Lymphoid Neoplasms Flashcards
Lymphocytosis
Lymphocytosis is an increase in lymphocytes in the peripheral blood.
Absolute Lymphocytosis vs. Relative Lymphocytosis
- Absolute lymphocytosis, a real increase in lymphocytes to greater than 4,000/uL, must be distinguished from relative lymphocytosis, which results from a decrease in neutrophils and/or monocytes.
- In the latter situation, when the neutrophils are decreased, the percentage of lymphocytes in the CBC differential will increase. This does not mean there are more lymphocytes, it just indicates that the neutrophils are reduced—with very different clinical implications.
Absolute Lymphocytosis vs. Relative Lymphocytosis Causes
- Absolute lymphocytosis occurs most often during viral infections or in lymphoid neoplasms.
- Neutropenia, with consequent relative lymphocytosis, occurs most commonly during drug reactions, severe infections, and myelodysplasia (ineffective production) or myeloid leukemia (bone marrow is replaced with malignant blast cells). Lymphopenia can also be caused by viruses, most notably HIV, which destroys the CD4(+) T-helper cells.
Absolute Lymphocytosis Differentials
• Infections
– Viruses: EBV, CMV, HIV
– Chronic bacterial: Tb, cat-scratch
– Pertussis, toxoplasmosis
– LYMPHOCYTOSIS USUALLY TRANSIENT
• Lymphoid neoplasms
– Chronic lymphocytic leukemia
– Others
– Distinguish using morphology, clinical history +/- immunophenotype
Benign (reactive) vs. Neoplastic Lymphocytosis
- Reactive lymphocytes (see image) have many different appearances. They are usually larger than normal lymphocytes with more abundant cytoplasm (light blue to dark blue) and have round to irregular nuclear contours and even prominent nucleoli. These may also be classified as “atypical lymphocytes”. These are seen in a wide variety of clinical settings.
- Clinical note: Be careful when the percent of “atypical” lymphocytes is high. Morphologic distinction between reactive and malignant lymphocytes can be difficult. You can always ask for a Pathologist review of the blood smear. More than 1 lineage (red blood cells, white blood cells, platelets) either high or low is particularly suspicious.
Lymphadenopathy
- Lymphadenopathy is not an uncommon clinical presentation and is usually a reaction to infection, medication, vaccination, immune abnormality or foreign material.
- The key question: is the enlarged lymph node most likely part of a reactive or neoplastic process? The clinical scenario is most helpful: Is there a history of infection, autoimmune disease, immunodeficiency, lymphoma, or other malignancy? Location, timing, and duration may give you clues
Lymphadenopathy Symptoms
- Benign (inflamed) lymph nodes: typically, hot, red, swollen but soft, painful, draining infected areas.
- Malignant lymph nodes are more often painless and hard
- Systemic symptoms – fever, night sweats, weight loss
Three histological patterns of benign (reactive) lymphadenopathy:
1) Cortex containing lymphoid follicles (B-cell zone)
2) Paracortex (T-cell zone; between and deep to follicles)
3) Medulla with medullary sinuses (contain histiocytes)
•In most cases of benign lymphadenopathy, there is distortion or expansion of a functional compartment of the lymph node, but not complete effacement, of the normal lymph node architecture. (Complete effacement or loss of normal nodal architecture is more likely to represent a neoplastic process over a reactive condition)
Benign (reactive) Lymphadenopathy - Follicular Hyperplasia
- Follicular (reaction of B cell germinal centers) hyperplasia: autoimmune, bacterial, HIV, toxoplasmosis
- Increase # of secondary lymphoid follicles
Benign (reactive) Lymphadenopathy - Paracortical Hyperplasia
•Paracortical (T cell) expansion: vaccinations, drug reaction (especially phenytoin), viral infections (especially infectious mononucleosis), skin disorders
Benign (reactive) Lymphadenopathy - Sinus Histiocytosis
•Sinus histiocytosis (expansion of sinus histiocytes): drainage of surgical site or malignancy.
