Download hodgkin disease

LYMPHOMAS
INTRODUCTION
• Lymphomas are cancers that begin by the
malignant transformation of a lymphocyte
in the lymphatic system.
– the prefix "lymph-" indicates their origination
in the malignant change of a lymphocyte and
– the suffix "-oma" is derived from the Greek
word meaning "tumor."
INTRODUCTION
• Lymphoma encompasses 2 large groups of
neoplasms, namely non-Hodgkin lymphoma
(NHL) and Hodgkin disease.
• NHL includes many clinicopathologic subtypes,
each with distinct epidemiologies; etiologies;
morphologic, immunophenotypic, genetic, and
clinical features; and responses to therapy.
HODGKIN DISEASE
(HD)
Hodgkin’s Disease
• Hodgkin disease (HD) is a potentially curable
malignant lymphoma with distinct histology,
biologic behavior, and clinical characteristics.
• Histologically, the picture is unique, with 1-2%
of neoplastic cells (Reed-Sternberg [RS] cells)
in a background of a variety of reactive mixed
inflammatory cells consisting of lymphocytes,
plasma cells, neutrophils, eosinophils, and
histiocytes
Hodgkin’s Disease - In the Beginning
First described in 1832 by Dr. Thomas Hodgkin
Neoplasm of B lymphocytes – large pleomorphic prominent
nucleolus in a halo - Hodgkin cells
Reed-Sternberg cell – binucleate Hodgkin cell with owl eye
appearance
Classification:
Classical Hodgkin’s
Nodular sclerosis – low grade
Mixed cellularity
Lymphocyte rich classical
Lymphocyte depleted. – high grade
Nodular lymphocyte-rich Hodgkin’s
1798-1866
Hodgkin’s Disease - Epidemiology
• Accounts for ~ 30% of all malignant lymphomas
• Socioeconomic class is associated with a higher risk
of HD.
• Composed of two different disease entities:
– Lymphocyte-predominant Hodgkin’s (LPHD), making up
~ 5% of cases
– Classical HD, representing ~ 95% of all HDs.
• A common factor of both HD types is that neoplastic
cells constitute only a small minority of the cells in
the affected tissue, often corresponding to < 2% of
the total tumor
Hodgkin’s Disease - Epidemiology
• Bimodal age distribution
– first peak between 2nd - 3rd decade of life
– second peak between 5th - 6th decade of life
• Male: Female 2:1 in kids, adults almost equal M:F
• Mixed cellularity (MC) Hodgkin’s Disease is more
common at younger ages
• More common in immune deficiency patients
Hodgkin’s Disease - Epidemiology
• Fatal disease with 90% of untreated patients dying within 2 to
3 years
• With chemotherapy, >80% of patients suffering from HD are
cured.
• Pathogenesis of HD is still largely unknown.
• HD nearly always arises and disseminates in lymph nodes
H D – Etiology
• The etiology of HD is unknown.
– Infectious agents, especially the Epstein-Barr virus (EBV),
may be involved in the pathogenesis of HD.
– Patients with HIV infection have a higher incidence of HD
compared to the population without HIV infection.
– Genetic predisposition may play a role in the pathogenesis of
HD.
• Approximately 1% of patients with HD have a family history of the
disease.
• Siblings of an affected individual have a 3- to 7-fold increased risk
for developing HD.
• This risk is higher in monozygotic twins.
H D - Pathophysiology
• The RS cells represent a clonal proliferation of B
lymphocytes that derive from the germinal centers of
lymph nodes and that have lost their ability to express
their antibodies.
• The RS cell is chracterised by its large size and classic
binucleated structure with large eosiniphilic nucleoli.
• They consistently express CD15 (Leu-M1) and CD30
(Ki-1) antigens.
• Some of the clinical manifestations of HD (eg,
eosinophilia) are attributed to the production of
cytokines.
H D - Pathophysiology
H D - History
• Asymptomatic lymphadenopathy may be
present (above the diaphragm in 80% of
patients).
• Constitutional symptoms (eg, unexplained
weight loss, fever, night sweats) are present
in 40% of patients.
• Chest pain, cough, and/or shortness of
breath may be present due to a large
mediastinal mass or lung involvement.
Rarely, hemoptysis is observed.
H D - History
• Patients may present with pruritus.
• Alcohol-induced pain at sites of nodal disease is
specific for HD and occurs in less than 10% of patients.
• Intermittent fever is observed in approximately 25% of
cases. Infrequently, the classic Pel-Ebstein fever (high
fever for 1-2 wk followed by an afebrile period of 1-2
wk) is observed.
• Back or bone pain occurs rarely.
