Hematology Lesson 8

Lymphoid tissue disorders

 Lymphadenopathy
Locations of lymphoid tissue
 Normal locations
a. Regional lymph nodes
b. Tonsils and adenoids (Waldeyer tonsillar ring)
c. Peyer patches and appendix
d. White pulp of the spleen
 Locations of B cells (Fig. 14-1)
a. Germinal follicles in lymph nodes
b. Peripheral areas of the spleen white pulp
 Lymphadenopathy
 Location of T cells (see Fig. 14-1)
a. Paracortex (parafollicular) in the lymph nodes
b. Periarteriolar sheath in the spleen
c. Thymus (primary site for T cell synthesis)
 Locations for histiocytes
a. Sinuses in lymph nodes (see Fig. 14-1)
b. Skin (called Langerhans cells)
 Locations of selected lymphoid disorders
Lymphadenopathy

Epidemiology
 Age and lymphadenopathy
1) Persons <30 years old
• Lymph node enlargement is usually a benign disease (∼80% of cases).
2) Persons >30 years old
• Lymph node enlargement is usually a malignant disease (∼60% of cases)
• Malignant disease may be metastatic cancer (most common) or a primary
lymph node malignancy (e.g., malignant lymphoma).
Causes of lymphadenopathy

1) Reactive lymphadenitis
• Hyperplasia of B cells, T cells, or histiocytes
2) Infiltrative disease
• Examples—metastasis (most common) and malignant lymphoma
 Painful lymph nodes imply inflammation
(e.g., infection, autoimmune disease)
 Localized painful lymphadenopathy
a) Localized lymphadenopathy occurs when nodes drain sites of infection
(e.g., tonsillitis).
b) Most common sites are the anterior cervical nodes (e.g., tonsillitis) and the
inguinal nodes (e.g., lymphogranuloma venereum, chancroid).
 Generalized painful lymphadenopathy
a) Primarily seen in systemic disease
b) Examples—infectious mononucleosis, SLE
Painless nodes imply a malignancy.

 Lymph nodes usually indurated and often fixed to the surrounding tissue
Localized painless lymphadenopathy
a) Occurs when lymph nodes are draining a primary cancer site
• Examples—axillary lymph nodes in breast cancer and inguinal lymph nodes in
vulvar squamous cell carcinoma
b) Also occurs in Hodgkin lymphoma (HL) and other types of malignant lymphoma
Generalized painless lymphadenopathy
a) Occurs in the majority of acute and chronic leukemias except hairy cell
leukemia
b) Occurs in follicular B-cell lymphoma and other types of malignant lymphoma
Key lymph node groups involved in primary
or metastatic cancer
 Submental lymph nodes • Metastatic squamous cell carcinoma in the floor of
the mouth
 Cervical lymph nodes
a) Metastatic head and neck tumors (e.g., larynx; thyroid, nasopharynx)
b) Hodgkin lymphoma
 Left supraclavicular lymph nodes (Virchow nodes) • Metastatic abdominal
cancers (e.g., stomach; pancreas)
 Right supraclavicular lymph nodes
a) Metastatic lung and esophageal cancers
b) Hodgkin lymphoma
 Axillary lymph nodes • Metastatic breast cancer
 Epitrochlear lymph nodes • Non-Hodgkin lymphoma (NHL)
 Hilar lymph nodes • Metastatic lung cancer
Key lymph node groups involved in
primary or metastatic cancer
 Mediastinal lymph nodes
a) Metastatic lung cancer
b) Hodgkin lymphoma (particularly the nodular sclerosing type)
c) T-cell lymphoblastic lymphoma
 Tonsillar (superior jugular node) • Metastatic squamous cancers in the oral
cavity
 Pre-aortic lymph nodes
a) Metastatic testicular cancer • Testicles migrate to the scrotum from the
abdomen.
b) Burkitt lymphoma
 Inguinal lymph nodes • Metastatic vulvar and penile squamous cancers
Types of reactive lymphadenitis

Follicular hyperplasia
 Definition—B-cell antigenic response (see Fig. 14-1)
1) Germinal follicles are sharply demarcated from the
paracortex.
2) Lymphocytes are in different stages of
development.
 Examples
1) Early stages of HIV infection
2) Other examples—rheumatoid arthritis and SLE
Types of reactive lymphadenitis

Paracortical hyperplasia
 Definition—T-cell antigenic response
Dermatopathic lymphadenitis
1) Lymph nodes are draining areas with a chronic dermatitis (e.g., psoriasis).
2) Lymph nodes contain macrophages with phagocytosis of melanin pigment.
• Because of the black pigment, it is confused with metastatic malignant
melanoma.
 Other examples—phenytoin and viral infections
Types of reactive lymphadenitis
Sinus histiocytosis

 Definition—benign histiocytic response in lymph nodes draining a tumor

 Favorable sign in the axillary lymph nodes in breast cancer
Mixed B- and T-cell hyperplasia