Lymphoid Neoplasms
- Lymphoid neoplasms are a diverse group of entities with heterogeneous morphologic and clinical features. Note that some of the entities can present as either lymphoma or leukemia, or both. These terms were initially used to designate what were considered distinct entities, but with additional study and understanding, these divisions have blurred. The term “leukemia” is used for neoplasms that present with widespread involvement of the bone marrow and usually, but not always, the peripheral blood. “Lymphoma” is used for proliferations that form a tissue mass in a lymph node or extranodal sites.
- Lymphoid neoplasms are grouped based on their clinical aggressiveness into indolent, aggressive and highly aggressive subtypes.
Leukemia Presentation
- Leukemias tend to come to attention as a result of replacement of normal bone marrow elements by the leukemia: anemia causing fatigue, neutropenia predisposing to infections, and low platelet counts with bleeding.
- Young children with acute leukemia may present with bone pain due to the rapid expansion of the leukemia in the bone marrow.
- Patients may also have CNS symptoms (sleepiness, lethargy, headaches) if the CNS is involved.
Lymphoma Presentation
- The majority of patients will present with lymphadenopathy.
- With indolent lymphomas, lymphadenopathy may wax and wane over months to years. In aggressive lymphomas, masses will grow over weeks, and, in highly aggressive lymphomas, the masses may double in size in days.
- The enlarged lymph nodes are usually painless and show no signs of overlying inflammation (if superficial) such as erythema or discharge that are typical of reactive lymph nodes.
- Extranodal disease is seen in about one third of patients, with bone marrow, GI tract and skin the most common sites. Any area of the body/organ can be involved.
-The most common malignancy of testis in men over 60 years of age is lymphoma
Systemic “B” Symptoms of Lymphoma Presentation
•About 1/3 of patients will have systemic (“B”) symptoms:
- Unexplained fever over 38oC
- Drenching night sweats (necessitating a change of clothes or sheets)
- Unexplained weight loss >10% of total body weight
Etiology of Lymphoid Neoplasms
• Chromosomal translocations involving oncogenes
– Immunoglobulin genes and T cell receptors rely on physiologic breakage, recombination and somatic mutations to produce antigen receptor diversity
– Oncogenes can easily be translocated to these regions, then over expressed by the Ig and TCR promoters
• Inherited genetic factors:
– Disorders of genomic instability, Down syndrome, NF type I
• Viruses:
– EBV: Burkitt, Hodgkin, and post-transplant lymphomas
– HTLV: T-cell lymphoma
• Chronic Immune Stimulation
–Helicobacter pylori and MALT lymphoma
–Gluten sensitive enteropathy and intestinal lymphoma
- Immunodeficiency (HIV, iatrogenic)
- Autoimmune diseases
– Sjogren, Hashimoto
Classification of Lymphoid Neoplasms
Histogenic Basis of Classification of Lymphoid Neoplasms
Non-Hodgkin Lymphoma (NHL) versus Hodgkin Lymphoma
Clinical Grouping of Lymphoid Neoplasms
Precursor Neoplasms - Lymphoblastic Leukemia/Lymphoma (ALL)
- These neoplasms are composed of immature B-cells or T-cells (lymphoblasts). The vast majority are B-cell (85%). Cytogenetic abnormalities further divide B-cell ALL into prognostic groups (B-cell lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities).
- Because of the biologic unity of precursor B lymphoblastic leukemia and precursor B lymphoblastic lymphoma, the use of one or the other term in some patients is arbitrary. If the patient presents with a mass lesion and <25% lymphoblasts in the marrow, the designation lymphoma is preferred.
Precursor Neoplasms - Lymphoblastic Leukemia/Lymphoma (ALL) Clinical Features
• The majority (~85%) of precursor lymphoid neoplasms are of precursor B-cell origin that manifest as leukemia with extensive bone marrow, and variable peripheral blood, involvement.
