L-22 Lymphoid Neoplasms: Leukemia, Lymphoma

• Lymphoid neoplasms are cancers that affect the cells of the lymphatic system.
• The primary lymphoid organs are the bone marrow and thymus.
• The secondary lymphoid tissues and organs are the lymph nodes and spleen.

Leukemia

• Leukemia is a malignancy of white blood cells.
• Bone marrow involvement and peripheral blood are features of leukemia.

Lymphoma

• Lymphoma is a malignancy of white blood cells.
• Lymphoma presents as a discrete tissue mass.

Classification of Lymphoid Neoplasms - Confusion

• Lymphomas can progress to leukemia.
• Lymphomas may show a leukemic peripheral blood picture.
• Leukemias can arise as lymphomatous masses without bone marrow involvement.

Classification of Lymphoid Neoplasms - REAL and WHO

• The Revised European-American Lymphoma (REAL) classification applies immunophenotypic and genetic features to identify clinicopathologic NHL entities.
• Immunophenotype features include cell markers (CD), cluster of differentiation, clinical behavior, and morphological criteria.
• The World Health Organization (WHO) classification is a modification of the REAL classification.
• The WHO classification is based on morphology and cell lineage, including chromosomal abnormalities and genetic mutations, and categorizes B-cell and T-cell neoplasms.
• WHO classification subtypes for NHL precursors: Precursor B-lymphoblastic leukemia/lymphoma, and Precursor T-lymphoblastic lymphoma/leukemia.

Classification of Lymphoid Neoplasms - B vs T Cells

• Tumors of B cells and T cells/NK cells can be broken down into precursor neoplasms, and peripheral neoplasms.
• Considerations for lymphoid neoplasms are that tissue is required for diagnosis; it is considered malignant unless proven otherwise; they originate from a single transformed cell (clone) and are B cell origin, and have normal immune disruption (functional and structural).

Acute Lymphoblastic Leukemia (ALL) / Lymphoma

• Immunophenotyping is used to classify ALL/Lymphoma.
• Most cases are precursor B-cell tumors (85%).
• Loss of function mutations includes B cell development, PAX5, E2, EBF and balanced t(12:21).
• Most cases occur in individuals under 15 years of age.
• ALL/Lymphoma is twice as common in whites and more frequent in boys than in girls.

Clinical Manifestations of ALL/Lymphoma

• Has an abrupt stormy onset.
• There are symptoms of bone marrow depression and bone pain and tenderness, including lymphadenopathy, splenomegaly, hepatomegaly, and CNS manifestations.

Pathology of ALL/Lymphoma

• Condensed chromatin
• Inconspicuous nucleoli
• Scant agranular cytoplasm
• Definitive diagnosis requires blast in marrow/circulation (>35%) and detection of B and/or T lymphocyte-specific markers.

Prognosis of ALL/Lymphoma

• Unfavorable Factors: Age under 2, presentation in adolescence or adulthood, peripheral blood blast counts greater than 100,000, and unfavorable cytogenetic aberrations like t(9;22).
• Favorable Factors: Age 2 to 10 years, low white count, and early pre-B phenotype.

Peripheral B Cell Neoplasms

• These are considered mature B cells.
• These include chronic lymphocytic leukemia, small lymphocytic lymphoma, and diffuse large B-cell lymphoma.

Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL)

• They are the most common lymphoid neoplasm in adults.
• They are morphologically, phenotypically, and genotypically indistinguishable; the difference lies in the degree of lymphocytosis.
• Median age of onset is 60 years
• There is a male predominance
• Often asymptomatic
• Nonspecific symptoms include: easy fatigability, weight loss, anorexia, generalized lymphadenopathy, and hepatosplenomegaly
• There is a highly variable total leukocyte count.
• They show lymph node effacement with slightly irregular nuclei, condensed chromatin, and scant cytoplasm.
• There are aggregates of small lymphocytes in bone marrow and organs
• In a peripheral blood smear, shows smudge cells.
• Tumor cells express CD19, CD20, CD23, plus CD5 (T-cell marker).

CLL/SLL Prognosis

• The median survival is 4 to 6 years.
• There is a survival of 10 years or more if there is tumor burden.
• Increased expression of CD38 or Zap-70 is associated with poor long-term survival; can undergo prolymphocytic transformation (15% to 30% of patients) or diffuse large B-cell lymphoma transformation (Richter Syndrome).

Plasma Cell Neoplasms

• Plasma cell neoplasms are terminally differentiated B cells that present clona populations with homogenous Ig.

Plasma Cell Neoplasms Types

• Multiple Myeloma
• Monoclonal Gammopathy of Undetermined Significance (MGUS)
• Waldenström Macroglobulinemia
• Heavy-Chain disease

Multiple Myeloma Features

• There is skeletal involvement and men are more likely to be affected.
• The neoplastic cells are IL-6 dependent for survival.
• There are plasma cells, myeloma cells w/ CD33, GPIIb/IIIa and Glycophorin antigens, flame cells, and Mott cells.
• Major pathological features include bone destruction mediated by IL-6 and Bence Jones Proteins.

