Leukocyte Disorders Part 2 Lymphomas and Other Disorders Walter C. Bell, MD

Normal Lymph Node

Acute Nonspecific Lymphadenitis Lymph node enlargement due to infection Most often involves cervical nodes (teeth, tonsils) or axillary nodes (skin infections involving arms) Nodes are enlarged due to edema and tender due to capsular distension Nodes may develop abscesses with redness of overlying skin, drainage through fistula tract

Chronic Lymphadenitis Follicular Hyperplasia: –Rheumatoid arthritis, toxoplasmosis, early HIV Paracortical Hyperplasia: –Viral infections (mono), vaccinations Sinus histiocytosis: –Filling of sinuses with histiocytes –Non-specific

Reactive Follicular Hyperplasia

Lymphoma Lymphoid neoplasm producing a mass either through enlargement of lymph nodes or involvement of another organ Lymphocytic leukemia vs lymphoma –Leukemia circulating, lymphoma mass effect –In reality, much overlap Non-Hodgkin or Hodgkin: broad grouping

Lymphoma Classified by cell type (B or T), growth pattern, immunophenotype, and genetic aberrations 5 broad categories –Precursor B-cell neoplasms (immature B cells) –Peripheral B-cell neoplasms (mature B cells) –Precursor T-cell neoplasms –Peripheral T-cell and NK cell neoplasms –Hodgkin lymphoma Histologic examination of tissue required for diagnosis

Lymphoma Vast majority of lymphoid neoplasms are of B-cell origin (80-85%)

Follicular Lymphoma 45% of adult lymphoma; most common form of lymphoma in the US Older patients Generalized lymphadenopathy, spleen frequently involved Indolent, but difficult to cure Bone marrow almost always involved at diagnosis Characteristic translocation t(14;18) Transformation into more aggressive diffuse large B-cell lymphoma with survival of less than 1 yr.

Follicular Lymphoma

Diffuse Large B-cell Lymphoma 20% of adult lymphomas Older pts as well as children Diffuse growth pattern Extranodal disease seen Marrow involvement uncommon at diagnosis Aggressive, but up to 50% are curable May be associated with immunodeficiency

Diffuse Large B-cell Lymphoma

Burkitt Lymphoma Three types –Endemic African Burkitt lymphoma –Sporadic Burkitt lymphoma –HIV associated Histologically identical All forms associated with c-MYC translocations on chromosome 8 (t(8;14) most common) EBV infection seen in all endemic cases and 20-25% of other types

Burkitt Lymphoma Children and young adults 30% of childhood NHL in US Endemic –Mass involving mandible; also frequently involves abdominal organs – kidneys, ovaries, adrenals Sporadic –Abdominal mass involving ileocecum and peritoneum Bone marrow involvement uncommon In general, children and young adults can be cured with chemotherapy, older patients have a poorer prognosis

Burkitt Lymphoma “Starry Sky” Appearance

Mantle Cell Lymphoma 3% of all NHL in US Older males Painless lymphadenopathy; GI tract frequently involved Most have t(11;14) Aggressive

Mantle Zone Lymphoma

Hodgkin Lymphoma Arises in a single node and spreads to contiguous nodes In advanced stages may spread to extranodal sites Reed-Sternberg cells (1-5% of tumor mass) –B-cell origin –Induce accumulation of reactive lymphocytes, histiocytes and granulocytes

Hodgkin Lymphoma Four subtypes: –Nodular sclerosing: most common –Mixed cellularity: most common over age 50 –Lymphocyte predominance –Lymphocyte depletion: rare

Hodgkin Lymphoma Tumor stage at diagnosis predicts outcome Low stage – 90% cure Advanced stage – 60 – 70% 5 year disease free survival Long term survivors have increased risk of developing second cancers secondary to radiation and chemotherapy (breast cancer particularly high in females treated with chest radiation as adolescents)

Reed-Sternberg Cells

Clinical Differences Between Hodgkin’s and Non-Hodgkin’s Lymphomas Hodgkin’s Disease More often localized to a single axial group of nodes (cervical, mediastinal, para-aortic) Spreads by contiguity Mesenteric nodes and Waldeyer’s ring rarely involved Extranodal involvement uncommon Non-Hodgkin’s Lymphoma More frequent involvement of multiple peripheral nodes Noncontiguous spread Waldeyer’s ring and mesenteric nodes commonly involved Extranodal involvement common

