Lymphomas int.med.

Lymphomas
Dr. Kasereka Kamabu Larrey, MMEN, I
MAKERERE UNIVERSITY
17th July 2020

Plan
• Introduction:
– Definition & Classification
– Etiology and Epidemiology
• Hodgkin lymphomas
• Overview on Non-Hodgkin lymphomas.
• Common NHL:
– DBCL, BL, LBL, ALCL, Follicular lymphoma, Mantle cell
lymphoma, MALT type lymphoma.

Definition and classification
• Lymphoma is a primary malignant process of
the lymphatic system.
• Classifications:
-Hodgkin lymphoma (HL)
-Non-Hodgkin lymphoma (NHL).

Updated classification of aggressive lymphomas

Etiology and epidemiology
• Hodgkin lymphoma:
– B-cell origin (preponderance of evidence).
– More common in M>>F, White >> Blacks
– A bimodal distribution of age at diagnosis :
• one peak incidence occurring in patients in their
twenties and the other in those in their eighties.
– Risk factors:
• HIV infection,
• EBV infection

• Non-Hodgkin’s lymphomas:
– B-cell or T-cell origin.
– ↑incidence rate of 2-8% per year globally.
– More frequent in elderly and in men.
– D/ses associated with increased risk:
• Primary or secondary immunodepression.
• H/o organ transplantation.
• Sicca syndrome
• Autoimmune d/se: Rhumatoid arthritis, SLE,…

• Non-Hodgkin’s lymphomas:
– Environmental factors:
• Infectious agents (HTLV-1, EBV, H.Pylori, Hepatitis C, .…)
• Chemical exposure (eg. Agricultural chemicals).
• Medical treatments (eg. Prior chemotherapy and
radiation therapy)

• In Uganda, the most common lymphomas:
– pediatric (age <15 yr):
• Burkitt’s lymphoma, followed by lymphoblastic lymphoma.
– For adolescents and young adults (age: 15 to 24 yr):
• Hodgkin’s lymphoma was the leading subtype,
• followed by lymphoblastic lymphoma.
– For adults:
• small lymphocytic lymphoma was the most common
subtype,
• followed by Hodgkin’s lymphoma
(Adriane Kamulegeya, 2013)

Immunology
Fig: Pathway of normal B-cell
differentiation and relationship to
B-cell lymphomas.

Immunophenotypic biomarkers
• A number of immunophenotypic biomarkers are routinely used,
including:
– T-cell markers (CD2, CD3, CD4, CD5, CD7, CD8, and T-cell receptors),
– B-cell markers (CD19, CD20, CD22, CD79, and Pax-5),
– cytotoxic markers (such as TIA-1, granzyme B, and perforin),
– germinal center markers (CD10, Bcl-6, and LMO2), and
– plasma cell markers (such as CD38, CD138).
• In addition, certain markers are highly associated with specific
diseases such as:
– CD15, CD30 in classical Hodgkin lymphoma;
– ALK-1, CD30 in anaplastic large cell lymphoma;
– cyclin D1 and SOX-11 in mantle cell lymphoma; and
– follicular T helper cell markers including CXCL13 and PD-1 in
angioimmunoblastic T-cell lymphoma.

2.1. Classification of HL
2 major categories:
• Classic HL (cHL) (90% of HL), with subtypes:
– Nodular sclerosis cHL (NSCHL)
– Mixed cellularity cHL (MCCHL)
– Lymphocyte rich cHL (LRCHL)
– Lymphocyte depleted cHL (LDCHL)
• Nodular lymphocyte predominant HL (NLPHL)

2.2. Clinical presentation
• Generally slow progress.
• Typical presentations (most of patients):
– Asymptomatic lymphadenopathy.
• Neck (60-80%), axillar (≈30%), inguinal (10%), mediastinal
(50-60%), retroperitoneal (30%).
– Mediastinal mass on chest radiograph.
– Constitutional symptoms “B symptoms” (40% of
cases):
• Fever – Persistent temperature >38°C (>100.4°F)
• Sweats – The presence of drenching night sweats
• Weight loss – Unexplained loss of >10 percent of body
weight over the past six months
– Other symptoms (eg, fatigue, pruritus, alcohol-
associated pain)

• Less common presentations (atypical):
– Liver disease.
– Other intra-abdominal disease.
– Skin lesions.
– Bone/marrow involvement.
– Neurologic findings.
– Nephrotic syndrome.
– Isolated laboratories abnormalities:
• Hypercalcemia.
• Anemia
• Eosinophilia.
• Other.

