that may be involved include skin, GI tract, CNS and
testes
⎼ Primary nodal presentation is rare
⎼ Aggressive NK-cell leukaemia/lymphoma is a rare presentation with fever,
rash, hepatosplenomegaly, pancytopenia and hemophagocytosis
⎼ An EBV-driven lymphoma
⎼ Treatment involves multi-agent chemotherapy comprising steroids,
ifosfamide, cisplatin, L-asparaginase, etoposide
Case scenarios
Case 1

• M/62
• Complained of easy bruising for 2 week
• P/E: generalized enlargement of LN (2-3cm),
palpable hepatosplenomegaly.
• CBC showed WBC 9.5 x 109 / L (N: 3.89-
9.93); Hb 12.2g/dL (N: 13.3-17.1); Platelet
count 3 x 109 / L (N:167-396)
• LDH 550 U/L
Case 1 – peripheral blood film
Case 1
• Numerous “smear” or “smudge” cells
• Abnormal small-to-medium sized lymphoid cells
with high N/C ratio, round nuclei, condensed
chromatin, no nucleoli and smooth cytoplasmic
border
• Little polychromasia and no spherocytes. No
“rouleaux” formation
• Genuine thrombocytopenia with no clumps.
Occasional giant platelets
Case 1
• Multiparametric flow cytometry – abnormal lymphoid cells light
chain-restricted expressing CD19, CD5, CD23, CD20 (dim),
surface Ig (dim), CD79b (dim). T-cell and NK cell markers negative
• BMA + trephine – heavy infiltration by abnormal lymphoid cells with
the identical immunophenotype. Megakaryocytic hyperplasia.
• CG – normal karyotype
• FISH – del(17p) consistent with TP53 loss
• Platelet serology: Ab vs GpIb/IX and GpIIb/IIIa +
• PET-CT – generalized LN and hepatosplenomegaly of “low grade”
SUVmax uptake
Case 1

• CLL - Binet stage C

• Adverse risk due to TP53 loss
• Started ibrutinib (BTK inhibitor) with initial
response but progressed after 6 months
• Did not response – given salvage treatment
with obinutuzumab and venetoclax (bcl-2
inhibitor) and achieved CR
Case 2
⎼ A 63 year-old man presented with weight loss and
rapidly enlarging bilateral cervical lymph nodes for 1
month
⎼ He had history of hypertension since the age of 50
that was well-controlled with one anti-hypertensive
⎼ Physical examination showed bilateral multiple firm
and non-tender cervical lymph nodes of 3-5cm in
size.
⎼ CBC, LRFT and serum electrolytes were normal
⎼ LDH and urate levels were grossly elevated
Diagnostic investigation - histology

1. Effaced nodal architecture

2. Sheets of large abnormal
lymphoid cells
3. Immunohistochemistry showed
CD19+, CD20+, CD79a+,
PAX5+. T-cell and NK cell
markers were negative

Consistent with DIFFUSE LARGE

B-CELL LYMPHOMA
Case 2 cont’d

⎼ PET-CT showed hypermetabolic LN in bilateral cervical,

thoracic and intraabdominal regions
⎼ BM biopsy – Not involved by lymphoma
⎼ Ann-Arbor Stage IIIB disease
⎼ ECG and Echocardiogram showed normal findings
⎼ CXR was clear
⎼ HBsAg positive, anti-HCV negative, anti-HIV 1/2 ab
negative
⎼ HBV DNA undetectable
⎼ G6PD normal
Case 2 cont’d

⎼ Patient started on entecavir prophylaxis

⎼ DLBCL was treated with R-CHOP
⎼ R=Rituximab; C=cyclophosphamide;
H=doxorubicin (hydroxyl-daunorubicin);
O=vincristine (Oncovin); P=prednisolone

What are the mechanisms of action and side-effects of each of the drugs in the regimen R-CHOP?
Case 2 cont’d

⎼ Patient achieved complete response (CR) after

3 cycles of R-CHOP

⎼ Completed 6 cycles of R-CHOP and remained in

CR
Case 3
⎼ A 35 years-old woman presented with dry cough for 2
months associated with fever and night sweats. Recent
loss of appetite and weight loss of 10kg over 2 months
⎼ She was a non-smoker with good past health
⎼ Physical examination showed a 3-cm palpable left
supraclavicular fossa lymph node that was rubbery in
consistency.
⎼ The liver and spleen were not palpable.
⎼ CVS and Resp exam were unremarkable
⎼ No upper limb or facial swelling
Mediastinal mass
Differential diagnoses:
1. LN – lymphoma /
metastatic LN
2. Thymoma
3. Germ cell tumour
4. Others – retrosternal
goitre, dilated aortic
arch, neurofibroma
Case 3 – CT thorax
Diagnostic investigation - histology
Excisional biopsy of L SCF LN:
1. Distorted nodal architecture with thick fibrotic
bands
2. Typical multinucleated Reed-Sternberg cells
were present
3. Prominent infiltration by inflammatory cells
(reactive lymphocytes, eosinophils and
plasma cells)
4. CD20 negative, CD15+, CD30+, T- and NK-
cell markers negative

CD15 CD30
Case 3 cont’d
⎼ Dx = Nodular Sclerosis Classical Hodgkin Lymphoma
⎼ Ann Arbor Stage IIB
⎼ CBC showed eosinophilia
⎼ LRFT was normal, serum electrolytes were normal
⎼ LDH and urate levels were elevated
⎼ Baseline ECG, echocardiogram, lung function studies were normal
⎼ HBsAg negative, anti-HBs positive, anti-HBc negative, anti-HCV ab
negative, anti-HIV 1/2 ab negative
⎼ Patient underwent oocyte preservation before starting chemotherapy
with Adriamycin, Bleomycin, Vinblastine and Dacarbazine (ABVD)
Case 3 cont’d

⎼ Cycle 1 ABVD started with adequate hydration and

febuxostat (xanthine oxidase inhibitor)
⎼ CBC and LRFT monitored regularly in between cycles
⎼ No cardiac or resp symptoms during treatment
⎼ Interim assessment PET-CT after 2 cycles of ABVD
showed complete response (CR)
⎼ Complete 4 cycles of ABVD and end-of-treatment PET-
CT showed continual remission
What are the mechanisms of action and side-effects of each of the drugs in the regimen ABVD?
Case 3 cont’d

⎼ Unfortunately, the patient had relapsed disease 8

months after remission with nodal involvement at
bilateral cervical, mediastinal, and intraabdominal
lymph nodes on PET-CT
⎼ Re-biopsy of the cervical LN confirmed recurrent
Classical Hodgkin Lymphoma, nodular sclerosis type.
⎼ This patient was started on the immuno-conjugate
Brentuximab vedotin (anti-CD30 monoclonal ab linked
to MMAE)
Case 3 cont’d

⎼ After 3 cycles of Brentuximab vedotin, the

patient failed to achieve a response

⎼ This patient was started on the check-point

inhibitor pembrolizumab (anti-PD1) as salvage
treatment
Case 3 cont’d

⎼ The patient achieved complete response after

4 cycles of pembrolizumab and treatment was
continued
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