H D - Physical
• Palpable painless lymphadenopathy occurs in the :
– cervical area (60-80%),
– axilla (6-20%), and, less commonly,
– inguinal area (6-20%).
• It is described as :
–
–
–
–
–
asymmetrical, discrete
painless, non-tender
elastic character on palpation ( rubbery)
not adherent to skin
fluctuate in size
• Involvement of the Waldeyer ring or occipital or
epitrochlear areas is observed infrequently.
• Splenomegaly may be present.
H D - Physical
• Patients may have hepatomegaly.
• Superior vena cava syndrome resulting from
massive mediastinal lymphadenopathy is
observed rarely.
• Central nervous system (CNS) symptoms or
signs may be due to paraneoplastic syndromes,
including cerebellar degeneration, neuropathy,
Guillain-Barré syndrome, or multifocal leukoencephalopathy.
H D - Physical
H D - Physical
H D – Lab studies
• CBP
:
Anemia
(normochromic/normocytic),
eosinophilia, neutrophilia, lymphopenia
• ESR -raised
• LFT- (liver infil / obs at porta hepatis)
• RFT- prior to treatment
• Urate , Ca,
• LDH - adverse prognosis
• CXR- mediastinal mass
• CT thorax / abdomen / pelvis-for staging
• Other: Gallium scan, PET, Lymphangiography ,
Laporotomy
H D – Lab studies
• Erythrocyte sedimentation rate (ESR) may
be elevated.
• Complete blood count (CBC) should be
performed.
– anemia usually is due to anemia of chronic
disease, but it may be due to bone marrow
involvement or the presence of an autoantibody
– Cytopenias are common in advanced disease.
– Platelet counts can be increased or decreased.
H D – Lab studies
• Lactate dehydrogenase (LDH) may be increased. LDH
may correlate with the bulk of disease.
• Rarely, HD is associated with nephrotic syndrome.
• Alkaline phosphatase may be increased due to the
presence of liver or bone involvement.
• Other uncommon laboratory findings include
hypercalcemia, hypernatremia, and hypoglycemia (due
to the presence of insulin autoantibodies).
• Beta-2-microglobulin correlate with tumor burden,
systemic symptoms, and prognosis.
H D – Imaging studies
• Chest radiography
• CT scans of the chest, abdomen, and pelvis
o Possible abnormal findings include enlarged lymph
nodes, hepatomegaly and/or splenomegaly with or
without focal parenchymal abnormalities, lung
nodules or infiltrates, and pleural effusions.
o A mediastinal mass, representing mediastinal
lymphadenopathy, is a very common finding.
• Gallium-67 scan or positron emission
tomography (PET) scan may be used as a
baseline test to assess response to therapy.
H D – Imaging studies
H D – Imaging studies
H D – Imaging studies
H D – Imaging studies
• Lymphangiography
o It is used infrequently because it is technically
challenging.
o Lymphangiography may demonstrate abnormalities,
even in normal-sized lymph nodes.
o One additional advantage of this technique is that
residual dye may be present in the lymph nodes for
months to years, and the size of affected lymph
nodes can be followed easily with plain radiographs.
H D – Diagnosis
• A histological diagnosis always is required.
• Because the lymph node architecture is
important for histological classification, an
excisional lymph node biopsy is recommended.
• Staging laparotomy includes splenectomy,
needle and wedge biopsy of the liver, and
biopsies of the paraaortic, mesenteric, portal,
and splenic hilar lymph nodes.
• Bilateral bone marrow biopsies - because HD is
seen as patchy infiltrates in the bone marrow,
bilateral bone marrow biopsies are advised.
H D – Histologic Findings
• According to the recent World Health
Organization (WHO) classification, the first 4
subtypes are referred to as classic HD.
–
–
–
–
Nodular sclerosis Hodgkin disease - 60-80%
Mixed-cellularity Hodgkin disease - 15-30%
Lymphocyte-depleted Hodgkin disease - Less than 1%
Lymphocyte-rich classic Hodgkin disease - 5%
H D – Histologic Findings
• Nodular sclerosis Hodgkin disease
– The morphology shows a nodular pattern. The
broad bands of fibrosis divide the node into
"nodules." The capsule is thickened. The
characteristic cell is the lacunar-type RS cell, which
has a monolobated or multilobated nucleus and a
small nucleolus with abundant and pale cytoplasm.
– NS frequently is observed in adolescents and young
adults and usually involves the mediastinum and
other supradiaphragmatic sites.
H D – Histologic Findings
• Mixed-cellularity Hodgkin disease
– Histologically, the infiltrate usually is diffuse. RS
cells are of the classic type (large, with bilobate,
double or multiple nuclei, and a large eosinophilic
inclusionlike nucleolus).
