L 20-21 Lymphoproliferative Disorders: An Overview

Lymphoproliferative Disorders: Overview

• Lymphoproliferative malignancies encompass various disorders affecting lymphoid cells.
• These disorders include lymphomas and leukemias, each with unique characteristics and clinical presentations.
• Lymphomas are clonal malignant disorders derived from lymphoid cells, either precursor or mature B or T cells.
• The two main subtypes of lymphoma are Hodgkin lymphoma and Non-Hodgkin lymphoma.

Hodgkin Lymphoma (HL)

• Roughly 8,200 Americans are diagnosed with HL annually, and ~1,070 deaths occur each year in the US.
• HL exhibits a bimodal age distribution.
• Dr. Thomas Hodgkin first described Hodgkin Lymphoma in 1834.
• Approximately half of HL cases are associated with the Epstein-Barr Virus.
• Clinical presentations of HL include B symptoms (fever, night sweats, weight loss), pruritus, fatigue, pallor, enlarged peripheral lymph nodes, chest pain, shortness of breath, and abdominal pain.
• HL is classified into classical HL and nodular lymphocyte predominant HL.

Classical HL Subtypes

• Nodular sclerosis presents with a large mediastinal mass and accounts for 60% of HL cases. It is more common in women and young adults. Collagen bands separate lymphoid tissue into nodules.
• Mixed cellularity accounts for 20% of cases and tends to present as a more aggressive disease with a diffuse infiltrate of eosinophils, plasma cells, PMN, and histiocytes.
• Lymphocyte-rich HL occurs more often in older males and presents at an early stage.
• Lymphocyte-depleted HL accounts for less than 5% of HL cases and is usually associated with HIV.

Reed Sternberg Cells in HL

• HL is characterized by the presence of Reed Sternberg cells, which are large multi- or bilobulated cells with an owl's eye appearance and conspicuous eosinophilic inclusion-like nucleoli.
• Reed Sternberg cells are CD30 and CD15 positive, and their absence has a high negative predictive value for HL diagnosis.

Workup for HL

• Workup for HL includes history and physical exam, CBC, CMP, LDH, ESR labs, lymph node biopsy (excisional), PET/CT scan, 2D-echo, and pulmonary function test.

Staging Considerations

• HL staging is based on the Ann Arbor staging system.
• Stage I involves a single lymph node region or extranodal site.
• Stage II involves two or more lymph node regions on the same side of the diaphragm.
• Stage III involves lymph node regions on both sides of the diaphragm.
• Stage IV involves diffuse or disseminated involvement of one or more distant extranodal sites.

Prognostic Factors for HL

• ESR and B symptoms, a mediastinal mass, greater than 3 nodal sites, an E lesion, and bulky disease are unfavorable risk factors for stages I-II Classical Hodgkin Lymphoma.
• International Prognostic Score (IPS) factors include albumin <4 g/dL, hemoglobin <10.5 g/dL, male sex, age ≥45 years, Stage IV disease, leukocytosis (white blood cell count at least 15,000/mm³), and lymphocytopenia (lymphocyte count less than 8% of white blood cell count, and/or lymphocyte count less than 600/mm³).

Treatment Approaches for HL

• Treatment for HL depends on the stage and the presence of risk factors.
• Front-line therapy involves chemotherapy, including ABVD (Adriamycin, Bleomycin, Vinblastine, Dacarbazine) followed by involved field Radiotherapy (RT). Note Bleomycin can cause pneumonitis
• If relapsed, alternative chemotherapy is followed by an autologous stem cell transplant, using new agents such as Brentuximab vedotin and PD-1 antibodies.

Non-Hodgkin Lymphoma (NHL)

• NHL is the 7th most common cancer diagnosed annually in men and the 6th in women.
• Approximately 72,200 new cases occur in the US annually, with 20,000 deaths reported each year.

NHL Classifications

• NHL is classified as indolent, aggressive, or highly aggressive.
• Indolent NHL includes follicular lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma, and small lymphocytic lymphoma

Follicular Lymphoma (FL)

• It is the 2nd most common NHL subtype and is the most common subtype of indolent NHL.
• FL cells are typically CD20+, CD5-, CD23-, CD10+, BCL6+, and BCL2+.
• FL presents mostly as Stage III-IV cancer.
• Clinical features of FL include a median overall survival estimated to be more than 15 years, often deemed incurable.
• Treatment may involve rituximab, bendamustine-rituximab, R-CHOP (chemotherapy), or rituximab with combination chemotherapy. Relapsed and refractory cases utilize idelalisib (PI3K delta inhibitor) or lenalidomide (immunomodulatory) with rituximab.

