WBC 2.pdf - Hematopoietic System Diseases PDF

Hematopoetic System Diseases of White Blood Cells, Composed of different cells Lymph Nodes, Spleen, Myeloid tissue (RBCs, Granulocytes, Monocytes) and Thymus...

Hematopoetic System Diseases of White Blood Cells, Composed of different cells Lymph Nodes, Spleen, Myeloid tissue (RBCs, Granulocytes, Monocytes) and Thymus Lymphoid tissue (thymus, lymph nodes, spleen) Normal Hematopoiesis Normal Hematopoiesis Yolk Sac: location where Liver: Chief site of blood cell progenitors first hematopoiesis from until appear during the third shortly after birth week of of embryogenic development Bone Marrow: HSCs Hematopoietic stem cells migrate to the BM by the arise from the 4th month of development intraembryonic and BM become the aorta/gonad/mesonephros primary hematopoiesis Migrate to the liver at the site by birth third month of embryogenesis Source: Oncohema Key Source: Oncohema Key Normal Hematopoiesis Normal Hematopoiesis Bone Marrow: After Pluripotent cells: formed puberty, hematopoiesis elements of blood that dwindles with specific have a common origin foci (red areas) from HSCs Some of these cells are called Colony-forming units (CFUs) to produce specific kinds of mature cells Source: Oncohema Key Source: Robbins 10th ed Normal Hematopoiesis Normal Hematopoiesis HSC Properties: Colony Stimulating Pluripotency Factors (CSFs) Ability of a single HC to Hematopoietic growth generate all mature blood factors that regulate cells committed progenitors Self-Renewal Multipotent progenitors When at least one daughter cell self renews more proliferative than Avoids stem-cell depletion HSCs but with lesser self- renewal Past the threshold in maturation, they lose capacity to self-renew Source: Robbins 10th ed Source: Robbins 10th ed Normal Hematopoiesis Normal Bone Marrow Feedback loops are Megakaryocytes lie next to sinusoids and present to tune the extend cytoplasmic processes that budd marrow output and off into the blood stream to produce maintain appropriate platelets ranges Altered production -> Red cell precursors surround disease macrophages that dispose their nuclear Often associated with remnants prior to release in to the blood mutations that block stream progenitor cell maturation or abrogate their Growth Factor dependence Source: Robbins 10th ed Source: Oncohema Key White Cell Disorders Leukopenia Can be classified into two categories Usually results from reduced numbers of neutrophils Proliferative disorders (neutropenia, granulocytopenia) Expansion of leukocytes Associated with diminished granulocyte function Leukopenias Lymphopenia is less common Deficiency of leukocytes Usually attributed to congenital immunodeficiency, advanced HIV infection, therapy (glucocorticoids, cytotoxic drugs, autoimmune disorders, malnutrition) In acute viral infections, lymphopenia is due to lymphocyte redistribution -> interferon 1 release -> T cell migration to lymph nodes and increased adherence to endothelial cells Neutropenia & Agranulocytosis Neutropenia & Agranulocytosis Neutropenia: reduction in the number of neutrophils in the blood Neutropenia: reduction in the number of neutrophils in the blood Causes: Causes: Inadequate or ineffective granulopoiesis Inadequate or ineffective granulopoiesis Suppression of HSCs (ie. Aplastic anemia, infiltrative marrow disorders) Increased destruction or sequestration of neutrophils in the periphery Suppression of committed granulocytic precursors by exposure to certain drugs Immunologically mediated injury to neutrophils (idiopathic, SLE, drug-induced) Ineffective hematopoiesis (megaloblastic anemia and myelodysplastic syndrome) Splenomegaly Congenital disorders (ie. Kostmann syndrome) Increased peripheral utilization Increased destruction or sequestration of neutrophils in the periphery Agranulocytosis: marked reduction of neutrophils Agranulocytosis: marked reduction of neutrophils Neutropenia & Agranulocytosis Neutropenia & Agranulocytosis Neutropenia: reduction in the number of neutrophils in the blood BONE MARROW MORPHOLOGY & CLINICAL PRESENTATION Agranulocytosis: marked reduction of neutrophils Vary depending on cause Causes: Hypercellular marrow: Drug toxicity (most common cause) compensatory if there is increased peripheral granulocytic destruction Alkylating agents and antimetabolites in cancer treatment Ineffective granulopoiesis (i.e. Megaloblastic Anemia, MDS) Antibiotics, anti-convulsants, anti-inflammatory drugs, antipsychotic drugs, diuretics Hypocellular marrow: Acute Idiopathic Neutropenia Agranulocytosis caused by agents that suppress or destroy granulocyte precursors Autoantibodies directed against neutrophil-specific antigens INFECTIONS Large Granular Lymphocyte Leukemia (LGL Leukemia) Common consequence of agranulocytosis Severe neutropenia associated with monoclonal LGL Presents with ulcerating necrotizing lesions of the mucosa (i.e gingiva, floor of Most likely due to suppression of