Chapter 13: Hematologic disorders Flashcards
Lymphoid hyperplasia
-‐ Affects LN, Waldeyer’s ring or lymphoid aggregates (soft palate, lateral tongue, FOM)
-‐ Acute lymphadenopathy: tender, soft, freely movable
-‐ Chronic lymphadenopathy: non-‐tender, rubbery, freely mov (~ lymphoma, but non progressive)
-‐ Tonsillar asymmetry: r/o metastatic tumor or lymphoma
-‐ Lymphoid aggregates: post lat tongue, cheek, post hard palate
-‐ Tingible bodies: phagocytized materials (nuclear debris from lymphocytes) inside macrophages
Hemophilia A
-‐ Hemophilia A: factor VIII deficiency (85% cases) (↑ PTT)
-‐ Hemophilia B: factor IX deficiency (Christmas disease) (↑ PTT)
-‐ Von Willebrand’s disease: von Willebrand factor (VWF) deficiency (↑PTT and BT)
-‐ Von Willebrand is most common inherited bleeding disorder
-‐ Failure of normal hemostasis after cirmcusion often initial sign of hemophilia A
-‐ Pt with > 25% of FVIII functions normally; mild symptoms < 5%; severe < 1%
-‐ Infants have oral laceration and ecchymoses on lips and tongue
-‐ Hemarthrosis: deep hemorrhage in muscles, ST, joints (knees) -‐> deformity of joints too
-‐ Pseudotumor of hemophilia: hemorrhage causing a tumor-‐like mass
-‐ Hallmark: increased coagulation time (↑PTT)
-‐ Partial thromboplastin test (PTT): monitors the intrinsic pathway
-‐ Prothrombin: evaluates the extrinsic system and measures the presence or absence of clotting factors I, II, V, VII, and X
Plasminogen deficiency
-‐ Plasminogen gene mutation, AR disorder
-‐ Fibrin build-‐up in mucosa (plasminogen-‐>plasmin-‐> degradation of fibrin in blood clot)
-‐ Ligneous conjunctivitis: plaques and nodules in conjunctival mucosa of upper eyelid. Can also involve oral, laryngeal (horseness) and vaginal mucosas
-‐ Ligneous: “wood-‐like” changes
-‐ Oral: patchy ulcerated papules and nodules on gingiva; wax and wane (~ ELP)
-‐ Histo: ~ to amyloid (acellular eosinophilic material). Fraser-‐Lendrum stain confirms it’s fibrin
Anemia
-‐ Decrease in volume of RBC (hematocrit) or in concentration of hemoglobin
-‐ Paleness of mucous membranes (especially palpebral conjunctiva)
Sickle cell anemia
-‐ T-‐A substitution (valine coded instead of glutamic acid in the β-‐globin chain of hemoglobin). Hemoglobine molecule is then prone to aggregation and become rigid and curved (“sickle”)
-‐ Sickle cell trait: only one gene affected, 40-‐50% of hemoglobin abnormal, no manifestations
-‐ Mutation confers resistance to malaria
-‐ Sickle cell disease: both genes mutated
-‐ RBCs block the capillaries due to their shape -‐> chronic hemolytic anemia, ischemia, infarction
-‐ Sickle cell crisis: pain and fever. Precipitated by hypoxia, infection, hypothermia and dehydration. Extreme pain from infarction of bones, lung and abdomen (lasts 3-‐10 days)
-‐ Acute chest syndrome: lung involvement in sickle cell crisis (due to fat embolism or pneumonia)
-‐ Pts susceptible to S.pneumoniae (most common cause of death in children)
-‐ Generalized rarefaction of MD and MX; enlarged marrow spaces
-‐ Coarse “stepladder”bone trabeculae (bone marrow hyperplasia and↑ hematopoiesis)
-‐ Hair-‐on-‐end appearance on skull radiograph (but more prominent in thalassemia)
Thalassemia
-‐ From greek thalassa, meaning sea (original cases reported in Mediterranean)
-‐ Reduced synthesis of α-‐ or β-‐globin chain. Increased protection against malaria.