– It commonly affects the abdominal lymph nodes
and spleen.
– Patients with this histology typically have
advanced-stage disease with systemic symptoms
and immunodeficiency.
H D – Histologic Findings
• Lymphocyte-depleted Hodgkin disease
– The infiltrate in lymphocyte-depleted Hodgkin
disease (LDHD) is diffuse and often appears
hypocellular. Large numbers of RS cells and bizarre
sarcomatous variants are present.
– It is associated with older age and HIV positivity.
– Patients usually present with advanced-stage disease.
– EBV proteins are expressed in many of these tumors.
– Many cases of LDHD diagnosed in the past actually
were non-Hodgkin lymphomas, often of the
anaplastic large-cell type.
H D – Histologic Findings
• Lymphocyte-rich classic Hodgkin disease
– In this type of HD, RS cells of the classic or lacunar
type are observed, with a background infiltrate of
lymphocytes.
– It requires immunohistochemical diagnosis.
– Some cases may have a nodular pattern.
– Clinically, the presentation and survival patterns are
similar to those for MCHD.
H D – Histologic Findings
H D – Histologic Findings
H D – Histologic Findings
CD 30 Immunostain
H D – Staging
• The
Ann
Arbor
classification (1971) is used
most commonly.
• Clinical staging involves
assessment of disease extent
by clinical examination and
imaging techniques.
• When staging laparotomies
are used as part of staging,
disease extent is designated
pathologic staging.
Hodgkin’s Disease – Staging
Stage Definition
I
Involvement of a single lymph node region (I) or of a single extralymphatic organ or site
(IE)
II
Involvement of two or more lymph node regions on the same side of the diaphragm (II) or
localized involvement of an extralymphatic organ or site and one or more lymph node
regions on the same side of the diaphragm (IIE)
III
Involvement of lymph node regions on both sides of the diaphragm (III) which may be
accompanied by involvement of the spleen (IIIS) or by localized involvement of an
extralymphatic organ or site (IIIE) or both (IIISE)
IV
Diffuse or disseminated involvement of one or more extra lymphatic organs or tissues
or without associated lymph node involvement
with
B symptoms: fever > 38ºC for three consecutive days, drenching night sweats or unexplained loss 10% or more of
weight the preceding 6 months
Hodgkin’s Disease – Staging
Hodgkin’s Disease – Staging
• The stage of HD correlates with prognosis.
• Also, the bulk of nodal disease and the extent of
subdiaphragmatic involvement have been found to
correlate with prognosis.
• Approximately one third of new patients have splenic
involvement based on laparotomy data.
• Spread in HD takes place via the lymphatics,
hematogenous routes, and direct extension.
• Contiguous involvement of extranodal sites, eg,
involvement of the lung parenchyma due to direct
extension of large mediastinal lymphadenopathy, is
not considered stage IV disease.
H D – Prognosis
• Early stages (I-IIA) - Early-stage disease is
considered unfavorable when at least 1 of the
following poor prognostic factors is present:
o Bulky disease (defined as a mass >5-10 cm or a
mediastinal mass larger than one third of the chest
diameter)
o Elevated ESR
o B-symptoms
o Multiple lymph node sites (>3) or extranodal
disease
H D – Prognosis
• Advanced stages (IIB-IV)
– The International Prognostic Factors Project on
Advanced Hodgkin's Disease has developed a
prognostic score based on 7 adverse factors in
advanced HD. These factors are
•
•
•
•
•
•
•
(1) an albumin level of less than 4 g/dL,
(2) a hemoglobin level of less than 10.5 g/dL,
(3) male sex,
(4) age older than 45 years,
(5) stage IV disease,
(6) a WBC count of higher than 15,000/mm3, and
(7) an absolute lymphocyte count of less than 600/mm3 or a
lymphocyte count of less than 8% of the total WBC count.
H D – Treatment
• Radiation therapy - is the use of high-energy x-rays (or
sometimes other radiation) to kill cancer cells and shrink tumors.
– The involved field encompasses the involved lymph node area plus one
contiguous region.
– Extended fields are the mantle (encompassing the cervical, axillary, and
mediastinal nodes) or the inverted Y (encompassing the paraaortic, pelvic,
and inguinal nodes).
– Subtotal nodal irradiation involves the mantle plus the paraaortic field.
The dose is 40-45 Gy when given alone or lower (usually 30 Gy) when
used in combination with chemotherapy.
– The mantle field is shaped accordingly in order to reduce radiation to the
heart and lungs.
• Careful avoidance of the spinal cord prevents myelitis. Shielding
the testes and oophoropexy are important during the reproductive
years. If these cannot be ensured, sperm and ova banking may be
advisable.