granulocytic progenitors by products of the neoplastic mouth, pharynx, vagina, anus, GI) cell (CD8+ T cell) Usual culprits: Candida & Aspergillus Leukocytosis Leukocytosis Increase in the number of Acute infection: WBCs in blood Other growth factors are more specific IL5: Eosinophils Acute infection: G-CSF: Neutrophils TNF and IL1 release -> Depends on the cause of the pathogenic stimuli stromal cells produce hematopoietic growth factors -> increased WBC proliferation and differentiation Source: Robbins 10th ed Source: Robbins 10th ed Leukocytosis Acute Nonspecific Lymphadenitis Notable findings in severe Most often due to drainage of microbes or microbial inflammatory disorders ie. products from infections of Kawasaki disease or sepsis) the teeth or tonsils (if cervical) Toxic granulations or the extremities (if axillary or inguinal) Coarser, darker, than normal neutrophilic granules, Occurs in mesenteric lymph represent abnormal primary nodes in the setting of acute granules appendicitis or other inflammatory conditions of Dohle bodies the gut Patches of dilated endoplasmic reticulum, Often generalized in systemic appearing as sky blue viral infections and cytoplasmic puddles bacteremia Source: Robbins 10th ed Source: Pathorama  Chronic Nonspecific Acute Nonspecific Lymphadenitis Lymphadenitis GROSS: Swollen grey-red Characteristically nontender, slowly and engorged lymph nodes enlarging MICROSCOPIC: Common in inguinal and axillary Prominence of large reactive nodes due to trivial injuries in the germinal centers extremities Macrophages contain Follicularization may be seen in particulate debris from dead bacteria and necrotic cells extranodal tissues due to chronic Germinal centers may infections (i.e. H. pylori) due to the undergo necrosis if pyogenic production of Lymphotoxin organism are the cause Source: Pathorama Source: Robbins 10th ed Chronic Nonspecific Chronic Nonspecific Lymphadenitis Lymphadenitis Follicular hyperplasia Follicular hyperplasia Presence of secondary follicles (large May be caused by Rheumatoid arthritis, oblong germinal centers) surrounded toxoplasmosis, and early HIV infection by a collar of resting B cells (mantle zone) Differentiated with Follicular Lymphobe Germinal centers are polarized with a by: dark zone (blast-like B cells or Preservation of lymph node architecture centroblasts) and light zone (B cells (interfollicular T cell zones and sinusoids) with irregular or cleaved nuclear Marked variation in the shape and size of contours) the follicles Tingible Body Macrophages: Antigen Presence of frequent mitotic figures, presenting cells that contain nuclear phagocytic macrophages, and debris of B cells recognizable light and dark zones Source: Robbins 10th ed Source: Robbins 10th ed Chronic Nonspecific Chronic Nonspecific Lymphadenitis Lymphadenitis Paracortical Hyperplasia Sinus histiocytosis Due to T cell mediated immune Aka Reticular hyperplasia responses (i.e. acute viral Increase in the number and size infections like EBV) of the endothelial cells lining Typically contain immunoblasts, lymphatic sinusoids and activated T cells (3-4x the size of increased numbers of resting lymphocytes with round intrasinusoidal macrophages nuclei, open chromatin, several May be particularly prominent in prominent nucleoli and moderate lymph nodes draining cancers amounts of pale cytoplasm) like Breast Ca May efface B cell follicles Source: Researchgate Source: LibrePathology Hemophagocytic Hemophagocytic Lymphohistiocytosis (HLH) Lymphohistiocytosis (HLH) Reactive condition marked by cytopenias and signs and Clinical Presentation: symptoms of systemic inflammation related to macrophage Acute Febrile Illness + activation Hepatosplenomegaly Pathogenesis: BM: hemophagocytosis (neither sufficient nor required) Activation of macrophages and CD8+ T cells -> phagocytosis of blood cell Labs: Anemia, progenitors in marrow and formed elements in the peripheral tissues -> thrombocytopenia, increased relase of mediators (INF-gamma, TNF-alpha, IL6 and IL12) suppressing ferritin and IL2 receptor, hematopoiesis and produce symptoms of systemic inflammation (hence: increased LFTs and CYTOPENIA & SHOCK) triglycerides, Coagulation May be associated with mutations that affect CD8+ T cells and NK cells studies suggestive of DIC Common trigger: EBV May lead to MODS, shock, and May also be caused by T cell lymphomas through immune dysregulation death Source: Pathology Outlines WBC Neoplasms WBC Neoplasms Classified into the following: Etiology: Chromosomal Translocations and Acquired Mutations Lymphoid neoplasms: either B-cell, T-cell or NK-cell origin Genes associated with development, growth or survival Myeloid neoplasms: arise from early hematopoietic progenitors Oncoproteins created by genomic aberrations Acute Myeloid Leukemias - from immature progenitor cells Proto-oncogenes that are activated Inherited genetic factors Myelodysplastic Syndroms – associated with ineffective