Path Final

Morphology of ALL

Important: to distinguish ALL from AML differentiate lymphoblast (ALL) from myeloblast (AML) treatment protocols are different histochemical stains help in differentiating Myeloperoxidase is positive for myeloblasts (AML), but negative for lymphocytes (ALL) Sudan black is positive for myeloblasts (AML), but negative for lymphocytes (ALL) t(12:15) TEL-1: TKC PAS positive for lymhoblasts (ALL), but negative for myeloblasts (AML)

Mechanism of cell-cycle regulation by RB

In a resting cell, RB is a component of the E2F/DP1/RB complex, which represses gene transcription through the recruitment of histone deacetylase, an enzyme that alters the conformation of chromatin, making it more compact. Phosphorylation of RB by cyclin D-CDK4 removes histone deacetylase from chromatin, allowing the activation of E2F transcriptional activity (RB can also be phosphorylated by cyclin E-CDK2). E2F-mediated transcription of cyclins E and A, and of genes required for DNA replication, permit the passage through the G1 restriction point.

Transfusion reaction (TR)

In contrast to GVH, TR occur immediately after transfusing a mismatched blood. (if you donate A+ blood to a person with B+ blood group etc)

Transfusion-related acute lung injury

In medicine, transfusion related acute lung injury (TRALI) is a serious blood transfusion complication characterized by the acute onset of non-cardiogenic pulmonary edema following transfusion of blood products Although the incidence of TRALI has decreased with modified transfusion practices, it is still the leading cause of transfusion-related deaths in the United States from fiscal year 2008 through fiscal year 2012 TRALI is defined as an acute lung injury that is temporally related to a blood transfusion; specifically, it occurs within the first SIX HOURS following a transfusion

BCL2 expression

In reactive and neoplastic follicles. BCL2 protein was detected by using an immunohistochemical technique that produces a brown stain. In reactive follicles (A), BCL2 is present in mantle zone cells but not follicular center B cells, whereas follicular lymphoma cells (B) exhibit strong BCL2 staining Most important translocation, which seen in 90% of cases t(14;18) this translocation results in over expression of BCL 2 BCL 2 is an anti-apoptotic protein molecule follicular lymphoma cells becomes immortal

Three-base deletion

In the common cystic fibrosis (CF) allele results in synthesis of a protein that is missing amino acid 508 (phenylalanine). Because the deletion is a multiple of three, this is not a frameshift mutation.

Acute Immune Thrombocytopenic purpura

Incidence: seen in children, usually following viral infection Pathogenesis: formation of anti platelet antibodies (against platelets membrane glycoproteins: IIb/IIIa or Ib/IX complex) self limited, resolves spontaneously within 6 months steroid therapy indicated, if, thrombocytopenia is severe Lab findings: thrombocytopenia bleeding time: prolonged coagulation study: normal Clinical Features: Petechial (or echimoses) hemorrhages on skin, epistaxis

Hemolytic-Uremic syndrome (HUS)

Incidence: children Pathogenesis: infectious gastroenteritis caused by E.coli strain 0157:H7 shiga like toxin is elaborated which binds and damages endothelial cells in glomerulus initiating platelet activation & aggregation Clinical Features bloody diarrhea similar to TTP, except that neurological features are less

Mantle cell lymphoma

Incidence: more in Europe 5th to 6th decade of life more in males Pathology: - tumor cells resemble the mantle zone B lymphocytes Lab Diagnosis: CBC: WNL Peripheral blood smear: - 20 to 40% show spillover Lymph node biopsy: -loss of architecture -few reactive germinal centers -these are surrounded by tumor cells -Cyclin D1 expression, CD19, CD20, CD5(as in CLL but absence of proliferative centres), (CD23 negative), express surface Ig Bone Marrow: frequently involved Cytogenetics associated with t(11;14) translocation cyclin D1 positive on imunohistochemistry Clinical features -painless lymphadenopathy, splenomegaly -occasional small bowel involvement: lymphomatoid polyp -patients presents in late stage (stage IV) -rarely curable, poor prognosis

Abnormalities of vessels

Increased fragility or Hemorrhagic diathesis (hypercoagulability)

Gum hypertrophy

Indicative of M5 Acute Monocytic Leukemia

Carcinogenesis

Initiation, promotion, progression

Frameshift mutations

Insertion and deletion mutations that change the reading frame of codons Single-base deletion at the ABO (glycosyltransferase) locus, leading to a frameshift mutation responsible for the O allele.

Normal RBC breakdown

Iron released from heme combines with iron binding-protein then carried to either bone marrow or body iron stores Tissue Iron - ferritin & hemosiderin

Nucleotide Excision Repair (NER)

It recognizes damage, then initiates repair incision on either side of the lesion excision (release) of the damage containing area Example: DNA damage caused by UV rays UV light causes cross-linking of 'pyrimidine' residues (normally repaired by NER) this prevents normal DNA replication

HMG-CoA reductase

Key enzyme in cholesterol biosynthesis

Diagnosis of Anemia of chronic disease

Lab Diagnosis anemia, normocytic normochromic serum iron is reduced serum ferritin is increased TIBC is reduced Bone marrow: normal usually macrophage iron is increased

Osmotic fragility test

Lab Investigations for Hereditary spherocytosis increased osmotic fragility (normal red cells are able to increase its size with increasing hypotonic concentration of saline solution) spherocytes rupture easily Hb: decreased Peripheral blood smear: spherocytes absence of central pallor Reticulocytes: increased

Myelofibrosis (Myelophtysis)

Leukoerythroblastosis - Teardrop RBCs

Leukemia

Lymphoid neoplasms presents with widespread involvement of bone marrow - usually associated with spillover of malignant cells into peripheral blood

Carcinoma uterine cervix

Malignant tumor infiltrates and destroy the surrounding tissue they are poorly demarcated (it is necessary to remove a wide margin of surrounding normal tissue when surgical excision is attempted - "clean margine" ) ! Note the invasion of bladder wall

Hepatitis B virus (HBV)

Mechanism of action immunologically mediated chronic inflammation (cytokines, O2 free radicals) regeneration & genomic instability activation of NF-κB pathway within hepatocytes block apoptosis HBV genome: HBx gene can directly or indirectly inactivate variety of transcription factors & signal transducing pathways Remember: Hepatitis C, though not a DNA virus is also linked to HCC

Malignant tumors

Mesenchymal tumors: sarcomas (fibrosarcoma, chondrosarcoma, osteosarcoma)

Meningioma

Mostly benign, compression

Molecular model for colorectal cancer

Multistep process- accumulation of multiple mutation Based on studies of Fearon ER, Vogelstein B: A genetic model of colorectal carcinogenesis.

Transcription factors

Mutations involving genes encoding nuclear transcription factors are associated with malignant transformation

BRCA-1 and BRCA-2 genes

Mutations of these are associated with breast carcinoma and ovarian cancers (male breast cancers too) first degree relatives, pre-menopausal women Function: transcription regulation, cell cycle control, also protecting DNA

Pelger-Huet cells

Myelodysplastic Syndrome Myeloid series neutrophils with 2 nuclear lobes

Xeroderma pigmentosum

NER defect Inherited disorder involving defective DNA repair genes increased risk of skin cancers: (squamous cell ca., basal cell ca.)

Platelet count (normal range)

NORMAL= 150,000 - 400,000/mm3 < 100,000=Thrombocytopenia 50,000 - 100,000=Mild Thrombocytopenia < 20,000=Sev. Thrombocytopenia

Tumor necrosis

Necrosis that may occur in rapidly growing neoplasms that out-grow their blood supply

Metastatic lymph node

Observe the presence of glandular elements in the lymph node

Colloid cyst

Obstructs CSF pathway

Role of signal transducing proteins

Oncoproteins can mimic the normal functioning of certain signal transducing proteins examples: RAS oncogene - RAS plays a role in mitogenesis, induced by growth factors

Hand-Shuller-Christian Disease

One of the four recognized clinical syndromes of Langerhans cell histiocytosis (LCH). Calvar bone deffects Diabetes insipidus Exophthalmus

Clinical course of Hodgkin's lymphoma

Painless lymph node enlargement neck, supraclavicular, axilla mediastinal lymph nodes in 50% subdiaphragmatic presentation is unusual -Eosinophils -presents with: fever (Pel-Epstein fever) Staging: history, physical examination, complete blood count, ESR, serum chemistry, CT scan chest, abdomen, pelvis, bone marrow Important to differentiate from NHL -mostly involve single group of nodes -orderly spread by contiguity -mesenteric and Waldeyer's ring rarely involved -extra nodal, rarely involved

Lab diagnosis of aplastic anemia

Pancytopenia -absolute neutrophil count is reduced -relative lymphocytosis, sometimes Bone marrow: -marked reduction in cellularity (less than 25%) -increase fatty marrow Importance: need to exclude other causes Myelodysplastic syndrome, leukemias, hairy cell leukemia Clinical features - pallor, weakness, easy bruising, infections

Oncogenic viruses

Papilloma virus (HPV) Epstein Barr virus (EBV) Hepatitis B virus (HBV) Kaposi sarcoma herpes virus (KSHV)

Hemosiderin

Partially degraded and aggregated ferritin insoluble in water and is not as accessible for cell use as is ferritin. most commonly seen as golden-brown granular material in macrophages and is readily demonstrated to be iron by a Prussian-blue stain.

Causes of aplastic anemia

Pathophysiology: Damaged stem cells can produce progeny expressing neo-antigens that evoke an autoimmune reaction, or give rise to a clonal population with reduced proliferative capacity. Either pathway could lead to marrow aplasia.

Anaplastic Large-cell Lymphoma

Peripheral T cell neoplasm Incidence: uncommon, children & young adults, Characterized by re-arrangement in ALK gene (2p23) that triggers JAK/STAT pathway Lab Diagnosis: CBC: WNL Skin biopsy: infiltrates of large anaplastic cells, horseshoe nuclei (hallmark cells) Lymph node: loss of architecture large anaplastic cells, "hallmark" cells Prognosis: good, ....for a T-cell neoplasm

Lab diagnosis of Primary Myelofibrosis

Peripheral blood smear: -nucleated rbc, 'TEAR DROP' RBC (AKA dacrocytes), early granulocytes -"leukoerythroblastosis" Bone Marrow: -marrow becomes hypocellular -Diffusely fibrotic (increase reticulin fibers) -atypical megakaryocytes

Delayed hypersensitivity in the skin

Perivascular infiltration

Crest syndrome (limited scleroderma)

Positive for anti-Centro mere antibody. C = Calcinosis in skin and elsewhere. R = Raynaud's phenomenon, sensitivity to cold. E = Esophageal dysmotility from sub-mucosal fibrosis. S = Sclerodactyly from dermal fibrosis. T = Telangiectasias .

The WHO Classification of Lymphoid Neoplasms

Precursor B-cell neoplasms - Immature B cells Peripheral B-cell neoplasms - Mature B cells Precursor T-cell neoplasms - Immature T cells Hodgkin lymphoma - Reed-Sternberg cells and variants

Follicular lymphoma in the spleen

Prominent nodules represent white pulp follicles expanded by follicular lymphoma cells. Other indolent B-cell lymphomas (small lymphocytic lymphoma, mantle cell lymphoma, marginal zone lymphoma) can produce an identical pattern of involvement.

Juvenile Rheumatoid Arthritis (JRA)

RF is typically absent Rheumatoid nodules absent Large joints (Pauciarticular) Still disease is a severe version of juvenile idiopathic arthritis (JIA), which occurs in children

Mutations

Random errors in gene replication that lead to a change in the sequence of nucleotides. The source of all genetic diversity.

Alpha thalassemias

Reduced or absent synthesis of α globin chains affects: Hb-A, Hb-A2 & Hb-F severity depends upon the number of α chains missing Genetics: total number: 4 α globin chains caused by deletion of α globin chains Clinical types: Silent carrier deletion of single α chain α thalassemia trait deletion of two α chains HbH disease deletion of three alpha chains HbF = a2g2 (1%) HbA = a2b2 (96%) HbA1 = glycosilated HbA2 = a2d2 (3%) HgH = b4 Barts = g4 Schistocytes = microangiopathic hemolytic anemia Teardrop RBCs = Leukoerithroblastosis (myelophtisic process in BM) Basophilic stripping = B. marrow injury

Toxic Granulations

Seen in severe infections- sepsis neutrophils contain numerous dark purple granules

Multiple Myeloma Labs

Serum electrophoresis > 3gm/dL of Ig in serum and or > 6gm/dL of Bence-Jones protein in urine Most cases the 'M' spike is IgG (55%), followed by IgA Complete blood counts: in the course of the disease, anemia, thrombocytopenia may occur due to marrow infiltration Peripheral blood smear: rouleaux formation (stack of coins) of red cells increased viscosity due to presence of immunoglobulins Bone marrow: > 30% abnormal plasma cells on histology ESR: increased Urine: proteinuria seen in 50 to 60% of cases presence of light chains (L), Bence-Jones proteins demonstrated by immune electrophoresis Radioimaging: punched out lesions (osteolytic) spine, ribs, skull, pelvis, femur

Lupus nephritis

Showing a glomerulus with several "wire loop" lesions representing extensive subendothelial deposits of immune complexes. (Periodic acid-Schiff [PAS] stain.)

Well differentiated adenocarcinoma

Shows glandular pattern, however cells exhibit features of malignancy

Antinuclear Antibodies in Various Autoimmune Diseases

Sjögren's syndrome -- a disease that causes dry eyes and mouth Scleroderma -- a connective tissue disease Rheumatoid arthritis -- this causes joint damage, pain, and swelling Polymyositis -- a disease that causes muscle weakness Mixed connective tissue disease -- a condition that has symptoms of lupus, scleroderma, and polymyositis Juvenile chronic arthritis -- a type of autoimmune arthritis that affects children Dermatomyositis -- a rare disease that causes weak muscles and a rash Polyarteritis nodosa -- a rare disease that causes the blood vessels to swell up and damage organs

Dermatomyositis

Skin + muscle weakness Clinical feature: Heliotrope Rash which can cause periorbital edema Perifascicular inflammation and atrophy in a skeletal muscle.

Xeroderma pigmentosum

Solar keratosis Mutated single strand nucleotide excision repair gene, which prevents repair of thymidine dimers.; Dry skin w/ melanoma and other cancers ("children of the night"). seen on sun exposed sites. Risk for malignancy.

Clinical features of CML

Splenomegaly 'BLAST CRISIS' or 'accelerated phase' CML transforms to a more aggressive disease after 2 to 5 years Characterized by rapidly increasing percentage of Blasts (majority are myeloid) now, resembling acute leukemia anemia, thrombocytopenia, basophilia

Human papilloma virus (HPV)

Squamous cell carcinoma of cervix and anogenital region some cases of oral and laryngeal cancers carcinoma cervix: HPV types 16, 18 in cancers, HPV genome viral DNA is integrated into host cell genome E6, E7 proteins (oncoproteins) are over expressed in HPV types 16, 18 genital warts (benign): HPV type 6, 11 (low risk for malignancy) in benign warts, HPV genome is maintained in an 'episomal' form (non integrated)

Origin of lymphoid neoplasms

Stages of B- and T-cell differentiation from which specific lymphoid and tumors emerge are shown. CD, cluster of differentiation; DR, human lymphocyte antigen-class II antigens; Ig, immunoglobulin; TCR, T-cell receptor; TdT, terminal deoxyribonucleotidyl transferase.

Lymph node metastases

Submental: metastases from squamous cell ca. floor of the mouth Cervical: head & neck tumors Virchow's node (left supraclavicular): stomach, pancreas cancers Axillary: breast cancers Hilar: lung cancers Mediastinal: lung cancers, Hodgkin lymphoma (nodular sclerosing), T- cell ALL Para-aortic: testicular, Burkitt lymphoma Inguinal: vulva, penis cancers

Cervix biopsy

Test for dysplais and Koilocytes: nucleus show wrinkled appearance, cleared out cytoplasm, condensed and prominent cytoplasmic outline

Two Hit Hypothesis of Carcinogenesis

The cell become homozygous for the mutant allele, in other words, loses of heterozygosity (LOH) of the normal RB gene Two mutations of the RB locus on chromosome 13q14 lead to neoplastic proliferation of the retinal cells. In the familial form, all somatic cells inherit one mutant RB gene from a carrier parent. The second mutation affects the Rb locus in one of the retinal cells after birth. In the sporadic form, on the other hand, both mutations at the RB locus are acquired by the retinal cells after birth.

RBC Distribution Width (RDW)

The coefficient of variation of RBC volume = 11.5% - 14.5%

Pathogenesis of amyloidosis

The deposition of these proteins may result from: excessive production of proteins that are prone to misfolding and aggregation; mutations that produce proteins that cannot fold properly and tend to aggregate; defective or incomplete proteolytic degradation of extracellular proteins.

Features of immunodeficiency diseases

The important diagnostic features and clinical manifestations of immune deficiencies affecting different components of the immune system are summarized. Within each group, different diseases, and even different patients with the same disease, may show considerable variation.

Ductal carcinoma of the breast

The lesion is retracted, infiltrating the surrounding breast substance, and would be stony hard on palpation.

Anemia of chronic disease

The most common form of anemia in hospitalized patients. Inflammation induced sequestration of iron within the cells of reticulo-endothelial system. Associated with: Low serum iron, RBC can be normocytic-normochromic, or hypochromic-microcytic, as in iron defic. anemia BUT: Increased Fe in marrow Mf. High serum ferritin level Decrease total iron-binding capacity Block in the transfer of iron from mono- pfagoc. storage pool to erythroid precursor Ferritin increases in chronic inflammation Associated with chronic disease, 3 categories Chronic microbial infections (osteomyelitis, bacterial endocarditis, lung abscess) Chronic immune disorders (Rheumatoid arthritis) Neoplasms (Hodgkin lymphoma)

Immune complex vasculitis

The necrotic vessel wall is replaced by smudgy, pink "fibrinoid" material.

Fibroadenoma of breast

The tan-colored, encapsulated small tumor is sharply demarcated from the whiter breast tissue

Chronic Myeloproliferative disorders

These include: 1. Chronic Myelogenous Leukemia (CML) 2. Polycythemia vera 3. Essential thrombocytosis 4. Primary myelofibrosis

Monogenic Disorders

Those caused by mutation in the single gene. haemophilia, Huntington's, cystic fibrosis

Lab diagnosis of CML

Total WBC: > 100,000/mm3 Platelet count: increased initially, later thrombocytopenia Peripheral blood smear: -myeloid series in all stages of development -EOSINOPHILS & BASOPHILS -VERY LOW alkaline phosphatase activity (high in reactive leukocytes) Bone Marrow: -marked hypercellularity -myeloid & megakaryocytic lineage -eosinophils & basophils are increased -myeloblasts are less than 5% -later stages show collagen proliferation Molecular diagnosis: Philadelphia chromosome (95%) may be seen associated with adult form of ALL

Labs for AML

Total white cell count: increased, sometimes may be normal or *decreased *25 to 40% of patients have counts less than 5,000 cell/mm3 Anemia, thrombocytopenia Peripheral blood smear: presence of atypical myeloid cells, circulating 'blasts' Bone marrow: >20% blasts Cytogenetic studies

Plummer-Vinson syndrome

Triad of findings microcytic hypochromic anemia atrophic glossitis esophageal webs Dg: - low Hb, low HCT, low MCV, hypochromic-microcytic RBC - low serum ferritin, low serum Fe, low transferin saturation, increased total iron-binding capacity - response to Th (persons frequently die with this form of anemia, but rarely of it)

Role of growth factors

Tumor cells acquire the ability to synthesize growth factors, to which they are responsive example: protooncogene SIS which promotes growth factor synthesis is overproduced in many tumors example: low grade astrocytoma, osteosarcoma

Diffuse large B-cell lymphoma

Tumor cells have large nuclei, open chromatin, and prominent nucleoli. Immunophenotype: tumor cell expresses CD19, CD20 surface Ig is seen negative for TdT T (14;18), CD79a Molecular Abnormality: dysregulation of BCL-6 (this is normally required for the formation of normal germinal centers) Most common lymphoma of adults Heterogeneous group of mature B-cell tumors that shares a large cell morphology and aggressive clinical behavior Rearrangements or mutations of BCL6 gene are recognized associations; one third carry a (14;18) translocation involving BCL2 and may arise from follicular lymphomas.

Tumor giant cells

Tumor giant cells represent anaplasia: -single huge polymorphic nucleus or >2 nuclei; -nuclei are hyper-chromatic and large

Secondary Infections due to neutropenia

Ulcerating necrotizing lesions of : gingiva, floor of mouth, buccal mucosa - severe life threatening infections: lungs, kidney deep fungal infections: Candida and Aspergillus fever, malaise, chills serious infections occur when absolute neutrophil counts fall below 500 cells/mm3 severe agranulocytosis: fulminant infection, death

Mitosis

Undifferentiated tumors have numerous mitosis Mitosis are abnormal (atypical, bizarre)

Autoimmune diseases

Usually chronic and progressive, and the type of tissue injury is determined by the nature of the dominant immune response.

Abnormalities in clotting factors

Von Willebrand disease Hemophilia A Hemophilia B

Action of RAS genes

When a normal cell is stimulated through a growth factor receptor, inactive (GDP-bound) RAS is activated to a GTP-bound state. Activated RAS recruits RAF and stimulates the MAP-kinase pathway to transmit growth-promoting signals to the nucleus. The mutant RAS protein is permanently activated because of inability to hydrolyze GTP, leading to continuous stimulation of cells without any external trigger. The anchoring of RAS to the cell membrane by the farnesyl moiety is essential for its action.