-‐ Hypochromic, microcytic anemia due to hemolysis of abnormal RBCs
-‐ Minor β-‐Thalassemia: one gene affected. No manifestations
-‐ Major β-‐Thalassemia (Cooley’s or Mediterranean anemia): two genes affected. Growth of MX/MD (chipmunk facies), bone marrow hyperplasia (↑ hematopoiesis with reduced trabecular pattern MD) and hepatosplenomegaly. Hair-‐on-‐end pattern.
-‐ α-‐Thalassemia: one gene-‐no disease. Two genes-‐ trait (mild anemia). Three genes-‐hemoglobin H disease (hemolytic anemia and splenomegaly). Four genes-‐hydrops fetalis (generalized fetal edema)
-‐ Hemochromatosis: deadly excess of iron in orgnas from repeated transfusions in thalassemia tx
Aplastic anemia
-‐ Failure of bone marrow cells to produce all types of blood cells (auto-‐immune pancytopenia)
-‐ Triggers: toxins (benzene), drugs (chloramphenicol) or infection (hepatitis)
-‐ Increased frequency in Fanconi’s anemia and dyskeratosis congenita
-‐ RBC def (palor, tiredness), platelet def (bleeding), and WBC def (most significant; infections).
-‐ Oral: petechiae, ecchymoses, pale mucosa, oral ulcerations, gingival hyperplasia
-‐ Histo: acellular marrow
Neutropenia
-‐ Neutrophils below 1500/mm3 (normal 2500-‐6000). Increased susceptibility to infections
-‐ Benign ethnic neutropenia: pts in certain regions of world have low neutrophils but are healthy
-‐ Genetic (infants): dyskeratosis congenita, cartilage-‐hair syndrome, Schwachamn-‐Diamond syndrome and severe congenital neutropenia
-‐ Acquired (adults): leukemia, Gaucher disease, osteopetrosis, drugs (chemo, ab, etc), vit B12 def, and infections (hepatitis A/B, HIV, measles, varicella, rubella, TB, typhoid)
-‐ Pts have bacterial infections (esp S.aureus). Abcess formation reduced.
-‐ Middle ear, perirectal and oral infections (ulcerations on gingival mucosa)
Cyclic neutropenia
-‐ Neutrophil elastase (ELANE) gene mutation.
-‐ 18-‐21 day cycle signs/symptoms
-‐ Oral: mucosal ulcerations (most severe in gingiva). Bone loss may occur.
-‐ Dx: sequential CBC (2x/week for 8 weeks)-‐ must be < 500 mm3 (3-‐5 days, 3 cycles)
Agranulocytosis
-‐ Absence of granulocytes, especially neutrophils (usually due to CT)
-‐ Kostmann syndrome: congenital agranulocytosis, low granulocyte colony stimulating factor
-‐ Features: ulcers of oral mucosa; gingivitis and gingival necrosis (NUG-‐like), periodontitis and decreased hematocrit
Thrombocytopenia
-‐ Reduced platelets. Clinical signs when count < 100,000/mm3(normal 200,000-‐400,000)
-‐ Reduced production (BM cancer, CT), increased destruction (drugs, most common heparin) or sequestration in spleen (Gaucher disease, portal HT).
-‐ SLE and HIV may cause increased destruction
-‐ Oral: petechiae, ecchymosis and hematoma, spontaneous gingival hemorrhage
-‐ Idiopathic (immune) thrombocytopenia purpura: in childhood after viral infection, resolves spontaneously in 4-‐6 wks (max 6 mths)
-‐ Thrombotic thrombocytopenia purpura: increased comsuption of platelets in abnormal clot formation. Leads to numerous thrombi formation within small vessels of body.
-‐ Gingival biopsy: 30-‐40% of cases show fibrin deposit (PAS+) in small vessels, causing occlusion
Polycythemia vera (primary acquired erythrocytosis)
-‐ Increase in the mass of RBC, along with uncontrolled production of platelets and granulocytes
-‐ JAK2 mutation.
