Pathology Supplement Handout Nov 2018

TOPNOTCH MEDICAL BOARD PREP PATHO SUPPLEMENT HANDOUT by KEVIN ELOMINA, MD For inquiries visit www.topnotchboardprep.com.ph or https://www.facebook.com/topnotchmedicalboardprep/ PLEASE READ BEFORE PROCEEDING In response to the trend of the Pathology board examinations, wherein the examinations test the student's ability to diagnose different diseases through case-based questions, the "Patho Supertable" has now been redesigned and renamed into "Patho Supplement Handout" that focuses on how to diagnose certain diseases, based on clinical clues and morphologic findings; the said change is most evident in the systemic pathology part. Because the handout has changed its focus and its utility, it cannot be used as an alternative to the main handout. You can consider this as a study outline or guide--that if a concept or a disease appears here, then you should study that disease in detail; because the exam might ask for concepts related to that disease. The supplement handout provides an avenue for you to apply the concepts in the main handout, by diagnosing cases. Even if the type of exam changes, your skill in diagnosing cases would be very important in conquering any examination in medicine. :) To the one who uses this, I hope that you will become a great physician, and become an agent of positive change in this world. You are always in my prayers. Good luck! :) Kevin A. Elomina, MD Pathology Resident, Mentor, and Instructor Facebook: Kevin Elomina Instagram: @keielomina

PATHO SUPPLEMENT HANDOUT PART I: GENERAL PATHOLOGY 1. CELLULAR RESPONSES TO STRESS QUESTION CELLULAR ADAPTATION Increase in SIZE of cells resulting in increased size of organ; cellular adaptation of non-dividing cells e.g. myocardial fibers Increase in NUMBER of cells REDUCTION in cell SIZE and NUMBER resulting in decreased size of organ A REVERSIBLE change wherein one differentiated cell type is replaced by another cell type PRACTICE CASES 55/M, with long-standing history of hypertension, eventually expired from myocardial infarction. Autopsy: increased thickness of the left ventricular wall with large areas of fibrotic scars. What is the diagnosis, and what cellular adaptation is seen in this case? 47 G0, with granulosa cell tumor, presented with menorrhagia. UTZ showed thickened endometrium. Patient underwent diagnostic curettage. Biopsy showed back-to-back endometrial glands with nuclear atypia. What is the diagnosis (for the endometrium), and what cellular adaptation is seen in this case? 35/M, with history of poliomyelitis, presented with disproportionately thinner right lower extremity. Muscle biopsy showed decrease in size of skeletal myocytes. What is the cellular adaptation seen in this case? 39/F, with long-standing history of heartburn and water brash. Endoscopy showed multiple pinkishtan areas at the GEJ. Biopsy showed fragments with simple columnar epithelium with goblet cells. What is the diagnosis, and what specific cellular adaptation is seen in this case? FORMS OF REVERSIBLE CELL INJURY The first manifestation of almost all forms of injury to cells; change is due to influx of ions (and consequently, water) due to failure of energydependent ion pumps (Na+-K+-ATPase) Appearance of lipid vacuoles in the cytoplasm; often seen in cells participating in fat metabolism (liver, heart) TYPES OF CELL DEATH Type of cell death that results from a pathologic cell injury Type of cell death that is energy-dependent, tightly regulated, and associated with normal cellular functions; often physiologic; "programmed cell death"

ANSWER Hypertrophy Hyperplasia Atrophy Metaplasia

Myocardial infarction; Left ventricular hypertrophy; Pathologic hypertrophy Complex atypical hyperplasia; Pathologic hyperplasia Denervation atrophy; Pathologic atrophy Barrett esophagus; Intestinal metaplasia

Cellular swelling Steatosis

Necrosis Apoptosis

Features Cell size Nucleus

Necrosis Enlarged (swelling) Pyknosis à Karyorrhexis à Karyolysis

Plasma membrane

Disrupted

Apoptosis Reduced (shrinkage) Fragmentation into nucleosome-sized fragments Intact; altered structure, especially orientation of lipids Intact; maybe released in apoptotic bodies No