Vascular dissemination and homing of tumors

Within circulation, tumor cells are clumped together arrest and extravasation of tumor emboli at distant sites involve adhesion molecules (CD44 molecule expressed on T lymphocytes are used by tumor cells in selective sites)

Xanthoma

Yellow tumor cholesterol deposits in tendon and in the skin

Miscellaneous carcinogenic agents

asbestos: bronchogenic carcinoma, mesotheliomas vinyl chloride (PVC): hemangiosarcoma of liver

Alterations in nonreceptor tyrosine kinase

c-abl codes for a cytoplasmic tyrosine kinase in chronic myeloid leukemia (CML) c-abl is translocated from chromosome 9 to bcr region of chromosome 22 resulting in a fusion gene (bcr-abl) causing increase tyrosine kinase activity importance: imatinib mesylate targets bcr-abl tyrosine kinase

Sinus histiocytosis

characterized by distension and prominence of lymphoid sinusoids - these changes are seen associated with lymph nodes draining cancers - endothelial cells lining lymph sinuses are hypertrophied - increase in number of macrophages

Bone Marrow in Pernicious Anemia

cytoplasm shows regular hemoglobinization (N / C asynchrony) granulocytic series: giant metamyelocytes platelets: abnormally large, multilobation of nuclei

Bleeding Disorders

excessive bleeding can result from -increased fragility of the blood vessels -platelet deficiency and dysfunction -derangement of coagulation -combination of these Caused by vessel wall abnormalities usually do not cause serious bleeding problems petechiae, purpuras platelet count, bleeding time, coagulation tests (PT, PTT) are normal DEFICIENCIES OF PLATELETS PT, PTT normal The bleeding time is always prolonged DERANGEMENTS OF BLOOD CLOTTING: PT, PTT prolonged, bleeding time normal hemorrhage in joints, lower extremities (areas of traumas)

Clinical features of iron deficiency anemia

fatigue, palpitation pica (craving for unusual things. example: clay) pallor, glositis (smooth red tongue) angular cheilitis koilonychia (spoon shaped concavity of nails)

Incidence of CLL/SLL

most common type of leukemia in the Western world risk increases progressively with age more than 60 years, more in males

Telomerase

normal cells following a certain number of cell division reach a non-dividing stage with each division there is shortening of 'telomeres' at one stage, the loss of telomere function will activate p53 this will cause proliferative arrest: apoptosis telomerase activity is seen in almost tumor cells telomerase prevents telomere shortening

Biochemical tests for iron deficiency

serum iron & serum ferritin are decreased TIBC (total iron binding capacity); measure of amount of transferritin in circulating blood)

RB Governor of the Cell Cycle

■ When hypophosphorylated, RB exerts antiproliferative effects by binding and inhibiting E2F transcription factors that regulate genes required for cells to pass through the G1-S phase cell cycle checkpoint. Normal growth factor signaling leads to RB hyperphosphorylation and inactivation, thus promoting cell cycle progression. ■ The antiproliferative effect of RB is abrogated in cancers through a variety of mechanisms, including: ■ Loss-of-function mutations affecting RB ■ Gene amplifications of CDK4 and cyclin D genes ■ Loss of cyclin-dependent kinase inhibitors (p16/INK4a) ■ Viral oncoproteins that bind and inhibit RB (E7 protein of HPV)

Lymphoid Neoplasms

"leukemia": lymphoid neoplasms involving bone marrow "lymphoma": proliferations arising from discrete tissue masses

Regulatory functions of free cholesterol

(1) Suppression of cholesterol synthesis by inhibition of HMGCoA reductase, (2) storage of excess cholesterol by activation of ACAT, and (3) reduced synthesis of LDL receptors. ACAT, acyl-CoA:cholesterol acyltransferase; HMG-CoA reductase, 3-hydroxy-3-methylglutaryl coenzyme A reductase.

Karyotype Changes in Tumors

1) BALANCED TRANSLOCATION (common in hematopoietic neoplasm) 2) Deletion (common in non - hematopoietic neoplasm) In follicular B cell lymphoma 8 - 14 translocation

Clinical features of Sickle cell anemia (HbS)

1. severe anemia 2. vaso-occlusive complications 3. chronic hyperbilirubinemia 4. susceptibility to infections (early) Due to: congestion and poor blood flow in spleen in children infarction and autosplenectomy in adults pneumococci and Hemophilus influenzae Vaso-occlusive crises Sequestration crises Aplastic crises Increased susceptibility to infections Others: Gall stones Chronic leg ulcers (medial surface of tibia) Loss of renal function

Burkitt lymphoma translocation

8; 14 c-myc and Ig Heavy chain = increased c-myc = transcription activator

Cystic medial necrosis

A death or degeneration of a part of an artery wall associated with Marfan's

Lymphoplasmocytic lymphoma

A low-grade, B cell neoplasm composed of small lymphocytes, plasmacytoid lymphocytes, and plasma cells that typically involve the bone marrow, and it is associated with an immunoglobulin M (IgM) gammopathy Incidence: older population, 6th to 7th decade of life Pathology: -malignant lymphoplasmactyoid cells secrete monoclonal IgM -major manifestation: hyperviscosity monoclonal IgM -Waldenström macroglobinemia (hyperviscosity syndrome) Different from multiple myeloma: -heavy and light chain synthesis is balanced NO Bence-Johns -no complications arising from secretion of light chains (renal failure, amyloidosis) -tumor dissemination to lymph nodes, spleen and liver (unlike MM) -infiltration of nerve roots and meninges later in the course of the disease (no bone lesions like in MM) -serum calcium levels: NORMAL (unlike MM) Lab diagnosis CBC: normal Peripheral blood smear: rouleaux seen Bone marrow: findings range from- lymphocytes, mature plasma cells, IgM producing plasmacytoid lymphocytes

Carcinoma

A malignant tumor that occurs in epithelial tissue Marker Cytokeratin + Nests of cancer cells

Role of miRNAs in tumorigenesis

A. Reduced activity of a miRNA that inhibits translation of an oncogene gives rise to an excess of onco-proteins. B. Overactivity of a miRNA that targets a tumor suppression gene reduces the production of the tumor suppressor protein. Question marks in A and B are meant to indicate that the mechanisms by which changes in the level or activity of miRNA are not entirely known.

Auer rods

Acute myelogenous leukemia (especially the promyelocytic type M3)

Naturally occurring carcinogens

Aflatoxin B1 mycotoxin from some strains of Aspergillus flavus hepatocellular carcinoma Gross: liver shows a large growth on the right lobe of liver. Histologically, cords of malignant cells. Observe : mitotic figure (arrow)

Thalassemia syndromes

Alpha Thalassemia: deficient / or lack of synthesis of alpha (α) chain Beta Thalassemia: deficient synthesis (β+ thalassemia) - total absence (β0 thalassemia)

Trinucleotide repeat mutations

Amplification of a sequence of three nucleotides, makes chromosome unstable

Clinical course of Primary Myelofibrosis

Anemia, splenomegaly, fatigue, night sweats, hyperuricemia (gout) survival rate 3 to 5 years -Myelofibrosis occur in the terminal phase of polycythemia vera

Fabry disease

Angiokeratoma corporis diffusum, and alpha-galactosidase A deficiency) is a rare genetic lysosomal storage disease, inherited in an X-linked manner. Fabry disease can cause a wide range of systemic symptoms. It is a form of sphingolipidosis, as it involves dysfunctional metabolism of sphingolipids Angiokeratoma, a common dermatological manifestation in sufferers A bilateral, whorl-like corneal pattern of cream -colored lines in a patient

Seronegative arthropaties

Ankylosing spondylitis Reiter syndrome (urethritis, conjuctivitis, uveitis) Psoriatic arthritis Spond. assoc. with inf.bowel.diseses Reactive arthropaties sacroiliitis

Develop Graft vs host reaction

Any situation in which immunologically competent cells are transplanted into immunologically crippled recipients. Example: bone marrow, whole blood. Results from the donor lymphocytes attacking the recipient tissues that has offending HLA antigens. Matching donor and recipient for HLA class I and II is particularly important in bone marrow transplantation HLA-identical bone marrow transplants cause GVHD through recognition of minor histocompatibility antigens

Role of Bcl-2 gene

Apoptosis occurs following an imbalance between anti apoptotic & pro apoptotic factors Bcl-2 is an anti apoptotic factor tumor cells can escape apoptosis by altering the apoptotic process 85% of B cell lymphoma (follicular lymphoma) has a t(14;18) translocation this leads to overexpression of Bcl-2 protein.....this upregulates anti apoptotic properties

Tripolar spindle

Atypical Mitotic figure

Carcinogenic agents

CHEMICALS RADIANT ENERGY MICROBIAL AGENTS

Folate deficiency

Causes: i) increased requirements: ii) decreased intake: pure vegans, alcoholism, phenytoin & oral contraceptives (these drugs interfere with absorption) iii) impaired utilization: folic acid antagonists (methothrexate) Lab diagnosis diagnosis is made only the demonstration of decreased folate levels in serum Clinical features: - similar to vit B12, except no neurological symptoms

Neuroblastoma

Childhood tumor arising from adrenals. These tumors vary considerably, sometimes regressing spontaneously!!. 90% of these tumors produce catecholamines.The breakdown products- VMA can be detected in urine. N-myc amplification if present, is associaated with poor prognosis.

Gene amplification

Chromosomal alterations that result in an increased copies of a gene : amplification amplified genes can be detected by molecular hybridization using DNA probes Examples of gene amplification: N-myc amplification in neuroblastoma signifies advanced disease with poor prognosis ERB B2 (HER-2/Neu) amplification in breast carcinoma Importance of gene amplification: amplified genes can be detected using DNA probes

Procoagulants

Coagulation factors, thromboxane A2 (platelet aggregation, vasoconstrictor)

Thrombocytopenia

Decreased production of platelets (aplastic anemia, leukemias) -decreased platelet survival (immunologic or non-immunologic) -sequestration (hypersplenism) -dilutional (massive transfusions)

Wiskott-Aldrich Syndrome

Def: Immunodeficiency with Thrombocytopenia and Eczema. X-linked recessive disease : thrombocytopenia, eczema, and recurrent infection, ending in early death.

DNA repair defects

Defects in the DNA repair system Mismatch repair Nucleotide excision repair (NER) Recombination repair

Beta thalassemia

Diminished synthesis of structurally normal β globin chains, along with unimpaired synthesis of α chains genetic mutation β0 thalassemia: total absence of β chain β+ thalassemia: reduced but detectable amount of β chain numerous mutations are seen associated with β thalassemia

Familial Hypercholesterolemia (FH)

Disease caused by mutation in receptor cells Autosomal dominant, mutation in gene coding for receptor for low-density lipoprotein (LDL) ■ Patients develop hypercholesterolemia as a consequence of impaired transport of LDL into the cells ■ In heterozygotes, elevated serum cholesterol greatly increases the risk of atherosclerosis and resultant coronary artery disease; homozygotes have an even greater increase in serum cholesterol and a higher frequency of ischemic heart disease. Cholesterol also deposits along tendon sheaths to produce xanthomas

Mendelian disorders

Diseases caused by single-gene defects

Autosomal Recessive Disorders

Eg. Galactosemia - a deficit of galacose-1 - phosphate uridil transferase Lack of tyrosinase -albinism a1-antitrypsin - emphysema

HIV mechanism

Envelope with transmembrane spikes. GP120 spikes enable HIV to attach to host cells with the CD4 receptor (t cells, macrophages, dendritic cells, monocytes). Upon entering a cell, viral RNA is transcribed into DNA by Reverse Transcriptase. Viral DNA becomes integrated into the host cell chromosome (proviral). Integrated DNA may be active or latent.

WBC proliferation

Etiological and pathogenetic factors in white cell neoplasia: 1) Chromosomal translocation and other acquired mutations 2) Inherited genetic factors Bloom syndrome, Fanconi anemia, Ataxia telangiectasia, Down syndrome 3) Viruses: HTLV-1, EBV, Kaposi sarcoma herpes virus/ human herpesvirus - 8 (KSHV/HHV-8) 4) Environmental agents: Helicobacter pylori association with gastric B- cell lymphoma - gluten sensitivity enteropathy with intestinal T- cell lymphoma HIV associated with B - cell lymphoma 5) Iatrogenic agents: radiation, chemotherapy

Hyperbilirubinemia & jaundice

Evidence of increased Hb breakdown -not a reliable guide to the rate of hemolysis -bilirubin is unconjugated & does not appear in urine

Atypical ductal hyperplasia breast

Florid proliferation of the ductal epithelial cells (more than 4 cell thickness). Associated with calcification, hence picked up on mammography.

AIDS-Defining Opportunistic Infections and Neoplasms

Found in Patients with HIV Infection

Cadherins

Glycoprotein act as cell to cell adhesive reduced cell surface expression of E-cadherins: favor cell disintegration cancers: esophagus, colon, breast, ovary, prostate Loss of cell adhesion characterized by loose clumps of cells. Reduced expression of E-cadherins are important in tumor mets.

Osteosarcoma

Gross morphology shows a large, bulky tumor arising from the metaphyseal region, involve the medullary canal , break thru' the cortex and invade the soft tissue around. Microscopic: tumor cells produce osteoid, which is focally calcified.

Small cell carcinoma

Gross: shows a grey-white tumor mass close to the main bronchus. Note the ill-defined margins of the tumor. Micro: sheets of small darkly staining cells forming islands.

Recombination repair

Group of autosomal disorders: Ataxia-telangiectasia, Bloom syndrome, Fanconi anemia are characterized by hypersensitivity to DNA damaging agents: ionizing radiation, DNA crosslinking agents ATM gene is mutation present in Ataxia-telangectasia ATM gene recognizes DNA double-strand breaks

Basal cell carcinoma

Histology shows islands of cells beneath the epidermis, these cells exhibit characteristic "pallisading" Mechanism of action: UVB rays exposure leads to formation of pyrimidine dimers in DNA this damage is repaired by nucleotide excision repair pathway (NER) with excessive sun exposure, NER pathway is overwhelmed (cannot cope up) DNA damage remains unrepaired Xeroderma pigmentosum: extreme photosensitivity 2000 fold increase of skin cancers

Drug induced lupus

Hydralazine, procainamide, INH, and D-penicillamine. Diagnoses: Positive antihistone antibodies. Negative (mostly dsDNA).

Bone marrow in iron deficiency

Hyperplastic marrow microcytic maturation of the erythroid series loss of stainable iron in macrophages demonstrated by Prussian blue

Vaso-occlusive crises

Hypoxic injury and infarction associated with severe pain sometimes triggered off by infection/dehydration/acidosis organs involved: bone, lung, brain, spleen and penis 'hand-foot' syndrome, dactylitis micro-infarction of carpal & tarsal bones differential diagnosis: osteomyelitis acute chest syndrome: fever, cough, chest pain and pulmonary infiltrates follows lung infection, pulmonary blood flow becomes sluggish CNS: seizures / strokes due to hypoxia

Neoplastic proliferation of white cells

I Lymphoid neoplasm: -Lymphocytic leukemia -Non-Hodgkin lymphomas -Hodgkin lymphomas -Plasma cell dyscrasias II Myeloid neoplasmas: - Acute myeloid leukemias - Chr. myeloprol. disorders - Myelodysplastic syndrom III Histiocytic neoplasms

Genetic predisposition to cancer

(26-42 % of cancer risk) Autosomal dominant inherited cancer syndromes Defective DNA repair syndromes Familial cancers

Occupational cancers

- Asbestos leading to Mesothelioma - Benzene leading to Leukemia

Paracortical lymphoid hyperplasia

- activation of cellular immune responses - reactive changes involve T- cell region - expansion of the interfollicular regions - presence of immunoblasts: activated T-lymphocytes - hypertrophy of sinusoidal and vascular endothelial cells associated with : immunologic reactions induced by drugs (Dilantin), acute viral infections (infectious mononucleosis), vaccination against certain viruses

Adenoma-Carcinoma sequence

- involved mutation from the normal colonic mucosa to adenomatous polyp to carcinoma - via mutation in APC, K-ras, and p53 since increased COX-2 is requried, aspirin can protect against.

Hypercalcemia

-A part of paraneoplastic syndrome -molecule secreted by the tumor cells which mimic PTH -referred to as PTH related protein (PTHrP) -associated with: carcinoma breast, lung, kidney and ovary -can occur following skeletal metastases -is not paraneoplastic syndrome -due to secretion of 'osteoclast stimulating factor'

Cutaneous syndromes

-Acantosis nigricans -hyperkeratosis and hyperpigmentation -axilla, neck, flexures, anogenital area GIT tumors (carcinoma stomach)

Common Forms of Lymphoid Leukemia and Lymphoma

-Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma Most common type of cancer in children, may be derived from either precursor B of T cells Highly aggressive tumors manifest with signs and symptoms of bone marrow failure, or as rapidly growing masses. Tumor cells contain genetic lesions that block differentiation, leading to the accumulation of immature, nonfunctional blasts. -Small Lymphocytic Lymphoma /Chronic Lymphocytic Leukemia Most common leukemia of adults Tumor of mature B cells that usually manifests with bone marrow and lymph node involvement Indolent course, commonly associated with immune abnormalities, including an increased susceptibility to infection and autoimmune disorders -Follicular Lymphoma Most common indolent lymphoma of adults Tumor cells recapitulate the growth pattern of normal germinal center B cells; most cases are associated with a (14;18) translocation that results in the overexpression of BCL2. -Diffuse Large B-Cell Lymphoma Most common lymphoma of adults Heterogeneous group of mature B-cell tumors that shares a large cell morphology and aggressive clinical behavior Rearrangements or mutations of BCL6 gene are recognized associations; one third carry a (14;18) translocation involving BCL2 and may arise from follicular lymphomas. -Burkitt Lymphoma Very aggressive tumor of mature B cells that usually arises at extranodal sites. Strongly associated with translocations involving the MYC proto-oncogene Tumor cells often are latently infected by EBV.

Functions of cellular genes

-BCL1 (cyclin genee) -BCL2 (antiapoptosis gene) -C-MYC (transcription factor gene) -p16 (cell cycle inhibitor) -p53 (DNA damage response gene) -BRCA1(DNA repair gene) -ERBB2 (growth factor receptor gene) -EGF (epidermal growth factor gene) -HST1 (fibroblast growth factor gene)-IL2 (T-cell growth factor gene) -K-RAS (GTP-binding protein gene) -Lyn (tyrosine kinase gene) -PDGF (growth factor overexpression) -NF1 (GTPase-activating protein)

Retinoblastoma

-Cases of familial retinoblastoma are at risk for a second malignancy -osteosarcoma and other soft tissue tumors -Inactivation of RB gene is also associated with other tumors: carcinoma breast, lung, bladder

Common variable immunodeficiency

-Defect in B-cell differentiation. Many causes. -Can be acquired in 20s-30s; increased risk of autoimmune disease, bronchiectasis, lymphoma, sinopulmonary infections. -Decreased plasma cells, decreased immunoglobulins. -Relatively common a heterogeneous group of disorders with low Igs. -They have normal B cell, but they do not differentiated to plasma cells.

Disease based anemia

-Hereditary Spherocytosis ▪ Autosomal dominant disorder caused by mutations that affect the red cell membrane skeleton, leading to loss of membrane and eventual conversion of red cells to spherocytes, which are phagocytosed and removed in the spleen ▪ Manifested by anemia, splenomegaly -Thalassemias ▪ Autosomal codominant disorders caused by mutations in α- or β-globin that reduce hemoglobin synthesis, resulting in a microcytic, hypochromic anemia. ▪ In β-thalassemia, unpaired α-globin chains form aggregates that damage red cell precursors and further impair erythropoiesis. -Sickle Cell Anemia ▪ Autosomal recessive disorder resulting from a mutation in β-globin that causes deoxygenated hemoglobin to self-associate into long polymers that distort (sickle) the red cell ▪ Blockage of vessels by sickled cells causes pain crises and tissue infarction, particularly of the marrow and spleen Red cell membrane damage caused by repeated bouts of sickling results in a moderate to severe hemolytic anemia -Glucose-6-Phosphate Dehydrogenase Deficiency ▪ X-linked disorder caused by mutations that destabilize G6PD, making red cells susceptible to oxidant damage -Immunohemolytic Anemias ▪ Caused by antibodies against either normal red cell constituents or antigens modified by haptens (e.g., drugs) ▪ Antibody binding results in either red cell opsonization and extravascular hemolysis or (uncommonly) complement fixation and intravascular hemolysis

Aplastic crises

-Transient bone marrow failure of erythropoiesis -infection by parvovirus B19 -worsening anemia and reduced reticulocytes

Disseminated Intravascular Coagulopathy (DIC)

-complex systemic thrombohemorrhagic disorder -disseminated intravascular clotting causes a hemostatic defect -resulting from utilization of the coagulation factors & platelets (consumption coagulopathy) Pathogenesis: it is not a primary disorder secondary to various causes obstetric complications, infections, neoplasms, massive tissue injury caused by a release or entry of a) tissue factors- these act as coagulants b) extensive endothelial injury activation of coagulation sequence results in formation of micro thrombi these are seen within microcirculation causes ischemia two proteolytic enzymes: thrombin and plasmin are activated their balance determines thrombotic or bleeding tendencies thrombin promotes fibrin clot formation plasmin is a clot inhibiting factor initial phase: widespread deposition of fibrin hemorrhage: consumption of platelets and clotting factors plasmin breaks down fibrin (fibrin split products), digests (proteolysis) of various clotting factors- hemostatic failure Morphology: thrombi seen in various organs (brain, heart, lungs, kidneys) E.g. WFS (Waterhouse-Friderichsen syndrome), Sheehan postpartum pituitary necrosis

Hereditary Spherocytosis (HS)

-inherited disorder due to intrinsic defects in the red cell membrane -resulting in red cells which are spherical and less deformable (red cells are rigid) -vulnerable to splenic sequestration and distortion Molecular pathology: mutation in ankyrin mutation in spectrin leads to increased permeability to sodium passive entry of Na+ is countered by active transport of Na+ out of the cell results in increase glycolytic rate depletes ATP Pathogenesis: shape change causes red cells to become spherical red cells are less deformable these cells are trapped within the splenic sinusoids pH falls, inhibiting glycolysis phagocytosis

Pure Red Cell Aplasia

. Acute: Parvovirus B19 infection (may persist in immunosuppressed patients) . Chronic: Associated with thymoma, large granular lymphocytic leukemia, presence of neutralizing antibodies against erythropoietin, and other autoimmune phenomenon

Aplastic Anemia

. Caused by bone marrow failure (hypocellularity) due to diverse causes, including exposures to toxins and radiation, idiosyncratic reactions to drugs and viruses, and inherited defects in telomerase and DNA repair

Iron Deficiency Anemia

. Caused by chronic bleeding or inadequate iron intake; results in insufficient hemoglobin synthesis and hypochromic, microcytic red cells

Megaloblastic Anemia

. Caused by deficiencies of folate or vitamin B12 that lead to inadequate synthesis of thymidine and defective DNA replication . Results in enlarged abnormal hematopoietic precursors (megaloblasts), ineffective hematopoiesis, macrocytic anemia, and (in most cases) pancytopenia . B12 deficiency also associated with neurologic damage, particularly in the posterior and lateral tracts of the spinal cord

Anemia of Chronic Disease

. Caused by inflammatory cytokines, which increase hepcidin levels and thereby sequester iron in macrophages, and also suppress erythropoietin production

Underproduction Anemias

. Marrow replacement (tumors, granulomatous disease; so-called myelophthisic anemias), renal failure, endocrine disorders, liver failure

Immunophenotyping in ALL

1) Terminal deoxynucleotidyltransferase (TdT) expressed by pre B and pre T (common to B and T) lymphoblasts is positive in 95% of cases 2) Pre B cell: CD19, CD10, PAX5 3) Precursor T cell ALL: CD1, CD2, CD5, CD7 are positive Lab Investigations (cont'd): Biochemical: serum lactate dehydrogenase (LDH): ↑ serum uric acid: ↑ (non-specific) Other investigations: Chest X-ray: thymic enlargement, mediastinal lymph node (with T- cell)

Six hallmarks of cancer

1. Self-sufficiency in growth signals 2. Insensitivity to anti-growth signals 3. Tissue invasion and metastasis 4. Limitless replicative potential 5. Sustained angiogenesis 6. Evading apoptosis

Prognosis of AML

15 to 30% remain disease free at the end of 5 years AML associated with t(15;17) and presence of RARα - PML fusion gene Derivative of all-trans-retinoic acid (ATRA) can overcome the block in maturation caused by this fusion gene RARα gene encodes a member of the nuclear hormone receptor family of transcription factors After binding retinoic acid, RARα can promote expression of various genes

Megaloblastic anemia

2 CAUSES: - Folate deficiency - B12 deficiency (PERNICIOUS ANEMIA) Vit B12 and folic acid are co enzymes required for synthesis of thymidine thymidine is one of the nucleotide of DNA deficiency of vit B12 and folic acid results in defective nuclear maturation delay or block in cell division cytoplasmic maturation is unaffected nuclear / cytoplasmic asynchrony (impaired DNA synthesis, however cellular RNA and protein synthesis unaffected)

Clinical features of CLL/SLL

25% are asymptomatic (incidental) non specific symptoms: tiredness, weight loss generalized lymphadenopathy, hepatosplenomegaly (50 to 60%) hypogammaglobulinemia, predisposes to infections 10 to 15% have antibodies which are directed against rbc and platelets: autoimmune hemolytic anemia (AIHA) or thrombocytopenia Transformations transformation of CLL / SLL into aggressive lymphoma: "prolymphocytic transformation" (leukopenia, splenomegaly and peripheral blood spill over of prolymphocyes) transformation to "Richter syndrome" which is a diffuse large B cell lymphoma survival is less than a year in these cases

Typical course of HIV infection

A During the early period after primary infection, there is widespread dissemination of virus and a sharp decrease in the number of CD4+ T cells in peripheral blood. An immune response to HIV ensues, with a decrease in viremia followed by a prolonged period of clinical latency. During this period, viral replication continues. The CD4+ T-cell count gradually decreases during the following years, until it reaches a critical level below which there is a substantial risk of opportunistic diseases. B, Immune response to HIV infection. A cytolytic T lymphocyte (CTL) response to HIV is detectable by 2 to 3 weeks after the initial infection and peaks by 9 to 12 weeks. Marked expansion of virus-specific CD8+ T cell clones occurs during this time, and up to 10% of a patient's CTLs may be HIV specific at 12 weeks. The humoral immune response to HIV peaks at about 12 weeks.