hematopoiesis and Bloom syndrome, Fanconi Anemia, ataxia telangectasia resultant PB cytopenias Down Syndrome (trisomy 21) and Type 1 Neurofibromatosis has increased risk of Myeloproliferative Neoplasms – Increased production of one or more terminally childhood leukemia differentiated myeloid elements, and increased PB counts Viruses HTLV1, EBV, HHV8, EBV Histiocytoses: arise from macrophages and dentritic cells Chronic inflammation H pylori infection Iatrogenic factors (i.e chemotherapy) Smoking Lymphoid Neoplasms Lymphoid Neoplasms Leukemias: present with widespread Clinical presentation most often determined by anatomic involvement of the bone marrow distribution and/or peripheral blood 2/3 NHLs and All HLs present as enlarged nontender lymph nodes (>2cm) Lymphomas: Proliferations that 1/3 NHLs present with symptoms related to the involved extranodal sites (skin, stomach, brain) present as discrete tissue masses Lymphocytic Leukemias: present with suppression of normal May be categorized broadly as hematopoiesis Hodgkin Lymphoma Plasma cell neoplasms (i.e. Multiple Myeloma), causes bone destruction Non-Hodgkin Lymphoma (NHLs) of the skeleton and pain due to pathologic fractures Special group: Plasma cell Neoplasms Hodgkin Lymphoma: associated with fever from cytokine release Source: Robbins 10th ed  Source: Robbins 10th ed Acute Lymphoblastic Acute Lymphoblastic Leukemia/Lymphoma Leukemia/Lymphoma Neoplasms composed of immature B (pre-B) or T (pre-T) cells Morphology 85% are B-cell ALLs BM: Hypercellular with lymphoblastic Peak incidence at about age of 3 proliferation T-cell ALLs usually seen in adolescent males as thymic lymphomas T-ALLL: Mediastinal masses B-ALL: Lymphadenopathy and Most common cancer of children splenomegaly Pathogenesis Tumor cells have scant basophilic cytoplasm, and enlarged nuclei Chromosomal aberrations dysregulate the expression and function of Nuclear chromatin is delicate and transcription factors for normal B- and T- cell development finely stipples with prominent nucleoli T-ALL: NOTCH1 mutations Lymphoblasts: more condensed B-ALL: mutations in PAX5, TCF3, ETV6 and RUNX1 chromatin, less conspicuous nucleoli, Numerical or structural chromosomal changes are seen in 90% of cases smaller amount of cytoplasm that Commonly hyperploidy lack granules Source: Robbins 10th ed Acute Lymphoblastic Acute Lymphoblastic Leukemia/Lymphoma Leukemia/Lymphoma Morphology Clinical presentation Immunophenotype: Similar presentation with AML TdT (+) Suppressed hematopoiesis by physical crowding and competition for B-Cell markers: CD19, PAX5, CD10 growth factors Late pre-B: CD10, CD19, CD20, IgM More characteristic features of ALL: heavy Abrupt stormy onset (days to few weeks) T-Cell markers: CD1, CD2, CD5, CD7 Symptoms of depressed marrow function (fatigue, recurrent infections, bleeding) Late pre-T: CD3, CD4, CD8 Mass effects (bone pain, generalized lymphadenopathy, splenomegaly, hepatomegaly, testicular enlargement) CNS manifestations (headache, vomiting) Source: Robbins 10th ed Chronic Lymphocytic Leukemia/ Small Acute Lymphoblastic Leukemia/Lymphoma Lymphocytic Lymphoma Favorable prognostic markers Peripheral B-cell neoplasms that differ in degree of peripheral Ages between 2 and 10 years blood lymphocytosis Low white cell count CLL has an absolute lymphocyte count of >5000/mm3) Hyperdiploidy CLL Trisomy of chromosomes 4, 7, and 10 Most common leukemia of adults in the western world Presence of t(12;21) Median age of diagnosis is 60 y/o with a 2:1 male predominance SLL 4% of NHLs  Chronic Lymphocytic Chronic Lymphocytic Leukemia/ Small Leukemia/ Small Lymphocytic Lymphoma Lymphocytic Lymphoma Pathogenesis Morphology Chromosomal translocations are rare Effaced lymph nodes Most common: del13q14.3, del11q, del17p, and trisomy 12q Small lymphocytes (6-12um) Growth is largely confined to proliferation centers where tumor cells with round to slightly irregular receive critical cues from the microenvironment nuclei, condensed chromatin, Clinical features and scant cytoplasm Often asymptomatic Proliferation centers Nonspecific symptoms (easy fatiguability, weight loss, anorexia) Loose aggregates of large Generalized lymphadenopathy, hepatosplenomegaly activated lymphocytes Variable WBC count Pathognomonic of CLL/SLL Hypogammaglobulinemia is common -> bacterial infection susceptibility Source: Robbins 10th ed Chronic Lymphocytic Leukemia/ Small Follicular Lymphoma Lymphocytic Lymphoma Morphology Most common form of indolent NHL BM: small round lymphocytes Pathogenesis: with scant cytoplasm Strongly associated with chromosomal translocations involving BCL2 Presence of smudge cells Hallmark: t(14:18) juxtaposing IGH locus on ch 14 to BCL2 locus on chr Immunophenotype 18 pan B-cell markers: CD19, Clinical Features CD20, CD23, CD5 Painless generalized lymphadenopathy GI, CNS and testicular involvement is uncommon Waxing and waning course May transform to DLBCL in 30-50% of cases