Clinical Features of Multiple Myeloma

• Hypercalcemia
• Suppression of humoral immunity
• Hyperviscosity syndrome
• Anemia
• Bence Jones (k-light chain) proteinuria
• Renal Failure
• There is an M protein (monoclonal antibody) in serum and Bence Jones proteins in the urine, both detectible by immunofixation.
• Prognosis is poor with multiple bony lesions if untreated; rarely survive > 6 to 12 months, but indolent disease can survive for many years.
• With chemotherapy, remission is seen in 50% to 70% of patients, but median survival is 3 years.

Burkitt Lymphoma

• Burkitt Lymphoma has genetic causation through chromosomal translocations and oncogenes.
• Inherited genetic factors include Bloom syndrome, Fanconi anemia, Ataxia telangiectasia, Down syndrome (trisomy 21), and Type I neurofibromatosis.
• Viral causes include HTLV-1, Epstein-Barr virus (EBV), and Kaposi sarcoma herpesvirus/(KSHV/HHV-8), also iatrogenic factors such as radiation and chemotherapy.

Burkitt Lymphoma Causation

• May be EBV-related or sporadic depending on geographic location.
• Endemic form shows EBV / C-myc translocation, presents in the Mandible/Abdominal organs, and occurs with malaria infection.
• Endemic also promotes pathogenesis of eBL and leads to inhibition of EBV-specific immune response.
• Sporadic form shows C-myc translocation, mass in the Ileocecal / Peritoneum, and HIV association.
• The C-MYC proto-oncogene plays a pivotal role in Burkitt lymphoma.
• Characterized by diffuse effacement of involved tissues, high mitotic rate, and apoptosis.
• Displays a "Starry Sky" pattern including tingible body macrophages.
• B cells stain with slgM and CD 10, 19, 20, and BCL 6

Hodgkin Lymphoma

• Hodgkin lymphoma accounts for 0.7% of all new cancers in the US, with 8000 new cases/year.
• Average age at diagnosis is 32 years, and is most common in young adults/adolescents.
• It was the first human cancer successfully treated with radiation therapy and chemotherapy, curable in most cases.
• The Reed-Sternberg (RS) cell is the neoplastic element.

Hodgkin Lymphoma Characteristics

• RS cells or their variants are essential for histologic diagnosis, and there is contiguous spread initially through nodal disease.
• Spread followed by splenic disease, and then hepatic disease
• Final spread is to involvement to the marrow and other tissues.

Hodgkin Lymphoma Pathogenesis

• Involves transcription factor NF-κB Activation, often paired with EBV infection.
• Pathogenesis further involves gene mutations promoting lymphocyte survival and proliferation and acquired loss-of-function mutations.
• Reed-Sternberg Cells secretion includes cytokines, chemokines, and immunomodulatory factor galectin-1 which leads ro florid accumulation of reactive cells in tissues, and reactivate cells to support growth and survival of the tumor cells.
• T cells activate CD30 and CD40 receptors on RS, up-regulating NF-κB.
• There are 5 subtypes: Nodular sclerosis, Mixed cellularity, Lymphocyte rich, Lymphocyte predominant, and Lymphocyte depleted.

Hodgkin Lymphoma Nodular Sclerosis Type

• Most common, accounting for 65% to 70% of cases.
• The lacunar variant predominates/diagnostic RS is uncommon.
• There is collagen deposition in bands that divide involved lymph nodes into circumscribed nodules.
• Reed-Sternberg cells are found in a polymorphous background.
• Positive for PAX5 (a B-cell transcription factor).
• Present with male:female ratio parity in young adults, with nodes in the heads/neck region and mediastinum.
• The background Infiltrate is T lymphocytes, Eosinophils, Macrophages, and Plasma cells.

Hodgkin Lymphoma Mixed-Cellularity Type

• Constitutes about 20% to 25% of cases.
• Lymph nodes diffusely effaced by a heterogeneous cellular infiltrate.
• Diagnostic Reed-Sternberg cells and mononuclear variants are usually plentiful.
• Reed-Sternberg cells are infected with EBV in about 70% of cases.
• Immunophenotype is identical to nodular sclerosis type.
• Microscopic Diagnosis shows frequent mononuclear and diagnostic RS cells
• The background infiltrate includes T lymphocytes, Eosinophils, Macrophages, and Plasma cells.

Hodgkin Lymphoma Staging

• The Lugano classification is based on the Ann Arbor system.
• Stage I: HL is found in only 1 lymph node area or lymphoid organ (I) or that the cancer is found only in 1 part of 1 organ outside the lymph system (IE).
• Stage II: HL is found in 2 or more lymph node areas on the same side of the diaphragm (II).or the cancer extends locally from one lymph node area into a nearby organ (IIE).
• Stage III: HL is found in lymph node areas on both sides of the diaphragm (III), or HL is in lymph nodes above the diaphragm and in the spleen.
• Stage IV has spread widely into at least one organ outside of the lymph system, such as liver, bone marrow, or lungs.

Hodgkin Lymphoma Clinical Features

• Are Painless enlargement of lymph nodes.
• Diagnosis by lymph node biopsy.
• Orderly spread by contiguity., localized to a single axial group of nodes.
• Extranodal involvement uncommon
• General Clinical Features for both Nodular Sclerosis and Mixed Cellularity is Fever, night sweats, weight loss