Cat-scratch disease
 Granulomatous microabscesses are present in regional lymph nodes (e.g.,
axillary, cervical).
 Bartonella henselae is the cause.
 Treatment is azithromycin.
Toxoplasmosis
 Approximately 50% of the population has been infected with Toxoplasma
gondii.
 It causes a syndrome like mononucleosis, with painful cervical
lymphadenopathy.
Mixed B- and T-cell hyperplasia
Tularemia
 Caused by Francisella tularensis, a gram-negative intracellular coccobacillus
 Zoonosis (infection transmitted from animals to humans) often seen in hunters and trappers
 Reservoirs of the bacteria include rodents, deer, and rabbits (90%).
 Transmission
• Bites by Dermacentor ticks
• Skin contact with an animal hide
• Aerosol
Ulceroglandular type of tularemia
 Most common presentation in the United States
 Localized papular lesion develops at the point of inoculation (tick bite) →
 Ulceration of the papule →
 Regional lymphadenitis (noncaseating granulomatous inflammation) →
 Sepsis leading to dissemination throughout the body (e.g., spleen, liver)
 Treatment is gentamicin.
Plague

 Caused by Yersinia pestis, a gram-negative facultative intracellular

bacterium
• Yop gene protein products inhibit phagocytosis of the bacterium and kill
phagocytes.
• Similar to all Yersinia species, it requires iron for growth.
 Transmission
• Bite of infected fleas that have bitten infected ground squirrels, prairie dogs,
wood rats, or chipmunks, which are the reservoir of the bacterium
• Droplet infection from a patient with the disease
Three main presentations

 Bubonic plague (most common presentation)

 Septicemic plague (second most common presentation)
 Pneumonic plague (transmits to others by aerosol [uncommon] or as a
secondary complication of septicemic plague)
 Plague mainly occurs in the Western United States (most commonly in
Arizona, New Mexico, and Colorado).
 Bubonic plaque may be limited to lymph node involvement or spread into
the bloodstream (secondary septicemic plague), with or without spread to
the lungs (secondary pneumonic plague).
Natural history of the infection
 Organism enters the body at the site of a flea bite, usually the lower leg.
 Infection spreads into the inguinal lymph nodes, where it produces buboes,
which appear edematous and congested early in the disease.
 Within the lymph nodes there is massive proliferation of the organisms
accompanied by an exudate without inflammatory cells causing the nodes to
swell to the size of hen’s eggs
 Eventually the nodes exhibit hemorrhagic necrosis and vessel thrombosis with
abscess formation, often leading to spontaneous rupture of the nodes.
 Bacteria often escape from the nodes and enter the bloodstream (secondary
septicemic phase), causing widespread necrosis within organs throughout the
body.
• Disseminated intravascular coagulation is a common complication in this phase.
• Endotoxemia produces septic shock (refer to Chapter 5).
 If the lungs are involved (secondary pneumonic phase), hemorrhagic and
necrotizing bronchopneumonia develops in all lobes, along with fibrinous
pleuritis.
Clinical findings

 Bubonic plague findings include:

• Fever, chills, myalgia, arthralgia, headache, and prostration
 Septicemic plague findings are those of septic shock from endotoxemia and
include:
• Vomiting, abdominal pain, refractory hypotension, and renal failure
 Pneumonic plague findings include:
• Chest pain, dyspnea, and productive cough (Gram stain reveals numerous
organisms)
 Treatment
a) Gentamicin is effective and has replaced streptomycin for treatment.
b) Tetracycline is effective in uncomplicated bubonic plague.
Lymphomas
Non-Hodgkin Lymphoma (NHL)
 Account for ∼60% of adult lymphomas
• Greater than 80% are of B-cell origin and derive from the germinal follicle.
 Second most common cancer in AIDS
 Median age in adults is 50 years old
 Approximately one-third arise from extranodal sites.
• Extranodal sites include the stomach (most common site), Peyer patches,
and central nervous system (CNS; particularly in AIDS).
 Childhood NHL
a. Account for 60% of cases of malignant lymphoma
• T-cell lymphoblastic lymphoma or a Burkitt lymphoma
b. NHL is generally more aggressive in children than adults.
Risk factors
 Viruses
1) Epstein-Barr virus (EBV)
 Burkitt lymphoma
 Diffuse large B-cell lymphoma
 Primary CNS lymphoma (HIV)
• Associated with AIDS
2) Human T-cell lymphotropic virus (HTLV) type I
• Adult T-cell lymphoma or leukemia
3) Hepatitis C virus (HCV)
• B-cell lymphoma
Risk factors
 Helicobacter pylori
1) Malignant lymphoma of the stomach
• Derives from mucosa-associated lymphoid tissue in the stomach
2) Treatment of peptic ulcer disease caused by H. pylori reduces the risk for
developing this lymphoma.
 Autoimmune disease
1) Sjögren syndrome
• Commonly associated with salivary gland and gastrointestinal lymphomas
2) Hashimoto thyroiditis
• Associated with malignant lymphoma arising within the thyroid gland
Risk factors

