LYMPHOID NEOPLASMS

LECTURE BY: DR. JANE PERMITES (HARRISON’S INTERNAL MEDICINE CHAPTER 104, 105)
3RD YEAR, 2ND SEMESTER- ONCOLOGY MODULE

LYMPHOID NEOPLASMS: - LYMPHOMA -

LEUKEMIA VS. LYMPHOMA? -
LEUKEMIA
● Lymphoid neoplasms presenting with widespread
involvement of bone accompanied by presence of large
numbers of tumor cells in the peripheral blood
LYMPHOMA
● Proliferations arising from a discrete mass
● Results from clonal expansion of tumor cells from B, T,
or NK cells
● Most are from B cells

FROM THE LECTURE

● To review the origin of lymphocytes: From the stem cell, it
would give rise to Lymphoid stem cell that would then give
rise to Lymphoblast
● Lymphoblast would then give rise to the following:
○ B- Lymphocyte
○ T- Lymphocyte
○ Natural Killer (NK) Cell
● Lymphomas arise from the proliferation of Lymphocytes

FROM THE LECTURE

FROM THE LECTURE
● Proliferations of the lymphocytes are formed from discrete
masses that could grow in the Tonsils, Spleen, or other
Lymph Nodes
● However, it can grow in any parts of the body
● This diagram shows the “Age of Diagnosis for
Hodgkin’s and Non-Hodgkin’s Lymphoma”
● It is measured in cases per 100,000 and are compared to
one another
● These are patients diagnosed within 1997 to 2001
● There is approximately:
● ~56,390 new cases of NHL per year
● ~7, 350 new cases of HL per year
● Non Hodgkin’s Lymphoma
● A disease predominantly of the elderly
● One of the most rapidly rising cancers
● Incidence has double since the early 1970’s
● Potential Explanation for its Inc. in Incidence:
■ Infectious agents
■ Congenital & Acquired
Immunodeficiency Syndrome
■ Environmental Exposure
■ Genetic Factors
● Hodgkin's Lymphoma
● Slightly bimodal distribution

LYMPHOID NEOPLASMS 1
 HODGKIN LYMPHOMA VS. -
NON-HODGKIN LYMPHOMA -
GENERAL RULE OF LYMPHOMAS→ REMEMBER!
● Histologic examination for lymph nodes/tissue involved is
required for diagnosis
● Daughter cells from the malignant progenitor cells has the
same antigen receptor gene configuration and sequence
and synthesize identical receptor protein
● 80-90% are B-cell origin
● Lymphoid neoplasms disrupt normal architecture and
function of the immune system FROM THE LECTURE
● Neoplastic T and B cells tend to recapitulate the ● The most common cell lineage in lymphoma→ B cell
behavior of their normal counterparts ● The most common type of lymphoma→ Non Hodgkin’s
● HL spreads in an orderly fashion in contrast to NHL

FROM THE LECTURE

● This photo is from Robbin’s Pathology
● B CELL NEOPLASMS: Bone Marrow Origin
● Pre-B Lymphoblast (BLB) → Precursor B
lymphoblastic lymphoma/leukemias
● Naive B Cell (NBC) → Small lymphocytic
lymphoma
● Mantle Zone B Cell (MC) → Mantle cell
lymphoma
● Germinal Center B Cell (GC) → (see below)
■ Follicular lymphoma
■ Burkitt lymphoma
■ Diffuse large B cell lymphoma FROM THE LECTURE
■ Hodgkin’s lymphoma ● 4 staging system→ most commonly used staging in NHL
● Plasma Cell (PC) → Multiple myeloma ● Originally designed for HL but has been adapted to NHL
● Marginal Zone B cell (MZ) → (see below) ● Staging defines the extent of cancer along the 3 axis
■ Diffuse large B cell lymphoma (tumor, node, metastasis)
■ Marginal zone lymphoma ● The rationale behind the staging system is to accomplish
■ Small lymphocytic lymphoma treatment strategies, to help evaluate treatment results, to
■ Chronic lymphocytic leukemia standardized information and to facilitate exchange
● T CELL NEOPLASMS: Thymus origin between healthcare professionals and treatment centers
● CD4-/CD8- (Double-Negative) Pro-T cell ● Also used to formulate a more accurate prognosis and
(DN);CD4+/CD8+ (Double-Positive) Pre-T cell promote continuity of cancer investigation
(DP) → Precursor T lymphoblastic ● Ann Arbor Staging System- Subclassified into A and B
lymphoma/leukemia categories
● Peripheral T-Cell (PTC) → Peripheral T-cell ● A→ Absence of “B symptoms”
lymphoma ● B→ Presence of “B symptoms”