-‐ Pts complain of generalized itching after bath without rash
-‐ Erythromelalgia: painful burning with erythema and warmth of hand and feet
-‐ Also, gingival hemorrhage and myocardial infarction
Chronic granulomatous disease of childhood (Bridges–Good syndrome, Chronic granulomatous disorder, Quie syndrome)
-‐ Inability of PMN’s to destroy bacteria due to defect in NADPH oxidase enzyme
-‐ Formation of granulomata in many organs; chronic oral ulcerative lesions
-‐ Most common infections (in order of frequency): pneumonia, abscesses, suppurative arthritis, osteomyelitis, bacteremia/fungemia, and superficial skin infections (cellulitis or impetigo)
-‐ Dx: nitroblue-‐tetrazolium test
Leukemia
-‐ Acute or chronic; myeloid or lymphoblastic/lymphocytic
-‐ Assoc w/: Down, Bloom, NF1, Schwachman-‐Diamond, Ataxia-‐telangiectasia, Klinefelter, Fanconi’s anemia and Wiskott-‐Aldrich
-‐ Environmental factors: chemicals, radiation, viruses (HTLV-‐1)
-‐ Acute myeloid (broad range-‐40% survival), acute lymphoblastic (children-‐80% survival), chronic myeloid (adults-‐80% survival), chronic lymphocytic (older adults-‐incurable but course variable)
-‐ Philadelphia chromosome: seen in chronic myeloid leukemia (22;9). Produces bcr-‐abl gene and a chimeric protein with tyrosine kinase activity
-‐ Myelodysplasia syndromes: groups of disorders that represent early stage AML
-‐ Myelophthisic anemia: subst of normal RBC and WBC by malignant cells, leading to symptoms
-‐ Patients may also thrombocytopenia and associated oral changes + gingival enlargement
-‐ Oral: ulcerations (esp gingival-‐ deep, punched-‐out), candidiasis, herpes
-‐ Granulocytic sarcoma or extramedullary myeloid tumor or chloroma: tumor-‐like growth from leukemic infiltrate in soft tissues. Gingival infiltration most seen in acute monocytic leukemia
-‐ Blast transformation: process seen in chronic myeloid leukemia where cells become less differentiated, proliferate wildly and cause pt death in 3-‐6 mths
-‐ Induction CT: to high doses of CT to destroy cancer cells, thus inducing a remission
-‐ Maitenance CT: lower doses of CT to maintain remission
-‐ Richter syndrome: chronic lymphocytic leukemia becoming a large cell lymphoma
Langerhans cell histiocytosis
-‐ Spectrum of disease affecting infants to adults, former often more severe than theadult form.
-‐ Eosinophilic granuloma of bone (mono or polyostotic), chronic disseminated histiocytosis (Hand-‐ Schuler-‐Christian disease) and acute disseminated histiocytosis (Leferer-‐Siwe disease)
-‐ Hand-‐Schuler-‐Christian disease: bone lesions, exophtalmos and diabetes insipitus
-‐ Pulmonary LCH: in smokers; probably a different entity and reactive process
-‐ X-‐ray: punched-‐out RL, “scooped out”, teeth floating in air, most in post MD
-‐ It can mimic severe localized periodontal disease in an adult.Birbeck granules: rod-‐shaped structures seen in the cytoplasm of Langerhans’cells in EM
-‐ CD1a or CD207 (+++). Also, Peanut agglutinin (PNA)+
Hodgkin’s lymphoma
-‐ EBV linked to a significant percentage of cases
-‐ 75% in cervical and supraclavicular lymph nodes. Bimodal: 15-‐35 and 50+
-‐ Typically begins as nontenderlymphadenopathy that progresses in an orderly manner from one lymph nodechain to another
-‐ Weight loss, fever, night sweats, pruritus (=Category B: worse prognosis)
-‐ Histo: nodular lymphocyte-‐predominant (popcorn cell, good prognosis) and classical (lymphocyte rich; nodular sclerosis-‐ 80%, more in females, 2nd decade, RS called “lacunar cells, good prognosis; mixed cellularity-‐ 20%, eosinophils present; lymphocyte depletion-‐ most aggressive; unclassifiable)
-‐ Reed-‐Sternberg: owl-‐eye or pennies on a plate (in classical). CD15+ and CD30++
-‐ Tx: ABVD (adriamycin, bleomycin, vinblastine and dacarbazine): scheme used for Hodgkin’s tx
Non-‐Hodgkin’s lymphoma
-‐ NHL grows as solid mass (leukemias have many malignant cells circulating in peripheral blood)
-‐ More in pts with immune problems: AIDS, Sjogrens, SLE, RA, organ transplant, Bloom syndrome
-‐ EBV in Burkitt, H.pylori in MALT lymphoma of the stomach
-‐ Oral NHL: usually extra-‐nodal. Diffuse large B cell (high-‐grade) most common, than follicular
-‐ Waldeyer’s ring most common, than hard palate
-‐ Follicular lymphoma: most common of salivary glands. Follicles are dumbbell shaped and back-‐ to-‐back with little mantle. Lacks starry sky (seen in reactive lesions). Prognosis depends on ratio of centroblasts to centrocytes.