 Immunodeficiency syndromes
• Chromosome instability syndromes (e.g., Bloom syndrome), AIDS
 Immunosuppressive therapy used to prevent rejection in recipients of organ
or bone marrow transplants
 High-dose radiation used in the treatment of Hodgkin lymphoma
 Pathogenesis

1. Mutation produces a block at a specific stage in the development of B or T

cells
2. Example—accumulation of small cleaved B cells in follicular lymphoma
B-cell NHL
Pathologic findings
T-cell lymphomas

 Precursor T-cell lymphoblastic leukemia/lymphoma

a. Accounts for 40% of childhood lymphomas
 Primarily involves the anterior mediastinal and cervical nodes
 Bone marrow and CNS involvement is common
 Precursor T-cell lymphoblastic leukemia
• Leukemic variant of the lymphoma
Mycosis fungoides and Sézary syndrome

 Epidemiology
1) Both conditions involve neoplastic peripheral CD4 helper T (TH) cells.
2) They usually occur in adults 40 to 60 years of age.
 Mycosis fungoides (MF)
1) Begins in the skin (rash to plaque to nodular masses)
• Progresses to the lymph nodes, lung, liver, and spleen
2) Groups of neoplastic cells that invade the epidermis are called Pautrier
microabscesses.
 Sézary syndrome
1) MF with a leukemic phase
2) Circulating malignant T cells are called Sézary cells.
Hodgkin Lymphoma (HL)

 Epidemiology
1. Accounts for ∼40% of adult lymphomas
2. Age and sex differences
 Slightly more common in men than women
• Exception—nodular sclerosing type is more common in women
 More common in adults than children
 More common in whites than blacks
 Bimodal age distribution
a. First large peak is 15 to 34 years old
b. Second smaller peak is >50 years old
c. Occurs in a younger age bracket than NHL
Hodgkin Lymphoma (HL)

 Most common site of initial involvement is the neck region

EBV has been identified in certain types of HL (e.g., 60%-70% of cases of mixed
cellularity HL).
 Persons with HIV infections have a higher incidence of HL relative to an
uninfected population.
 Defects in cell-mediated immunity (CMI)
• Example—defects in skin reactions to injection of common antigens (anergy;
refer to Chapter 4)
Pathogenesis

 Genetic susceptibility underlies HL in children.

 Activation of the transcription factor NF-κB (nuclear factor kappa-
lightchain-enhancer of activated B cells) is common in classical HL.
a. NF-κB is activated by EBV or other factors.
b. Once activated, it turns on genes that promote proliferation of B cells.
Hodgkin Lymphoma (HL)
Classification
 Lymphocyte rich classical
 Nodular sclerosing classical (most common type)
 Mixed cellularity classical
 Lymphocyte depleted classical
 Nodular lymphocyte predominant
Pathologic findings

 Involves localized groups of nodes and has contiguous spread to other

lymph node groups
 a. Most frequently involves cervical, supraclavicular, and anterior
mediastinal lymph nodes
 b. Cut section of involved lymph nodes has a bulging “fish-flesh”
appearance
Reed-Sternberg (RS) cell
 Neoplastic cell of HL
1) Immunophenotype markers are positive for CD15 and CD30.
2) Most (not all) RS cells are of B-cell origin, derived from lymph node germinal
centers.
Classic RS cell
• Two mirror image nuclei, each with an eosinophilic nucleolus surrounded by clear
halo (Fig. 14-10A)
RS variant: lacunar cell
1) Not a “classical” Reed-Sternberg cell
2) Monolobated or multinucleated cell with small nucleoli and abundant, pale
cytoplasm
3) Cell lies in a clear space (artifact of fixation in formalin-fixed tissue)
4) Present in the nodular sclerosis type of HL (Fig. 14-10B)
Diagnosis

 Presence of a classic Reed-Sternberg cell is required

Reed-Sternberg cells
Clinical findings and prognosis

 Constitutional signs
a. Fever, unexplained weight loss, night sweats (40% of cases)
b. Pruritus
c. Pel-Ebstein fever—uncommon variant of fever • Characterized by alternating
bouts of fever followed by remissions
 Hematologic findings
a. Normocytic anemia (presenting symptom 40% of cases) • Anemia of chronic
disease, immune hemolytic anemia
B. Painless enlargement of single groups of lymph nodes in the neck region •
Become painful if the patient drinks alcohol
 Chest pain, cough, and dyspnea usually indicate the presence of a large
mediastinal mass or metastasis to the lungs.
Primary factors that determine the prognosis
in HL

 Clinical stage is more important than the type of HL

 Majority have lymphadenopathy above the diaphragm (stages I and II),
which correlates with an excellent prognosis.
 Increased risk for developing second malignancies, usually acute
myeloblastic leukemia (AML) or NHL
• Increased risk is related to treatment with radiation and alkylating agents.
Treatment

Radiotherapy and chemotherapy are used depending on the stage of the

disease.
 Survival statistics
1. Cure rate for persons with stage I or IIA disease is over 90%.
2. In more advanced disease (e.g., stage IVA or IVB), the 5-year survival rate is
60% to 70%.