Source: Robbins 10th ed Follicular Lymphoma Follicular Lymphoma Morphology Immunophenotype Nodular or nodular and diffuse growth Resemble germinal center B cells pattern CD19, CD20, CD10, Surface Ig and BCL6 Two cell types: NO CD5 expression (diff. from CLL/SLL) Centrocytes (small cleaved cells) BCL2+ Centroblasts (larger with open nuclear chromatin) PBS: Lymphocytosis BM: paratrabecular lymphoid aggregates Often involve splenic white pulp and hepatic portal triad Source: Robbins 10th ed Source: Robbins 10th ed Diffuse Large B-cell Lymphoma Diffuse Large B-cell Lymphoma Most common form of NHL Clinical Features Median age of 60 years Presents as a rapidly enlarging mass at a nodal or extranodal Pathogenesis site Molecularly heterogenous Commonly involves the Dysregulation of BCL6 at chromosome 3q27 Waldeyer ring Also associated with t(14;18), similar to Follicular lymphoma -> BCL2 Secondary involvement of the overexpression liver and spleen may happen MYC translocation Histone acetyltransferace gene mutation Diffuse Large B-cell Lymphoma Diffuse Large B-cell Lymphoma Morphology Immunophenotype Large cells (usually 4-5x the CD19+, CD20+ size of a small lymphocyte) Germinal center markers Diffuse pattern of growth CD10, BCL6 Round to oval vesicular MYC+, BCL+ -> nore nucleus aggressive Large prominent nucleoli Moderately abundant cytoplasm Source: Robbins 10th ed Source: Robbins 10th ed Diffuse Large B-cell Lymphoma Burkitt Lymphoma Subtypes Lymphoma associated with translocation of the MYC gene on Immunodefficiency chromosome 8 -> increased MYC expression associated large BCL Usually partnered with the IGH locus as seen in t(8;14) T cell immunodeficiency, or HSC transplants May also be seen in Ig kappa (as in t(2;8)) or Ig Lambda (as in t(8;22)) EBV infection Primary effusion lymphoma All endemic Burkitt Lymphomas are latently infected with EBV Advanced HIV Clinical Features Anaplastic appearance Mainly seen in children or young adults Fail to express T or B cell markers but with clonal IGH Manifests as extranodal site tumors rearrangements HHV8 infection Source: Robbins 10th ed Burkitt Lymphoma Burkitt Lymphoma Morphology Immunophenotype Effaced architecture Mature B cell markers (germinal High mitotic index center) “Starry sky appearance” IgM, CD19, CD20, CD10, BCL6 numerous apoptotic cells that are Failure to express BCL2 phagocytosed by nearby macrophages BM: slightly clumped nuclear chromatin and royal blue cytoplasm containing clear cytoplasmic vacuoles Source: Robbins 10th ed Source: Robbins 10th ed Mantle Cell Lymphoma Mantle Cell Lymphoma Uncommon lymphoid neoplasm Morphology Presents in the 5th to 6th decade of life with a male predominance Tumor cells may surround germinal centers -> nodular appearance or may Resemble the mantle zone B cells diffusely efface the lymph node Pathogenesis Consists of homogenous population of small lymphocytes with cleaved t(11;14) -> involving the IGH locus (Chromosome 14) and Cyclin D1 locus nuclear contours (Chromosome 11) -> overexpression of Cyclin D1 Lack of centroblasta and proliferation Clinical features centers (Seen in CLL/SLL) Painless lymphadenopathy Spleen and gut-related symptoms Source: Robbins 10th ed Mantle Cell Lymphoma Marginal Zone Lymphoma Immunophenotype Hetererogenous B-cell tumors arising within lymph nodes spleen or Express increased CyclinD1, CD19, extranodal tissues CD20, moderately high surface Ig Initially recognized at mucosal sites -> MALTomas CD5+. CD23- Originate from memory B-cells Three characteristics Arise from tissues involved by chronic inflammatory disorders Helicobacter gastritis, Sjogren, Hashimoto’s Localized for prolonged periods prior to systemic spread May regress if the inciting agent is eradicated Though reversible, mutations may be acquired in time leading to transformation to DLBCL Source: Robbins 10th ed Hairy Cell Leukemia Hairy Cell Leukemia Rare leukemia Morphology Seen in middle aged white males with a median age of 55 and an Fine hair-like projections in leukemic cells M:F ratio of 5:1 Best seen in phase contrast microscopy Pathogenesis PBS: round oblong or reniform nuclei Activating point mutations in the serine/threonine kinase BRAF with moderate pale blue cytoplasm with threadlike or bleblike extensions Clinical features BM: Extraneous cells with reniform or Indolent course oblong nuclei Infiltration of bone marrow, liver and spleen cells are enmeshed in an extracellular Massive splenomegaly is the the most common symptom matrix -> “dry tap” Pancytopenia with atypical mycobacterial infections from monocytopenia Spleen: Obliteration of white pulp and infiltration of red pulp Source: Robbins 10th ed Hairy Cell Leukemia Peripheral T-cell Lymphoma, Unspecified Immunophenotype Mature T cell Lymphoma Pan B cell markers CD19, CD20 and Typically express CD2, CD3, surface Ig CD5, and either αβ or γδ T-cell Distinct markers: CD11c CD25, receptors. CD103, annexin A1 May express CD4 or CD8 