2.3. Evaluation of a patient with HL
• History and physical examination:
– Duration and extend of lymphadenopathy.
– Cough or other respiratory symptoms.
– Unexplained fever, sweating, weight loss, pruritis, and
alcohol induced pain.
– Previous malignancy.
– Prior treatment with chemotherapy or radiotherapy.
– Hiv or other immunosuppressive condition.
– Family h/o lymphoproliferative, myeloproliferative
and other malignancies.

• Physical examination:
– Lymphoid regions (lymph node, splenomegaly,
hepatomegaly, waldeyer ring, …).
– Staging.

• Laboratory studies:
– CBC and ESR.
– Serum chemistries: RFT, LFT, and albumin.
– HIV tests.
• Imaging: for evaluation of organ involvement.
– PET/CT or MRI
– Plain radiograph of the bone.
– Abnormal findings from FNA.

• Pathology:
• The Reed-Sternberg (RS) cell
is pathognomic.
• RS cells surrounded by an
inflammatory infiltrate of
lymphocytes, plasma cells,
and eosinophils.
• Immunophenotype:
Express CD30 and CD15.
but do not express CD45 or
CD3.

• Cytogenetics→Clonal genetic abnormalities.
• Molecular features:
– Immunoglobulin (Ig) and T cell receptor (TCR)
gene rearrangements.
– Mutations.
– Gene expression.

Immunophenotyping in Hodgkin's lymphoma

2.4. Differential diagnosis
• Reactive processes:
– Infectious, autoimmune or various malignant disorders.
• EBV-positive mucocutaneous ulcer
• Nodular lymphocyte-predominant HL
– Mainly reactive B cells.
– B cell Ag (eg. CD20) and absence of CD30 and CD15.
• Anaplastic large cell lymphoma:
– cHL: CD15+, CD30+, PAX/BSAP+, T cell antigens-, ALK-
– ALCL: CD15-, strongly CD30+, PAX5/BSAP-, positive for one or
more T cell antigens, ALK+/-, and positive for cytotoxic markers
(perforin, granzyme B, TIA-1)
• Other B cell lymphomas

2.5. Treatment of cHL
• Primarily guided by the clinical stage.
• Selection of initial treatment for HL is usually
based on presenting stage and and prognostic
factors:

Favorable prognosis
• Early disease (Stage I to II).
• EORTC Criteria:
– age<50, no large mediastinal
adenopathy, ESR<50mm (or
<30mm/h if B symptoms), d/se
limited to ≤3 regions.
• ABVD
(doxorubicin, bleomycin, vinbl
astine, dacarbazine) for 3-4
cycles,
• followed by involved-site
radiation therapy to 30 Gy.
• This approach has the lowest
relapse rate
Unfavorable prognosis
• Early disease (Stage I to II).
• Patients who do not fall into
favorable category.
• ABVD remains the "gold
standard" chemotherapy 4
cycles,
• Plus radiation therapy.

• Advanced stage HL (stage III-IV)
• Combination chemotherapy is the main treatment
for patients with advanced stage HL.
– treatment with brentuximab
vedotin plus doxorubicin, vinblastine, and dacarbazine (BV
+ AVD) >> ABVD.
– Escalated BEACOPP
(bleomycin, etoposide, doxorubicin, cyclophosphamide, vi
ncristine, procarbazine, and prednisone).
• Radiation therapy may be used for selected patients
as consolidation (controversial).

• Long-term complications: they include:
– Second malignancies.
– Cardiac disease.
– Radiation-induced hypothyroidism.

3. Overview on Non-Hodgkin
Lymphomas

• General:
– varies with the histologic subtype and sites of
involvement.
– Typical presentations of an aggressive NHL:
• Rapidly growing mass (eg. LBCL, BL,…) .
• Constitutional symptoms of fever, night sweats or weight
loss; and/or
• Tumor lysis syndrome.
– Indolent lymphomas are often insidious (eg. Follicular
lymphoma).
– A minority of patients initially present with extranodal
lymphoma

• Oncologic emergencies, especially for highly aggressive
lymphomas (eg. BL):
– Spinal cord compression.
– Lymphomatous meningitis and/or CNS mass lesions.
– Airway obstruction , Pericardial tamponade , SVC obstruction
– GIT obstruction or liver failure.
– Hydronephrosis or renal failure
– Tumor lysis syndrome
– Hypercalcemia
– Leukostasis, hyperviscosity syndrome, VTE disease, AIHA, ITP,
cold agglutinin disease.
– Angioedema.