Multiple Myeloma Plasma cell disorder characterized by multiple masses of neoplastic plasma cells throughout the skeletal system (plasmacytoma if solitary) Can spread to lymph nodes and skin Incidence higher in older men and people of African descent

Multiple Myeloma Infiltration of bone, punched out defects on radiographs –Pathologic fractures –Hypercalcemia Production of excess immunoglobulins –M protein on protein electrophoresis –Rouleaux formation in peripheral blood –Renal failure (light chains toxic to renal tubular epithelial cells) Suppression of normal humoral immunity –Bacterial infections

Multiple Myeloma Rouleaux Formation

Langerhans Cell Histiocytoses Clonal proliferation of Langerhans cells which are dendritic antigen-presenting cells in many organs, including skin Old name: Histiocytosis X

Langerhans Cell Histiocytoses Multifocal multisystem type –Usually in children before the age of 2 yrs –Cutaneous lesions on back, trunk, scalp –Hepatospenomegaly, lymphadenopathy, pulmonary lesions, destructive bone lesions –Infiltration of marrow leads to anemia, thrombocytopenia, infection (otitis media mastoiditis) –Rapidly fatal, 50% 5 year survival with therapy

Langerhans Cell Histiocytoses Unifocal/Multifocal type –Eosinophilic granuloma –Accumulation within medullary cavity of bone with associated eosinophilic infiltrate Pulmonary disease seen in adult smokers –Can regress spontaneously on cessation of smoking –Polyclonal, likely reactive Langerhans cells contain the characteristic Birbeck granule by electron microscopy and stain for CD1a and S-100

Birbeck Graunules

Pathology of the Spleen Acute Splenitis: Associated with bloodborne infections –May be painful with necrosis and abcess formation Congestive Splenomegaly: –Systemic: due to right sided heart failure –Cirrhosis –Partal vein thrombosis

Splenic Infarcts Due to emboli from thrombi in the heart May be septic if associated with bacterial endocarditis Wedge shaped infarcts May also be associated with splenomegaly due to outgrowing blood supply

Splenic Pathology Primary neoplasms are rare –Hemangioma most common primary neoplasm Accessory spleens: common, 20-30% Rupture –Usually associated with crushing injury, severe blow –Extensive intraperitoneal hemorrhage; surgical emergency

Thymic Pathology

Hyperplasia –Follicular hyperplasia with prominent lymphoid follicles –Associated with myasthenia gravis (present in 70% of cases) –Occasionally seen in other autoimmune disorders

Thymoma Neoplasm of thymic epithelial cells Tumors of adults usually over the age of 40. Occur in the anterior superior mediastinum Most are benign, may be malignant (thymic carcinoma) Present due to compression of mediastinal structures. Associated with myasthenia gravis.

Case 1 A 67- year old male presents with weakness, fatigue, and weight loss worsening over several months. Headaches

Slide 15.19

Multiple Myeloma

Case 2 A 12 year old male presents with a mandibular mass.

X-Ray 7 cm expansile mass in mandible

Biopsy

Bx Interpretation Lymphoid neoplasm with “starry sky” appearance, c/w Burkitts lymphoma Diagnosis confirmed by flow cytometry (monoclonal B cell population) and cytogenetics (t8:14)

Case 3 A 4 year old child has been increasingly listless for about a week. He now complains of pain when picked up and has bruising on his arms and legs.

CBC Anemia Thrombocytopenia Blasts on smear

Flow Cytometry Blasts are CD19 positive (B-cell marker)

Case 3 Dx: ALL

Case 4 A 45 year old male experienced gradual weight loss, weakness, anorexia increasing over several months. Physical exam reveals splenomegaly

CBC Nl Hct, platelets White count 168,000 ( normal )

Smear

Case 4 Dx: CML Patient treated with chemotherapy with resolution of symptoms

Case 5 A 38 year old female presents with dyspnea.

Chest radiograph Mediastinal widening CT- 10 cm mediastinal mass impinging on trachea

Biopsy

Case 5 Dx: Hodgkin’s Lymphoma

End