Papilloma

A benign, superficial, wartlike growth on the epithelial tissue or elsewhere in the body, such as in the bladder. (growing on any surface) of the colon with finger-like projections into the lumen.

Anaplasia

A change in the structure of cells and in their orientation to each other

Crohn's disease

A chronic autoimmune disorder that is most often found in the ileum and in the colon Dense inflammation with non-caseating granuloma (blackarrow).

IgG4-related disease

A chronic inflammatory condition characterized by tissue infiltration with lymphocytes and IgG4-secreting plasma cells, various degrees of fibrosis (scarring) and a usually prompt response to oral steroids Low power view of IgG4-related prostatitis. The prostatic stroma shows a dense inflammatory infiltrate and fibrosis (H&E, 100x)

Serum iron

A measure of the amount of iron bound to transferrin in the plasma Bone Marrow aspirate or biopsy material stained with Prussian blue provides a sensitve estimate of iron stored in marrow macrophages. This storage iron or hemosiderin is idenified as bright blue granules in the cytoplasm of macrophages. You may also note that about 40% of normoblasts have small scattered blue staining granules. These cells are known as sideroblasts or if the nucleus has been expelled, siderocytes.

Hemostasis

A process which causes bleeding to stop, meaning to keep blood within a damaged blood vessel (the opposite of hemostasis is hemorrhage). It is the first stage of wound healing. This involves coagulation, blood changing from a liquid to a gel.

Reiter syndrome

A rare complication associated with untreated Chlamydia and is characterized by arthritis and skin lesions Chlamydia trachomatis Conjunctivitis, Arthritis, and Urethritis Keratoderma blennorrhagia --> kyperkeratotic lesion on palms and soles Balanitis Circinate --> shallow, painless ulcer on penis

Pituitary adenoma

A slow-growing benign tumor of the pituitary gland;compress normal pituitary & optic nerve

Polyarteritis nodosa

A systemic necrotizing inflammation of blood vessels (vasculitis) affecting medium-sized muscular arteries, typically involving the arteries of the kidneys and other internal organs but generally sparing the lungs' circulation. Polyarteritis nodosa may present in infants.In polyarteritis nodosa, small aneurysms are strung like the beads of a rosary, therefore making "rosary sign" an important diagnostic feature of the vasculitis

Nodular sclerosis

A type of Hodgkin's lymphoma -commonest form (65%) -presence of RS cell variant: 'lacunar cell' -fibrous bands, circumscribing the lymph node into nodular areas

Type 1 hypersensitivity reaction

A variety of compounds that act on blood vessels, smooth muscle, and leukocytes mediate type I hypersensitivity reactions. Some of these compounds are released rapidly from sensitized mast cells and are responsible for the intense immediate reactions associated with conditions such as systemic anaphylaxis. Others, such as cytokines, are responsible for the inflammation seen in late-phase reactions. ■ They are induced by environmental antigens (allergens) that stimulate strong TH2 responses and IgE production in genetically susceptible individuals ■ IgE coats mast cells by binding to Fcε receptors; reexposure to the allergen leads to cross-linking of the IgE and FcεRI, activation of mast cells, and release of mediators. ■ The principal mediators are histamine, proteases, and other granule contents, prostaglandins and leukotrienes, and cytokines. ■ The mediators are responsible for the immediate vascular and smooth muscle reactions and the late-phase reaction (inflammation). ■ The clinical manifestations may be local or systemic, and range from mildly annoying rhinitis to fatal anaphylaxis.

Morphologic patterns of graft rejection

A, Hyperacute rejection of a kidney allograft showing endothelial damage, platelet and thrombin thrombi in a glomerulus. B, Acute cellular rejection of a kidney allograft with inflammatory cells in the interstitium and between epithelial cells of the tubules. C, Acute humoral rejection of a kidney allograft (rejection vasculitis) with inflammatory cells and proliferating smooth muscle cells in the intima. D, Chronic rejection in a kidney allograft with graft arteriosclerosis. The arterial lumen is replaced by an accumulation of smooth muscle cells and connective tissue in the intima.

T cell-mediated (type IV) hypersensitivity

A, In delayed type hypersensitivity reactions, CD4+ T cells (and sometimes CD8+ cells) respond to tissue antigens by secreting cytokines that stimulate inflammation and activate phagocytes, leading to tissue injury. B, In some diseases, CD8+ cytolytic T lymphocytes (CTLs) directly kill tissue cells. APC, antigen-presenting cell.

Systemic sclerosis slide

A, Normal skin. B, Skin biopsy from a patient with systemic sclerosis. Note the extensive deposition of dense collagen in the dermis with virtual absence of appendages (e.g. hair follicles) and foci of inflammation (arrow).

Carcinoma in situ

A. The entire thickness of the epithelium is replaced by atypical dysplastic cells. There is no orderly differentiation of squamous cells. The basement membrane is intact and there is no tumor in the subepithelial stroma. B, A high-power view of another region shows failure of normal differentiation, marked nuclear and cellular pleomorphism, and numerous mitotic figures extending toward the surface. The basement membrane (below) is not seen in this section.

Familial Adenomatous Polyposis

APC mutation involves chromosome 5q21 based on clinical presentation FAP is further classified into: Classic FAP, Attenuated FAP, Gardener syndrome & Turcot syndrome Classic FAP requires more than 100 polyps for diagnosis histologically most polyps are tubular adenomas Gardener synd: intestinal polyps, osteomas (mandible, skull & long bones), epidermal cysts & fibromatosis Turcot synd: polyps in colon, and tumors in CNS

X-linked agammaglobulinemia (Bruton)

Abnormal Ig due to lack of light chain ( abnormal B cell)= low Ig in serum. Seen after 6 months. Infection: H. influenzae, S. pneumoniae. Pathogenesis: lack of opsonization by Ig but opsonization by complement may be normal. No germinal center in LN. Polio vaccination may produce disease! C/F: Chronic pharyngitis, sinusitis infection with bacterial organisms (Hemophilus, Staphylococcus). More in male. Rarely infection with Virus( because of intact T cell immunity).

Leukopenia

Abnormal low white cell count - results mostly from reduced neutrophils (neutropenia) - lymphopenia is rare; congenital immunodeficiency states, advanced HIV

Classification of anemia

According to Underlying Mechanism

Extrinsic causes of hemolytic anemia

Acquired: Immune mechanisms: hemolytic disease of the newborn, incompatible blood transfusion, drug induced Non-immune: Mechanical- micro angiopathic hemolytic anemia (MAHA), cardiac prosthetic valve Miscellaneous: due to infections, burns, lead poisoning Site of red cell destruction is based on the presence or absence of free Hb & Hb products Shortened rbc life span, produces a compensatory bone marrow hyperplasia (6x to 8x) anemia only occurs when marrow hyperplasia is not able to compensate for the rbc destruction 'compensated hemolytic disorders'- anemia is absent, reticulocytosis & erythroid hyperplasia of bone marrow are seen

Follicular hyperplasia

Activation of humoral immune responses - formation of "secondary follicle": large round to oblong B- cell rich germinal centers surrounded by a collar of resting B lymphocytes (mantle zone) A, Low-power view showing a reactive follicle and surrounding mantle zone. The dark-staining mantle zone is polarized, being much more prominent adjacent to the germinal center light zone in the left half of the follicle. The right half of the follicle consists of the dark zone. B, High-power view of the dark zone shows several mitotic figures and numerous macrophages containing phagocytosed apoptotic cells (tingible bodies).

Intravascular hemolysis

Acute process destruction of red cells within circulation with release of free Hb (example: incompatible blood transfusion)

Colonic Polyp

Adenoma glandular tumor projects into colonic lumen This benign glandular tumor (adenoma) is projecting into the colonic lumen and is attached to the mucosa by a distinct stalk. B, Gross appearance of several colonic polyps.

Polycythemia Vera

Adult age group Neoplasm arising in a multipotent myeloid stem cell Characterized by increased marrow production of erythroid, granulocytic and megakaryocytic elements Erythroid proliferation is not regulated by erythropoietin (absence of physiologic stimulus) Decreased erythropoietin levels but, erythrocytes are sensitive to erythropoietin Pathogenesis: JAK2 mutation seen in 97% this exposes hematopoietic cells to excessive proliferation

DiGeorge Syndrome

Age : Children Etiology: Deletion on the long arm of chromosome 22. Pathogenesis : Markedly decreased numbers of circulating T lymphocytes and Thymic hypoplasia. T-cell deficiency that results from failure of development of the third and fourth pharyngeal pouches CATCH 22 C = Cardiac defect A = Abnormal facies T = Thymic hypoplasia C = Cleft palate H = Hypocalcemia

Neoplasia

An abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissues and persists in the same excessive manner after the cessation of the stimuli which has evoked the change (Tumor)- "New growth" - Fundamental to the origin is loss of responsiveness to normal growth control I Benign - Will remain localized (but can be malignant by localization) II Malignant (Cancer) - Spread to distant sites (Metastasize) - arising from mesenchymal tissues - sarcomas (spindle cell Tu) - epithelial origin - carcinomas (nest of cells) All tumors (benign and malignant) have 2 basic components: The parenhimma (transformed cells from which the tumor derives its name) The supporting (non-neoplastic) stroma (conective tissue and blood vessels)

Infectious mononucleosis

An infection caused by the Epstein-Barr virus (EBV) that is characterized by fever, a sore throat, and enlarged lymph nodes Pathology: EBV is transmitted via intimate contact with body secretion (oropharyngeal) EBV infects B lymphocytes (CD 21) elicits a T- cell response (cytotoxic CD 8) against the infected B cells it was recognized as a clinical syndrome of fever, pharyngitis and lymphadenopathy 'glandular fever'

Pyruvate kinase deficiency

An inherited metabolic disorder of the enzyme pyruvate kinase which affects the survival of red blood cells. Both autosomal dominant and recessive inheritance have been observed with the disorder; classically, and more commonly, the inheritance is autosomal recessive. Pyruvate kinase deficiency is the second most common cause of enzyme-deficient hemolytic anemia, following G6PD deficiency. Pyruvate kinase deficiency is due to a mutation in the PKLR gene. There are four pyruvate kinase isoenzymes, two of which are encoded by the PKLR gene (isoenzymes L and R, which are used in the liver and erythrocytes, respectively). Mutations in the PKLR gene therefore cause a deficiency in the pyruvate kinase enzyme. Pyruvate kinase is the last enzyme involved in the glycolytic process, transferring the phosphate group from phosphenol pyruvate to a waiting adenosine diphosphate (ADP) molecule, resulting in both adenosine triphosphate (ATP) and pyruvate. With insufficient ATP in an erythrocyte, all active processes in the cell come to a halt. Sodium potassium ATPase pumps are the first to stop. Since the cell membrane is more permeable to potassium than sodium, potassium leaks out. Intracellular fluid becomes hypotonic, water moves down its concentration gradient out of the cell. The cell shrinks and cellular death occurs, this is called 'dehydration at cellular level'.This is how a deficiency in pyruvate kinase results in hemolytic anaemia, the body is deficient in red blood cells as they are destroyed by lack of ATP at a larger rate than they are being created.

Clinical features of ALL

Anemia, neutropenia and thrombocytopenia (DD: pancitopenia ... aleukemic leukemia ? Aplastic anemia) Typical features include, abrupt stormy onset, bone marrow depression, bone pain and tenderness, generalized lymphadenopathy, splenomegaly, hepatomegaly (dissemination) CNS manifestations Lab Investigations: anemia, neutropenia and thrombocytopenia Total WBC counts: elevated Platelet count: decreased Hb: decreased Peripheral smear: circulating leukemic blast cells

Clinical features of Hereditary spherocytosis (HS)

Anemia, splenomegaly, jaundice, gall stones Aplastic crises: associated with acute parvovirus infection virus kills red cell progenitors worsening anemia, reduced reticulocytes Hemolytic crises increased splenic destruction of spherocytes enlarged tender spleen, increasing jaundice & darkening of urine sometimes associated with infectious mononucleosis Treatment: splenectomy (done after 7 yrs. of age) prior immunization with polyclonal pneumococcal vaccine antibiotics post splenectomy *spherocytes can be still seen following splenectomy

Systemic lupus erythematosus (SLE)

Antibodies for dsDNA and sm RNA The prototype of a multisystem disease of autoimmune origin a failure of the mechanisms that maintain self-tolerance. Skin rash - Malar or discoid Sensitivity to light (photo dermatitis) Serositis/synovitis - inflammation of serosal surfaces along with effusions Decreased serum complement - especially C1q. ■ SLE is a systemic autoimmune disease caused by autoantibodies produced against numerous self antigens and the formation of immune complexes. ■ The major autoantibodies, and the ones responsible for the formation of circulating immune complexes, are directed against nuclear antigens. Other autoantibodies react with erythrocytes, platelets, and various complexes of phospholipids with proteins. ■ Disease manifestations include nephritis, skin lesions and arthritis (caused by the deposition of immune complexes), and hematologic and neurologic abnormalities. ■ The underlying cause of the breakdown in self-tolerance in SLE is unknown; it may include excess or persistence of nuclear antigens, multiple inherited susceptibility genes, and environmental triggers (e.g., UV irradiation, which results in cellular apoptosis and release of nuclear proteins).

Tumor markers

Antigens expressed on the surface of tumor cells or substances released from normal cells in response to the presence of tumor

Myeloid Neoplasms

Arise from hematopoietic stem cells that give rise to cells of myeloid series: eryhtroid, granulocytic and/or thrombocytic lineage

Craniopharyngioma

Arise from squamous epithelial remnants of anterior lobe of pituitary gland. Commonly are symptomatic due to large size. Most common suprasellar mass in children. Peak incidence between 5 and 10 years of age and 50 and 60 years. Solid and cystic components are typical. Large cystlike sellar/suprasellar mass with enhancing rim and some calcification. T1 (liquid crystal) and T2 hyperintense cyst. Location: Suprasellar region destroy hypothalamus

Myelodysplasia

Associated with MDS Characteristic forms of dysplasia are shown. A, Nucleated red cell progenitors with multilobated or multiple nuclei. B, Ringed sideroblasts, erythroid progenitors with iron-laden mitochondria, seen as blue perinuclear granules (Prussian blue stain). C, Pseudo-Pelger-Hüet cells, neutrophils with only two nuclear lobes instead of the normal three to four, are observed at the top and bottom of this field. D, Megakaryocytes with multiple nuclei instead of the normal single multilobated nucleus. (A, B, D, marrow aspirates; C, peripheral blood smear.)

Ringed sideroblasts

Associated with Myelodysplastic Syndrome erthyroid series

Pawn ball megakaryocyte

Associated with Myelodysplastic Syndrome megakaryocyte series

Pseudomyxoma peritonei

Associated with primary mucinous tumor arising from appendix Associated with mucinous ovarian tumor

Epstein Barr virus (EBV)

Associated with: Burkitt lymphoma (African) B- cell lymphomas (immunosuppressed) Hodgkin lymphoma Nasopharyngeal carcinoma Mechanism of action EBV infects B lymphocytes (CD21) B lymphocytes are immortalized (EBV gene: LMP-1 acts as oncogene, LMP-1 activates bcl-2) lymphoma may arise if these cells acquire mutations t(8;14) translocation activation of c-MYC, resulting in over expression Burkitt lymphoma

Sjögren syndrome (SS)

Autoimmune disease that involves:- Salivary glands (with xerostomia) and Lacrimal glands (with xerophthalmia). Most patients are middle-aged women. The disease is believed to be caused by an autoimmune T-cell reaction against an unknown self antigen expressed in these glands, or immune reactions against the antigens of a virus that infects the tissues Infiltration by CD4, B cells, DC....destruction of architecture 40 X risk of developing a non-Hodgkin B-cell lymphoma

Familial adenomatous polyposis

Autosomal dominant -mutation of adenomatous polyposis coli (APC) tumor suppressor gene -all of them develop carcinoma colon by the age of 50 yrs.

Li-Fraumeni Syndrome (LFS)

Autosomal dominant Germ line mutation of p53 gene (sarcomas, breast cancer, leukemia, brain tumor)

Childhood Retinoblastomas

Autosomal dominant about 40% are inherited mutation of Rb tumor suppressor gene 10,000 fold increased risk of developing bilateral retinoblastoma also carries a risk for second malignancy: osteogenic sarcoma Cat's eye

Galactosemia

Autosomal recessive Vomiting and diarrhea a few days of milk ingestion Jaundice, hepatomegaly, mental retardation, opacity of the lens (cataracts) Early removal of galactose from diet at least the first 2 years of life The liver has an extensive fatty change and delicate fibrosis Dg: Deficiency of the transferase in Le and RBC

Phenylketonuria (PKU)

Autosome recessive — strong musty or mousy odor and Alkaptonuria - (black urine ).. (homogentisate 1,2-dioxygenase (HGD)) Impaired brain development by 6 month of life - sever mental retardation Impaired synthesis of all phenylalanine derivatives L-DOPA Dopamine, Norepinephrine and Epinephrine Having the disease yourself doesn't necessarily mean the disorder will be passed on to your baby. However, your unborn child is nonetheless at risk of complications. High levels of Phenylalanine (Phe) in your blood will expose the developing fetus to the serious likelihood of brain damage. Other problems like intrauterine growth retardation, congenital heart defects and facial deformity are also possible.

Cat-scratch disease

Bartonella henselae; granulomatous microabscesses Granuloma (caseating) with accumulation of Neutrophils (the microb is extracellular)

Characteristics of Benign and Malignant Neoplasms

Benign and malignant tumors can be distinguished from one another based on the degree of differentiation, rate of growth, local invasiveness, and distant spread. ■ Benign tumors resemble the tissue of origin and are well differentiated; malignant tumors are less well differentiated or completely undifferentiated (anaplastic). ■ Benign tumors are more likely to retain functions of their cells of origin, whereas malignant tumors sometimes acquire unexpected functions due to derangements in differentiation. ■ Benign tumors are slow growing, while malignant tumors generally grow faster. ■ Benign tumors are circumscribed and have a capsule; malignant tumors are poorly circumscribed and invade surrounding normal tissues. ■ Benign tumors remain localized at the site of origin, whereas malignant tumors metastasize to distant sites.

Leiomyoma uterus

Benign tumor Arise from smooth muscle Hormonal dependent Well demarcated tumors arising from smooth muscle layer of uterus. This benign, well-differentiated tumor contains interlacing bundles of neoplastic smooth muscle cells that are virtually identical in appearance to normal smooth muscle cells in the myometrium.

Local invasion

Benign tumor cells grows as cohesive expansile mass -do not have the capacity to infiltrate, invade or metastize to distant sites -develop a fibrous tissue capsule *Exception unencapsulated benign tumor: hemangioma

Leiomyoma vs leiomyosarcoma

Benign tumor of the myometrium (leiomyoma) and a malignant tumor of similar origin (leiomyosarcoma). leiomyoma -multiple, white whorled -pre-menopausal leimoyosarcoma -single, hemorrhagic/necrotic center -post-menopausal

Rate of growth

Benign tumors grow slowly Cancers proliferate much faster As the cell population expands, a progressively higher percentage of tumor cells leaves the replicative pool by reversion to G0, differentiation, and death.

Nomenclature of tumors

Benign tumours of most tissues are usually simply designated the suffix -oma. Malignant tumours of the parenchyma are designated the term carcinoma, while malignant tumours of mesenchymal tissues are designated the term sarcoma.

Adenoma of the thyroid

Benign, solitary, hyper functioning thyroid tumor. Microscopic view shows follicles filled with colloidal material. Benign tumor (adenoma) Note the normal-looking (well-differentiated), colloid-filled thyroid follicles

Adenomatous polyposis coli

Beta-catenin pathway The role of APC in regulating the stability and function of β-catenin. APC and β-catenin are components of the WNT signaling pathway. In resting cells (not exposed to WNT), β-catenin forms a macromolecular complex containing the APC protein. This complex leads to the destruction of β-catenin, and intracellular levels of β-catenin are low. B, When cells are stimulated by secreted WNT molecules, the destruction complex is deactivated, β-catenin degradation does not occur, and cytoplasmic levels increase. β-catenin translocates to the nucleus, where it binds to TCF, a transcription factor that activates several genes involved in the cell cycle. C, When APC is mutated or absent, the destruction of β-catenin cannot occur. β-Catenin translocates to the nucleus and coactivates genes that promote the cell cycle, and cells behave as if they are under constant stimulation by the WNT pathway.