Present with generalized lymphadenopathy with accompanying eosinophilia, pruritus, fever and weight loss Source: Robbins 10th ed Source: Robbins 10th ed Anaplastic Large-Cell Peripheral T-cell Lymphoma, Unspecified Lymphoma Morphology Defined by the presence of No pathognomonic feature rearrangements in the ALK gene on Effacement of lymph nodes are chromosome 2p23 present Tend to occur in children or young Typically composed of a adults pleomorphic mixture of variably Frequently involve soft tissues sized malignant T cells Infiltrates of reactive cells ALK+ tumors have a better prognosis (eosinophils and macrophages) Morphology Brisk neoangiogenesis Large anaplastic cells, some containing Source: Robbins 10th ed horseshoe shaped nuclei and voluminous cytoplasm (hallmark cells) Source: Robbins 10th ed Adult T-cell Leukemia/Lymphoma Mycosis Fungoides/ Sezary Syndrome CD4+ T cell neoplasm observed in adults infected by HTLV-1 Different manifestations of a tumor of CD4+ T cells that home to Commonly present with generalized lymphadenopathy, the skin hepatosplenomegaly, Peripheral blood lymphocytosis, and Clinical Presentation hypercalcemia Mycosis Fungoides: cutaneous lesions progress through three stages: premycotic, plaque, and tumor phase Rapidly progressive disease Sezary Syndrome: generalized exfoliative erythroderma, with skin lesions Morphology that rarely proceed to tumefaction Tumor cell appearance varies but cells with multilobated nuclei Indolent tumors with occasional transformation to aggressive T cell (“cloverleaf” or ”flower” cells) are frequently observed lymphoma Mycosis Fungoides/ Extranodal NK/T-cell Lymphoma Sezary Syndrome Morphology Rare neoplasm Epidermis and upper dermis are Highly associated with EBV, with no consistent chromosome infiltrated by neoplastic T cells, aberration which often have a cerebriform appearance dure to marked Most frequently presents as a destructive nasopharyngeal mass infolding of the nuclear membrane Less commonly presents in the testis and skin Immunophenotype Histology: CCR4 and CCR10+ Large azurophilic granules are seen in touch preparations Immunophenotype: CD3-, CD21- Source: Pathology Outlines Plasma Cell Neoplasms Multiple Myeloma B-cell proliferations containing neoplastic plasma cells that Plasma Cell Neoplasm commonly associated with lytic bone virtually always secrete monoclonal Ig or Ig fragments lesions, hypercalcemia, renal failure and acquired immune Often synthesize excess light chains along with complete Igs abnormalities Different Clinicopathologic entities fall under this category Pathogenesis: Multiple myeloma (plasma cell myeloma) Genetically heterogenous Waldenström macroglobulinemia Associated with frequent rearrangement involving the IGH locus on Heavy-chain disease chromosome 14q32 and various protooncogenes Primary or immunocyte-associated amyloidosis Factors produced by neoplastic plasma cells mediate bone destruction Monoclonal gammopathy of undetermined significance (MGUS) (most common is MIP1α) -> pathologic fractures Multiple Myeloma Multiple Myeloma Clinical Presentation Morphology Presents as destructive plasma cell tumor involving the axial skeleton BM: increased number of plasma (commonly the vertebral column, ribs, cells (>30% of cellularity) skull, pelvis, femur, clavicle) Lesions begin at the medullary cavity, Neoplastic plasma cells have a eroding cancellous bone and perinuclear clearing due to progressively destroying bony cortex prominent Golgi Apparatus CRAB Criteria (HyperCalcemia, Renal Dysfunction, Anemia, Bone Lesions) Plasmablasts (vesicular nuclear Radiologic: Punched out bone lesions chromatin, single nucleolus) or usually 1-4cm in diameter bizarre multinucleated forms may Morphology predominate Gross: soft gelatinous red tumor Source: Robbins 10th ed masses Source: Robbins 10th ed Multiple Myeloma Multiple Myeloma Morphology Laboratory Analysis Morphologic variants include Increased levels of Igs in the blood Flame cells: fiery red cytoplasm and/or light chains in the urine Mott cells: grape like cytoplasmic IgG>IgA: most common monoclonal droplets gammopathy Russell Bodies (cytoplasmic) or Dutcher IgA and IgG3 leads to hyperviscocity bodies (nuclear) globular inclusions Immunophenotype: CD138+ CD56+ Source: Robbins 10th ed Source: Robbins 10th ed Plasma Cell Neoplasms Hodgkin Lymphoma Other entities: Group of lymphoid neoplasms Monoclonal gammopathy of undetermined significance (MGUS): common in that differ from NHL older adults, progresses to myeloma at a rate of 1% per year. Smoldering myeloma: disseminated disease that pursues an unusually Arises in a single node or chain of indolent course. nodes and spreads first to Solitary osseous plasmacytoma: solitary bone lesion identical to disseminated myeloma; most progress to myeloma within 7 to 10 years. anatomically contiguous Extramedullary plasmacytoma: solitary mass, usually in the upper lymphoid tissues aerodigestive tract; rarely