H D – Radiotherapy
Irradiation fields used in Hodgkin’s Lymphoma
H D – Chemotherapy
• Conventional chemotherapy :
–
–
–
–
–
–
MOPP
ABVD
Alternating regimens – MOPP/ABVD
Hybrid regimens – MOPP/ABV
Stanford V
BEACOPP
• High-dose chemotherapy with transplantation
– High-dose chemotherapy (HDC) at doses that ablate the bone
marrow is feasible with reinfusion of the patient's previously
collected
hematopoietic
stem
cells
(autologous
transplantation) or infusion of stem cells from a donor source
(allogeneic transplantation).
H D – Response Assesment
• The goal of treatment is to induce a complete
response (CR).
• Any other outcome is considered a treatment
failure.
• In assessing response, note that residual
masses do not always represent active
disease.
• Gallium and PET scans are useful in this
setting because they can differentiate active
and inactive residual masses.
H D – Treatment Guidelines
o The treatment of early-stage favorable - options include
the following:
o Extended-field radiotherapy, if pathologically staged (20%
will be upstaged upon laparotomy)
o Subtotal nodal irradiation, if clinically staged (approximately
20% will relapse, usually at nonirradiated sites)
o Combined modality therapy - usually represents
chemotherapy (ABVD) for 2-4 cycles, followed by
radiotherapy of the involved field
o ABVD alone without radiation, which may be adequate
therapy for early-stage disease (under investigation).
H D – Treatment Guidelines
o Treatment for early-stage unfavorable disease
is as follows:
o Combined
modality
therapy,
which
is
chemotherapy (ABVD) for 4-6 cycles followed by
involved-field radiotherapy, is used.
o Approximately 80% of patients are cured, and
treatment fails in 20%. Of these, 5% progress
during treatment and 15% relapse.
– The use of more aggressive chemotherapy for the
treatment of unfavorable early-stage HD is being
explored.
H D – Treatment Guidelines
o Treatment for special presentations includes
the following:
o For patients with clinical stage IA disease with neck
involvement and NLPHD histology, radiotherapy
alone is adequate therapy.
o For patients with clinical stage IA disease that is
nonbulky and involves the mediastinum with NS
histology, mantle irradiation alone may be adequate
therapy.
H D – Treatment Guidelines
• Advanced stages (IIB-IV)
o Chemotherapy is used, followed by involved-field
radiotherapy in selected cases (eg, bulky disease).
o The overall cure rate is 60-70%.
o ABVD is the regimen of choice, but other
combinations are under investigation.
o The optimal duration of treatment is uncertain. In
most cases, treatment continues for 2 cycles post
CR. Usually, a total of 6 cycles is administered.
o Two new regimens (Stanford V and BEACOPP) are
being evaluated in advanced HD and have shown
promising results
H D – Treatment Guidelines
• Relapsed or resistant HD
o Relapse after radiotherapy:
o Approximately 25% of patients treated with
radiation therapy alone relapse.
o These patients are successfully salvaged with
conventional
combination
chemotherapy
(ABVD). More than 60% of patients are cured.
H D – Treatment Guidelines
o Relapses after conventional chemotherapy can be divided into 3
groups:
o Induction failure includes patients who never achieve a complete response
or those who relapse very early (within 2-3 mo) following completion of
therapy  HDC with autologous hematopoietic stem cell transplantation
is the treatment of choice. Second-line (salvage) conventional-dose
chemotherapy regimens often are used before HDC in an attempt to
achieve minimal disease.
o Early relapse represents relapse within 12 months after chemotherapy
completion  HDC with autologous transplantation is the treatment of
choice.
o Late relapse represents relapse after 12 or more months postchemotherapy
completion.
H D – Complications
•
•
•
•
•
•
•
•
•
•
Cardiac disease
Pulmonary disease
Myelodysplasia/leukemia
Infertility
Breast cancer
Non-Hodgkin lymphoma
Other solid tumors
Infectious complications
Hypothyroidism after neck/mediastinal radiotherapy
Immunodeficiency after chemotherapy and/or
radiation therapy
NON-HODGKIN
LYMPHOMAS (NHL)
NHL - Epidemiology
• Since the early 1970s, the incidence rates of NHL have
nearly doubled.
• NHL is the most prevalent hematopoietic neoplasm 4% of all cancer diagnoses and seventh in frequency
among all cancers.
• NHL is more than 5 times as common as Hodgkin
disease.
• Incidence varies with race; white people have a higher
risk than black and Asian American people.
NHL - Epidemiology
• In general, incidence is slightly higher in men
than in women, with a male-to-female ratio of
approximately 1.4:1.