Myc protein

Binds to the DNA causing transcr. of several growth-related genes, including cyclin-dependent kinases (CDKs). (N-Myc genes are amplifierd in Neuroblastoma and L-Myc in small cell cancer of lung)

Severe Combined Immunodeficiency (SCID)

Both limbs of lymphocyte system are missing or defective; no adaptive immune response Autosomal recessive: Adenosine deaminase deficiency. (50 %) No IgM or IgA Ineffective B/T cell. Morphology: Lymph node and Thymic atrophy can occur. Infants develop Candida skin rashes and thrush, Persistent diarrhea, severe respiratory tract infections Pneumocystis carinii and Pseudomonas soon after birth

Plasmodium species

Burst the red cells at different time intervals. Plasmodium vivax and Plasmodium ovale burst loose every 48 hours. The people who discovered all this started numbering things with one (they didn't have a zero) and so zero hours was called one, 24 hours called two, and 48 hours called three. So, P. vivax and P. ovale produce chills and fever followed by drenching sweats every 48 hours, which is called tertian malaria. P. malariae bursts loose every 72 hours, causing a regular 3-day cycle of fevers and chills, followed by sweats. This is called quartan malaria. P. falciparum, the most common and deadly of the Plasmodia, bursts red cells more irregularly, between 36-48 hours. Thus the chills and fevers tend to either fall within this period or be continuous, with less pronounced chills and sweats.

Lab Diagnosis of Polycythemia Vera

CBC: increased red cell count, increased Hb, Increased Hct, leukocytosis, thrombocytosis Peripheral blood: increased basophils, large platelets Bone marrow: hypercellular late stages: marrow fibrosis Biochemical: hyperuricemia

Immunophenotype of CLL/SLL

CD19 + CD20 (Pan B-cell markers) CD23 and CD5 (CD5 is normally on Tcells so seeing the first two with this is odd!!) Low level Ig's on surface is typical too. CLL and SLL expresses pan B cell markers (CD19 and CD20) CD23 and CD5 are positive

Mycosis fungoides/Sezary syndrome

CUTANEOUS T CELL LYMPHOMA Are different manifestations of tumor arising from CD4+ helper cells Immuophenotype: mature T cell markers: CD2, CD3, CD4, on skin biopsies Clinical features: Mycosis fungoides progresses from premycotic phase to plaque and tumor phase indolent disease Histology shows infiltration of epidermis and dermis by neoplastic T cells may spread to lymph nodes

WBC disorders

Can be classified into two broad categories: - proliferative - leukopenias Proliferative disorders: reactive/inflammatory neoplastic

Congenital disorders of the platelets

Can be due to: Defective adhesion Bernard-Soulier syndrome: deficiency of platelet membrane glycoprotein complex (a deficiency of glycoprotein Ib (GpIb), the receptor for von Willebrand factor ) Defective aggregation Glanzmann's thromboasthenia (the platelets lack glycoprotein IIb/IIIa. Hence, no fibrinogen bridging can occur, and bleeding time is significantly prolonged). Defective platelet secretion Storage pool defects

Invasion of the ECM

Carcinoma must breach the basement membrane, then cross the interstitial connective tissue then, enter the circulation by penetrating the basement layer of vascular channel these steps are reversed when the tumor cells reach a distant site has several steps: Detachment of tumor cells from each other Attachment to matrix components Degradation of the ECM Migration of tumor cells

Helicobacter pylori

Cause gastric ulcers, risk for cancer appear as curved structures. Highlighted by silver stain.

Marfan Syndrome

Caused by a mutation in the FBN1 gene encoding fibrillin, which is required for structural integrity of connective tissues and regulation of TGF-β signaling. ■ The major tissues affected are the skeleton, eyes, and cardiovascular system. ■ Clinical features may include tall stature, long fingers, bilateral subluxation of lens, mitral valve prolapse, aortic aneurysm, and aortic dissection. ■ Clinical trials with drugs that inhibit TGF-β signaling such as angiotensin receptor blockers are ongoing, as these have been shown to improve aortic and cardiac function in mouse models. (autosomal dominant) Abnormal fibrillin 1 (FBN1 gene) Fibrillin is scaffolding for elastin Hyperextensibility Kyphosis, pectus excavatum a pigeon-breast deformity Bilateral dislocation or sublocation of the lens (suspens ligaments weakness) Elongated habits, abnormally long legs, arms, fingers Fragmentation of elastic fibers in the tunica media - aortic dissection

Congenital immunodeficiencies

Caused by defects in lymphocyte maturation. Immunodeficiencies caused by genetic defects in lymphocyte maturation are shown. ADA, adenosine deaminase; PNP, purine nucleoside phosphorylase; RAG, recombination activating gene.

Hypoxia in tumor

Causes the release of Hypoxia inducible Factor-a (HIF-1) which controls transcription of VEGF and RAS onc gene e.g. Human breast Ca cells express high level of chemokine receptor Genes (CXCR4 and CCR7)

E-cadherin

Cell adhesion molecule that plays an important role in contact-mediated growth inhibition of epithelial cells; also binds and sequesters β-catenin, a signaling protein that functions in the WNT pathway ■ Germline loss-of-function mutations in the E-cadherin gene (CDH1) associated with autosomal dominant familial gastric carcinoma ■ Loss of expression seen in many sporadic carcinomas; associated with loss of contact inhibition, loss of cohesiveness, increased invasiveness, and increased WNT signaling

Cyclins and cyclin dependent kinases

Cell cycle has check points this is to confirm that the DNA is in order these check points are regulated by cyclins and cyclin dependent kinases (CDK) dysregulation of cyclin D and CDK4 results in neoplastic transformation

Defective DNA repair syndromes

Characterized by defects in DNA repair and resultant DNA instability mostly are autosomal recessive pattern of inheritance Example: Xeroderma pigmentosum, Ataxia-telangectasia, Bloom syndrome HNPCC Hereditary Non Polyposis Colon Cancer is a autosomal dominant condition, caused by inactivation of DNA mismatch repair gene

Systemic Sclerosis

Characterized by progressive fibrosis involving the skin, gastrointestinal tract, and other tissues ■ Fibrosis may be the result of activation of fibroblasts by cytokines produced by T cells, but what triggers T-cell responses is unknown. ■ Endothelial injury and microvascular disease are commonly present in the lesions of systemic sclerosis, perhaps causing chronic ischemia, but the pathogenesis of vascular injury is not known.

Sézary syndrome

Characterized by tumor dissemination to other organs and spill over into peripheral blood (Mycosis fungoides with a leukemic phase) Cells are characterized by cerebriform nuclei

Familial cancers

Characterized by: -early age at onset -tumors arising in 2 or more close relatives -sometimes, multiple or bilateral tumors breast carcinomas: BRCA-1, BRCA-2 familial melanomas: p16INK4a Examples: carcinoma colon, carcinoma breast, ovary, brain tumors and melanomas

Chronic Myeloid Leukemia

Chronic Myeloproliferative disorder Incidence: adults between 25 to 60 yrs Pathophysiology presence of a distinctive molecular abnormality Philadelphia Translocation involving ABL gene on chromosome 9 and BCR gene on chromosome 22

Multiple myeloma

Chronic, progressive & fatal malignant condition characterized by neoplastic proliferation of plasma cells which infiltrate the BONE MARROW Incidence: -average age at diagnosis: 71 yrs -genetic: rearrangements of the Ig heavy chain gene on ch. 14q32 deletion, deletion of 13q -association with radiation Etiology and Pathogenesis: -proliferation and survival of myeloma cells are dependent on several cytokines -IL- 6: produced by neoplastic plasma cells and normal stromal cells in bone marrow -serum levels of IL- 6 is elevated -high IL- 6 levels are associated with poor prognosis -neoplastic plasma cells produce various factors which destroy the bone -MIP 1α and RANKL serve as 'osteoclast activating factors' -bone marrow involvement produces destruction of both medullary & cortical bone -pathological fractures -HYPERCALCEMIA

Multiple myeloma: clinical course

Clinical features result from: -infiltration of organs by plasma cells (bones) -production of excessive immunoglobulins -SUPPRESSION of normal humoral immunity Recurrent infections due to decreased production of normal imunoglobulins Streptococcus pneumoniae, Staphylococcus aureus, E.coli Renal failure -seen in 50% of the patients -deposition of proteinaceous tubular casts (Bence-Jones protein) -nephrocalcinosis: metastatic calcification -amyloidosis: light chains are converted to amyloid Apple green birefringence on polarized microscope, using Congo Red stain Hypercalcemia - bone resorption leads to pathologic fractures neurologic changes, weakness, lethargy, constipation & polyuria, anemia, recurent infections, hyperviscositi syndrom Prognosis - generally poor biphosphonates inhibit bone resorption, thus reduce the incidence of pathologic fractures and limiting hypercalcemia

Hemophilia B

Clinically similar to Hemophilia A decrease in Factor IX activity X linked recessive Factor IX is reduced

Acute Myelogenous Leukemia

Clonal malignant disease of hematopoietic tissue Characterized by: proliferation of abnormal (leukemic) BLAST cells, mainly in the MARROW impaired production of normal blood cells Incidence: small proportion of cases in childhood (15 to 20%) adults (80%) Etiology: - radiation exposure, chronic BENZENE exposure, chemotherapeutic drugs, Down synd, Bloom synd, Fanconi anemia Pathophysiology: - most associated with acquired genetic alteration that inhibit terminal myeloid differentiation -marrow is then replaced by undifferentiated 'blasts' with features of early myeloid differentiation -chromosomal translocations: t(15;17) with M3, inv 16 with M4, t(8;21) with M2

RAS protooncogene

Codes for a protein p21. This protein is active when bound to GTP & inactive when bound to GDP. Bound GTP is converted to GDP by GTPase. This enzyme activity is normally low. But can increase 100 fold by an GTPase activating protein: GAP. Mutant forms of p21 has persistence of GTP binding. Importance of RAS: K-RAS: colon, lung & pancreas H-RAS: bladder & kidney N-RAS: melanoma & hematologic malignancies

X-Linked Recessive Disorders

Color blindness, duchenne muscular dystrophy, hemophilia more commonly affect males than females. Chances of gene passing to progeny are different for males and females.

Mixed connective tissue disease

Combines features of scleroderma, myositis, systemic lupus erythematosus, and rheumatoid arthritis (with some sources adding polymyositis, dermatomyositis, and inclusion body myositis) and is thus considered an overlap syndrome. MCTD commonly causes: joint pain/swelling, malaise, Raynaud phenomenon, Sjögren's syndrome, muscle inflammation, and sclerodactyly (thickening of the skin of the pads of the fingers) Distinguishing laboratory characteristics are a positive, speckled anti-nuclear antibody and an anti-U1-RNP antibody

Investigation of Mononucleosis

Complete Blood Counts (CBC): WBC is increased Peripheral blood smear: atypical lymphocytes 'Downey cells' Lymph node: paracortical lymphoid hyperplasia (D/D: Hodgkin lymphoma) Lab Investigation: positive antiviral capsid antigen test, Monospot test (nonspecific antibodies) Clinical Features fever, lymphadenopathy, pharyngitis, rash (when treated with ampicillin), splenomegaly *risk of splenic rupture B-cell lymphoma

CDKN2A

Complex locus that encodes two tumor suppressive proteins, p16/INK4a, a cyclin-dependent kinase inhibitor that augments RB function, and ARF, which stabilizes p53 ■ Germline loss-of-function mutations are associated with autosomal dominant familial melanoma ■ Biallelic loss-of-function seen in diverse cancers, including leukemias, melanomas, and carcinomas

Primary immunodeficiency syndromes

Congenital B- cell deficiency: X-linked Agammaglobulinemia of Bruton Selective IgA Deficiency Common Variable Immunodeficiency Congenital T- cell deficiency DiGeorge Syndrome Wiskott-Aldrich Syndrome Congenital B cell and T cell deficiency Severe Combined Immunodeficiency

Iron deficiency anemia

Deficiency due to Dietary lack Impaired absorption Increased requirements (menstruation, pregnancy) Chronic blood loss (peptic ulcer, hemorrhoids, carcinoma stomach/colon, aspirin, ulcerative colitis, esophageal varices, hookworm infestation) Lab diagnosis Hb: reduced Hematocrit: reduced Red cell indices: MCV, MCH, MCHC are decreased Peripheral smear Red cells: microcytic hypochromic anisocytosis (variation in size), poikilocytosis (variation in shape) For unknown reason increase in platelet count !

Hydrops fetalis

Deletion of all four α globin chains in fetus, excess gamma chains form tetramers (Hb Barts) very high affinity for oxygen no oxygen delivered to tissue South-East Asia clinical picture similar to severe Rh-incompatibility (erythroblastosis fetalis) fetal distress occur in 3rd trimester intra uterine death fetus: pallor, generalized edema, massive hepatosplenomegaly mother frequently has toxemia of pregnancy

Ultraviolet rays

Depend on: the type, intensity of exposure, presence of melanin in skin UV rays are of three spectrum: UVA, UVB, UVC UVB is the most important in causation of cutaneous tumors squamous cell carcinoma, basal cell carcinoma, malignant melanoma

PAP smear

Described by George N. Papaniccolaou Screening procedure, all women above 18 and sexually active need to have a yearly smear done cytobrush is used to scrape off cells at the squamo-columnar junction smeared onto a clean glass slide with is immersed in a fixative and the transported to pathology lab, where it is stained (Pap stain)

Grading of tumors

Determined by cytologic appearance; based on the idea that behavior and differentiation are related, with poorly differentiated tumors having more aggressive behavior To estimate the agressiveness or level of malignancy based on the cytologic differentiation of Tu cells and the number of mitoses within the tumor (I, II, III, or IV, in order of increasing anaplasia) E.g. WHO grading system grades astrocytoma from grades I to IV Low-grade means the cancer cells tend to be slow-growing, look quite similar to normal cells (are well differentiated), tend to be less aggressive, and are less likely to spread quickly. Intermediate-grade is a middle grade. High-grade means the cancer cells tend to be fast growing, look very abnormal (are poorly differentiated), tend to be more aggressive, and are more likely to spread quickly. -based on nuclear atypia, cellularity, vascular proliferation & necrosis

Staging of tumors

Determined by surgical exploration or imaging, is based on size, local and regional lymph node spread, and distant metastases; of greater clinical value than grading Based on the size of the primary lesion, the spread to regional lymph and the presence or absence of metastases (TNM and AJC-American Joint Committee) T-1 means the primary tumor is still in the stomach wall. T-2 T-3 means the primary tumor has grown right through the stomach wall T-4 means it is invading nearby structures such as the pancreas. N-0 means there is no spread to lymph nodes. N-1 means that some local lymph nodes are affected. N-2 means more extensive spread to local lymph nodes. M-0 means there are no metastases. M-1 means that there are metastases to some other area of the body such as the liver or brain. M-X waiting for the diagnosis

Molecular basis of cancer

Development of sustained angiogenesis angiogenesis plays a role in : supply of nutrients and oxygen new endothelial cells present can stimulate the growth of adjacent tumor cells through secretion of growth factors VEGF basic fibroblast growth factor (bFGF)

Sentinel lymph node mapping

Diagnostic tool used before therapeutic surgery, which identifies the first lymph node most likely to drain cancerous cells; used in axillary lymph node biopsy, specifically in breast cancer staging. Lymphoscintigraphy done first Technetium-99 is used Technetium-99 uptake is more in LN containing malignant cells Blue dye is also used

Monoclonality of neoplasms

Diagram depicting the use of X-linked isoenzyme cell markers as evidence of the monoclonality of neoplasms. Because of random X inactivation, all females are mosaics with two cell populations (with G6PD isoenzyme A or B in this case). When neoplasms that arise in women who are heterozygous for X-linked markers are analyzed, they are made up of cells that contain the active maternal (XA) or the paternal (XB) X chromosome but not both.

Primary Myelofibrosis

Disease of adults, presents with anemia -rapid development of obliterative marrow fibrosis -there is suppression of hematopoiesis -resulting in extra medullary hematopoiesis Pathogenesis: -extensive deposition of collagen -fibrogenic factors: PDGF and TGF-β -released from neoplastic megakaryocytes -JAK2 mutation in 50 to 60%

Dysplasia

Disordered growth seen in epithelial lined structures (cervix) when entire thickness of the epithelium is involved: carcinoma in situ not always progresses to malignancy (mild to moderate dysplasia are reversible)

Marginal zone Lymphomas

Distinct B cell neoplasms with variable clinical features Clinicopathologic entities include: 1. extra nodal marginal zone MALT lymphoma (stomach, orbit, intestine, lung, thyroid, salivary gland, bladder, CNS) 2. nodal marginal zone lymphoma 3. splenic marginal zone lymphoma Extra nodal involvement are associated with important features -seen arising from areas involved in chronic inflammation by autoimmune or infectious etiology (Sjörgen syndrome, Hashimoto's thyroiditis, Helicobacter pylori) -these remain localized for a long time -may regress, if inciting agent is eradicated Immunophenotype: B cell markers: CD19, CD20 Clinical course: eradication of Helicobacter pylori results in tumor regression in gastric lymphomas 5 yr survival rate is about 75%

VHL

Encodes a component of a ubiquitin ligase that is responsible for degradation of hypoxia-induced factors (HIFs), transcription factors that alter gene expression in response to hypoxia ■ Germline loss-of-function mutations cause von HippelLindau syndrome, autosomal dominant disorder associated with a high risk of renal cell carcinoma and pheochromocytoma ■ Acquired biallelic loss-of mutations are common in sporadic renal cell carcinoma Von Hippel-Lindau disease Autosomal dominant Capillary hemangioblastomas within cerebellar hemispheres, retina Cysts in pancreas, liver & kidneys pheochromocytoma Risk for renal cell carcinoma Mutation involving VHL located on chromosome 3

PTEN

Encodes a lipid phosphatase that is an important negative regulator of PI3K/AKT signaling ■ Germline loss-of-function mutations associated with Cowden syndrome, autosomal dominant disorder associated with a high risk of breast and endometrial carcinoma ■ Biallelic loss-of-function common in diverse cancers mutations associated with Cowden Syndrome (association with benign skin tumors) others: endometrial carcinomas, breast, thyroid

WT1

Encodes a transcription factor that is required for normal development of genitourinary tissues ■ Germline loss-of-function mutations associated with Wilms tumor, a pediatric kidney cancer; similar WT1 mutations also found in sporadic Wilms tumor Located on chromosome 11 associated with Wilms' tumor WT-2 is also located on ch 11 (distinct from WT-1 risk for Wilms' tumor associated with Beckwith-Wiedemann syndrome

PTCH1

Encodes membrane receptor that is a negative regulator of the Hedgehog signaling pathway ■ Germline loss-of-function mutations cause Gorlin syndrome, autosomal dominant disorder associated with a high risk of basal cell carcinoma and medulloblastoma. Acquired biallelic loss-of-function mutations of PTCH1 are seen frequently in sporadic basal cell carcinomas and medulloblastomas

NF1

Encodes neurofibromin 1, a GTPase that acts as a negative regulator of RAS ■ Germline loss-of-function mutations cause neurofibromatosis type 1, autosomal dominant disorder associated with a high risk of neurofibromas and malignant peripheral nerve sheath tumors Neurofibromatosis - 1, benign tumor, café-au-lait, Lisch nodules (hamartomas in iris), association with phaeochromocytoma Autosomal dominant

NF2

Encodes neurofibromin 2 (merlin), a cytoskeletal protein involved in contact inhibition ■ Germline loss-of-function mutations cause neurofibromatosis type 2, autosomal dominant disorder associated with a high risk of bilateral schwannomas Associated with neurofibromatosis-2 benign bilateral schwannomas of the acoustic nerve also associated with: sporadic meningiomas, ependymoma

Clinical course of Burkitt Lymphoma

Endemic and sporadic types are seen in children and young adults most tumors involve extra nodal sites ENDEMIC type, often presents as mass arising from mandible seen in association with involvement of kidney, ovary, adrenal SPORADIC: ileocecal involvement presents as abdominal mass (ileocecum), and peritoneum bone marrow involvement is rare though aggressive, Burkitt's responds well to short term, high dose chemotherapy

Raynaud's Phenomenon

Episodic digital ischemia: digital blanching, cyanosis, rubor on exposure to cold Blanching represents ischemic phase, results from vasospasm of digital arteries During ischemic phase, capillaries & venules dilate, and cyanosis result from the the increase in de-oxygenated blood With rewarming, a reactive hyperemia appears (red color) Sensation of cold or numbness is felt

Plasma hemopexin

Evidence of increased Hb breakdown binds to free heme in 1:1 ratio does not bind to Hb if large amounts of Hb is released & plasma haptoglobin level is exceeded some of the unbound Hb is converted to methemoglobin methemoglobin disassociates into ferriheme and globin ferriheme is bound to hemopexin therefore ferriheme is not lost thru' glomerular filtration intravascular hemolysis: plasma hemopexin level is low

Plasma haptoglobin

Evidence of increased Hb breakdown haptoglobin is synthesized in the liver haptoglobin binds to free Hb in plasma Hb is small enough to pass thru' the normal glomerulus Hb combined with haptoglobin is a large molecule thus cannot pass thru' the glomerulus following transient release of Hb into circulation, the plasma haptoglobin level falls & returns to normal after 3 to 6 days if there is persistent hemolysis, then plasma haptoglobin level remains low haptoglobin is reduced in both types of hemolysis- intrinsic & extrinsic

Extravascular hemolysis

Exaggeration of the normal mechanism of removal of aging red cells -red cells are recognized as abnormal by reticulo endothelial system -and phagocytosed prematurely (example: hereditary spherocytosis)

PAP smear

Examination for 'koilocytosis' which characterizes HPV infection

Aromatic amines

Example: β- napthylamine (aniline dye, rubber industry) Transitional cell carcinoma (TCC)

Cyclins and cyclin dependent kinases

External signals activate multiple signal transduction pathways, including those involving the MYC and RAS genes, which lead to synthesis and stabilization of cyclin D (there are several D cyclins, but, for simplification, we refer to them as "cyclin D"). Cyclin D binds to CDK4, forming a complex with enzymatic activity (cyclin D can also bind to CDK6, which appears to have a similar role as CDK4). The cyclin D-CDK4 complex phosphorylates RB, located in the E2F/DP1/RB complex in the nucleus, activating the transcriptional activity of E2F (E2F is a family of transcription factors, which we refer to as "E2F"), which leads to transcription of cyclin E, cyclin A and other proteins needed for the cell to go through the late G1 restriction point. The cell cycle can be blocked by the Cip/Kip inhibitors p21 and p27 (red boxes) and the INK4A/ARF inhibitors p16INK4A and p14ARF (green boxes). Cell-cycle arrest in response to DNA damage and other cellular stresses is mediated through p53. The levels of p53 are under negative regulation by MDM2, through a feedback loop that is inhibited by p14ARF.