progresses to systemic disease. Lymphoplasmacytic lymphoma: B-cell lymphoma that exhibits plasmacytic Reed-Sternberg Cell Source: Robbins 10th ed differentiation; clinical symptoms dominated by hyperviscosity related to high Distinctive feature levels of tumor-derived IgM; highly associated with mutations in the MYD88 Release factors providing the HL gene. milleu Hodgkin Lymphoma Hodgkin Lymphoma Clinical Presentation Morphology Average age of diagnosis is 32 years Identification of RS cells is essential Presents as painless lymphadenopathy Large (45um) with multiple nuclei or a single nucleus with multiple nuclear lobes with a large inclusion-like nucleolus about the size of a lymphocyte (5-7um) Staged according to extent of involved Abundant cytoplasm sites Variants include: Disseminated disease is associated with Mononuclear variants: single nucleus with large inclusion-like nucleus constitutional symptoms (fever night sweats and weight loss) Lacunar cells: seen in Nodular Sclerosis Subtype, have more delicate folder or multilobate nuclei Spread is usually nodal -> splenic -> hepatic -> Lymphohistiocytic variant: seen in Lymphocyte predominant subtype, polypoid nuclei, marrow and other tissues moderately abundant cytoplasm Source: Robbins 10th ed Hodgkin Lymphoma Source: Robbins 10th ed Source: Robbins 10th ed Myeloid Neoplasms Myeloid Neoplasms Primarily involve the marrow, and involve the secondary Primarily involve the marrow, and involve the secondary hematopoietic organs to a lesser degree hematopoietic organs to a lesser degree Three broad caregories Three broad caregories Acute myeloid leukemias Acute myeloid leukemias an accumulation of immature myeloid forms (blasts) in the bone marrow an accumulation of immature myeloid forms (blasts) in the bone marrow suppresses normal hematopoiesis suppresses normal hematopoiesis Myelodysplastic syndromes Myelodysplastic syndromes defective maturation of myeloid progenitors gives rise to ineffective hematopoiesis, defective maturation of myeloid progenitors gives rise to ineffective hematopoiesis, leading to cytopenias leading to cytopenias Myeloproliferative neoplasms Myeloproliferative neoplasms there is usually increased production of one or more types of blood cells there is usually increased production of one or more types of blood cells Acute Myeloid Leukemia Acute Myeloid Leukemia Tumor of hematopoietic progenitors caused by acquired Pathogenesis oncogenic mutations that impede differentiation -> accumulation Driver mutations fall into four functional categories of immature myeloid blasts in the marrow Transcription factor mutations that interfere with normal myeloid differentiation t(8;21) and inv (16) Clinical Features t(15;17) Present within weeks or few months of the onset of symptoms Mutation of signaling proteins that result in constitutive activation of pro-growth/ Symptoms related to anemia, neutropenia, and thrombocytopenia are survival pathways present (fatigue, fever, spontaneous mucosal and cutaneous bleeding) t(15;17) Mutation of genes that regulate or maintain the epigenome DNA methylation abnormalities Mutation of TP53 or genes that regulate p53  Acute Myeloid Leukemia Morphology Diagnosis is based on the presence of at least 20% myeloid blasts in bone marrow Myeloblasts: characterized by delicate nuclear chromatin, two or four nucleoli and more voluminous cytoplasm than lymphoblasts; cytoplasm has fine peroxidase positive azurophilic granules Auer Rods: Needle-like azurophilic granules Source: Robbins 10th ed Source: Robbins 10th ed Acute Myeloid Leukemia Myelodysplastic Syndrome Immunophenotype Group of clonal stem cell disorders characterized by maturation Diagnosis is confirmed by defects that are associated with ineffective hematopoiesis performing stains for myeloid specific antigens high risk of transformation to AML Cytogenetics The bone marrow is partly or wholly replaced by the clonal Used in the classification of AML, as particular chromosomal progeny of a neoplastic multipotent stem cell that retains the abnormalities correlate with capacity to differentiate but does so in an ineffective and certain clinical features disordered fashion De Novo AML in the young: t(8;21), inv(16) and t(15;17) Can be primary/idiopathic or secondary from therapy AML from MDS or DNA-damaging agents: deletions or monosomy of Chromosome 5 and 7 Source: Robbins 10th ed Myelodysplastic Syndrome Myelodysplastic Syndrome Pathogenesis Clinical Features Associated with driver mutations that partially overlap with AML PRIMARY MDS Epigenetic factors Disease of older adults (mean age of 70) DNA Methylation, Histone modification, chromatin looping Discovered in routine testing in up to half of cases RNA splicing factors Median survival is less than 6 months Mutations involving components of the 3’ end of RNA splicing machinery Patient frequently succumb to the complications of thrombocytopenia and neutropenia Transcription