Precursor Neoplasms - Lymphoblastic Leukemia/Lymphoma (ALL) - B-lymphoblastic leukemia
- Usually blasts (presenting as a leukemia) and cytopenia
- Packed marrow (due to blast proliferation) with decreased normal precursors
•Highly aggressive
Precursor neoplasm
•t(9;22) (bcr/abl)– poor prognosis, not present in all cases - more commonly positive in adults than children
-(Remember, this is translocation is also seen in CML)
•hypoploidy —> prognosis unfavorable
•Cytopenia
Bone pain
Precursor Neoplasms - Lymphoblastic Leukemia/Lymphoma (ALL) - T-lymphoblastic leukemia/lymphoma
- May be normal if only lymphoma presentation; if also leukemia, then same as B - Usually blasts (presenting as a leukemia) and cytopenia
- Mediastinal mass (thymus, classic location) – sheets of blasts
•Highly aggressive
Precursor neoplasm
- Mediastinal mass in adolescent male
- Sxs from mediastinal mass (tracheal obstruction, superior vena cava syndrome)
Acute leukemia: Morphology
• Lymphoblasts, as compared to myeloblasts:
– Smaller
– More condensed chromatin
– Inconspicuous nucleoli
– Scant cytoplasm
– Auer rods are not present (as they are in AML)
– Cannot distinguish B-cell versus T-cell by morphology
– Need phenotyping (usually flow cytometry) to distinguish different blasts.
Lymphoblastic leukemia Bone Marrow Morphology
Lymphoblastic leukemia/lymphoma: Morphology
B-lymphoblastic leukemia: prognosis
Mature B Cell Neoplasms
– Chronic lymphocytic leukemia
– Hairy cell leukemia
– Follicular lymphoma
– Diffuse large B cell lymphoma
– Burkitt lymphoma
– MALToma
– Mantle cell lymphoma
– Lymphoplasmacytic lymphoma
– Plasma cell neoplasms
Mature B Cell Neoplasms - Chronic lymphocytic leukemia (CLL) and small cell lymphocytic lymphoma (SLL)
- CLL is the most common leukemia of adults in the Western world. 15,000 new cases are diagnosed per year in the U.S.
- CLL and SLL differ only in the degree of peripheral blood lymphocytosis and some consider them to be one disease at different stages.
- This is a disease of adults with a median age of diagnosis at 60 yrs.
•Mature B Cell Neoplasms - Chronic lymphocytic leukemia (CLL) and small cell lymphocytic lymphoma (SLL) Features
- By definition, the patient has lymphocytosis; +/- cytopenias
- Small, mature lymphocytes with scant cytoplasm and smudge cells
- Indolent; treated when criteria met
- Anemia can be multifactorial: marrow infiltration, red blood cell aplasia, marrow suppression, autoimmune hemolysis.
Immunodeficiency
- hypogammaglobulinemia, cell mediated immunity
- Flow cytometry: CD5+ monoclonal B-cells
- Richter’s transformation to diffuse large B-cell lymphoma
Mature B Cell Neoplasms - Chronic lymphocytic leukemia (CLL) and small cell lymphocytic lymphoma (SLL) Clinical Manifestations
- Asymptomatic
- 25% with lymphocytosis on routine CBC
- Nonspecific symptoms
- Easy fatigability, weight loss, anorexia
- Generalized lymphadenopathy and hepatosplenomegaly
- <10% of patients present with a non-leukemic picture having only nodal involvement (SLL)
- Leukocyte count is highly variable
-Diagnostic criteria for CLL:
Sustained monoclonal lymphocytosis > 5,000/uL
Mature B Cell Neoplasms - Chronic lymphocytic leukemia (CLL) and small cell lymphocytic lymphoma (SLL) - Morphology
Mature B Cell Neoplasms - Chronic lymphocytic leukemia (CLL) and small cell lymphocytic lymphoma (SLL) - Immunophenotype
•Monoclonal B-cells (CD20+, CD19+) that express CD23 and CD5
Mature B Cell Neoplasms - Chronic lymphocytic leukemia (CLL) and small cell lymphocytic lymphoma (SLL) - Prognosis and Survival
- Staging: based on presence/absence of lymphadenopathy, organomegaly, anemia and/thrombocytopenia
- Genetic Features also predict prognosis
– Most common findings
* Good: del13q, trisomy 12
* Poor: del17p (p53 gene)
• Survival:
– Natural history of CLL is extremely variable
– >10 years for patients with minimal tumor burden
– If large cell transformation (Richter transformation) occurs, then survival is less than 1 year
Mature B Cell Neoplasms - Hairy Cell Leukemia
•Hairy cell leukemia is an uncommon, indolent, lymphoid malignancy accounting for only 2% of all leukemia with <1000 cases per year nationwide.