Clinical features of G6PD deficiency

Features of acute hemolysis (2 to 3 days following oxidant stress & lasting about 7 days) -associated with stress: drug administration (anti-malarial), infection, fava bean ingestion

Clinical Feature of AML

Fever, splenomegaly, hepatomegaly, lymphadenopathy sternal tenderness, evidence of infection, hemorrhage M3: DIC gastrointestinal, intrapulmonary or intracranial hemorrhages M5: gingival infiltration, meningeal involvement

Clotting mechanism

Fibrinous meshwork at the site of injury to protect adjacent tissues and keeps foreign substances corralled at the site and mediates inflammation; forms future framework for the repair process

Desmoplasia

Fibrous tissue formation in response to a neoplasm. Irreversible. abundant collagenous stroma

Reactive Hyperplasia of Lymph nodes

Follicular hyperlasia - Increase in # and size of cortical lymphoid follicles - Reflects B-cell response - Results in production and clonal expansion of ab-secreting plasma cells Paracortical (parafollicular) hyperplasia - Expansion of the T-cell parafollicular zone - Small inconspicuous B-cell follicles pushed to periphery of node beneat the capsule - Commonly seen in response to viral infection Sinus hyperplasia/histiocytosis - No great increase in lymphoid component of the node - Medullary sinuses are prominent due to dilatation and hyperplasia of histiocytic cells lining the sinuses - Seen in nodes draining tissues from which endogenous particular matter such as lipid is released - Necrotic tumor

Carcinoma in-situ

Full thickness epithelial dysplasia. Note, there is an intact basement membrane. Microinvasion, characterized bb breach in BM and invasion of underlying stroma.

Atrophic gastritis

Gastric mucosa is thinned out. The gastric glands are atrophic (small). There is a layer of chronic inflammation.

Protoncogenes

Genes responsible for turning replication on and off. Mutations lead to development of oncogenes

Oncogenes

Genes that promote autonomous (self) cell growth in cancer cells Genes that cause cancer by blocking the normal controls on cell reproduction ability to promote cell growth in the absence of mitogenic signals example: RET protooncogene can undergo point mutation to become an oncogene products of oncogene: oncoproteins

G6PD deficiency

Glucose 6 phosphate dehydrogenase reduces NADP to NADPH -while oxidizing glucose 6 phosphate: -NADPH helps in conversion of oxidized glutathione to reduced glutathione which protects against oxidant injury (glutathione normally neutralizes H2O2, an oxidant which can result in oxidant stress/injury) Pathogenesis hemolysis follows oxidant stress Drugs: anti malarials (primaquine, chloroquine, sulfonamides, nitrofurantoins) Infections: viral hepatitis, pneumonia, typhoid fever Fava bean ingestion (favism): mostly in children between 2 to 5 yrs. - Sardinia, Greece, Sicily G6PD deficient red cells when exposed to oxidants, results in oxidation of reactive sulfhydryl group on Hb chain which becomes denatured, forms a membrane bound inclusion: 'Heinz body' Heinz bodies damages cell membrane results in intravascular hemolysis in spleen macrophages pluck out Heinz bodies (bite cells)

Myelodysplastic Syndrome

Group of 'clonal stem cell' disorders characterized by maturation defects associated with ineffective hematopoiesis Poorly understood myeloid tumors characterized by disordered and ineffective hematopoiesis and dysmaturation Recently shown to frequently harbor mutations in splicing factors and epigenetic regulators Manifest with one or more cytopenias and progress in 10% to 40% of cases to AML Increased risk of transformation to AML (abnormal steam cells are genetically unstable, accumulate mutation AML (loss of chromosome 5 or 7 or deletion) Usually presents as peripheral blood cytopenias (fall in total counts) Clinical course: -older age group (> 60 years) -weakness, infections, hemorrhages -progression to AML in 10 to 40% -therapy related- MDS has very poor prognosis

Sideroblastic anemia

Group of disorders of varying etiology characterized by abnormal erythropoeisis in bone marrow and, abnormal intramitochondrial accumulation of iron within red cell precursors sideroblasts are erythroblasts with iron granules in their cytoplasm Pathogenesis: defect in heme synthesis within mitochondria iron begins to accumulate within mitochondria (erythroid precursors) characterized by increased iron stores (BM & macrophages) Lab Findings: Peripheral blood smear red cells are dimorphic, sideroblasts, siderocytes Bone Marrow: hyperplastic, abnormal forms "ring sideroblasts"

Role of growth factor receptors

Growth factor receptors in tumors can be activated by: mutations, gene rearrangements and overexpression -example: point mutation in protooncogene RET, seen in inherited types of tumors- MEN (types 2A, 2B) and familial medullary carcinoma of thyroid -point mutation of c-KIT in gastrointestinal stromal tumor (GIST) gene rearrangements in myeloid leukemias overexpression: increased expression of c-MET in papillary carcinoma thyroid ERB B1 overexpression in squamous cell carcinoma of lung, glioblastoma overexpression of ERB B2 (HER-2/Neu) in breast carcinoma

Viral Oncogenesis

HTLV-1: a retrovirus that is endemic in Japan, the Caribbean, and parts of South America and Africa that causes adult T-cell leukemia/lymphoma ■ HTLV-1 encodes the viral protein Tax, which turns on progrowth and pro-survival signaling pathways (PI3K/AKT, NF-κB), leading to a polyclonal expansion of T cells. ■ After a long latent period (decades), a small fraction of HTLV-1-infected individuals develop adult T-cell leukemia/ lymphoma, a CD4+ tumor that arises from an HTLV-1 infected cell, presumably due to acquisition of additional mutations in the host cell genome. HPV: an important cause of benign warts, cervical cancer, and oropharyngeal cancer ■ Oncogenic types of HPV encode two viral oncoproteins, E6 and E7, that bind to Rb and p53, respectively, with high afinity and neutralize their function. ■ Development of cancer is associated with integration of HPV into the host genome and additional mutations needed for acquisition of cancer hallmarks. ■ HPV cancers can be prevented by vaccination against high-risk HPV types. EBV: ubiquitous herpesvirus implicated in the pathogenesis of Burkitt lymphomas, B-cell lymphomas in patients with T-cell immunosuppression (HIV infection, transplant recipients), and several other cancers ■ The EBV genome harbors several genes encoding proteins that trigger B cell signaling pathways; in concert, these signals are potent inducers of B cell growth and transformation. ■ In the absence of T-cell immunity, EBV-infected B cells can rapidly "grow out" as aggressive B-cell tumors. ■ In the presence of normal T-cell immunity, a small fraction of infected patients develop EBV-positive B-cell tumors (Burkitt lymphoma, Hodgkin lymphoma) or carcinomas (nasopharyngeal, gastric carcinoma) Hepatitis B virus and hepatitis C virus: cause of between 70% and 85% of hepatocellular carcinomas worldwide ■ Oncogenic effects are multifactorial; dominant effect seems to be immunologically mediated chronic inflammation, hepatocellular injury, and reparative hepatocyte proliferation. ■ HBx protein of HBV and the HCV core protein can activate signal transduction pathways that also may contribute to carcinogenesis. H. pylori: implicated in gastric adenocarcinoma and MALT lymphoma ■ Pathogenesis of H. pylori-induced gastric cancers is multifactorial, including chronic inflammation and reparative gastric cell proliferation. H. pylori pathogenicity genes, such as CagA, also may contribute by stimulating growth factor pathways. ■ Chronic H. pylori infection leads to polyclonal B-cell proliferations that may give rise to a monoclonal B-cell tumor (MALT lymphoma) of the stomach as a result of accumulation of mutations.

Lab diagnosis of G6PD

Hb: decreased, mild to severe Peripheral smear Heinz bodies, bite cells G6PD levels: low Plasma Hb: increased (hemogobinemia) Haptoglobin: reduced Hemoglobinuria X-chomosome Drugs(anti-malar., sulfonam., nitrofurantoin, phenacetin, aspirin, vit K derivates toxins, infections

Lab diagnosis of Beta Thalassemia

Hb: severe anemia RBC Indices: Peripheral blood smear: ansiopoikilocytosis microcytic, hypochromic, taget cells, fragmented red cells, reticulocytosis, nucleated red cells Biochemical: bilirubin, iron studies Hb Electrophoresis On lab investigation: (differentiation from iron deficiency anemia total iron binding capacity (TIBC) increased in iron deficiency normal in β-thalassemia minor serum iron and serum ferritin decreased in iron deficiency normal or slightly increased in thalassemia minor

Microangiopathic hemolytic anemia

Hemolitic anemia resulting from mechanical trauma to red cells Cardiac valve prostesis Narrowing or partial obstruction of the vasculature A peripheral blood smear from a patient with hemolytic-uremic syndrome shows several fragmented red cells.

Hodgkin's vs Non-Hodgkin's lymphoma

Hodgkin -Presence of Reed Sternberg cells -Mediastinal widening -Fever, sweats, weight loss -50% of cases associated with EBV. bimodal distribution-young and old; more common in men except for nodular sclerosing type. -Good prognosis = increased lymphocytes and decreased RS. -Localized single group of nodes; extranodal is rare; contiguous spread (stage is strongest predictor of prognosis) Non Hodgkins -May be associated with HIV and immunosuppresion -Multiple peripheral nodes common; extranodal involvement is common, noncontiguous spread. -Majority involve B cells (except those of lymphoblastic T-cell origin) -Fewer constitutional signs -Peak incidence is around 20-40 in certain subtypes.

Types of Myelodysplastic Syndromes

Idiopathic Primary MDS Therapy related MDS (t-MDS) Morphology: dysplastic maturation affecting all non lymphoid lineage erythroid, granulocytic, monocytic, megakaryocyctic Erythroid series: ringed sideroblasts, megaloblastoid cells Fig. B Myeloid series: pseudo Pelger-Huet cells; neutrophils with 2 nuclear lobes Fig. C Megakaryocyte: pawn ball megakaryocytes (single nuclear lobes) - myeloblasts less than 20% in bone marrow

Rheumatoid arthritis

IgM (and to lesser extent IgG) auto Abs against Fc portion of IgG In 20% of RA - RF absent Rheumatoid nodule. Subcutaneous nodule with an area of necrosis (top) surrounded by a palisade of macrophages and scattered chronic inflammatory cells. Bouchard's Nodes proximal PIP

Leukoerythroblastic reaction

Immature granulocytes and eryhtroid precursors enter peripheral blood Pathogenesis: bone marrow infiltration marrow fibrosis, metastatic cancers Peripheral blood smear: - myeloblasts, promyelocytes, nucleated red cells Peripheral blood smear: note numerous nucleated red cells (red arrow and immature granulocytes-white cells (green arrow)

Bleeding related to thrombocytopenia

Immune Thrombocytopenic purpura (ITP) Thrombotic thrombocytopenic purpura (TTP) Hemolytic uremic syndrome (HUS)

Increased susceptibility to infections

Impaired splenic function Streptococcus pneumoniae sepsis, especially children osteomyelitis caused by Salmonella paratyphi

Virchow triad

In thrombosis. Endothelial integrity is the single most important factor. Note that injury to endothelial cells can affect local blood flow and/or coagulability; abnormal blood flow (stasis or turbulence) can, in turn, cause endothelial injury. The elements of the triad may act independently or may combine to cause thrombus formation.

Pernicious Anemia

Incidence older age group (5th to 8th) decade of life most common cause for vitamin B12 defn. Pathogenesis chronic atrophic gastritis (immune mediated, possibly autoimmune) achlorhydria (reduced gastric acid) 3 types of antibodies (Ab) are present in these patients Macrocytes (abnormally large RBC) premature destruction by monocyte- macrophage. Hypersegmented neutrophils - earliest change, before anemia ! MCV 110 fL. (normal 82-92 fL) Type I Ab, blocks the binding of vitB12 to IF Type II Ab, blocks the binding of vitB12-IF complex to ileal receptors Type III Ab, are produced against α and β subunits of the gastric proton pump

Follicular Lymphoma

Incidence: - Most common indolent lymphoma of adults USA middle aged, males and females Pathology: neoplastic cells resemble normal germinal center B cells presents as non tender lymphadenopathy lymph node): numerous follicles of varying sizes - very different from follicular hyperplasia Bone Marrow biopsy: Follicular lymphoma infiltration Morphology bone marrow involvement in 85% splenic and hepatic involvement is frequent Immunophenotype: -tumor expresses CD19, CD20, CD10 (CALLA) -CD 5 is NOT expressed but CD10 is -tumor cells express BCL 2 protein (90%) Cytogenetics and Molecular genetics: - most important: t(14;18) translocation, which seen in 90% of cases this translocation results in over expression of BCL 2 BCL 2 is an anti-apoptotic protein molecule follicular lymphoma cells becomes immortal Clinical features: painless generalized lymphadenopathy incurable, but has an indolent course median survival: 7 to 9 years transformation to diffuse large B cell lymphoma

von Willebrand Disease

Incidence: inherited, autosomal dominant disease clinically resembles Hemophilia Pathogenesis: characterized by: 1) defect of platelet function leading to prolonged bleeding 2) coagulation defect due to deficiency of factor VIII activity in plasma Role of vWF: -synthesized by endothelial cells and megakaryocytes Functions: platelet adhesion molecule binds platelets to exposed collagen platelets have glycoprotein Gp Ib receptor for vWF Complexes with factor VIII:C in circulation VIII: vWF complex prevents degradation of factor VIII: C decrease in vWF secondarily decreases VIII:C activity Lab investigations: platelet count: normal bleeding time: prolonged, (this is due to a platelet adhesion defect) PT: normal PTT: increased ! vWF activity: reduced Factor VIII activity: reduced Factor VIII activity is the most sensitive Ristocin test

Thrombotic Thrombocytopenic Purpura (TTP)

Incidence: mostly women Pathogenesis: deficiency of enzyme ADAMTS 13-tissue metalloproteinases that degrades very-high- mol. W. multimers of vWF leads to excess of vWF (as it cannot be cleared) this increases platelet adhesion in areas of endothelial injury platelets are involved in the thrombus formation resulting in thrombocytopenia Clinical features (pentad) fever thrombocytopenia renal failure microangiopathic hemolytic anemia neurological symptoms

Henoch-Schönlein purpura

Incidence: seen in childhood & adolescence frequently following upper respiratory tract infection Pathogenesis: systemic hypersensitivity disease of unknown cause characterized by widespread inflammatory reaction of the capillaries & small vessels purpuric rash, abdominal colic, polyarthralgia, acute glomerulonephritits deposition of immune complexes (IgA) Lab Investigations: Platelet count: normal Bleeding time: normal Coagulation work-up: normal Skin biopsy: IgA, C3, fibrin deposits Renal biopsy: IgA, C3 deposits Causes: Immune disorder Children Follows infection Vasculitis Purpura GI bleed Glomerulonephritis

Polymyositis

Inflammatory myopathy Antibody system: Jo-1 antibodies against histidyl-tRNA synthetase Weakness and/or loss of muscle mass in the proximal musculature Common in women Associate with visceral cancer Symmetric weakness of the large muscles. (difficulty in getting up from the chair/climbing steps) Diagnosis: Jo-1 autoantibody Lymphocytic inflammation (mainly cytotoxic T lymphocytes).

Hemophilia A

Inheritance: X linked recessive trait females are asymptomatic carriers transmits the abnormal X chromosome to 50% of male offspring no family history in 30% Lab investigations: Platelet count: normal Bleeding time: normal Prothrombin time: normal Partial Thromboplastin Time: prolonged Factor VIII levels: reduced detection of female carriers Clinical features: concentration of clotting factor in plasma ranges from complete deficiency to 30% of normal activity below 1% is associated with severe disease easy bruising, hemorrhage following trauma or operative procedures 'spontaneous' hemorrhages to knee joints (hemarthroses) petechiae are absent Bleed into joints

Li-Fraumeni syndrome

Inherited predisposition to develop cancer germline mutation of p53 25 fold increase to develop tumor by the age of 50 yrs. (sarcomas, carcinoma breast, leukemia, brain tumors, adrenocortical cancers)

Acute Lymphoblastic Leukemia (ALL)

Introduction: - group of neoplasms composed of immature precursor B (pre B) or T (pre T) lymphocytes 85% of ALL are of precursor B cell type presents as childhood 'acute leukemias' extensive bone marrow involvement and variable peripheral blood involvement precursor T cell ALL are infrequent affects adolescent males as "thymic lymphomas" Important note: clinically pre B and pre T cell ALL have almost similar clinical behavior morphologically, both pre B and pre T cell leukemia/lymphoma are similar Incidence: common malignancy under 15 years peak age : 2 to 5 years Risk factors: Down's syndrome, Ataxia-Telangectasia, Bloom syndrome translocations: t(12;21), t(9;22), t(4;11) T-ALL: 70% of T-ALL show NOTCH1 mutation B-ALL: B-ALL show PAX5 mutation or t(12;21) involving TELL and AML1 gene

E6 and E7 proteins

Involved in HPV result in in infected cells being immortal and transformed E6 binds to p53 E6 protein of HPV 16, 18, 31 inactivates p53 (degradation) E7 binds to RB, and interferes with transcriptional activities E7 protein also degrades RB gene E6, E7 disables the tumor suppressor genes

Systemic lupus erythematosus (SLE) in the skin

Involving the skin. A, An H&E-stained section shows liquefactive degeneration of the basal layer of the epidermis and edema at the dermoepidermal junction. B, An immunofluorescence micrograph stained for IgG reveals deposits of immunoglobulin along the dermal-epidermal junction.

Growth fraction

Is important for chemotherapy most anti cancer drugs act on cells that are in cell cycle Tumors containing about 5% of all cells in replicative pool, will be slow growing and therefore refractory to treatment (less no. of cells dividing) malignant tumors grow more rapidly than benign tumors most malignant tumors grow faster than benign tumors.....exception: uterine leiomyomas (benign) after menopause, leiomyomas may atrophy replaced by fibrous tissue or sometimes calcify during pregnancy, leiomyomas have increased growth hormonal variation is responsible for these features

Hematogenous spread

Is typical of sarcomas, but also seen with carcinomas -veins are commonly involved* -liver and lungs are most frequently involved -vertebral metastases in carcinoma thyroid and prostate (Baston paravertebral venous plexus) -renal cell carcinoma involves renal vein (in a snakelike fashion up to inferior vena cava, sometimes reaching the right side of the heart - such intravenous growth may not be accompanied by widespread dissemination!) *Arteries have thicker wall than veins, hence more difficult for tumor cells to break thru'.

Sicca syndrome

Isolated Autoimmune destruction of salivary and Lacrimal glands. This is not common. Same ANAs are present like Sjogren syndrome (SS-A and SS-B)

Chronic Immune Thrombocytopenic Purpura

Lab investigations: Platelet count: decreased Bleeding time: prolonged Prothrombin time: normal Partial Thromboplastin Time: normal Bone marrow: bone marrow is indicated, to rule out other causes for thrombocytopenia slight increase in megakaryocytes Clinical features: easy bruising, menorrhagia, melena, bleed from mucus membranes subconjunctival & retinal hemorrhages maybe seen complications: sub arachnoid hemorrhages, intracerebral hemorrhages transplacental transfer of IgG may produce transient thrombocytopenia in infants corticosteroids & splenectomy immunosuppressive therapy

Pathogenesis of Beta thalassemia

Lack of adequate HbA (α2 β2) production imbalance between alpha & beta chains synthesis: excess free α chains in comparison to reduced β chains: insoluble precipitated aggregates in rbc inclusions of α chains damages cell membrane , vulnerable to phagocytosis (extra-vascular hemolysis). HbA synthesis is low, resulting in poorly hemoglobinized 'microcytic hypochromic' red cells Imbalance between α & β chains synthesis - inclusions containing erythroblasts are destroyed (intra-medullary) ineffective erythropoiesis increased absorption of dietary iron iron overload (secondary hemochromatosis)

Point mutation

Leading to premature chain termination. Partial mRNA sequence of the β-globin chain of hemoglobin showing codons for amino acids 38 to 40. A point mutation (C→U) in codon 39 changes glutamine (Gln) codon to a stop codon, and hence protein synthesis stops at the 38th amino acid.

BCR-ABL fusion gene

Leads to increase in cell division and inhibition of apoptosis affects mostly the granulocytic progenitors The Philadelphia chromosome (Ph) is created by a balanced chromosomal translocation that replaces the telomeric portion of 22q with the telomeric portion of 9q. At a molecular level, the breaking and rejoining of the DNA results in the formation of fusion gene on the Ph derived from the 5' end of BCR and the 3' end of ABL and hence brings BCR and ABL sequences that are normally far apart into close physical proximity. This abnormal co-localization of BCR and ABL can be detected by in situ hybridization with pairs of fluorescently tagged DNA probes complementary to genomic DNA sequences lying near the BCR and ABL breakpoints.

Chronic Discoid Lupus Erythematosus

Less severe. Skin plaques showing varying degrees of edema, erythema, scaliness. Diagnosis: positive ANA test, but dsDNA are rarely present.

Malaria

Life cycleMalarial parasites are transmitted by the infected female anopheline mosquito which injects sporozoites present in the saliva of the insect (Figure 18). Sporozoites infect the liver parenchymal cells where they may remain dormant (hypnozoites) or undergo stages of schizogony to produce schizonts and merogony to produce merozoites (meronts). When parenchymal cells rupture, thousands of meronts are released into blood and infect the red cells. P. ovale and P. vivax infect immature red blood cells whereas P. malariae infects mature red cells. P. falciparum infects both. In red cells, the parasites mature into trophozoites. These trophozoites undergo schizogony and merogony in red cells which ultimately burst and release daughter merozoites. Some of the merozoites transform into male and female gametocytes (figure 19) while others enter red cells to continue the erythrocytic cycle. The gametocytes are ingested by the female mosquito, the female gametocyte transforms into ookinete, is fertilized, and forms an oocyst in the gut. The oocyte produces sporozoites (sporogony) (figure 20) which migrate to the salivary gland and are ready to infect another host. The liver (extraerythrocytic) cycle takes 5-15 days whereas the erythrocytic cycle takes 48 hours or 72 hours (P. malariae). Malaria can be transmitted by transfusion and transplacentally.

Morphology of CLL/SLL

Loss of normal lymph node architecture replaced by sheets of small lymphocytes these cells are admixed another population of larger lymphocytes: 'prolymphocytes' prolymphocytes aggregates to form, 'proliferation centers' but hypogammaglobulinemia (and auto Abs against RBCs, Trombocytes?) when present, they are typical for SLL Anemia: very late in the disease Total white cell count: markedly elevated (100,000 cells/mm3) Peripheral blood smear: lymphocytosis, 'smudge cells' bone marrow involvement seen in all cases of CLL and also most cases of SLL splenic and hepatic involvement is seen sometimes

Ehler-Danlos syndrome (OI)

Lysine hydroxylase (for type I and III collagen) - collagen fibers lack adequate tensile strength Joints are hypermobile Skin is hyperextensible Retinal detachment Blue Sclerae There are six variants of Ehlers-Danlos syndromes, all characterized by defects in collagen synthesis or assembly. Each of the variants is caused by a distinct mutation involving one of several collagen genes or genes that encode other ECM proteins like tenascin-X. ■ Clinical features may include fragile, hyper extensible skin vulnerable to trauma, hypermobile joints, and ruptures involving colon, cornea, or large arteries. Wound healing is poor.