Cellular Enzymatic digestion; may contents leak out of cell Adjacent Frequent inflammation Physiologic or Invariably pathologic Often physiologic; may be pathologic role pathologic FORMS OF NECROSIS Component cells are dead but the basic tissue Coagulative architecture is PRESERVED ("acidophilic necrosis tombstone"); often seen in ischemic injury to most solid organs (heart, spleen, kidney) EXCEPT the brain Digestion of dead cells, resulting in transformation of Liquefactive the tissue into a viscous liquid mass; often seen in necrosis infections (pus) and in hypoxic death of cells within the CNS The term reserved for ischemic coagulative necrosis Gangrenous of the limbs (dry); may have superimposed bacterial necrosis infection with liquefactive necrosis (wet) Cheese-like gross appearance of necrotic areas; often Caseous seen in tuberculous infections; tissue architecture is necrosis NOT PRESERVED Focal areas of fat destruction, typically seen in acute Enzymatic fat pancreatitis; foci of necrosis contain shadowy necrosis outlines of necrotic fat cells with basophilic calcium deposits (saponification), surrounded by an inflammatory reaction Seen in immune reactions involving blood vessels; Fibrinoid deposits of immune complexes, together with fibrin necrosis that have leaked out of vessels, result in a bright pink and amorphous appearance TYPES OF APOPTOSIS (INIATOR PATHWAYS) Inactivation of anti-apoptotic BCL2 protein that Intrinsic leads to activation of BAX/BAK channel, allowing (mitochondrial) cytochrome c to leak out of the mitochondria, pathway activating apoptosis Activation of "death receptors" by appropriate Extrinsic (Death ligands that leads to activation of apoptosis receptor) pathway TYPES OF CALCIFICATIONS Calcium deposition occurring in dead tissues, in the Dystrophic absence of calcium metabolic derangements; calcification examples: Psammoma bodies in cancers with papillary architecture, and meningioma Calcium deposition in normal tissues occurring in Metastatic the setting of hypercalcemia; example: Calcinosis calcification

2. INFLAMMATION AND REPAIR QUESTION GENERAL CONCEPTS Response of vascularized tissues to infections and damaged tissues that brings cells and molecules of host defense from the circulation to the sites where they are needed, in order to eliminate the offending agent The initial response to infections and tissue damage

ANSWER Inflammation

Acute inflammation Chronic inflammation

Inflammatory response of prolonged duration in which inflammation, tissue injury, and attempts at repair coexist, in varying combinations Restoration of tissue architecture and function after Tissue repair and injury GENERAL TYPES OF INFLAMMATION Feature Acute Chronic Onset Fast: minutes or hours Slow; days Cellular infiltrate Mainly neutrophils Monocytes/macropha ges and lymphocytes Tissue injury, Usually mild and selfOften severe and fibrosis limited progressive Local and systemic Prominent Less signs

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TOPNOTCH MEDICAL BOARD PREP PATHO SUPPLEMENT HANDOUT by KEVIN ELOMINA, MD For inquiries visit www.topnotchboardprep.com.ph or https://www.facebook.com/topnotchmedicalboardprep/ ACUTE INFLAMMATION Components of acute inflammation

Initial vascular response to injury Most notable mediator that produces vasodilation; stored in mast cells, platelets, and basophils Most common mechanism of increased microvascular permeability in acute inflammation Morphologic hallmarks of acute inflammation Outcomes of acute inflammation

RECRUITMENT OF LEUKOCYTES Steps in leukocyte recruitment

1. Dilation of small vessels 2. Increased microvascular permeability 3. Emigration of leukocytes and their activation Vasoconstriction Histamine Endothelial cell contraction 1. Vasodilation 2. Accumulation of leukocytes and fluid in the extravascular tissue 1. Resolution 2. Pus formation (abscess) 3. Healing by fibrosis 4. Progression to chronic inflammation A. Margination B. Rolling C. Adhesion D. Transmigration E. Chemotaxis Margination