LYMPHOID NEOPLASMS 2
 APPROACH TO THE PATIENT - HODGKIN BIOLOGY
HODGKIN’S LYMPHOMA ● RS is “crippled” germinal center B cell
● Dictated mainly by where the disease is located (results of ○ Does not have normal B cell surface antigens
staging) rather than the exact histologic subtype ■ Somatic mutations result in stop codon
NON-HODGKIN’S LYMPHOMA ■ No apoptotic death → Malignant
● Often dedicated more by the histologic subtype than the transformation
results of staging ○ Unclear how this occurs; EBV?
○ Unclear how cells end up with RS phenotype
WHO 2016 LYMPHOMA CLASSIFICATION - REED STERNBERG CELLS
● Neoplastic giant cell of B cell origin (from germinal center
CATEGORIES or post-germinal center B cells)
1. Mature B-cell ● Induce accumulation of reactive lymphocytes, histiocytes
2. Mature T and NK cell neoplasm and granulocytes
3. Hodgkin Lymphoma ● 1-5% of the total tumor cell mass
4. Post-transplant lymphoproliferative disorders ● Large (15-45 μm diameter)
5. Histiocytic and Dendritic cell neoplasms ● Multiple or Single nuclei
● Variants: Classic RS Cell→ Binucleated cell with nucleoli
HODGKIN LYMPHOMA - (also known as “Owl’s Eye”)

FROM THE LECTURE

● He first described the functional relationship between the
lymph nodes and the spleen
● He then described the pathologic relationship between the
lymph nodes and the spleen
INCIDENCE
● 2-3/ 100,000/ year
● Bimodal Distribution
○ 1st peak: 25-30 years old
○ 2nd peak: 50-70 years old
● M>F, especially in pediatric cases
● M=F nodular sclerosing subtype
CLINICAL FEATURES
● Painless lymphadenopathy (cervical lymph nodes)
● B symptoms (night sweats, fever, weight loss)
● Pruritus (focal or generalized)
HODGKIN LYMPHOMA
● Arises in single node or chain of nodes
● Spreads first to anatomically contiguous node
● Presence of giant cells (RS cells)

FROM THE LECTURE

● At the center: RS Cell
● It releases different cytokines that would recruit the
different inflammatory cells

FROM THE LECTURE

● The presence of Reed-Sternberg cells is pathognomonic
to Hodgkin Lymphoma

LYMPHOID NEOPLASMS 3
RS VARIANTS (5) CLASSIFICATION OF HODGKIN LYMPHOMA
1. Nodular sclerosis
2. Mixed cellularity
3. Lymphocyte-rich
4. Lymphocyte depletion
5. Lymphocyte predominance
NOTE:
● Numbers 1 to 4 → CLASSIC FORMS OF HL

1. HL, NODULAR SCLEROSIS

● Most common form (65-70%)
● Variant RS cell→ Lacunar
● Collagen bands dividing cellular areas into nodules
● RS cells (Immunohistochemistry):
○ (+) CD15 and CD30
○ (-) CD45
○ EBV (-)
● Background: Eosinophils, Macrophages, Plasma cells
● F=M
FROM THE LECTURE ● Most young adults
● 1st Photo: Mononucleate/ Hodgkin/ Cell ● Frequent mediastinal involvement
● A single nuclei, giant cell
● The most common cell
● Differs from lacunar by the pink cytoplasm
● 2nd Photo: Binucleated Cell
● Also known as: Classic Cell, “Owl-eye” Cell
● 3rd Photo: Lacunar Cell
● With delicate cytoplasm that is often disrupted
during the cutting of sections, leaving the
nucleus sitting in an empty hole- a lacuna
● 4th Photo: Multinucleated/ “Coins on a Plate”
● 5th Photo: “Popcorn” Cell
● With a fluffy, lobulated nucleus
● 6th Photo: “Mummified” Cell
● Also known as: Pyknotic Cell
● Pyknosis or karyopyknosis→ the irreversible
condensation of chromatin in the nucleus of a
cell undergoing necrosis or apoptosis.

FOR THIS PICTURE:

● Cellular areas are divided into nodules by collagen bands
● Composed of fibrous tissue
● Cellular areas are composed of eosinophils,
macrophages, plasma cells and RS cells

FOR THIS PICTURE: RS VARIANTS

● Lacunar Cells

FOR THIS PICTURE: RS VARIANTS

● Multinucleated Cell
● Classic/ Binucleated Cell
FOR THIS PICTURE: SCANNED VIEW
● Blue-Purple Areas: Cellular areas surrounded by
collagen bands

LYMPHOID NEOPLASMS 4
 3. HL, LYMPHOCYTE-RICH TYPE
● Uncommon
● Reactive lymphocytes make up the majority of cell
infiltrate
● Lymph nodes are diffusely effaced
● (+) CD15 and CD30; 40% EBV +
● Diagnostic RS cells→ Mononuclear
● M>F
● Older adults

FOR THIS PICTURE: HIGH POWER VIEW

● There are several binucleated RS cells

FOR THIS PICTURE:

● Lymphocytes make up majority of cell infiltrates
FOR THIS PICTURE: ANTIGEN STAINING
● You can also see the diagnostic RS cells
2. HL, MIXED CELLULARITY TYPE 4. HL, LYMPHOCYTE DEPLETION TYPE
● 20-25% of HL ● Least common form (<5%)
● Diagnostic RS cells→ Mononuclear ● Paucity of background lymphocytes
● Background infiltrate rich in T lymphocytes, eosinophils, ● Relative abundance of RS cells or pleomorphic variants
macrophages, plasma cells ● (+) CD30, (+) CD15, EBV (+)
● Antigen Staining: ● Older males
○ (+) CD15 ● More likely to present in an advanced stage
○ (+) CD30
○ 70% EBV (+)
● M>F
● Biphasic incidence