Inclusion body myositis

Mainly seen in people 50+. Begins with weakness of distal muscles (extensors of the knee and flexors of the wrist and fingers) and presents with vacuoles (lysosomes), β-amyloid & tau protein inclusions. It's also CD8+ and anti-cN1A+.

Lymphatic spread

Major route by which carcinoma metastasizes Observe the presence of glandular elements in the lymph node Metastatic lymph node Primary malignancy from colon Enlargement of nodes in cancers: (2 causes for LN enlargement) 1. spread and growth of cancer cells 2. reactive hyperplasia: drainage of tumor cell debris or tumor antigen, or both

Seeding of body cavities

Malignant neoplasm penetrates into a natural open field characteristic of carcinomas arising from the ovaries malignant cells exfoliate from surface and implant & invade tissue in body cavity. Examples: peritoneal cavity: ovaries, appendix (pseudomyxoma peritonei) subarachnoid space: acute lymphoblastic leukemia, glioblastoma multiforme

Adenocarcinoma of the colon

Malignant tumor Note that compared with the well-formed and normal-looking glands characteristic of a benign tumor the cancerous glands are irregular in shape and size and do not resemble the normal colonic glands. This tumor is considered differentiated because gland formation can be seen. The malignant glands have invaded the muscular layer of the colon.

Sarcoma

Malignant tumor of connective tissue Marker Vimentin/Desmin + etc Spindle cells

Autosomal dominant disorders

Manifested in heterozygous state - one parent is usually affected) penetrance variable the age at onset is delayed in some diseases

Uncommon Lymphoid Neoplasms

Mantle cell lymphoma: Tumor of naive B cells that pursues a moderately aggressive course and is highly associated with translocations involving the cyclin D1 gene Marginal zone lymphoma: Indolent tumors of antigen-primed B cells that arise at sites of chronic immune stimulation and often remain localized for long periods of time Hairy cell leukemia: Morphologically distinct, very indolent tumor of mature B cells that is highly associated with mutations in the BRAF serine/threonine kinase Peripheral NK/T cell lymphomas and leukemias Anaplastic large cell lymphoma: Aggressive T cell tumor, associated in a subset with activating mutations in the ALK tyrosine kinase Adult T cell leukemia/lymphoma: Aggressive tumor of CD4+ T cells that is uniformly associated with HTLV-1 infection Large granular lymphocytic leukemia: Indolent tumor of cytotoxic T cells or NK cells that is associated with mutations in the transcription factor STAT3 and with autoimmune phenomena and cytopenia Extranodal NK/T cell lymphoma: Aggressive tumor, usually derived from NK cells, that is strongly associated with EBV infection

Clinical features of Beta thalassemia major

Marked pallor, jaundice requires blood transfusion growth retardation splenomegaly by 3 years skeletal system abnormalities gall stones infections Importance: differentiation from iron deficiency anemia iron deficiency anemia improves with iron therapy, whereas β Thalassemia trait or minor worsened by iron therapy estimation of serum iron, ferritin & transferrin are important

Hamartoma

Mass of disorganized, but mature specialized cells or tissue indigenous to that site In lung: showing hyaline cartilage, compressed air spaces and connective tissue.

Sequestration crises

Massive sequestration of sickled cells in spleen rapid splenic enlargement, hypovolemia, sometimes shock (dangerous) seen in children

Polycythemia vera

Massive splenomegaly (3020 gm; normal: 1500 to 2000 gm) largely owing to extramedullary hematopoiesis occurred in the setting of advanced marrow myelofibrosis.

Splenomegaly

Massive splenomegaly (weight more than 1000 gm) 1. Chronic myeloproliferative disorders (chronic myeloid leukemia, myeloid metaplasia with myelofibrosis) 2. Chronic lymphocytic leukemia 3. Hairy cell leukemia 4. Lymphomas 5. Malaria 6. Gaucher disease Primary tumors of the spleen (rare) Moderate splenomegaly (weight 500-1000 gm) 1. Chronic congestive splenomegaly (portal hypertension or splenic vein obstruction) 2. Acute leukemias (inconstant) 3. Hereditary spherocytosis 4. Thalassemia major 5. Autoimmune hemolytic anemia 6. Amyloidosis 7. Niemann-Pick disease 8. Langerhans histiocytosis 9. Chronic splenitis (especially with infective endocarditis) 10. Tuberculosis, sarcoidosis, typhoid Metastatic carcinoma or sarcoma Mild splenomegaly (weight <500 gm) 1. Acute splenitis 2. Acute splenic congestion 3. Infectious mononucleosis 4. Miscellaneous acute febrile disorders, including septicemia, SLE,

Prothrombin time

Measures effectiveness of the Extrinsic Pathway (till the formation of fibrin clot) Factors VII, X, V, II and I NORMAL VALUE 11-15 SECS Test: exogenously added source of tromboplastin and Ca++ Warfarin affects this pathway Importance: -follow of patients on warfarin for 'anticoagulation' -prolonged PT is associated with liver diseases -for detection of Factor VII deficiency

Partial thromboplastin time

Measures effectiveness of the Intrinsic Pathway (till the formation of fibrin clot) Factors XII, XI, IX, VIII, X, V, II and I NORMAL VALUE 25-40 SECS Test: Kaolin - activation of contact-depen. Factor XII Cephalin - substitutes platelet phospholipid Heparin acts on this pathway Importance: follow-up cases on heparin therapy detect Factor deficiencies in the intrinsic system

Bleeding time (BT)

Measures the time required for cessation of bleeding after standardized capillary puncture; focuses on the number of platelets present and their ability to form a plug NORMAL VALUE 2-7 MINUTES Evaluates platelet function up to the formation of temporary platelet plug Prolonged BT: aspirin/NSAID- plt. count is normal Bernard-Soulier, thrombocytopenia, giant platelets Glanzman's disease, Renal failure, Scurvy, thrombocytopenia von Willebrand disease- combined platelet and coagulation factor defect

Intrinsic causes of hemolytic anemia

Membrane defects: hereditary spherocytosis Hb defects: sickle cell disease thalassemias Enzyme defects: G6PD deficiency Acquired: paroxysmal nocturnal hemoglobinuria

Clinical features of pernicious anemia

Middle & older age group anemia (lemon tint) mild icterus 'glazed' and 'beefy' red tongue atrophy of papillae (burning pain on swallowing) autoimmune gastritis: atrophy of fundic glands, metaplasia- intestinalization....risk for cancer Anemia + neurological changes: symetric numbness, tingling, loss of gait and position sense demielinisation of posterior and lateral columns of the spinal cord Th: Vit B12 fails to resolve neurological manifestation Dg: low serum B12 megaloblstic anemia leukopenia (hypersegm. granulocytes) antibodies to IF: present in most cases Shilling test, ... dramatic (2-30) reticulocyte response to parenteral B12 administration assays vit B12 absorption by measuring urinary radioactivity, after an oral dose of radioactive Vit B12 Urine: increased methylmalonic acid

Hereditary Nonpolyposis Cancer Syndrome (HNPCC)

Mismatch repair also referred to as: Lynch syndrome HNPCC is characterized by familial carcinomas of colon most arise from cecum & proximal colon they do not arise from adenomatous polyps as in APC mutation normally, when one strand of DNA is replicating mismatch repair genes act as "spell checkers" if there is an error of pairing then, mismatch repair corrects the defect defects in mismatch gene leads to tumorsmicrosatellite instability

Libman-Sacks endocarditis

Mitral valve in lupus erythematosus. The vegetations attached to the margin of the thickened valve leaflet are indicated by arrows. Attached on both sides.

Secondary ITP

Most common Drug induced: most causing aplastic anemia Leukemias: Bone marrow infiltration Hypersplenism SLE

Selective IgA Deficiency

Most common Incidence:1 in 700 Asymptomatic. Virtual lack of circulating IgA as well as secretory IgA. Increased risk for respiratory, gastrointestinal (diarrhea). Increased risk of blood transfusion reaction

Small Lymphocytic Lymphoma/Chronic Lymphocytic Leukemia

Most common leukemia of adults Tumor of mature B cells that usually manifests with bone marrow and lymph node involvement Indolent course, commonly associated with immune abnormalities, including an increased susceptibility to infection and autoimmune disorders

Acute Lymphoblastic Leukemia (ALL)

Most common type of cancer in children, may be derived from either precursor B of T cells Highly aggressive tumors manifest with signs and symptoms of bone marrow failure, or as rapidly growing masses. Tumor cells contain genetic lesions that block differentiation, leading to the accumulation of immature, nonfunctional blasts.

Polycyclic aromatic hydrocarbons

Most potent carcinogen require metabolic activation ingredients of tobacco smoke, broiling of animal fat/fish cause lung and bladder malignancies Carcinoma lung: tumor arising close to the main bronchus. Histology shows squamous cell carcinoma. Note production of keratin by tumor cells (arrow).

Chronic lymphocytic leukemia

Mostly blood involvement absolute lymphocyte count is more than 4000 per mm3 This peripheral blood smear is flooded with small lymphocytes with condensed chromatin and scant cytoplasm. A characteristic finding is the presence of disrupted tumor cells (smudge cells). A coexistent autoimmune hemolytic anemia explains the presence of spherocytes (hyperchromatic, round erythrocytes). A nucleated erythroid cell is present in the lower left-hand corner of the field. In this setting, circulating nucleated red cells could stem from premature release of progenitors in the face of severe anemia, marrow infiltration by tumor (leukoerythroblastosis), or both.

Clinical features of Polycythemia Vera

Mostly due to expanded total blood volume and slowing of blood flow due to increased VISCOSITY -headache, dizziness, tinnitus, visual disturbances "ruddy" color of skin, especially face -DVT deep vein thrombosis and INFARCTS (↑ red cell mass) -PRURITUS (release of histamine from basophils), 'aquagenic pruritis' -PEPTIC ulceration (histamine release) -hyperuricemia (GOUT) -complications: Myelofibrosis, Acute Leukemia

Small Lymphocytic Lymhoma (SLL)

Mostly involves lymph nodes aleukemic form of CLL - both are morphologically phenotypically and genotypically similar only difference: degree of lymphocytosis in peripheral blood A, Low-power view shows diffuse effacement of nodal architecture. B, At high power, the majority of the tumor cells are small round lymphocytes. A "pro-lymphocyte," a larger cell with a centrally placed nucleolus, is also present in this field (arrow).

Iron absorption

Mucosal uptake of heme and nonheme iron is depicted. When the storage sites of the body are replete with iron and erythropoietic activity is normal, most of the absorbed iron is lost into the gut by shedding of the epithelial cells. Conversely, when body iron needs increase or when erythropoiesis is stimulated, a greater fraction of the absorbed iron is transferred into plasma transferrin, with a concomitant decrease in iron loss through mucosal ferritin

APC gene

Mutations lead to development of thousands of adenomatous polyps (benign) in colon -seen during teens and early twenties -(Familial Adenomatous Polyposis) -one or more of these adenomatous polyp will turn malignant APC is a component of the WNT signaling pathway role of APC protein is to down regulate β-catenin (growth promoting signal) inactivation of APC gene increase cellular levels of β catenin this leads to increased cellular proliferation & mutation.....malignancy Encodes a factor that negatively regulates the WNT pathway in colonic epithelium by promoting the formation of a complex that degrades β-catenin ■ Mutated in familial adenomatous polyposis, autosomal dominant disorder associated with development of thousands of colonic polyps and early onset colon carcinoma; tumor development associated with loss of the single normal APC allele ■ Mutated in about 70% of sporadic colon carcinomas; tumor development associated with acquired biallelic defects in APC

Myeloid Neoplasms

Neoplasms originating from hematopoietic progenitor cells capable of giving rise to terminally differentiated cells of myeloid series erythrocytes, granulocytes, monocytes and platelets primarily involves: bone marrow Includes: Acute Myelogenous Leukemia (AML) Aggressive tumors comprised of immature myeloid lineage blasts, which replace the marrow and suppress normal hematopoiesis Associated with diverse acquired mutations that lead to expression of abnormal transcription factors, which interfere with myeloid differentiation Often also associated with mutations in genes encoding growth factor receptor signaling pathway components or regulators of the epigenome Chronic Myeloproliferative disorders (CML, polycythemia vera, essential thrombocytosis, primary myelofibrosis) Myeloid tumors in which production of formed myeloid elements is initially increased, leading to high blood counts and extramedullary hematopoiesis Commonly associated with acquired mutations that lead to constitutive activation of tyrosine kinases, which mimic signals from normal growth factors. The most common pathogenic kinases are BCR-ABL (associated with CML) and mutated JAK2 (associated with polycythemia vera and primary myelofibrosis). All can transform to acute leukemia and to a spent phase of marrow fibrosis associated with anemia, thrombocytopenia, and splenomegaly. -Myelodysplastic Syndrome (Differentiation is disordered and ineffective)

Langerhans cell histiocytosis

Neoplastic proliferation of dendritic cells (antigen-presenting immune cells) of the skin with characteristic Birbeck (tennis racket) granules seen on electron microscopy; cells are CD1a+, HLA DR+,and S100+ by immunohistochemistry Letterer-Siwe syndrome (acute disseminated form) Eosinofilic granuloma (unifocal lesions in skeletal system) Hand-Shuller-Christian disease: - calvar bone deffects - diabetes insipidus - exophthalmus

Hairy cell leukemia

Neoplastic proliferation of mature B cells characterized by hairy cytoplasmic processes Immunophenotype: B cell markers: CD19, CD2O, CD11c, CD103 Special stain: - stains strongly for tartarate-resistant acid phosphatase (TRAP) Hb: decreased (anemia) Total WBC: decreased Platelet count: decreased Peripheral blood smear: neutropenia, presence of hairy cells Bone Marrow: "DRY TAP" Pancytopenia bone marrow is involved, where they are enmeshed in extra cellular matrix, infiltrate spleen splenomegaly bone marrow biopsy indicated leukemic cells have hair-like structure on surface of cytoplasm Clinical features: -infiltration of bone, spleen, liver -massive splenomegaly -pancytopenia (50%) -prone for infection (Mycobacterium avium intracellulare) -indolent course, survival rate is high -responds well to IFN α

Clinical features of Paroxysmal nocturnal hemoglobinuria

Nocturnal hemoglobinuria passage of red/brown urine in the morning (respiratory acidosis during night time augments complement attachment to cell) cyclic pattern Chronic hemolysis most common feature (hemosiderinuria) Lab diagnosis Hb: low at the time of diagnosis Reticulocyte count: increased WBC counts: reduced Platelets: reduced Urine: hemoglobinuria, hemosiderinuria Bone Marrow: hyperplastic Screening test: sucrose hemolysis test Confirmatory test: HAM test

Molecular basis of cancer

Non lethal genetic damage (mutation) may be: acquired: environmental agents (chemicals, radiation, virus) inherited: germline mutations Clonal expansion of a single precursor cell that suffered genetic damage Mode of assessment: in uterine leiomyoma, smooth muscle fibers in the tumor will produce either A or B isoenzyme of G6PD, but never both however, the non-neoplastic smooth muscle produce both isoenzymes of G6PD Targets of genetic damage belong to four classes of normal regulatory genes Growth promoting protooncogenes Growth inhibiting tumor suppressor genes Genes that regulate apoptosis Genes involved in DNA repair

Steps of Invasion

Normal cells are glued to each other by adhesion molecules Cadherins are the most important family (E-cadherins) tumors down regulate E-cadherin expression next, the tumor cells need to break through the basement membrane to reach the stroma tumor cells attach to lamina and fibronectin through receptors (integrins) following attachment to basement membrane components or ECM components tumor cells produce proteolytic enzymes (collagenases, cathepsin-D,...) or make host cells (fibroblasts, macrophages) to produce these proteolytic enzymes

Choristoma

Normal tissue in a foreign location Ectopic example: pancreatic tissue in stomach wall, gastric mucosa in Meckel diverticulum's

Chemical carcinogenesis

Note that promoters cause clonal expansion of the initiated cell, thus producing a preneoplastic clone. Further proliferation induced by the promoter or other factors causes accumulation of additional mutations and emergence of a malignant tumor. ■ Chemical carcinogens have highly reactive electrophile groups that directly damage DNA, leading to mutations and eventually cancer. ■ Direct-acting agents do not require metabolic conversion to become carcinogenic, while indirect-acting agents are not active until converted to an ultimate carcinogen by endogenous metabolic pathways. Hence, polymorphisms of endogenous enzymes such as cytochrome P-450 may influence carcinogenesis. ■ After exposure of a cell to a mutagen or an initiator, tumorigenesis can be enhanced by exposure to promoters, which stimulate proliferation of the mutated cells. ■ Examples of human carcinogens are direct-acting agents (e.g., alkylating agents used for chemotherapy), indirect acting agents (e.g., benzo[a]pyrene, azo dyes, alatoxin), and promoters or agents that cause pathologic hyperplasias of the endometrium or regenerative activity in the liver.

Sickling test

Observation of sickling of red cells containing HbS under cover slip when treated with 2% sodium metabisulfite Hb electrophoresis Chorionic villi biopsy fetal DNA analysis in first trimester to detect point mutation Lab investigations Hb: decreased Red cell indices: increased MCHC Peripheral blood smear microcytic hypochromic sickled cells (10 to 15%)

Majord disorders associated with DIC

Obstetric Complications Abruptio placentae Retained dead fetus Septic abortion Amniotic fluid embolism Toxemia Infections Sepsis (gram- negative and gram-positive) Meningococceimia Rocky Mountain spotted fever Histoplasmosis Aspergilosis Malaria Neoplasms Carcinomas of pancreas, prostate. lung. and stomach Acute promyelucylic leukemia Massive Tissue Injury Trauma Burns Extensive surgery Miscellaneous Acute intravascular hemolysis. snake bite, giant bemangioma, shock, heat stroke, vasculitis, aortic aneurism, liver disease

Human T- cell leukemia / lymphoma virus

Oncogenic RNA virus endemic in Caribbean, Japan route of transmission: sexual, blood transfusion, breast milk Mechanism of action HTLV-1 has tropism for CD4+ T lymphocytes neoplastic transformation virus contains TAX gene TAX protein can activate several host transcription genes these genes then promote proliferation & differentiation of T cells

Helicobacter pylori

Oncogenic RNA virus infection is linked to gastric carcinomas and lymphomas very strongly linked to gastric lymphomas treatment of infection with antibiotics leads to regression of gastric lymphomas lymphomas arise from 'mucosa- associated lymphoid tissue' (MALTomas) Histology shows infiltration by sheets of lymphocytes with atypical features (silver stain)

Letterer-Siwe syndrome

One of the four recognized clinical syndromes of Langerhans cell histiocytosis (LCH). It causes approximately 10% of LCH disease and is the most severe form. Prevalence is estimated at 1:500,000 and the disease almost exclusively occurs in children less than three years old. Characterized by skin lesions, ear drainage, lymphadenopathy, osteolytic lesions, and hepatosplenomegaly. The skin lesions are scaly and may involve the scalp, ear canals, and abdomen Cause Oncogenic mutation of BRAF 50-70% cases The disease is often rapidly fatal, with a five year survival rate of 50%. The development of thrombocytopenia is a poor prognostic sign.

Ferritin

Only small amounts of ferritin, derived from iron stores, circulates in the plasma. The intravascular half-life of ferritin is of the order of 5-10 minutes;however, the amount of serum ferritin closely reflects iron stores, thus providing a good assessment of body iron storage, short of bone marrow biopsy. Three exceptions must be noted: 1) ferritin increases in chronic inflammation, 2) ferritin is increased in hepatocellular disease, and 3) ferritin may be increased in some neoplasias. An elevated ferritin may reflect iron overload; however, ferritin is an acute phase protein, so may also be increased in liver disease, malignancy, infection and inflammation. Therefore, a normal ferritin concentration alone does not necessarily exclude iron deficiency.

Loss of polarity

Orientation is disordered epithelial lined structures: cervix, tracheobronchial, stomach, etc

Translocation t: 15; 17

PML on 15 RARA on 17 Myeloperoxidase + red cytoplasmic inclusion (Auer rods) Monocyte:+ for lysosomal nonspecific esterase A. Acute myelogenous leukemia Bone marrow aspirate shows neoplastic promyelocytes with abnormally coarse and numerous azurophilic granules. Other characteristic findings include the presence of several cells with bilobed nuclei and a cell in the center of the field that contains multiple needlelike Auer rods. B, Acute monocytic leukemia (FAB M5b subtype). Peripheral smear shows one monoblast and five promonocytes with folded nuclear membranes.

Aplastic anemia

Pancytopenia! Suppression of multipotent myeloid stem cell. very serious disorder and usually chronic results from aplasia of the bone marrow reduction in the amount of hemopoietic tissue in the marrow leads to an inability to produce normal numbers of mature cells NO:- splenomegaly - reticulocytosis absent Markedly hypocellular marrow contains mainly fat cells. BM transplantation extremely effective Pathogenesis stem cells are antigenically altered by drug exposure/infection activated TH1 T cells produces: IL-1, TNF, IFN gamma suppress & kill hematopoietic progenitors

T-Cell-Mediated diseases

Patients with T cell defects can present with a variety of organ specific autoimmune diseases (e.g., type 1 diabetes mellitus in infancy, hypothyroidism, and Addison's disease) caused by the attack on these organs by the patient's own immune cells. The basis for these clinical complications is unclear, but are thought to be caused by a breakdown in immune tolerance in which a lack of T regulatory cells or the participation of Th17 cells plays a critical role in the pathogenesis of these disorders

Adult T cell Leukemia / Lymphoma

Peripheral T cell neoplasm Lymphoproliferative disorder seen in adults, associated with HTLV 1 infection -transplacental, blood, sexual transmission -breast milk.....low risk -latency average: 55 yrs !! - Japan, West Africa, Caribbean are endemic regions Skin lesions, generalized lymphadenopathy, hepatosplenomegaly, lymphocytosis and HYPERcalcemia Clinical features: rapidly progressive disease, aggressive lymphadenopathy, hepatosplenomegaly, skin infiltration, hypercalcemia, lytic bonelesion, and high mortality Pathogenesis: activation of TAX gene which inhibits the p53 suppressor gene leads to monoclonal proliferation of CD4 helper cells Lab Diagnosis: CBC: leukocytosis Peripheral blood smear: lymphocytosis, 'Flower Cells' Biochemical: Hypercalcemia Skin Biopsy: CD markers Serum: HTLV-1

Precancerous conditions

Pernicious anemia: atrophic gastritis of stomach -solar keratosis of skin: squamous cell carcinoma -Sjorgen syndrome, Hashimoto's thyroiditis: MALT lymphoma -atypical hyperplasia of ductal epithelium (breast) -leukoplakia of oral cavity, vulva and penis: squamous cell carcinoma -chronic irritation of sinus orifice (osteomyelitis): squamous cell carcinoma -Barrett's esophagus: adenoca. esophagus -dysplastic nevus: malignant melanoma -myelodysplastic syndrome : AML -regenerative nodules in cirrhosis: hepatocellular carcinoma -villous adenoma rectum: adenocarcinoma -complete hydatidiform mole: choriocarcinoma -endometrial hyperplasia: adenoca. endometrium -scar tissue in lung : adenocarcinoma

Internal Iron cycle

Plasma iron bound to transferrin is transported to the marrow, where it is transferred to developing red cells and incorporated into hemoglobin. Mature red blood cells are released into the circulation and, after 120 days, are ingested by macrophages in the reticuloendothelial system (RES). Here iron is extracted from hemoglobin and returned to the plasma, completing the cycle.