• The median age at presentation for all subtypes
of NHL is older than 50 years, except for
patients with high-grade lymphoblastic and
small noncleaved lymphomas, which are the
most common types of NHL observed in
children and young adults.
NHL - Etiology
• Chromosomal translocations and molecular rearrangements
play an important role in the pathogenesis of many lymphomas
and correlate with histology and immunophenotype.
• Some viruses are implicated in the pathogenesis of NHL – EBV,
HTLV-1, HCV, KSHV
• Environmental factors linked to the development of NHL
include chemicals, chemotherapy, and radiation exposure
• Congenital, acquired , and induced (eg, immunosuppression)
immunodeficiency states are associated with increased incidence
of NHL
• The chronic inflammation
NHL - Patophysiology
• NHL represents a progressive clonal expansion
of B cells or T cells and/or natural killer (NK)
cells, arising from the accumulation of genetic
lesions that affect proto-oncogenes or tumor
suppressor genes, resulting in the uncontrolled
and excessive growth and cell immortalization.
• The accumulation of these dividing cells results
in the tumor masses in lymph nodes and other
sites
ALL
CLL
Lymphomas
MM
naïve
B-lymphocytes
Lymphoid
progenitor
AML
Hematopoietic
stem cell
Myeloid
progenitor
Plasma
cells
T-lymphocytes
Myeloproliferative disorders
Neutrophils
Eosinophils
Basophils
Monocytes
Platelets
Red cells
B-cell development
CLL
stem
cell
mature
naive
B-cell
germinal
center
B-cell
lymphoid
progenitor
memory
B-cell
MM
progenitor-B
ALL
pre-B
immature
B-cell
DLBCL,
FL, HL
plasma cell
NHL - Patophysiology
• Most NHLs are of B-cell origin (almost 85%);
only 15% are derived from T/NK cells, and the
small remainder stem from macrophages.
• NHLs are tumors originating from lymphoid
tissues, mainly of lymph nodes. Various neoplastic
tumor cell lines correspond to each of the cellular
components of antigen-stimulated lymphoid
follicles.
NHL - Classification
• NHL are characterized by the level of
differentiation, the size of the cell of origin,
the origin cell's rate of proliferation, and the
histologic pattern of growth  a
heterogenous group with a great diversity of
subtypes  several NHL classification
schemas exist, reflecting the growing
understanding of the complex diversity of
the NHL subtypes.
NHL - Classifications
• The Working Formulation, originally proposed in
1982, classified and grouped lymphomas by
morphology and clinical behavior (ie low,
intermediate, or high grade).
• In the 1990s, the Revised European-American
Lymphoma (REAL) classification attempted to
apply immunophenotypic and genetic features in
identifying distinct clinicopathologic NHL
entities.
• The
recently
proposed
World
Health
Organization (WHO) classification further
elaborates upon the REAL approach.
NHL - Classifications
Biologically rational
classification
Diseases that have distinct
• morphology
• immunophenotype
• genetic features
• clinical features
Clinically useful
classification
Diseases that have distinct
• clinical features
• natural history
• prognosis
• treatment
NHL – TYPES AND FREQUENCY
A) B-Cell Lymphomas
1. Diffuse Large B-Cell Lymphomas (31%)
2. Follicular Lymphoma (22%)
3. Mucosa-Associated Lymphatic Tissue (MALT) Lymphoma (7.5%)
4. Small Lymphocytic Lymphoma-Chronic Lymphocytic Leukemia (7%)
5. Mantle Cell Lymphoma (6%)
6. Mediastinal (Thymic) Large B-Cell Lymphoma (2.4%)
7. Lymphoplasmacytic Lymphoma-Waldenstrom Macroglobulinemia (<2%)
8. Nodal Marginal Zone B-Cell Lymphoma (<2%)
9. Splenic Marginal Zone Lymphoma (<1%)
10. Extranodal Marginal Zone B-Cell Lymphoma (<1%)
11. Intravascular Large B-Cell Lymphoma (<1%)
12. Primary Effusion Lymphoma (<1%)
13. Burkitt Lymphoma-Burkitt Leukemia (2.5%)
14. Lymphomatoid Granulomatosis (<1%)
NHL – TYPES AND FREQUENCY
• B) T and NK Cell Lymphomas (~12%)
1. Extranodal T or NK-Lymphoma
2. Cutaneous T-Cell Lymphoma (Sézary Syndrome and Mycosis
Fungoides)
3. Anaplastic Large Cell Lymphoma
4. Angioimmunoblastic T-Cell Lymphoma
• C) Immunodeficiency-Associated Lymphoproliferative Disorders
NHL – History
A.