FOR THIS PICTURE:

● Shows the paucity of lymphocyte depletion HL
FOR THIS PICTURE: ● Lymphocytes are decreased or not common compared to
● Shows the diagnostic RS cells, including: lymphocyte rich HL
● Mononuclear Giant Cell
● Binucleated Giant Cell
● Background shows infiltrates of lymphocytes, eosinophils,
macrophages and plasma cells

LYMPHOID NEOPLASMS 5
5. HL, LYMPHOCYTE-PREDOMINANCE TYPE NON-HODGKIN LYMPHOMA -
● Uncommon (5%) INTRODUCTION
● Young males ● Individual stages of B-cell differentiation are identified by
● Nodular infiltrate of small lymphocytes with variable characteristic morphology and expression patterns of cell
benign histiocytes surface antigen
● Rare RS cells ● CD19→ Marker of B-cell commitment
● LH variants→ Popcorn cells ○ Its expression is first detected during Pre-B cell
● Necrosis or fibrosis stage
● (+) CD20, (+) CD15, (+) CD30, EBV (-) ● Changes in morphology and antigen expression during B
cell differentiation are reflected in the malignant
counterparts of individual B-cells
● Detection of specific subsets of antigens has become an
important method of identifying leukemia and lymphoma
subtypes
● Example:
○ CLL: It is a malignancy of intermediate B-cells
characterized by expression of CD19, CD20,
CD23, and CD5 antigen
○ The malignant clone of follicular lymphoma (FL)
is a more mature B cell that is expressing CD19,
CD20 and CD22, but not CD5

FOR THIS PICTURE:

● Shows infiltrates of small lymphocytes with variable
benign histiocytes
● You can also see the diagnostic RS cell that is the LH type
or Popcorn Cells

ETIOLOGY AND PATHOGENESIS

● Exact cause unknown:
○ Somatic hypermutation NON-HODGKIN LYMPHOMA BIOLOGY
○ EBV virus AGGRESSIVE NHL
○ Immunodeficiency (organ transplantation, ● Short natural history (patients die within months if
immunosuppressants, HIV infection, untreated)
chemotherapy) ● Disease of rapid cellular proliferation
○ Autoimmune disease ● Potentially curable with chemotherapy
INDOLENT NHL
CLINICAL COURSE ● Long natural history (patients can live for many years
● HL is considered one of the most treatable cancers with untreated)
more than 90% of patients surviving more than 5 years ● Disease of slow cellular proliferation
● Long term survivors of Hodgkin Lymphoma who undergo ● Generally incurable with chemotherapy
chemo-radiotherapy develop secondary cancers
○ MDS NHL: PRESENTATION AND STAGING
○ AML ● AGGRESSIVE NHL
○ Lung cancers ○ Patients likely to present with symptoms
○ Others ● INDOLENT NHL
● This can be due to alkylating drugs for HL ○ Patients likely to present with painless
adenopathy
HODGKIN'S DISEASE SUMMARY ● Initial workup similar to Hodgkin Lymphoma
● B cell lymphoma
● Several histologic subtype NHL: APPROACH TO THE PATIENT
● Histologic subtype does not affect the approach to the APPROACH
patient ● Dictated mainly by histology of tumor
● Reed-Sternberg Cells ● Reliable hematopathology crucial
● Mediastinal disease common AGGRESSIVE NHL
● Spreads to contiguous nodes ● Cure is often the goal
● Common to have a “localized” presentation INDOLENT NHL
● Highly curable with current treatments ● Cure is rarely the goal
● Control is the goal

LYMPHOID NEOPLASMS 6
 FOR THIS PICTURE:
● Some cases respond to multi-agent chemotherapy and
have prolonged survival
● However, around 60% of cases are incurable
● The clinical heterogeneity may be due to the existence of
multiple unidentified tumor subtypes

LYMPHOMA SUMMARY -
● NHL incidence increasing
● Hodgkin incidence stable or decreasing
● Hodgkin Lymphoma
FOR THIS PICTURE: ○ Characterized by the Reed-Sternberg Cells
● The neoplastic cells are arranged into follicles ○ Stage more important that histologic subtype
○ Often limited stage (stage I or II)
○ Spreads to contiguous nodes
○ Often affects younger patients
○ Very responsive to therapy
○ Cure rate quite high
● NHL cure rate mediocre
○ Many histologic subtypes
■ Often more important that the stage
○ Indolent:
■ Often asymptomatic
■ Treatment: Less is more beneficial
○ Aggressive:
■ Often symptomatic
■ Require aggressive treatment ASAP to
achieve cure
FOR THIS PICTURE: SCAN VIEW OF FL
● Prominent follicles are noted

FOR THIS PICTURE:

● Contains several lymphocytes

LYMPHOID NEOPLASMS 7