factors Treatment-related MDS t(8;21), inv(16), and t(15;17) ARE NOT SEEN Poorer prognosis Loss of function mutations in genes such as RUNX1 Myelodysplastic Syndrome Morphology BM: Hypercellular at diagnosis, sometimes normocellular, less commonly hypocellular Most characteristic: disordered (dysplastic) differentiation affecting erythroid, granulocytic, and megakaryocytic lineages in varying degrees Source: Robbins 10th ed Myeloproliferative Neoplasms Most pathogenic feature: presence of mutated, constitutively activated tyrosine kinases or other acquired aberrations in signaling pathways that lead to growth factor independence Most common consequence: Increased production of one or more mature blood elements Most common features: Increased proliferative drive Homing of the neoplastic stem cells to secondary hematopoietic organs - > extramedullary hematopoiesis Variable transformation to a spent phase (myelofibrosis and peripheral blood cytopenias) Source: Robbins 10th ed Variable transformation to acute leukemia Chronic Myeloid Leukemia Chronic Myeloid Leukemia Distinguished from other MPN by Clinical Features the presence of a chimeric BCR-ABL Primarily a disease of adults (peak incidence in 5th to 6th decade of life) gene Insidious onset derived from portions of the BCR gene Mild to moderate anemia and hypermetabolism -> easy fatiguability, (Chromosome 22) and ABL gene weakness, weight. Loss and anorexia (Chromosome 9) Splenomegaly and possible splenic infarction Philadelphia chromosome reciprocal “accelerated phase” seen in increasing anemia and thrombocytopenia (9;22)(q34;q11) translocation) “blast crisis”: picture like acute leukemia Cell of origin: pluripotent HSC Source: Robbins 10th ed Chronic Myeloid Polycythemia Vera Leukemia Morphology Characterized by increased marrow production of red cells, BM: Markedly hypercellular granulocytes, and platelets (panmyelosis) (increased maturing granulocytic precursors, increased dystplastic Clinical symptoms are mostly due to increase in red cells megakaryocytes), myelofibrosis, (polycythemia) Blasts abnormal blood flow -> stasis -> increased risk extramedullary hematopoiesis for bleeding and thrombotic episodes High cell turnover -> hyperuricemia Source: Robbins 10th ed Polycythemia Vera Essential Thrombocytosis Morphology Associated with diverse mutations that increase JAK-STAT BM: hypercellular, increased red signaling and mimic constitutive growth factor receptor signaling cell progenitors with increased Pathogenesis: JAK2 or MPL signaling rendering progenitors granulocytic precursors and megakaryocytes thrombopoietin-independent -> hyperproliferation Mild organomegaliy Clinical Features Late stage: Spent Phase: extensive Usually occurs past 60y/o marrow fibrosis increased Platelet dysfunction -> thrombosis and hemorrhage extramedullary hematopoiesis Characteristic: Erythromyalgia: thrombbing and burning of hands and feet due to occlusion of small arterioles Source: Robbins 10th ed Indolent course with long asymptomatic episodes Essential Thrombocytosis Primary Myelofibrosis Morphology Hallmark: obliterative marrow fibrosis BM: Mildly increased bone Leads to reduced bone marrow hematopoiesis -> cytopenias & marrow cellularity with markedly extramedullary hematopoiesis increased megakaryocytes with Pathogenesis abnormal large forms Inappropriate release of fibrogenic factors (PDGF and TGF-β) from Large platelets are seen neoplastic megakaryocytes -> Extensive deposition of collagen in the accompanied by mild marrow by nonneoplastic fibroblasts leukocytosis Clinical Features Modest degrees of Usually occurs in individuals older than 60 years of age extramedullary hematopoiesis Labs: moderate to severe Normochromic normocytic anemia with Source: Robbins 10th ed leukoerythroblastosis May present with infections, thrombotic episodes and bleeding Primary Myelofibrosis Langerhans Cell Histiocytosis Morphology “histiocytosis” is an umbrella designation for a variety of Early: hypercellular marrow, proliferative disorders of dendritic cells or macrophages similar to PCV, but with large Pathogenesis dysplastic and abnormally clustered megakaryocytes Majority have driver mutations in cancer-associated genes Most common: Val-to-Glu at residue 6000 in BRAF Late: Fibrotic obliteration of the marrow space Others: TP53, RAS, MET Spleen: extensive extramedullary hematopoiesis Source: Robbins 10th ed Langerhans Cell Histiocytosis Langerhans Cell Histiocytosis Clinical Features Clinical Features Several clinicopathologic entities Several clinicopathologic entities Multifocal Multisystem Langerhans Cell Histiocytosis (Letterer-Siwe disease) Unifocal and multifocal unisystem Langerhans cell histiocytosis (eosinophilic Before 2 years of age granuloma) Cutaneous lesions resembling a seborrheic eruption Proliferations of Langerhans cells admixed with variable numbers of eosinophils, Most with concurrent hepatosplenomegaly, lymphadenopathy, pulmonary