•
•
•
•
•
Low-grade lymphomas
Peripheral adenopathy that is painless and slowly progressive
is the most common clinical presentation in these patients.
Spontaneous regression of enlarged lymph nodes can occur in
low-grade lymphoma.
Primary extranodal involvement and B symptoms (ie,
temperature >38°C, night sweats, weight loss >10% from
baseline within 6 mo) are not common at presentation, but both
are common in patients with advanced or end-stage disease.
Bone marrow is frequently involved and may be associated
with cytopenia.
Fatigue and weakness are more common in patients with
advanced-stage disease.
NHL – History
B. Intermediate- and high-grade lymphomas
• These types of lymphomas cause a more varied
clinical presentation.
• Most patients present with adenopathy.
• More than one third of patients present with
extranodal involvement; the most common sites are
the GI tract (including the Waldeyer ring), skin, bone
marrow, sinuses, genitourinary (GU) tract, thyroid,
and CNS.
• B symptoms are more common, occurring in
approximately 30-40% of patients.
NHL – History
B. Intermediate- and high-grade lymphomas
•
•
•
•
Lymphoblastic lymphoma, often manifests with an anteriorsuperior mediastinal mass, superior vena cava (SVC)
syndrome, and leptomeningeal disease with cranial nerve
palsies.
Patients with Burkitt lymphoma (occurring in the United
States) often present with a large abdominal mass and
symptoms of bowel obstruction.
Obstructive
hydronephrosis
secondary
to
bulky
retroperitoneal lymphadenopathy obstructing the ureters can
also be observed in these patients.
Primary CNS lymphomas are high-grade neoplasms of B-cell
origin. These lymphomas are more commonly observed in
patients who are immunodeficient.
NHL – Clinical
A. Low-grade lymphomas
• Peripheral adenopathy
• Splenomegaly: Splenomegaly is observed in
approximately 40% of patients; the spleen
rarely is the only involved site at
presentation.
• Hepatomegaly
NHL – Clinical
B. Intermediate- and high-grade lymphomas
•
•
•
•
•
•
•
Rapidly growing and bulky lymphadenopathy
Splenomegaly
Hepatomegaly
Large abdominal mass: This usually occurs in Burkitt
lymphoma.
Testicular mass
Skin lesions: Lesions are associated with cutaneous T-cell
lymphoma (mycosis fungoides), anaplastic large cell
lymphoma, and angioimmunoblastic lymphoma.
Chest radiograph: The chest radiograph may demonstrate a
bulky mediastinal mass, which is associated with primary
mediastinal large B-cell lymphoma or lymphoblastic
lymphoma.
Gastric NHL
Intestinal NHL
Extranodal NHL
• Splenic NHL
• Bone NHL
Extranodal NHL
• Mycosis fungoides
• ATLL
NHL – Diagnosis
Biopsy of peripheral (or most accessible)
lymphadenopathy
– Excisional lymph node biopsy is required because
lymphoma diagnosis relies heavily on careful
assessment
of
altered
nodal
architecture
accompanying lymphomatous infiltrates.
– Fine-needle aspiration (FNA) is insufficient for
establishing a diagnosis; needle-core biopsies have a
limited role in establishing a diagnosis of NHL.
– A well-processed hematoxylin and eosin (H&E)–
stained section of an excised lymph node is the
mainstay of pathologic diagnosis.
NHL – Diagnosis
Bone marrow aspirate and biopsy
– Perform this procedure for staging rather than
diagnostic purposes.
– Bilateral bone marrow aspirate and biopsy should be
performed because bone marrow involvement is
usually patchy.
– In bone marrow sections, the neoplastic cells may
infiltrate in a focal (ie, paratrabecular or
nonparatrabecular, depending on the type of
lymphoma), interstitial, or diffuse pattern.
NHL – Diagnosis
Biopsy of extranodal sites
– In approximately 30-35% of adult patients with
NHL, the extranodal sites are the primary
presenting sites, and the most common site is the GI
tract.
– Processing extranodal biopsy material for
lymphoma protocol studies is important whenever
suspicion of a hematolymphoid neoplasm exists.
– Lumbar puncture for cerebrospinal fluid (CSF)
examination
NHL – Diagnosis
• Histologic Findings:
– NHLs
are
a
heterogenous
group
of
lymphoproliferative malignancies with varying
morphologic features depending on the specific type
of this disorder.
– The abnormal lymphocytes in the lymph node, bone
marrow, or extranodal sites can be small cleaved or
noncleaved, intermediate, or large cell and can have
a follicular or diffuse pattern.
– In contrast with reactive follicular hyperplasia,
lymphomas usually alter the lymph node
architecture, and the capsule is usually involved.