Marginal Zone Lymphoma (MZL)

• Marginal Zone Lymphoma (MZL) is referred to as indolent.
• MZL accounts for approximately 10% of all lymphomas.
• Subcategories of MZL include extranodal (MALT), nodal, and splenic types.
• MZL is linked to specific microorganisms based on location including Helicobacter pylori (gastric), Campylobacter jejuni (intestine), and Chlamydia psittaci: (orbital/ocular)

Diffuse Large B Cell Lymphoma (DLBCL)

• DLBCL is an aggressive disease and the most common form of NHL in the US.
• 40% of patients with DLBCL present with extranodal involvement
• DLBCL is characterized by large neoplastic B lymphoid cells and has cure rates of approximately 60%.

Gene Expression in DLBCL

• Gene expression profiling (GEP) subdivides morphologically indistinguishable DLBCL into three distinct cell of origin (COO) subtypes.
• Treatment may involve R-CHOP chemotherapy with chemotherapy or salvage chemotherapy followed by autologous stem cell transplant if relapsed.
• Immunotherapies for DLBCL include chimeric antigen receptor T cells and antibody drug conjugates.

Mantle Cell Lymphoma (MCL)

• MCL is considered an aggressive disease that involves the GI tract.
• MCL accounts for ~6% of all lymphomas.
• It is considered incurable with a standard treatment approach.
• The genetic hallmark of MCL is translocation t(11;14), leading to overexpression of Cyclin D1.

Burkitt Lymphoma (BL)

• Burkitt lymphoma is deemed a very aggressive form
• Endemic (EBV-related, jaw, Africa) and sporadic forms occur.
• Extranodal sites are often involved, especially the GI tract
• Hallmark translocation in Burkitt Lymphoma: t(8;14) leads to overexpression of myc.
• "Starry sky" appearance is a common histopathologic feature.

HIV Associated Lymphomas

• Commonly in patients with AIDS.
• It's associated with EBV and HHV8.
• Subtypes include DLBCL, Burkitt and Plasma blastic, among others.

Leukemia vs Lymphoma

• Leukemia originates in bone marrow
• Chronic leukemia originates from mature cells and often have a chronic clinical course.
• Acute leukemia originates from immature hematopoietic precursors and has an acute clinical course that is fatal if untreated.
• Lymphoma originates outside the marrow, usually in the lymph node.
• Some diseases have overlapping features with both lymphadenopathy and circulating cells in the blood.

Lymphocyte Antigens

• B-cells exhibit CD19 and CD20, while monotypic kappa or lambda indicates monoclonality.
• T-cells exhibit CD2, CD3, CD5, and CD7, while CD4:CD8 ratio can be skewed in non-neoplastic disorders. Aberrant immunophenotype indicates clonality.
• Natural killer cells exhibit CD2, CD7 and CD56.
• Immature cells exhibit CD34 and TdT.

Flow Cytometry

• Flow cytometry classifies cells by B- or T-cell origin and differentiates leukemia from non-neoplastic lymphocytosis. It can also distinguish acute vs. chronic leukemia.

Chronic Lymphocytic Leukemia (CLL)

• CLL is the most common leukemia in the US, accounting for 30% of all leukemias, with 15,000 cases diagnosed annually.
• The median age at diagnosis is 70.
• CLL involves B-cell accumulation in bone marrow, blood, liver, spleen, and lymph nodes, referred to as small lymphocytic lymphoma (SLL).
• Clinical features include lymphocytosis greater than 5000 monoclonal lymphs/uL, lymphadenopathy, splenomegaly, anemia, thrombocytopenia, and increased susceptibility to infections. These clinical signs are often immune-mediated.
• Cells are CD5-positive.
• CLL is a chronic indolent disease, often asymptomatic at diagnosis. Typically reserved for those with symptoms and complications.

Hairy Cell Leukemia

• HCL is an uncommon chronic lymphoproliferative leukemia with a peak incidence between 40-60 years.
• Clinical features include pancytopenia (predominantly anemia), infections, splenomegaly, and an absence of lymphadenopathy.
• A distinguishing diagnostic feature is Tartrate-resistant acid phosphatase (TRAP).
• A ten year survival rate is over ninety percent.

Acute Lymphoblastic Leukemia (ALL)

• It is the most common malignancy of childhood and surges again in older adults.
• ALL is the most common malignancy of childhood, but incidence surges again in older individuals. The origin of this malignancy if lymphoblast in the bone marrow.
• B-cell ALL is the most common subtype, while T-cell ALL predominates in males.
• Has a predisposition to spread into the CNS.

Clinical Signs for ALL

• Anemia, neutropenia, thrombocytopenia, infections, bleeding, and blast accumulation in blood and organs/tissues.

Prognostic markers

• FISH and cytogenetics are used as prognostic markers in the diagnosis of cancer

Summary of Lymphocyte Disorders

CLL/SLL:

• reactive lymphocytosis is most often due to infection
• CD5-positive chronic leukemia/lymphoma of B cells in predominantly adults.

HCL:

• CD103+ chronic leukemia of B cells, often associated with dry tap”.

ALL:

• acute leukemia of lymphoblasts, more common as a B cell, and more common in children than adults.