lesions, and lymphocytes, plasma cells, and neutrophils. (eventually) destructive osteolytic bone lesions Location: medullary cavities of bones, most commonly the calvaria, ribs, and femur Anemia and thrombocytopenia, and recurrent infections Pulmonary LCH Most often seen in adult smokers Described as reactive proliferations of Langerhans cells Langerhans Cell Histiocytosis Spleen Morphology Secondary lymphoid organ Cells with abundant often Functions: vacuolated cytoplasm and Phagocytosis of blood cells and vesicular nuclei with linear grooves or folds particulate matter Characteristic: Birbeck Granules Antibody Production (pentalaminar tubules with a Hematopoiesis dilated terminal end producing a Sequestration of formed blood tennis racket like appearance elements Stains: HLA-DR, S-100, CD1a Source: Robbins 10th ed Source: Robbins 10th ed Splenomegaly Nonspecific Acute Splenitis Clinical features: dragging sensation in Enlargement of the spleen occurs in any blood-borne infection the left upper quadrant Caused by both the microbiologic agents themselves and the Hypersplenism: anemia, leukopenia cytokines that are released as part of the immune reponse and/or thrombocytopenia Morphology Enlarged (200 to 400 g) and soft Microscopic: Acute congestion of the red pulp which may efface the lymphoid follicles; white pulp may undergo necrosis in hemolytic streptococcus infections Source: Robbins 10th ed Congestive Splenectomy Splenic infarcts Chronic venous outflow obstruction causes a form of splenic Common lesions caused by the enlargement occlusion of the major splenic artery or any of its branches May be caused by intrahepatic disorders that retard portal venous drainage or extrahepatic disorders that directly impinge Morphology: Bland infarcts: characteristically upon the portal or splenic veins -> portal or splenic vein pale, wedge shaped and hypertension subcapsular with an overlying Liver cirrhosis: main cause of massive congestive splenomegaly fibrin in the overlying capsule Septic infarcts: suppurative Morphology necrosis large (1kg to 5kg) and firm with a thickened and fibrous capsule Old infarcts: large depressed Source: Robbins 10th ed Microscopic: collagen deposition in the sinusoid basement membrane scars can develop Splenic Neoplasms Splenic Congenital Anomalies Rare except in myeloid and lymphoid tumors Complete absence of the spleen: rare, associated with congenital Benign entities may occur abnormalities (situs inversus, cardiac malformations) Fibromas, osteomas, chondromas, lymphangiomas and hemangiomas Hypoplasia are more common Most common: Cavernous Hemangioma and Lymphangioma Accessory spleens: common, small spherical structures that are histologically and functionally identical to the normal spleen Clinically important in Hereditary spherocytosis Splenic Rupture Thymus Usually precipitated by blunt trauma Secondary lymphoid organ with a starring role in cell mediated Rarely spontaneous by if so, investigation for an underlying immunity condition is warranted Progenitor cells migrate from the marrow to the thymus and Infectious mononucleosis, malaria, typhoid fever, lymphoid neoplasm mature into T cells which are exported to the periphery Developmental Disorders of the thymus Thymic follicular hyperplasia Thymic hypoplasia or Hypoplasia Appearance of B-cell germinal Seen in DiGeorge Syndrome, often associated with other developmental centers within the thymus defects as part of the 22q11 deletion syndrome (Thymic Follicular Hypoplasia) Thymic Cysts Can occur in chronic Uncommon lesions that are usually incidental findings inflammatory and immunologic Rarely exceed 4cm in diameter, lined by stratified squamous to columnar states epithelium Most commonly encountered in Serous or mucinous contents, often modified by hemorrhage myasthenia gravis Others: Graves, SLE, Scleroderma, Rheumatoid arthritis Source: Pathology Outlines Thymoma Thymoma Tumor of thymic epithelial cells Morphology Gross: lobulated, firm gray-white masses up Three histologic subtypes to 15 to 20 cm in size, some with areas of cystic necrosis, but most are encapsulated Tumors that are cytologically benign and invasive Noninvasive thymomas Most often are composed of medullary-type Tumors that are cytologically benign but invasive or metastatic epithelial cells or a mixture of medullary- and cortical-type epithelial cells. Tumors that are cytologically malignant (thymic carcinoma) Invasive Thymoma Cytologically benign but locally invasive Clinical features More likely to metastasize Usually occur in adults >40y/o, M:F::1:1 Epithelial cells are most commonly of the cortical variety with abundant cytoplasm Most arise in the anterior superior mediastinum, but sometimes may Invade through the capsule occur in the neck thyroid, pulmonary hilus or elsewhere Thymic carcinoma Represents about 5% of thymomas Most are SCCas, but some may be Lymphoepithelioma-like carcinoma Source: Robbins 10th ed Thank you!