NHL – Diagnosis
Immunophenotypic analysis of lymph node, bone
marrow, and/or peripheral blood
– Compliments and confirms the results of routine tissue section
and may be useful in resolving a diagnostic dilemma in
patients with an atypical morphology.
– Helps to distinguish reactive from neoplastic lymphoid
infiltrates, lymphoid from nonlymphoid malignancies, and
specific lymphoid neoplasms.
– Provides information about lineage and clonality, which are
complimentary to the histology of a given case.
– Useful for subclassifying certain lymphoma subtypes, which
has therapeutic and prognostic importance.
NHL – Diagnosis
Cytogenetic studies
• Have contributed to the understanding of
the biology and prognosis of lymphoma.
• Are critical to the discovery of oncogene
abnormalities that now are known to be
intimately involved in the pathogenesis of
NHL.
NHL – Staging
• Staging is important in selecting a treatment and also
for prognosis
–
–
–
–
–
–
–
–
–
–
–
–
Careful history
Physical examination
Biopsy of lymphadenopaty
Chest X-ray
CT-scan 0f chest, abdomen and pelvis
Bilateral bone biopsy
CBC with differential count
General chemistry panel (beta-2-microglobulin and LDH included)
HIV, HTLV, HCV serology
CSF study
Upper GI series
Ultrasound of testis
NHL – Staging

Stage I involves a single lymph node region (I) or localized
involvement of a single extralymphatic organ or site (IE).
 Stage II involves 2 or more lymph node regions on the same
side of the diaphragm (II) or localized involvement of a single
associated extralymphatic organ in addition to criteria for stage
II (IIE).
 Stage III involves lymph node regions on both sides of the
diaphragm (III) that also may be accompanied by localized
involvement of an extralymphatic organ or site (IIIE), spleen
(IIIS), or both (IIISE).
 Stage IV represents disseminated or multifocal involvement of
one or more extralymphatic sites with or without associated
lymph node involvement or isolated extralymphatic organ
involvement with distant (nonregional) nodal involvement.
Staging of lymphoma
Stage I
Stage II
Stage III
A: absence of B symptoms
B: fever, night sweats, weight loss
Stage IV
NHL – Staging
• Subscript
letters
designate
involvement
of
extralymphatic organs, as follows: L, lung; H, liver; P,
pleura; O, bone; M, bone marrow; and D, skin.
• The designation E is used when extranodal lymphoid
malignancies arise in tissues that are separate from but
near the major lymphatic aggregates.
• In this system, stages I-IV can be appended by A or B
designations. The B designation is applied in patients
with any of the following symptoms: unexplained loss
of more than 10% of body weight in the preceding 6
months before diagnosis, unexplained fever with
temperature above 38°C, and drenching night sweats.
NHL – Prognosis
• The International Prognostic Index (IPI) :
o
o
o
o
o
Age - Younger than 60 years versus older than 60 years
LDH level - Within the reference range versus elevated
Performance status - ECOG 0-1 versus 2-4
Ann Arbor stage - Stage I-II versus III-IV
Number of extranodal sites - 0-1 versus more than 1
o Patients with 0-1, 2-3, and 4-5 risk factors have
75%, 50%, and 25% chance, respectively, of
having a relapse-free and OS at 5 years.
NHL – Medical care
• A. Indolent stage I and contiguous stage II NHL
– Involved-field radiation therapy may be the treatment of
choice in patients with localized low-grade NHL, especially
of the head and neck. For these patients, radiation therapy
(2500-4000 cGy) produces a 10-year failure-free survival
(FFS) rate of 50-60%, with an overall survival (OS) rate of
60-80%.
– Offer adjuvant chemotherapy to selected patients with stage
I-II NHL who have unfavorable prognostic factors (eg, B
symptoms, >2 nodal sites) and to those with follicular mixed
histology.
NHL – Medical care
• B. Indolent noncontiguous stage II, III, and IV NHL
– Treatment for symptomatic patients includes
• (1) purine nucleoside analogues (ie, fludarabine, 2-CDA), which have
significant antitumor activity in low-grade NHL;
• (2) oral alkylating agents with or without steroids (ie,
cyclophosphamide, chlorambucil);
• (3) combination chemotherapy using cyclophosphamide, vincristine,
and prednisone (CVP) or cyclophosphamide, hydroxydaunomycin,
Oncovin (vincristine), and prednisone (CHOP).
• (4) intensive therapy with chemotherapy and total body irradiation
(TBI) followed by autologous or allogeneic bone marrow or peripheral
stem cell transplantation, especially for younger patients with poor
prognostic factors, is under clinical investigation.
• (5) For patients who are unable to tolerate other options, anti-CD20
monoclonal antibody (rituximab) may be considered as the first-line
therapy, either alone or with combination chemotherapy.