Mature B Cell Neoplasms - Hairy Cell Leukemia Features
•Pancytopenia; rare hairy cells in circulation (lymphocytosis not typical)
•Fried-egg appearance
Hairy projections
Dry tap
Marrow fibrosis
•Indolent; good prognosis
•-TRAP+
-BRAF mutation (treatment with BRAF inhibitor – Vermurafenib)
•Cytopenia
Splenomegaly
Mature B Cell Neoplasms - Hairy Cell Leukemia Clinical Features
•HCL is most common in older men, who present with pancytopenia and splenomegaly. Infectious associated with neutropenia, fatigue from anemia, petechiae from thrombocytopenia, and abdominal fullness or early satiety from splenomegaly are common symptoms.
Mature B Cell Neoplasms - Hairy Cell Leukemia Morphology
- The name is derived from the characteristic appearance of the neoplastic B-cells seen in the blood and bone marrow with “hairy” cytoplasmic projections.
- The bone marrow is frequently fibrotic leading to a “dry tap” (meaning no liquid bone marrow is obtained when attempting a bone marrow aspirate). •The abundant cytoplasm causes the cells to be spaced relatively far apart in the bone marrow leading to a “fried egg” appearance.
- The red pulp of the spleen is characteristically infiltrated.
Mature B Cell Neoplasms - Follicular Lymphoma Morphology
- Neoplastic germinal center cells recapitulate a normal germinal center resulting in a nodular pattern.
- The cells are a mixture of small and large cells with irregular nuclear contours (“cleaved”).
- Some cases transform to diffuse large B-cell lymphoma (sheets of large cells, no germinal center formation)
Mature B Cell Neoplasms - Follicular Lymphoma Pathogenesis
- Diagnostic hallmark: t(14;18) that translocates the BCL-2 gene next to the promoter of the immunoglobulin heavy chain gene (on chromosome 14).
- This leads to increased expression of the anti-apoptotic BCL-2 protein and immortalizes the cells.
Mature B Cell Neoplasms - Mantle Cell Lymphoma Morphology
•Composed of small lymphocytes with slightly irregular nuclear contours.
Mature B Cell Neoplasms - Diffuse Large Cell Lymphoma (DLBCL) Morphology
•Large lymphocytes in a diffuse sheet-like pattern (no nodular areas as we see in follicular lymphoma)
Mature B Cell Lymphomas - Burkitt Lymphoma Clinical Features
- Highly aggressive neoplasms with explosive growth.
- Three epidemiologic variants are recognized which differ in geographical distribution, clinical presentation, and biological features.
1) Endemic:
o Africa (regions endemic for malaria). Most common childhood malignancy.
o >95% EBV+
o Jaw, other facial bones in majority of cases; other sites: GI tract, kidney, breast
2) Sporadic:
o Worldwide, mainly children and young adults
o ~30% EBV+
o Abdominal masses – ileocecal region; other sites include ovaries, kidney, breast
3) Immunodeficiency-associated:
o HIV+ patients
o 25-40% EBV+
o Nodal, bone marrow
Mature B Cell Lymphomas - Burkitt Lymphoma Morphology
•Medium-sized cells in a starry sky pattern created by macrophages engulfing apoptotic tumor cells (tingible-body macrophages); numerous mitoses
Mature B Cell Lymphomas - Marginal Zone Mymphoma of MALT (MALToma) - Pathogenesis
- These lymphomas arise in chronically inflamed tissues involved by either autoimmune disorders (thyroid, salivary glands) or infection (stomach, lung, skin, conjunctiva).