Lab diagnosis of DIC

Platelet count: decreased Prothrombin time (PT): prolonged Partial thromboplastin time (PTT): prolonged Thrombin time- prolonged Fibrinogen levels: reduced Fibrinogen degradation products: increased Peripheral blood smear: fragmented rbc's Treatment: treat underlying cause volume replacement correction of hypotension and oxygenation Fresh-frozen plasma heparin (some cases) Acute DIC (in obst. Complications) is dominated by bleeding diathesis Chronic DIC (in pat. With Ca) thrombotic complications

Mixed Tumor

Pleomorphic adenoma)of the parotid gland contains epithelial cells forming ducts and myxoid stroma that resembles cartilage. Admixture of epithelial & stromal elements Arises frequently from parotid gland Microscopy shows epithelial elements forming ducts/acini/sheets of cells Background shows myxoid areas which may contain cartilage (stromal) Sites: parotid (80%), submandibular (10%), remaining from minor salivary glands Age: middle age, very rare in young Surgery: every effort should be made to safeguard the facial nerve risk of recurrence Histogenesis: both epithelial & myoepithelial Clinical behavior: slow growing tumor

Sickle cell anemia (HbS)

Point mutation at the 6th position of the β globin chain resulting in substitution of valine for glutamic acid 8% of African Americans are heterozygous for HbS (sickle cell trait) 40 to 45% of the Hb is HbS in homozygous state, almost all Hb in red cells are HbS (90 to 95%) HbA2: 1 to 3% HbF : 1 to 5% HbS : 90 to 95% Level of HbS is important heterozygous HbS undergo sickling only under severe hypoxic state homozygous HbS expresses all features of sickle cell disease Types of Hb fetal Hb newborns do not manifest the disease until 5 to 6 months of age

TGF-β pathway

Potent inhibitor of cellular proliferation in normal tissues ■ Frequent loss-of-function mutations involving TGF-β receptors (colon, stomach, endometrium) or downstream signal transducers (SMADs, pancreas) in diverse carcinomas ■ Complex role in carcinogenesis; may also have a prooncogenic role by enhancing the immune evasiveness of tumors pathway when impaired affect SMAD molecules SMAD4: is inactivated in pancreatic ca. & colonic cancers

Anticoagulants

Prevent clot formation

Acute Non-specific Lymphadenitis

Primary, mesenteric lymphadenitis is a self-limiting inflammatory condition affecting the mesenteric lymph nodes, whose presentation mimics appendicitis or intussusception. It typically occurs in children, adolescents, and young adults. White blood count and C-reactive protein are of limited usefulness in distinguishing between patients with and without mesenteric lymphadenitis. Once the diagnosis is established, supportive care including hydration and pain medication is advised. Furthermore, it is crucial to reassure patients and families by explaining the condition and stating that affected patients recover completely without residuals within 2-4 weeks.

Fibrinolysis

Pro- and antifibrinolytic properties. vWF, von Willebrand factor; PGI2, prostacyclin; NO, nitric oxide; t-PA, tissue plasminogen activator. Thrombin receptor is referred to as protease activated receptor (PAR; see text).

Chronic inflammation and cancer

Production of cytokines increases pool of tissue stem cells promote genomic instability Example: ulcerative colitis, Crohn's disease, Helicobacter pylori gastritis, viral hepatitis, chronic pancreatitis Aspirin's role in colonic cancer COX-2 inhibitors and cancer RX

Scleroderma

Progressive Systemic Sclerosis, PSS Limited scleroderma, or CREST syndrome. Def : Characterized by excessive fibrosis in a variety of tissues due to collagen deposition. About 75% of cases are in women, mostly middle aged. Patient may have hypertension. The extensive subcutaneous fibrosis has virtually immobilized the fingers, creating a clawlike flexion deformity. Loss of blood supply has led to cutaneous ulcerations. And difficulty in swallowing.

Cancer cachexia)

Progressive loss of body fat and lean body mass, accompanied by profound weakness, anorexia, and anemia, that is caused by release of factors by the tumor or host immune cells Anorexia and weight loss due to the action of cytokines produced by tumor and by host TNF, IL-1, IFN-γ, proteolysis-inducing factor (PIF)

Plasma cell neoplasms

Proliferation of B cell clone that synthesizes and secretes a homogenous immunoglobulin or its fragments -most cases of proliferation (dyscrasias) are malignant -monoclonal immunoglobulin identified in blood are called as M COMPONENT These Antibodies have high molecular weights, hence seen only in plasma or extracellular fluid excluded from urine in the absence of glomerular damage Multiple Myeloma Plasma cell tumor that manifests with multiple lytic bone lesions associated with pathologic fractures and hypercalcemia Neoplastic plasma cells suppress normal humoral immunity and secrete partial immunoglobulins that are nephrotoxic Associated with diverse translocations involving the IgH locus; frequent dysregulation and overexpression of D cyclins May be associated with AL amyloidosis (as may other neoplasms later) Neoplastic plasma cells synthesize excess of 'L' (light) chains along with complete immunoglobulins Free L chains are known as Bence-Jones proteins these are small enough to be excreted in urine Others: MGUS (monoclonal gammopathy of unknown significance): common in older adults, progresses to myeloma at a rate of 1% per year Smoldering myeloma: disseminated disease that pursues an unusually indolent course Solitary osseous plasmacytoma: solitary bone lesion identical to disseminated myeloma; most progress to myeloma within 7 to 10 years Extramedullary plasmacytoma: solitary mass, usually in the upper aerodigestive tract; rarely progresses to systemic disease Lymphoplasmacytic lymphoma: B cell lymphoma that exhibits plasmacytic differentiation; clinical symptoms dominated by hyperviscosity related to high levels of tumor-derived IgM; highly associated with mutations in the MYD88 gene

Unregulated Cell Proliferation

Proto-oncogenes: normal cellular genes whose products promote cell proliferation Oncogenes: mutated or overexpressed versions of proto-oncogenes that function autonomously, having lost dependence on normal growth promoting signals Oncoprotein: a protein encoded by an oncogene that drives increased cell proliferation through one of several mechanisms Constitutive expression of growth factors and their cognate growth factor receptors, setting up an autocrine cell signaling loop ■ Mutations in growth factor receptors, non-receptor tyrosine kinases, or downstream signaling molecules that lead to constitutive signaling, such as: ■ Activation of the EGF receptor tyrosine kinase by point mutations (lung cancer); activation of the HER2 receptor tyrosine kinase by gene amplification (breast cancer); activation of the JAK2 tyrosine kinase by point mutations (myeloproliferative disorders) Activation of the ABL nonreceptor tyrosine kinase by chromosomal translocation and creation of a BCR-ABL fusion gene (chronic myelogenous leukemia, acute lymphoblastic leukemia) ■ Activation of RAS by point mutations (many cancers) ■ Activation of the PI3K and BRAF serine/threonine kinases by point mutations (many cancers) ■ Increased expression of MYC, a master transcription factor that regulates genes needed for rapid cell growth by deregulation through chromosomal translocations (Burkitt lymphoma, other hematologic malignancies); gene amplification (neuroblastoma); increased activity of upstream signaling pathways (many cancers) ■ Mutations that increase the activity of cyclin-dependent kinase 4 (CDK4)/D cyclin complexes, which promote cell cycle progression

DNA microarray

RNA is extracted from tumor and normal tissue. cDNA synthesized from each preparation is labeled with fluorescent dyes (in the example shown, normal tissue cDNA is labeled with a green dye; tumor cDNA is labeled with a red dye). The array consists of a solid support in which DNA fragments from many thousands of genes are spotted. The labeled cDNAs from tumor and normal tissue are combined and hybridized to the genes contained in the array. Hybridization signals are detected using a confocal laser scanner and downloaded to a computer for analysis (red squares, expression of the gene is higher in tumor; green square, expression of the gene is higher in normal tissue; black squares, no difference in the expression of the gene between tumor and normal tissue). In the display, the horizontal rows correspond to each gene contained in the array; each ventrical row corresponds to single samples.

Paroxysmal nocturnal hemoglobinuria

Rare, acquired disorder, chronic intravascular hemolysis, intermittent hemoglobinuria (occurs during the night) acquired defect of red cell membrane Pathogenesis: acquired mutation in phosphatidylinositol glycan A gene (PIGA) an enzyme which is important for the production of certain cell surface proteins anchored by GPI linked proteins ....decay accelerating factor these are deficient due to gene mutation abnormal sensitivity of erythrocytes to "complement mediated hemolysis" 1) Decay accelerating factor (DAF) or CD55 normally DAF neutralizes complements that fixes onto red cells, neutrophils, and platelets loss of DAF leads to greater binding of complement to red cells complement activation follows: fall in pH, infections, surgery, strenuous exercise 2) Membrane inhibitor of reactive lysis or CD59 3) C8 binding protein results in intravascular hemolysis due to activation of the membrane attack complex: C5b-C9

Leukocytosis

Refers to an increase in the number of blood leukocytes

Warburg effect

Refers to glycolysis even in the presence of adequate oxygen (possibly, hypoxia followed by normoxia, as seen in tumors, select for tumor cells that constitutively upregulate glycolysis) Most tumors are PET-positive (patients are injected with 18F-fluorodeoxyglucose, a non-metabolizable derivative of glucose that is preferentially taken up into the "glucose hungry" tumor cells )

Hemolytic anemia

Results from an increase in the rate of red cell destruction premature destruction of red cells may be due to: Intrinsic abnormality of rbc Extrinsic abnormality of rbc Hemolytic anemias are classified as due to intrinsic causes due to extrinsic causes

RB gene and cell cycle

Role of RB as a cell-cycle regulator. Various growth factors promote the formation of the cyclin D-CDK4 complex. This complex (and to some extent cyclin E-CDK2) phosphorylates RB, changing it from an active (hypophosphorylated) to an inactive state (hyperphosphorylation). RB inactivation allows the cell to pass the G1/S restriction point. Growth inhibitors such as TGF-β and p53 and the Cip/Kip and INK4a (p16INK4a and p19ARF) cell-cycle inhibitors prevent RB activation. Transforming proteins of oncogenic viruses bind hypophosphorylated RB and cause its functional inactivation. Virtually all cancers show dysregulation of the cell cycle by affecting the four genes marked by an asterisk.

Functional and Positional Cloning

Schematic illustration of the strategies employed in functional and positional cloning. Functional cloning begins with relating the clinical phenotype to biochemical-protein abnormalities, followed by isolation of the mutant gene. Positional cloning, also called candidate gene approach, begins by mapping and cloning the disease gene by linkage analysis, without any knowledge of the gene product. Identification of the gene product and the mechanism by which it produces the disease follow the isolation of the mutant gene.

Graft Rejection

Schematic representation of the events that lead to the destruction of histoincompatible grafts. In the direct pathway, donor class I and class II antigens on antigen-presenting cells in the graft (along with B7 molecules, not shown) are recognized by CD8+ cytotoxic T cells and CD4+ helper T cells, respectively, of the host. CD4+ cells proliferate and produce cytokines that induce tissue damage by a local delayed hypersensitivity reaction and stimulate B cells and CD8+ T cells. CD8+ T cells responding to graft antigens differentiate into cytotoxic T lymphocytes that kill graft cells. In the indirect pathway, graft antigens are displayed by host APCs and activate CD4+ T cells, which damage the graft by a local delayed hypersensitivity reaction. The example shown is of a kidney allograft.

Pathways of spread

Seeding of body cavities and surfaces Lymphatic spread Hematogenous spread

Döhle bodies

Seen along with toxic granulations light blue smudge within mature neutrophils

Koilocytes

Seen in HPV. Dysplastic squamous cervical cells with nuclear enlargement and hyperchromasia

INK4a/ARF locus

Seen in several cancers: bladder, head & neck, cholangiocarcinoma mutations seen in 20% of familial melanomas (familial melanomas) note: dermis shows heavy infiltration by atypical appearing melanocytes

M protein detection

Serum protein electrophoresis (SP) is used to screen for a monoclonal immunoglobulin (M protein). Polyclonal IgG in normal serum (denoted by the arrow) appears as a broad band; in contrast, serum from a patient with multiple myeloma contains a single sharp protein band in this region of the electropherogram. The suspected monoclonal immunoglobulin is confirmed and characterized by immunofixation. In this procedure, proteins separated by electrophoresis within a gel are reacted with specific antisera. After extensive washing of the gel, only proteins that are cross-linked by antisera are retained. These are detected with a protein stain. Note the sharp band in the immunoglobulin region of the patient SP that is recognized by antisera against IgG heavy chain (G) and kappa light chain (κ), indicating the presence of a IgGκ M protein. Levels of polyclonal IgG, IgA (A), and lambda light chain (λ) are also decreased in the patient serum relative to normal, a common finding in multiple myeloma.

Anaplastic tumor

Shows poor differentiation and bears no semblance to parent tissue Characterized by: Pleomorphism: variation in size and shape of the cells / nuclei Abnormal nuclear morphology: hyperchromatism Hyperchromatism by itself is NOT a feature of malignancy. Hyperchromatism is seen in process of regeneration, hyperplasia & in Benign tumors. Altered N:C ratio, presence of nucleoli Appreciate the variation in size and shape of the nuclei. Numerous mitosis are abnormal (atypical, bizarre) Loss of polarity: orientation is disordered Other changes: tumor giant cells, ischemic necrosis

Leukemoid Reaction

Some inflammatory states or chronic infections, the total white cell count is elevated immature granulocytes appear in peripheral blood - which is similar to that seen in myelogenous leukemia (CML) 'band' neutrophils in peripheral smear Neutrophil metamyelocyte in peripheral smear

Immune Complex-Mediated Diseases

Sometimes called an antigen-antibody complex, is a molecule formed from the integral binding of an antibody to a soluble antigen. ... Such hypersensitivity progressing to disease states produces the immune complex diseases. Type III HS

Paraneoplastic syndromes

Symptom complexes in individuals with cancer that cannot be explained by tumor spread or release of hormones that are indigenous to the tumor "cell of origin." may be earliest indication of an occult neoplasm these may be the dominant clinical picture and may be lethal may mimic metastatic disease For example: ■ Endocrinopathies (Cushing syndrome, hypercalcemia) ■ Neuropathic syndromes (polymyopathy, peripheral neuropathies, neural degeneration, myasthenic syndromes) ■ Skin disorders (acanthosis nigricans) ■ Skeletal and joint abnormalities (hypertrophic osteoarthritis) ■ Hypercoagulability (migratory thrombophlebitis, disseminated intravascular coagulation, nonbacterial thrombotic endocarditis)

Mean Cell Hb Content (MCHC)

The average concentration of Hb in a given volume of Packed RBCs, expressed in gr/deciliter = Hgb/Hct = 32 to 36 grams/deciliter

Mean Cell Hemoglobin (MCH)

The average content (mass) of Hb per RBC (in picograms) = Hgb/RBC = 27 to 31 picograms/cell

Mean Cell Volume (MCV)

The average volume of an RBC, expressed in fentoliters=micrometer cubed= cubic micrometer, normal 80-96 fL)

p53 (guardian of the genome)

The central monitor of stress in the cell and can be activated by anoxia, inappropriate signaling by mutated oncoproteins, or DNA damage. p53 controls the expression and activity of proteins involved in cell cycle arrest, DNA repair, cellular senescence, and apoptosis. ■ DNA damage is sensed by complexes containing kinases of the ATM/ATR family; these kinases phosphorylate p53, liberating it from inhibitors such as MDM2. Active p53 then upregulates the expression of proteins such as the cyclind ependent kinase inhibitor p21, thereby causing cell-cycle arrest at the G1-S checkpoint. This pause allows cells to repair DNA damage. ■ If DNA damage cannot be repaired, p53 induces additional events that lead to cellular senescence or apoptosis. ■ The majority of human cancers demonstrate biallelic lossof-function mutations in TP53. Rare patients with Li-Fraumeni syndrome inherit one defective copy of TP53 and have a very high incidence of a wide variety of cancers. ■ Like RB, p53 is inactivated by viral oncoproteins, such as the E6 protein of HPV

Amyloidosis of the kidney

The glomerular architecture is almost totally obliterated by the massive accumulation of amyloid.

Biology of tumor growth

The left panel depicts minimal estimates of tumor cell doublings that precede the formation of a clinically detectable tumor mass. It is evident that by the time a solid tumor is detected, it has already completed a major portion of its life cycle as measured by cell doublings. The right panel illustrates clonal evolution of tumors and generation of tumor cell heterogeneity. New subclones arise from the descendants of the original transformed cell, and with progressive growth the tumor mass becomes enriched for those variants that are more adept at evading host defenses and are likely to be more aggressive.

Transferrin

The major function of transferrin is to transport iron to cells. Apotransferrin has two binding sites for ferric iron, however, usually only 1/3 of the available binding sites are occupied. It is important that iron be bound to transferrin because unbound iron is toxic (iron is an important catalyst of free radical reactions). Serum iron has a normal concentration of 60-150 mg/dL and largely reflects iron bound to transferrin. Total iron binding capacity (TIBC) is the sum of the unbound apotransferrin plus the iron bound transferrin and represents the maximum capacity for iron binding or 300- 360 mg/dL. The percent of transferrin saturated with ferric iron is the best indicator of storage iron as serum iron is nonspecific. Serum iron is a measure of the amount of iron bound to transferrin in the plasma

Classification of Amyloidosis

The type of the amyloid protein can be determined in various ways: the detection of abnormal proteins in the bloodstream (on protein electrophoresis or light chain determination); binding of particular antibodies to the amyloid found in the tissue (immunohistochemistry); or extraction of the protein and identification of its individual amino acids. Immunohistochemistry can identify AA amyloidosis the majority of the time, but can miss many cases of AL amyloidosis. Laser microdissection with mass spectrometry is the most reliable method of identifying the different forms of amyloidosis

Antibody Mediated Injury

Three major mechanisms of antibody-mediated injury. A, Opsonization of cells by antibodies and complement components and ingestion by phagocytes. B, Inflammation induced by antibody binding to Fc receptors of leukocytes and by complement breakdown products. C, Antireceptor antibodies disturb the normal function of receptors. In these examples, antibodies against the thyroid stimulating hormone (TSH) receptor activate thyroid cells in Graves disease, and acetylcholine (ACh) receptor antibodies impair neuromuscular transmission in myasthenia gravis.

Thrombin Time (TT)

Time for Thrombin To Convert Fibrinogen to Fibrin A Measure of Fibrinolytic Pathway NORMAL VALUE 9-13 SECS

Genetic Lesions in Cancer

Tumor cells may acquire several types of oncogenic mutations, including point mutations and other nonrandom chromosomal abnormalities, such as translocations, deletions, and gene amplifications. ■ Balanced translocations contribute to carcinogenesis by overexpression of oncogenes or generation of novel fusion proteins with altered signaling capacity. Deletions frequently cause loss of tumor suppressor gene function, and occasionally activate proto-oncogenes. Gene amplification generally increases the expression and function of oncogenes. ■ Genomic sequencing has revealed numerous "cryptic" (subcytogenetic) rearrangements, mainly small deletions and insertions ("indels"), as well as chromothrypsis, in which a chromosome is "shattered" and then reassembled in a haphazard way

Metastases

Tumor implants discontinuous with the primary tumor benign tumors never metastasize malignant tumors metastasize exceptions: gliomas, basal cell carcinomas (skin) Lung showing multiple metastatic tumor deposits from a primary breast carcinoma X-ray: "canon ball" appearance

Thymoma

Tumor of the thymus gland A, Benign thymoma (medullary type). The neoplastic epithelial cells are arranged in a swirling pattern and have bland, oval to elongated nuclei with inconspicuous nucleoli. Only a few small, reactive lymphoid cells are interspersed. B, Malignant thymoma, type I. The neoplastic epithelial cells are polygonal and have round to oval, bland nuclei with inconspicuous nucleoli. Numerous small, reactive lymphoid cells are interspersed. The morphologic appearance of this tumor is identical to that of benign thymomas of the cortical type. In this case, however, the tumor was locally aggressive, invading adjacent lung and pericardium.