NHL – Medical care
• A. Aggressive stage I and contiguous
stage II (nonbulky or <10 cm) NHL
– Patients with intermediate-grade NHL combination chemotherapy (3 cycles of CHOP)
plus involved field radiation therapy.
– Patients with high-grade disease should be
strongly considered for treatment with more
aggressive regimens beyond CHOP.
NHL – Medical care
• B. Aggressive noncontiguous stage II, III,
and IV NHL
– The treatment of choice for these patients is
combination chemotherapy, either alone or
supplemented by involved field irradiation.
– Doxorubicin-based combination chemotherapy
produces long-term disease-free survival (DFS)
in 35-45% of patients.
– For intermediate-grade lymphomas, CHOP
chemotherapy remains the standard of care at
this time.
NHL – Medical care
• B. Aggressive noncontiguous stage II, III, and IV
NHL
– Autologous and allogeneic bone marrow or peripheral stem
cell transplantation for patients at high risk of relapse are
under clinical investigation.
– Innovative approaches to improve the results of CHOP for
patients at high risk of relapse, such as monoclonal antibody
therapy, are under clinical investigation.
– CNS prophylaxis, usually with 4-6 injections of methotrexate
intrathecally, is recommended for patients with paranasal sinus
or testicular involvement, diffuse small noncleaved cell or
Burkitt lymphoma, or lymphoblastic lymphoma.
NHL – Medical care
• B. Aggressive noncontiguous stage II, III, and
IV NHL
– Treatment of acute lymphoblastic lymphoma, a very
aggressive form of NHL, is usually patterned after
acute lymphoblastic leukemia (ALL) therapy.
Intensive combination chemotherapy with CNS
prophylaxis is the standard treatment of this
aggressive histologic type of NHL.
– Other subtypes of high-grade lymphomas are
usually treated with more aggressive variations of
CHOP chemotherapy, including the addition of
high-dose methotrexate or other chemotherapy drugs
and higher doses of cyclophosphamide
NHL – Medical care
• Further Inpatient Care:
– Further inpatient care depends on the patient's active
problem, tumor type and stage, and overall
prognosis.
– Admit patients for complications of disease
progression (eg, pain control for intractable pain) or
adverse effects from chemotherapy (eg, neutropenic
fever, dehydration secondary to diarrhea, vomiting
requiring IV hydration, severe mucositis).
– Admit patients for infusional chemotherapy or highdose chemotherapy followed by stem cell
transplantation.
NHL – Medical care
• Further Outpatient Care:
– Treatment and follow-up care of patients with NHL are
usually performed on an outpatient basis.
– Monitoring the patient's blood cell count while receiving
chemotherapy (eg, prior to each treatment cycle and 10-14 d
after each treatment cycle) is important.
– Monitor adverse effects of chemotherapy with a detailed
patient history, an examination, a CBC count, and
chemistries
(especially
LFTs,
electrolytes,
LDH,
BUN/creatinine).
– Treat symptomatic adverse effects such as nausea, vomiting,
diarrhea, mucositis, anorexia, pain, and fatigue.
NHL – Medical care
• Further Outpatient Care:
– Administer packed red blood cell (PRBC)
transfusions for patients with symptomatic anemia
and provide platelet transfusions for patients with a
platelet count less than 10-20 k/CU mm.
– Provide growth factor (eg, GCSF, GM-CSF,
erythropoietin) support as necessary.
– Perform a disease and response to treatment
evaluation by obtaining patient history, physical
examination (at intervals q2-3mo), and imaging
studies (eg, CT scans at intervals q4-12mo).
– Provide psychosocial support for the patient and
family.
NHL – Complications
• Disease-related complications
o
o
o
o
o
o
o
o
Cytopenias.
Bleeding
Infection
Cardiac problems
Respiratory problems
SVC syndrome secondary to a large mediastinal tumor
Spinal cord compression secondary to vertebral metastases
Neurologic problems secondary to primary CNS lymphoma
or lymphomatous meningitis
o GI obstruction, perforation, and bleeding
o Pain secondary to tumor invasion
o Leukocytosis (lymphocytosis) in leukemic phase of disease
NHL – COMPLICATIONS
• Chemotherapy
complications
o
o
o
o
o
o
o
o
o
o
o
and
other
treatment-related
Cytopenias (ie, neutropenia, anemia, thrombocytopenia)
Nausea or vomiting
Infection
Fatigue
Neuropathy
Dehydration after diarrhea or vomiting
Cardiac toxicity from doxorubicin
Catheter-related sepsis
Catheter-related thrombosis
Secondary malignancies
Tumor lysis syndrome