-‐ DLBCL: CD5 (+/-‐) CD10 (+/-‐) CD19 (+) CD20 (+). Translocation 3q27 and t(14;18)
-‐ FL: CD5 (-‐) CD10 (+) CD19 (+) CD20 (+). Translocation 14;18 with BLC-‐2 overexpression
-‐ SLL (CLL): CD5 (+), CD19 (+), CD20 (+), CD23 (+).
-‐ MCL: CD5 (+), CD19 (+), CD 20 (+), CD23 (-‐). Translocation 11;14
-‐ MALT: CD10 (-‐), CD20 (+), CD21 (+), CD22 (+)
-‐ Techniques for monoclanity: IHC light chains, gene rearrangement studies and flow cytometry
Angioimmunoblastic T-‐cell lymphoma (angioimmunoblastic T cell lymphadenopathy with dysproteinemia)
-‐ Most common subtype of peripheral T cell lymphomas
-‐ Can mimic Hodgkin’s lymphoma
-‐ Characterized by a polymorphous lymph node infiltrate showing a marked increase in follicular dendritic cells (FDCs) and high endothelial venules (HEVs)
-‐ Signs include fever, malaise, joint pain, and skin rash.
Mycosis fungoides (cutaneous T cell lymphoma)
-‐ Derived from T helper CD4+ lymphocytes
-‐ Epidermotropism: propensity to invade epidermis of skin
-‐ Stages: eczematous (similar psoriasis-‐ histo very subtle), plaque (sezary cells in epith) and tumor (sezary cells in dermis and epidermis)
-‐ Oral: erythematous, indurated plaques or nodules that are typically ulcerated
-‐ Sezary syndrome: aggressive form of mycosis fungoides. It’s a dermatophathic T cell leukemia affecting multiple organs (mostly kidney and liver)
-‐ Sezary cells (mycosis cells): atypical lymphocytes
-‐ Cerebriform nucleus: marked infolding of nuclear membrane of Sezary cells
-‐ Pautrier’s microabscesses: aggregates of Sezary cellss in epithelium (plaque stage)
-‐ IHC: CD4
-‐ Tx with antibody against CD52
Burkitt’s lymphoma
-‐ Endemic (African, 95% EBV), sporadic (American; 25% EBV) and immunodef associated
-‐ Boys (peak 7 yo), post MX more (younger pts have more jaw involvement)
-‐ Patchy loss of lamina dura: early xray sign
-‐ CD10+, Ki67 almost 100%
-‐ Starry-‐sky appearance: reactive lightly-‐stained histiocytes (tingible macrophages) in a background of dark tumor cells
-‐ Molecular analysis recommended: 8;14 translocation with c-‐MYC overexpression
Extranodal NK/T-‐cell lymphoma (angiocentric T-‐cell lymphoma)
-‐ Aggressive destruction of midline structures of palate and nasal fossa
-‐ Deep necrotic ulcer in midlate palate with oronasal fistula
-‐ Lymphomatoid granulomatosis: B cell proliferation induced by EBV
-‐ Histo: mixed inflammatory cells around blood vessels (angiogentric), necrosis
-‐ IHC: CD56 and granzyme B
Plasmacytoma
-‐ Unifocal prolif of plasma cells. Most common site is spine. Cyclin D1 and CD56 +
-‐ Extramedullary plasmacytoma: in ST. 90% HN. Cyclin D1 and CD56 negative
-‐ Plasmacytoma: < protein M than MM; no evidence of bone marrow infiltration; no signs of anemia, hypercalcemia or renal failure
-‐ 50% develop MM in 3 years (extramedullary only 30%)
Multiple myeloma
-‐ 2x blacks (most common hematologic malignancy in blacks)
-‐ Most characteristic symptom: lumbar spine pain,
-‐ Metastatic calfications: caused by hypercalcemia secondary to tumor osteolysis
-‐ Bence Jones proteins: excess light chain proteins (kappa or lamba) produced by tumo cells.