Teratoma

Tumors representing more than one germ layer Mature teratoma (mature cystic teratoma, dermoid cyst) arising from ovary, partly cystic lesions containing hair, sebaceous material, cartilage, thyroid, etc. Immature teratoma (contains embryonal tissue)

Pathogenesis of Sickle cell anemia (HbS)

Two major pathological effects: distorted & rigid red cells block small blood vessels, impairing flow and producing ischemia repeated 'sickle-unsickle' cycles results in red cells that are more fragile which are then removed by the splenic macrophages When deoxygenated, HbS undergoes polymerization with continued deoxygenation, aggregated HbS molecules form needle like fibres within red cells producing distorted sickle cell or holly-leaf shaped structures -red cell containing large amounts of HbS begin to sickle at low oxygen tension this is seen in microcirculation sickling reduces the flow rate & red cells begin to stagnate this further reduces the oxygen tension, promoting sickling finally resulting in vessel blockage- ischemia (painful crisis)

Chronic Non-specific Lymphadenitis

Types: Follicular Hyperplasia (B Ly) Paracortical Hyperplasia (T) Sinus Histiocytosis (Mf)

Immune Thrombocytopenic Purpura (ITP)

Types: 1) Primary or Idiopathic Two clinical sub types: Acute or Chronic Acute is usually self-limiting, seen in children Chronic shows recurring bleeding over months & years 2) Secondary

Hodgkin lymphoma

Unusual tumor consisting mostly of reactive lymphocytes, macrophages, eosinophils, plasma cells and stromal cells mixed with rare tumor giant cells called Reed-Sternberg cells and variants Two broad types, classical (which has several subtypes) and lymphocyte predominant, which are distinguished based on morphologic and immunophenotypic grounds Reed-Sternberg cells of classical types make multiple cytokines and chemokines that influence the host response, and the host response in turn makes factors that support the growth of the tumor cells Classical forms are frequently associated with acquired mutations that activate the transcription factor NF-κB and with EBV infection Lymphocyte predominance type expresses B cell markers and is not associated with EBV Origin of RS cell - derived from germinal center / post germinal center B cells Classification: -Nodular sclerosis: "lacunar variant" -Mixed cellularity: classical RS Owl Eyes -Lymphocyte rich -Lymphocyte depletion -Lymphocyte predominant: Reed Sternberg: "popcorn cell variant" Incidence: - young adults, average age: 32 yrs bimodal distribution, rising through early life, peaking in 3rd decade declining until 45 yrs, again rising Etiology and pathogenesis: -RS cell is of transformed germinal center B cell origin in most cases -frequent presence of EBV in RS cells raises a possibility of viral induced transformation -RS cells produces cytokines, which creates a reactive response in the surrounding cells Immunophenotype: CD15, CD30 positive mostly involve lower cervical, supra clavicular and mediastinal lymph nodes

Burkitt Lymphoma

Very aggressive tumor of mature B cells that usually arises at extranodal sites. Three categories are present: 1. African (endemic) 2. Sporadic (non endemic) 3. Aggressive form associated with HIV Morphology: -involved tissues show diffuse infiltrate of intermediate-sized lymphoid cells -HIGH MITOTIC INDEX, extensive apoptotic cell death -benign macrophages are scattered within the tumor tissue forming, -numerous pale tingible body macrophages are evident, producing a "STARRY SKY" pattern Immunophenotype: mature B cell origin, expresses CD19, CD20, CD10 surface IgM, қ (kappa) or λ (lambda) light chains Cytogenetic and molecular genetics: -all forms of Burkitt's show translocation of C-MYC gene located on chromosome 8 -this translocation may be in association with t(8;14) or sometimes with t(2; 8), t(8; 22) -endemic cases, tumor cells are infected with EBV -about 25% cases of HIV associated tumors also show EBV

Classification of Immunohemolytic Anemias

Warm-antibody type Primary Secondary Cold-antibody type Primary chronic cold agglutinin disease Secondary cold agglutinin syndrome Associated with malignant disease Acute, infection-associated (acute cold antibody mediated AIHA complicating Mycoplasma pneumoniae or viral infections[11]) Paroxysmal cold hemoglobinuria Mixed cold- and warm-antibody type

Clinical course of Lymphoplasmacytic lymphoma

Weakness, weight loss, visual disturbances, hemostatic disturbance lymphadenopathy, hepatomegaly, splenomegaly, hyperviscosity Hyperviscosity syndrome: - visual impairment, neurologic problems, bleeding, Cryoglobulinemia (precipitation of macroglobulins at low temperatures leading to symptoms such as Raynaud's phenomenon) and cold urticaria

Acute Rejection

Weeks (before 15 days) Donor cells infiltrate host's epithelia, liver, bile duct , gut, lymphnode and dysfunction them. Infection - CMV Clinical: Jaundice, skin rash, bloody diarrhea, hepatomegaly heavy infiltration of lymphocytes in the host tissue.

Amyloidosis

a disorder characterized by the extracellular deposits of misfolded proteins that aggregate to form insoluble fibrils. ■ The deposition of these proteins may result from: excessive production of proteins that are prone to misfolding and aggregation; mutations that produce proteins that cannot fold properly and tend to aggregate; defective or incomplete proteolytic degradation of extracellular proteins. ■ Amyloidosis may be localized or systemic. It is seen in association with a variety of primary disorders, including monoclonal B-cell proliferations (in which the amyloid deposits consist of immunoglobulin light chains); chronic inflammatory diseases such as rheumatoid arthritis (deposits of amyloid A protein, derived from an acute-phase protein produced in inflammation); Alzheimer disease (amyloid b protein); familial conditions in which the amyloid deposits consist of mutants of normal proteins (e.g., transthyretin in familial amyloid polyneuropathies); amyloidosis associated with dialysis (deposits of β2-microglobulin, whose clearance is defective). ■ Amyloid deposits cause tissue injury and impair normal function by causing pressure on cells and tissues. They do not evoke an inflammatory response.

Reticulocytosis

normal: 0.2 to 2.0% Presence of nucleated red cells in peripheral blood smear Bone marrow hyperplasia (erythroid) Extra medullary hematopoiesis (liver, spleen, LN) Cholelithiasis (pigment gall stones) Skeletal abnormalities

Tumor suppressor genes

p53 (guardian of the genome) located on: chromosome 17 (17p13.1) more than 50% of tumors contain mutation of p53 gene p53 acts as a "gate keeper" prevents propagation of genetically damaged cells

Neutropenia

significant reduction of neutrophils Agranulocytosis: severe form of neutropenia or total absence of neutrophils Pathogenesis: 1) reduced or ineffective production of neutrophils (aplastic anemia, infiltrative marrow disease) 2) accelerated removal of neutrophils from circulating blood (SLE, drugs, splenic sequestration of neutrophils) Morphology: - bone marrow features vary according to the underlying causes hypercellular: i) increased neutrophilic destruction ii) ineffective granulopoiesis (megaloblastic anemia) Hypocellular: agranulocytosis

Chromosomal translocations in cancer

specific chromosomal abnormalities are present in leukemias and lymphomas Translocations: Burkitt lymphoma myc gene gets tranlocated from ch. 8 to ch. 14 (close to immunoglobulin heavy chain gene) Mantle cell lymphoma CYCLIN D1 gene on ch. 11 is overexpressed when translocated to ch. 14 Follicular lymphoma, translocation between ch. 14 and ch. 18 activates bcl-2 gene Chronic myeloid leukemia CML reciprocal translocation between ch. 9 (c-abl) and ch. 22 (bcr) Ewing Sarcoma EWSR11 gene at 22

Benign tumors

suffix 'oma' Mesenchymal tumors: fibroma, chondroma, osteoma Epithelial tumors: adenoma, papilloma, cystadenoma

Amyloid fibrils

β-pleated sheet structure and binding sites for the Congo red dye, which is used for diagnosis of amyloidosis. Structure of amyloid. A, Schematic diagram of an amyloid fiber showing fibrils (4 shown, may be up to 6) wound around one another with regularly spaced binding of the Congo red dye. B, Congo red staining shows an apple-green birefringence under polarized light, a diagnostic feature of amyloid. C, Electron micrograph of 7.5-10 nm amyloid fibrils.

Limitless Replicative Potential

■ A least some cells in all cancers must be stem cell-like; these cells are sometimes referred to as cancer stem cells. These may arise through transformation of a normal stem cell or through acquired genetic lesions that impart a stemlike state on a more mature cell. ■ Cancer cells acquire lesions that inactivate senescence signals and reactivate telomerase, which act together to convey limitless replicative potential. Replication of somatic cells, which do not express telomerase, leads to shortened telomeres. In the presence of competent checkpoints, cells undergo arrest and enter nonreplicative senescence. In the absence of checkpoints, DNA repair pathways are inappropriately activated, leading to the formation of dicentric chromosomes. At mitosis, the dicentric chromosomes are pulled apart, generating random double-stranded breaks, which then activate DNA repair pathways, leading to the random association of double-stranded ends and the formation, again, of dicentric chromosomes. Cells undergo numerous rounds of this bridge-fusion-breakage cycle, which generates massive chromosomal instability and numerous mutations. If cells fail to re-express telomerase, they eventually undergo mitotic catastrophe and death. Re-expression of telomerase allows the cells to escape the bridge-fusion-breakage cycle, thus promoting their survival and tumorigenesis.

Invasion and Metastasis

■ Ability to invade tissues, a hallmark of malignancy, occurs in four steps: loosening of cell-cell contacts, degradation of ECM, attachment to novel ECM components, and migration of tumor cells. ■ Cell-cell contacts are lost by the inactivation of E-cadherin through a variety of pathways. ■ Basement membranes and interstitial matrix degradation is mediated by proteolytic enzymes secreted by tumor cells and stromal cells, such as matrix metalloproteases and cathepsins. ■ Proteolytic enzymes also release growth factors sequestered in the ECM and generate chemotactic and angiogenic fragments from cleavage of ECM glycoproteins. ■ The metastatic site of many tumors can be predicted by the location of the primary tumor. Many tumors arrest in the first capillary bed they encounter (lung and liver, most commonly). ■ Some tumors show organ tropism, probably due to expression of adhesion or chemokine receptors whose ligands are expressed by endothelial cells the metastatic site. ■ Genes that promote epithelial-mesenchymal transitions, like TWIST and SNAIL, may be important metastasis genes in epithelial tumors

Pathogenesis of Diseases Caused by Antibodies and Immune Complexes

■ Antibodies can coat (opsonize) cells, with or without complement proteins, and target these cells for phagocytosis by phagocytes (macrophages), which express receptors for the Fc tails of lgG and for complement proteins. The result is depletion of the opsonized cells. ■ Antibodies and immune complexes may deposit in tissues or blood vessels, and elicit an acute inflammatory reaction by activating complement, with release of breakdown products, or by engaging Fc receptors of leukocytes. The inflammatory reaction causes tissue injury. ■ Antibodies can bind to cell surface receptors or other essential molecules and cause functional derangements (either inhibition or unregulated activation) without cell injury.

Evasion of Apoptosis

■ Apoptosis can be initiated through intrinsic or extrinsic pathways, both of which result in the activation of a proteolytic cascade of caspases that destroys the cell. ■ Abnormalities of both pathways are found in cancer cells, but lesions that incapacitate the intrinsic (mitochondrial) pathway appear to be most common. ■ In greater than 85% of follicular B-cell lymphomas, the anti-apoptotic gene BCL2 is overexpressed due to a (14;18) translocation. ■ Overexpression of other BCL2 family members such as MCL-1 is also linked to cancer cell survival and drug resistance.

Transmission Patterns of Single-Gene Disorders

■ Autosomal dominant disorders are characterized by expression in heterozygous state; they affect males and females equally, and both sexes can transmit the disorder. ■ Enzyme proteins are not affected in autosomal dominant disorders; instead, receptors and structural proteins are involved. ■ Autosomal recessive diseases occur when both copies of a gene are mutated; enzyme proteins are frequently involved. Males and females are affected equally. ■ X-linked disorders are transmitted by heterozygous females to their sons, who manifest the disease. Female carriers usually are protected because of random inactivation of one X chromosome.

Mechanisms of T Cell-Mediated Hypersensitivity Reactions

■ Cytokine-mediated inflammation: CD4+ T cells are activated by exposure to a protein antigen and differentiate into TH1 and TH17 effector cells. Subsequent exposure to the antigen results in the secretion of cytokines. IFN-γ activates macrophages to produce substances that cause tissue damage and promote fibrosis, and IL-17 and other cytokines recruit leukocytes, thus promoting inflammation. ■ The classical T cell-mediated inflammatory reaction is delayed type hypersensitivity. ■ T cell-mediated cytotoxicity: CD8+ cytotoxic T lymphocytes (CTLs) specific for an antigen recognize cells expressing the target antigen and kill these cells. CD8+ T cells also secrete IFN-γ.

Radiation Carcinogenesis

■ Ionizing radiation causes chromosome breakage, translocations, and, less frequently, point mutations, leading to genetic damage and carcinogenesis. ■ UV rays induce the formation of pyrimidine dimers within DNA, leading to mutations. Therefore, UV rays can give rise to squamous cell carcinomas and melanomas of the skin. Individuals with defects in the repair of pyrimidine dimers suffer from Xeroderma pigmentosa and are at particularly high risk. ■ Exposure to radiation during imaging procedures such as CT scans is linked to a very small, but measurable, increase in cancer risk in children.

Genomic Instability as Enabler of Malignancy

■ Persons with inherited mutations of genes involved in DNA repair systems are at greatly increased risk for the development of cancer. ■ Patients with HNPCC syndrome have defects in the mismatch repair system, leading to development of carcinomas of the colon. These patients' genomes show microsatellite instability, characterized by changes in length of short repeats throughout the genome. ■ Patients with xeroderma pigmentosum have a defect in the nucleotide excision repair pathway and are at increased risk for the development of cancers of the skin exposed to UV light, because of an inability to repair pyrimidine dimers. ■ Syndromes involving defects in the homologous recombination DNA repair system constitute a group of disorders— Bloom syndrome, ataxia-telangiectasia, and Fanconi anemia—that are characterized by hypersensitivity to DNA-damaging agents, such as ionizing radiation. BRCA1 and BRCA2, which are mutated in familial breast cancers, are involved in DNA repair. ■ Mutations incurred in lymphoid cells due to expression of gene products that induce genomic instability (RAG1, RAG2, AID) are important causes of lymphoid neoplasms.

Laboratory Diagnosis of Cancer

■ Several sampling approaches exist for the diagnosis of tumors, including excision, biopsy, fine-needle aspiration, and cytologic smears. ■ Immunohistochemistry and low cytometry studies help in the diagnosis and classification of tumors, because distinct protein expression patterns define different entities. ■ Molecular analyses are used to determine diagnosis, prognosis, the detection of minimal residual disease, and the diagnosis of hereditary predisposition to cancer. ■ Molecular profiling of tumors by RNA expression profiling, DNA sequencing, and DNA copy number arrays are useful in molecular stratiifcation of otherwise identical tumors or those of distinct histogenesis that share a mutation for the purpose of targeted treatment and prognostication. ■ Proteins released by tumors into the serum, such as PSA, can be used to screen populations for cancer and to monitor for recurrence after treatment. ■ Assays of circulating tumor cells and of DNA shed into blood, stool, sputum, and urine are under development.

Immunity

■ The early reaction to microbes is mediated by the mechanisms of innate immunity, which are ready to respond to microbes. These mechanisms include epithelial barriers, phagocytes, NK cells, and plasma proteins, for example, of the complement system. The reaction of innate immunity is often manifested as inflammation. Innate immunity, unlike adaptive immunity, does not have fine antigen specificity or memory. ■ The defense reactions of adaptive immunity develop slowly, but are more potent and specialized. ■ Microbes and other foreign antigens are captured by dendritic cells and transported to lymph nodes, where the antigens are recognized by naïve lymphocytes. The lymphocytes are activated to proliferate and differentiate into effector and memory cells. ■ Cell-mediated immunity is the reaction of T lymphocytes, designed to combat cell-associated microbes (e.g., phagocytozed microbes and microbes in the cytoplasm of infected cells). Humoral immunity is mediated by antibodies and is effective against extracellular microbes (in the circulation and mucosal lumens). ■ CD4+ helper T cells help B cells to make antibodies, activate macrophages to destroy ingested microbes, stimulate recruitment of leukocytes, and regulate all immune responses to protein antigens. The functions of CD4+ T cells are mediated by secreted proteins called cytokines. CD8+ cytotoxic T lymphocytes kill cells that express antigens in the cytoplasm that are seen as foreign (e.g., virus-infected and tumor cells) and can also produce cytokines. ■ Antibodies secreted by plasma cells neutralize microbes and block their infectivity, and promote the phagocytosis and destruction of pathogens. Antibodies also confer passive immunity to neonates.

Epidemiology of Neoplasia

■ The incidence of cancer varies with geography, age, race, and genetic background. Cancers are most common in adults older than 60 years of age, but occurs in adults at all ages and in children and infants. The geographic variation is thought to mainly stem from different environmental exposures. ■ Important environmental factors implicated in carcinogenesis include infectious agents, smoking, alcohol, diet, obesity, reproductive history, and exposure to environmental carcinogens. ■ The risk of cancer is increased by reparative proliferations caused by chronic inflammation or tissue injury, certain forms of hyperplasia, and immunodeficiency. ■ Interactions between environmental factors and genetic factors may be important determinants of cancer risk Cancer incidence: Men: carcinoma prostate, lung and colon Women: carcinoma breast, lung and colon Geographic and environmental factors: - carcinoma stomach incidence is highest in Japan (7 to 8 times than in US) -carcinoma lung is more in US than in Japan -melanoma is highest in New Zealand

Normal Immune Response

■ The innate immune system uses several families of receptors, notably the Toll-like receptors, to recognize molecules present in various types of microbes and produced by damaged cells. ■ Lymphocytes are the mediators of adaptive immunity and the only cells that produce specific and diverse receptors for antigens. ■ T (thymus-derived) lymphocytes express antigen receptors called T cell receptors (TCRs) that recognize peptide fragments of protein antigens that are displayed by MHC molecules on the surface of antigen-presenting cells. ■ B (bone marrow-derived) lymphocytes express membrane bound antibodies that recognize a wide variety of antigens. B cells are activated to become plasma cells, which secrete antibodies. ■ Natural killer (NK) cells kill cells that are infected by some microbes, or are stressed and damaged beyond repair. NK cells express inhibitory receptors that recognize MHC molecules that are normally expressed on healthy cells, and are thus prevented from killing normal cells. ■ Antigen-presenting cells (APCs) capture microbes and other antigens, transport them to lymphoid organs, and display them for recognition by lymphocytes. The most efficient APCs are dendritic cells, which live in epithelia and most tissues. ■ The cells of the immune system are organized in tissues, some of which are the sites of production of mature lymphocytes (the generative lymphoid organs, the bone marrow and thymus), and others are the sites of immune responses (the peripheral lymphoid organs, including lymph nodes, spleen, and mucosal lymphoid tissues)

Recognition and Rejection of Transplants (Allografts)

■ The rejection response against solid organ transplants is initiated mainly by host T cells that recognize the foreign HLA antigens of the graft, either directly (on APCs in the graft) or indirectly (after uptake and presentation by host APCs). ■ Types and mechanisms of rejection of solid organ grafts: ■ Hyperacute rejection. Preformed antidonor antibodies bind to graft endothelium immediately after transplantation, leading to thrombosis, ischemic damage, and rapid graft failure. ■ Acute cellular rejection. T cells destroy graft parenchyma (and vessels) by cytotoxicity and inflammatory reactions. ■ Acute humoral rejection. Antibodies damage graft vasculature. ■ Chronic rejection. Dominated by arteriosclerosis, this type is caused by T-cell activation and antibodies. The T-cells may secrete cytokines that induce proliferation of vascular smooth muscle cells, and the antibodies cause endothelial injury. The vascular lesions and T-cell reactions cause parenchymal fibrosis. ■ Treatment of graft rejection relies on immunosuppressive drugs, which inhibit immune responses against the graft. ■ Transplantation of hematopoietic stem cells (HSCs) requires careful matching of donor and recipient and is often complicated by graft-vs-host diseases (GVHD) and immune deficiency

Primary (Inherited) Immune Deficiency Diseases

■ These diseases are caused by inherited mutations in genes involved in lymphocyte maturation or function, or in innate immunity. ■ Deficiencies in innate immunity include defects of phagocyte function, complement, and innate immune receptors. ■ Some of the common disorders affecting lymphocytes and the adaptive immune response are: ■ X-SCID: failure of T-cell and B-cell maturation; mutation in the common γ chain of a cytokine receptor, leading to failure of IL-7 signaling and defective lymphopoiesis ■ Autosomal recessive SCID: failure of T-cell development, secondary defect in antibody responses; approximately 50% of cases caused by mutation in the gene encoding ADA, leading to accumulation of toxic metabolites during lymphocyte maturation and proliferation ■ X-linked agammaglubulinemia (XLA): failure of B-cell maturation, absence of antibodies; caused by mutations in the BTK gene, which encodes B-cell tyrosine kinase, required for maturation signals from the pre-B cell and B-cell receptors ■ Common variable immunodeiciency: defects in antibody production; cause unknown in most cases ■ Selective IgA deiciency: failure of IgA production; cause unknown ■ X-linked hyper-IgM syndrome: failure to produce isotype-switched high-afinity antibodies (IgG, IgA, IgE); mutation in gene encoding CD40L ■ X-linked lymphoproliferative disease (XLP): defect in a signaling molecule causing defective responses against Epstein-Barr virus and lymphoproliferation ■ These diseases present clinically with increased susceptibility to infections in early life

Immunologic Tolerance

■ Tolerance (unresponsiveness) to self antigens is a fundamental property of the immune system, and breakdown of tolerance is the basis of autoimmune diseases. ■ Central tolerance: immature lymphocytes that recognize self antigens in the central (generative) lymphoid organs are killed by apoptosis; in the B-cell lineage, some of the self-reactive lymphocytes switch to new antigen receptors that are not self-reactive. ■ Peripheral tolerance: mature lymphocytes that recognize self antigens in peripheral tissues become functionally inactive (anergic), or are suppressed by regulatory T lymphocytes, or die by apoptosis. ■ The factors that lead to a failure of self-tolerance and the development of autoimmunity include (1) inheritance of susceptibility genes that may disrupt different tolerance pathways, and (2) infections and tissue injury that may expose self antigens and activate APCs and lymphocytes in the tissues.

Evasion of Immune Surveillance

■ Tumor cells can be recognized by the immune system as non-self and destroyed. ■ Antitumor activity is mediated by predominantly cellmediated mechanisms. Tumor antigens are presented on the cell surface by MHC class I molecules and are recognized by CD8+ CTLs. ■ The different classes of tumor antigens include products of mutated proto-oncogenes, tumor suppressor genes, overexpressed or aberrantly expressed proteins, tumor antigens produced by oncogenic viruses, oncofetal antigens, altered glycolipids and glycoproteins, and cell typespeciic differentiation antigens. ■ Immunosuppressed patients have an increased risk for development of cancer, particularly types caused by oncogenic DNA viruses. ■ In immunocompetent patients, tumors may avoid the immune system by several mechanisms, including selective outgrowth of antigen-negative variants, loss or reduced expression of histocompatibility antigens, and immunosuppression mediated by expression of certain factors (e.g., TGF-β, PD-1 ligand, galectins) by the tumor cells. ■ Antibodies that overcome these mechanisms of immune evasion are showing promise in clinical trials conducted in patients with advanced cancer.

Angiogenesis

■ Vascularization of tumors is essential for their growth and is controlled by the balance between angiogenic and antiangiogenic factors that are produced by tumor and stromal cells. ■ Hypoxia triggers angiogenesis through the actions of HIF- 1α on the transcription of the proangiogenic factor VEGF. ■ Many other factors regulate angiogenesis; for example, p53 induces synthesis of the angiogenesis inhibitor thombospondin-1, while RAS, MYC, and MAPK signaling all upregulate VEGF expression and stimulate angiogenesis. ■ VEGF inhibitors are used to treat a number of advanced cancers and prolong the clinical course, but are not curative.

Pathogenesis and Course of HIV Infection and AIDS

■ Virus entry into cells: requires CD4 and co-receptors, which are receptors for chemokines; involves binding of viral gp120 and fusion with the cell mediated by viral gp41 protein; main cellular targets are CD4+ helper T cells, macrophages, and DCs ■ Viral replication: provirus genome integrates into host cell DNA; viral gene expression is triggered by stimuli that activate infected cells (e.g., infectious microbes, cytokines produced during normal immune responses) ■ Progression of infection: acute infection of mucosal T cells and DCs; viremia with dissemination of virus; latent infection of cells in lymphoid tissue; continuing viral replication and progressive loss of CD4+ T cells ■ Mechanisms of immune deficiency: ■ Loss of CD4+ T cells: T-cell death during viral replication and budding (similar to other cytopathic infections); apoptosis as a result of chronic stimulation; decreased thymic output; functional defects ■ Defective macrophage and DC functions ■ Destruction of architecture of lymphoid tissues (late) ■ Clinical manifestations of AIDS include opportunistic infections, tumors such as B-cell lymphomas, and CNS abnormalities.