• Abnormal laboratory results, especially
– Hematologic→anemia, thrombocytopenia, leukopenia,
and/or lymphocytosis.
– Hypercalcemia, hyperuricemia.
– Elevated LDH.
– Abnormal serum protein electrophoresis
(SPEP)→Relatively large M-spikes (>0.5 g/dL) .

• Paraneoplastic syndromes : Examples include:
• CNS manifestations,
– eg. Gait instability, visual changes
• Cutaneous manifestations.
– Eg. Sweet syndrome, pruritic or inflammatory seborrheic
keratoses.
• Hematologic manifestations
– Eg. Esosinophilic fasciitis.
• Renal manifestations
– Eg. Membraneous nephropathy, proteinuria,…

3.2. Evaluation of a patient with NHL
• History:
– Peripheral lymphadenopathy
– Systemic B-symptoms.
– PMH: ?d/se, infectious agents, drugs, toxins.
– Associated disorders: autoimmune, ID,
Inflammatory GI d/se.
– Fever of unknown origin.

• Physical examination:
– Lymphoid survey.
– Extranodal sites:
• GIT, skin, testicular NHL,
• Bone (disseminated disease),
• Epidural spinal cord compression.
• CNS exam.
• ?Renal involvement: eg. Ureteral obstruction.

• Imaging:
– To identify sites of lymph
node or organ involvement.
– Ultrasound or CT-guided
biopsy.
– PET/CT imaging.
• Lymph node and tissue
biopsy:
– Lymph nodes (>2 cm,
persistence for >4-6wk,
progressive increase in size).
– Other tissue: BM (rare), CSF,
Pleural/pericardial fluid,
spleen.
Posteroanterior (PA) chest radiograph shows a
large mass in the right parahilar region
extending into the right upper and middle
zones, with silhouetting of the right
pulmonary artery.

• Immunophenotype:
• Flow cytometry:
– detection of multiple markers (antigens),
– rapid turnaround,
– reproducible quantitation (ie, high versus lower levels of
antigen expression),
– and substantial sensitivity for certain markers (eg, surface
immunoglobulin light chains)
• Cytogenetic studies: Karyotype or FISH.
• Molecular analysis.

3.2. Evaluation of a patient with lymph nodes

• Diagnosis:
• Based on a comprehensive evaluation of
histologic, immunophenotypic, cytogenetic,
and molecular studies that are interpreted in
the context of the clinical scenario.

4.1. Diffuse Large B-cell Lymphoma
• DLBL most common type of NHL (≈1/3 of all cases).
• Most of “aggressive” or “intermediate-
grade”lymphoma.
• Can present as:
– Mediastinal involvement.
– Primary lymph node disease or
– Extranodal sites or
– Widely disseminated lymphoma.

• Diagnosis:
• by an expert
hematopathologist
• Biopsy
• BM bisopsy

Primary mediastinal LBCL
• A subtype of DLBCL (20% of DLBCL)
• Poorer prognosis subtype 5yr EFS:66% on FAB/LMB 96
• Seen mostly in older female adolescents
• Primary presentation: mediastinal mass
• Arises from thymic B cells

• Treatment:
–CHOP+ Rituximab.
–Salvage therapy or autologous BMT if
relapse

4.2. Burkitt’s Lymphoma
• High grade mature B cell lymphoma
• The incidence of BL in Africa is approximately 50-fold higher than that
seen in the USA.
• Accounts for 40% of NHL in children in HIC, higher proportion in Uganda
• Incidence: 10 in 100,000 for endemic; 0.2 in 100,000 for sporadic
• Males > females
• Peak age group is 4-7yrs for endemic BL; 6-12yrs for sporadic BL
• Epidemiological classification
 Endemic: in ‘malaria belt’
 Sporadic: US, Europe
 Epidemic: HIV associated

• Clinical presentation:
– This is the most rapidly progressive human tumor
• The disease is rapidly progressive and has a propensity
to metastasize to the CNS
– Peripheral lymphadenopathy or an intraabdominal
mass.
• Initial evaluation should always include
– Staging evaluation and
– CSF analysis to r/o metastasis.