Found in urine of 30-‐50% of patients. Can cause renal failure.
-‐ 15% of patients show deposition of amyloid (oral cavity and periorbital skin)
-‐ IHC: CD138; kappa and lamba to show monoclonality
-‐ Monoclonal gammopathy: excess immunoglobulin (M protein) seen in serum and urine
-‐ Worse prognosis with high β2-‐microglobulin, low albumin and in older patients
Castleman’s disease (angiofollicular lymph node hyperplasia)
-‐ Solitary or multicentric benign growth of lymphoid tissue in young pts (<30y)
-‐ Node architecture obliteration with scattered depleted small follicular centers surrounded by a cuff of small lymphocytes (“onion skin”) divided by concentric rings of reticulin fibers resembling Hassall’s corpuscules and penetrated by hialanized vessels
-‐ Systemic form: adenopathy, fever, anemia, elevated ESR and hypergammaglobunemia; seen in older patients with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes) and has poor prognosis (assoc w/ lymphoma)
-‐ HHV8
Kikuchi-‐Fujimoto disease (histiocytic necrotizing lymphadenitis)
-‐ Self-‐limiting benign inflamm condition affecting cervical lymph nodes.
-‐ Mostly Asians (F>M). Fever and leucopenia common.
-‐ Necrosis surrounded by histiocytes, lymphocytes and plasma cells (lacks neutrophils)
-‐ Three patterns: proliferative, necrotic and xanthomatous (histiocytes)
Rosai-‐Dorfmann disease (sinus histiocytosis with massive lymphadenopathy)
-‐ 90% in cervical LN.
-‐ May occur in pts with AI lymphoproliferative syndrome with Fas mutation.
-‐ Emperipolesis: aka lymphocytophagocytosis. Lymphocytes inside histiocytes, often forming wreath-‐like rings within cytoplasm. Plasma cells, neutrophils and RBCs may be found inside histiocytes too. Also seen in a cutaneous T cell lymphoma (granulomatous slack skin).
-‐ IHC: S100+ CD68+ CD1a neg
-‐ Resolves spontaneously
Kawasaki disease (mucocutaneous lymph node syndrome)
-‐ Acute febrile vasculitic syndrome of early childhood. Assoc w/ HLA-‐BW22
-‐ Leading cause of acquired heart disease in children; risk factor for adult ischemic heart disease
-‐ High fever lasting 1 to 2 weeks; Bilateral congestion of ocular conjunctivae
-‐ Dryness, redness, and fissuring of lips; diffuse reddening of oral and pharyngeal mucosa
-‐ Lymphadenopathy (necrotic lymph node)
-‐ Oral: strawberry tongue
Angiolymphoid hyperplasia with eosinophilia (epithelioid hemangioma)
-‐ Frequent in HN of young Asian men (but may affect both sexes)
-‐ Usually more superficial (dermis), forming multiple papules or nodules.
-‐ Other sites: oral cavity (upper lip), salivary glands, lungs and bone
-‐ Trauma, pulsatile sensation and pruritus reported in some cases.
-‐ Proliferation of small vessels lined by plump endothelial cells
Kimura’s disease
-‐ Affects HN of young adult asian men (strong racial predilection)
-‐ Similar to ALHE, but deeper (subcutaneous tissue, salivary glands and lymphnodes)
-‐ Fever, malaise, lymphadenopathy (ALHE has no symptoms)
-‐ Peripheral blood eosinophilia present, as well as elevated IgE
-‐ Endothelial cells not very large and flatter (ALHE is more prominent vascular condition)
-‐ Can show germinal centers (rare in ALHE)