- In the stomach, MALT lymphomas are highly associated with presence of helicobacter pylori.
- The lymphoma begins as a reactive polyclonal process, over time a monoclonal B cell population emerges, which then acquires further genetic changes.
Mature B Cell Lymphomas - Marginal Zone Mymphoma of MALT (MALToma) Morphology
•Neoplastic cells surround reactive germinal centers and infiltrate surrounding epithelium (lymphoepithelial lesions).
Mature B Cell Lymphomas Lymphoplasmacytic Lymphoma (Waldenstrom Macroglobulinemia) Morphology
•Mixture of small lymphocytes, plasmacytoid lymphocytes, and plasma cells
Mature B Cell Neoplasms - Plasma Cell Neoplasms - Plasma Cell Myeloma CRAB
1) Growth of plasma cells in bones, leading to lytic bone lesions and pathologic fractures. Bone pain is the most common presenting symptom. Hypercalcemia can give rise to confusion, weakness, lethargy, constipation and polyuria, and can contribute to renal disease.
2) Production of excessive immunoglobulins: Renal insufficiency is multifactorial; however, the most important risk factor is Bence-Jones proteinuria (free light chains in urine) – light chains are toxic to renal tubular epithelial cells.
3) Suppression of normal humoral immunity: Impairment of normal Ig production leads to risk of bacterial infection. Cellular immunity is relatively unaffected.
Mature B Cell Neoplasms - Plasma Cell Neoplasms - Plasma Cell Myeloma Lytic Bone Lesions
Mature B Cell Neoplasms - Plasma cell neoplasms Morphology
- Biopsies of bone lesions (or extraskeletal lesions), or bone marrow biopsies show a proliferation of monoclonal plasma cells.
- The peripheral blood may demonstrate RBCs sticking together in a linear array (Rouleaux formation).
- Rarely, plasma cells may enter the peripheral blood (plasma cell leukemia). Solitary lesions can occur in bone or soft tissue (plasmacytoma).
Hodgkins Lymphoma Morphology
•Infrequent large atypical cells called Reed-Sternberg cells are seen in a cellular background rich in lymphocytes, eosinophils, plasma cells, and/or histiocytes.
-Reed-Sternberg cells are large mononucleated or multinucleated cells, with prominent nucleoli resembling viral inclusions.
•Four morphologic variants are described:
1) Nodular sclerosis: Most common type. Nodules of inflammatory cells and lacunar cells (Reed-Sternberg variant) surrounded by bundles of collagen. Lacunar cell cytoplasm retracts leaving the cell sitting in an empty hole (lacuna).
2) Mixed cellularity: Inflammatory cells plus RS cells. No fibrosis.
3) Lymphocyte rich: Reactive lymphocytes make up the majority of the infiltrate.
4) Lymphocyte depleted: Paucity of lymphocytes and a relative abundance of RS cells.
Mature T Cell Neoplasms Mycosis Fungoides (MF) Clinical Features
- Most common of the T-cell lymphomas, most common cutaneous lymphoma. Usually adults.
- Older adults. Erythematous patch–> plaque–> tumor nodule.
Mature T Cell Neoplasms Mycosis Fungoides (MF) Morphology
•Band like infiltrate of CD4+ T-lymphocytes with convoluted nuclei that show clustered invasion of the epidermis forming Pautrier microabscesses.
Mature T Cell Neoplasms Sezary Syndrome Clinicopathologic Features
•Seen in Adults. Defined by the following triad:
- Erythroderma
- Generalized lymphadenopathy
- Presence of clonally related T-cells with cerebriform nuclei (Sezary cells) in skin, lymph nodes, and blood.
Mature T Cell Neoplasms Sezary Syndrome Morphology
•Microscopic features in skin may be similar to MF. Sezary cells have cerebriform nuclei.
Mature T Cell Neoplasms Adult T-cell leukemia/lymphoma (ATLL) Morphology
•Leukemic cells show remarkable pleomorphism with multilobed nuclei (“flower cells”).
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