4.2.BL- clinical presentation
• Pathology
 Translocation t(8:14).
 Histology: Starry sky
appearance
 Cytology- large lymphoid cells
with dark blue cytoplasm and
vacuolation
 EBV presence in tumour cells:
95% in endemic, 15% in
sporadic
• Excellent outcomes with
modern therapy : > 90% 5yr
EFS
• Aggressive tumour -doubling time
24hrs
• Varied presentation
 Jaw mass
 abdominal disease: mass, ascitis,
intestinal obstrution
 Orbital tumours
 Ovarian mass, testicular mass
 CNS disease- CNS disease e.g nerve
palsy, spinal cord compression, raised
ICP
• lymphadenopathy-
• leukaemia with features of marrow
failure
• Constitutional symptoms: fever,
weight loss, excessive night sweats

• Treatment:
• begin within 48 h of
diagnosis.
• Manage oncologic
emergency.
• Intensive combination
chemotherapy regimens
incorporating high doses of
cyclophosphamide.
• Prophylactic therapy to CNS
is mandatory.
• Cure rate: 70–80%

4.3. Lymphoblastic Lymphomas (LBL)
• Precursor cell lymphomas (immature T or B cell)
• Constitute 20% of childhood NHL
• 80% is T cell
• Thought to originate from thymic T cells ( T-LBL) or
bone marrow precursor B cells (B-LBL)
• Morphology and biologically similar to ALL
• Treated on similar protocols to ALL

4.4. Anaplastic large cell lymphoma
• Accounts for 8-13% of childhood
NHL
• Mostly T cell phenotype
• Pathology
 Anaplasia, large horseshoe like
cells
 Tumour cells express CD30 and
CD45
 t(2;5) forming the NPM-ALK in
60%
 Varied presentation: nodal and
extranodal
• A third present with localized
disease
• Majority present with advanced
disease
• BM and CNS involvement are
rare.
• Systemic symptoms common in
advanced disease
• Cutaneous lesions are common
and occasionally resolve
spontaneously.
• Rx: multi-agent chemotherapy.
Conjugated monoclonal antibody
may have a role (Brentuximab)
• OS: 70 -85%

4.4. Anaplastic large cell lymphoma
• Eg. (B) Breast implant–
associated ALCL.
• (C) Nodule on the ear.
• (E) EATL. The somewhat
pleomorphic intestinal infiltrate
extends into the epithelium and
would be associated with
enteropathic changes elsewhere
in the intestine.
• F) MEITL. The monotonous
intestinal infiltrate is very
epitheliotropic.
• (G) Small nodule on scalp.
(A,E,F,H) Hematoxylin and eosin stain; (B) Romanowsky-type stain; (D) CD8 immunoperoxidase stain

4.5. Follicular lymphoma
• ≈22% of NHL worldwide and at least
30% NHL in USA.
• “low-grade” lymphoma
• The most common presentation:
new, painless lymphadenopathy (
epitrochlear, extranodal, any organ
can be involved).
• No B symptoms in most of patients .
• Diagnosis: follicular pattern of
growth, B-cell immunophenotype
and the existence of the t(14;18)
and abnormal expression of BCL-2
protein are confirmatory.
• Responsive to chemotherapy and
radiotherapy.

4.6. Mantle cell lymphoma
Mantle cell lymphoma (MCL)
classically has been
recognized as an aggressive
but incurable small B-cell
lymphoma that developed in
a linear fashion from naïve B
cells.
2 subtypes:
-Classical→ leukemic
nonnodal MCL, usually
involving the PB, bone
marrow, and often spleen.
- in situ mantle cell
neoplasia (ISMCN)→Low rate
of progression.
Most common presentation: palpable lymphadenopathy, frequently
accompanied by systemic symptoms

4.7. Extranodal Marginal Zone B-Cell
Lymphoma of MALT Type
• Clinical presentation:
– ~8% of NHL.
– H. pylori infection was associated with gastric presentation (95% of
cases).
– An autoimmune or inflammatory process in most patients.
– MALT lymphoma may occur in the stomach, orbit, intestine,
lung,thyroid, salivary gland, skin, soft tissues, bladder, kidney, and
CNS→ new mass, be found on routine imaging studies, or be associated
with local symptoms.
• Diagnosis:
– pattern of infiltration of small lymphocytes that are
monoclonal B cells and CD5 negative.

Immunophenotype of the MALT lymphoma

4.7. Extranodal Marginal Zone B-Cell
Lymphoma of MALT Type
• Treatment:
– Patients with gastric MALT lymphomas who are
infected with H. pylori can achieve remission in the
80% of cases with eradication of the infection.
– Additional therapy is not indicated unless
progressive disease is documented.
– single-agent chemotherapy such as chlorambucil or
combination with Rituximab.

Other rare adult lymphomas
• Peripheral T-cell NHL
• small lymphocytic lymphoma, etc…

References
• Harrison's’ Principles of Internal medicine Textbook ,
19th edition
• Up-to-Date 2020
• Nelson Textbook of Pediatrics, 20th edition.
• The 2016 revision of the WHO classification of
lymphoid neoplasms. Blood. 2016 May 19; 127(20):
2375–2390.

Lymphomas int.med.

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