The process of leukocyte accumulation at the periphery of blood vessels Transient binding and detachment of Rolling leukocytes to the endothelium, mediated by selectins Firm adhesion of leukocytes to the endothelium, Adhesion mediated by integrins The process of migration of the leukocytes Transmigration or through the endothelium, mediated by PECAMDiapedesis 1/CD31 Process of leukocyte migration toward sites of Chemotaxis infection or injury along a chemical gradient, mediated by exogenous or endogenous substances MEDIATORS OF INFLAMMATION Type of inflammatory mediators that are Cell-derived normally sequestered in intracellular granules, mediators and can be rapidly secreted by granule exocytosis, or are synthesized de novo in response to a stimulus; examples: Histamine, Serotonin, Cytokines, and Arachidonic acid derivatives (Prostaglandins and Leukotrienes) Type of inflammatory mediators that are Plasma-derived produced mainly in the liver, and are present in mediators the circulation as inactive precursors that must be activated by proteolytic cleavage to acquire their biologic properties; examples: Complement, Coagulation, and Kinin systems Vasoactive amine found in platelets and Serotonin neuroendocrine cells; causes vasoconstriction ARACHIDONIC ACID METABOLITES Action Eicosanoids Vasodilation PGI2 (Prostacyclin), PGE1, PGE2, PGD2 Vasoconstriction TXA2, LTC4, D4, E4 Increased vascular LTC4, D4, E4 permeability Chemotaxis, LTB4, Hydroxyeicosatetraenoic acid (HETE) leukocyte adhesion COMPLEMENT SYSTEM Most abundant complement C3 Complement that acts as an opsonin C3b Anaphylatoxins C3a, C4a, C5a Membrane attack complex C5b, C6-C9 Common complement deficiencies Deficiency of the following complementC1 inhibitor deficiency related protein causes hereditary angioedema Deficiency of the following complement C3 protein increases susceptibility to infections involving pyogenic bacteria Deficiency of the following complement C1q, C2 and C4 proteins increases susceptibility to immune complex-mediated disease Deficiency of the following complement C5-C9 proteins increases susceptibility to Neisseria infections

CHRONIC INFLAMMATION Main cells involved in chronic inflammation Collections of activated macrophages; some of which form multinucleated giant cells, often with T lymphocytes, and sometimes associated with central necrosis Two kinds of cells seen in granulomas Precursor cell of epithelioid cells and giant cells REPAIR Type of tissue whose cells can readily regenerate as long as the pool of stem cells is preserved; examples: Bone Marrow and Vaginal Epithelium Type of tissue whose cells are quiescent and have only minimal replicative activity in their normal state; capable of proliferating in response to injury or loss of tissue mass; examples: Smooth muscles, Endothelium, and Liver Parenchyma Type of tissue whose cells are considered to be terminally differentiated and are nonproliferative in postnatal life; examples: Neurons and Cardiac muscle Type of repair that happens in labile and stable tissues; influenced by growth factors Type of repair that happens in chronic, severe inflammation, and in permanent tissues Steps in healing by connective tissue deposition

Most notable growth factor in angiogenesis Most important cytokine for synthesis and deposition of connective tissue Hallmark of repair Components of granulation tissue

1. Macrophages 2. Lymphocytes Granuloma

1. Epithelioid cells 2. Giant cells Macrophages

Labile tissues

Stable tissues

Permanent tissues

Regeneration Connective tissue deposition A. Angiogenesis B. Formation of granulation tissue C. Remodeling of the scar VEGF TGF-β Granulation tissue 1. Proliferation of fibroblasts 2. Loose connective tissue 3. Angiogenesis 4. Inflammatory cells



3. HEMODYNAMIC DISORDERS QUESTION GENERAL CONCEPTS Accumulation of fluid in tissues or body cavities Increased blood volume within tissues Pathologic counterpart of hemostasis A detached intravascular solid, liquid, or gaseous mass that is carried by the blood from its point of origin to a distant site, where it often causes tissue dysfunction or infarction Area of ischemic necrosis caused by occlusion of either the arterial supply or the venous drainage State in which diminished cardiac output or reduced effective circulating blood volume impairs tissue perfusion and leads to cellular hypoxia

ANSWER Edema (tissues) and effusion (body cavities) Hyperemia and congestion Thrombosis Embolus

Infarct Shock

EDEMA AND EFFUSION Four main mechanisms 1. Increased hydrostatic pressure of edema formation 2. Decreased oncotic pressure 3. Increased vascular permeability 4. Lymphatic obstruction General morphologic 1. Clearing and separation of ECM appearance of edema 2. Subtle cell swelling PRACTICE CASES 58/M, with history of MI, presented with Congestive heart paroxysmal nocturnal dyspnea and failure; Increased orthopnea. CXR showed bilateral pleural hydrostatic effusion. What is the diagnosis, the mechanism pressure; of edema in this case, and the kind of effusion? Transudate 32/M, with history of remittent fever and Parapneumonic productive cough, developed dyspnea. CXR effusion; CAP MR; showed right pleural effusion with left Increased vascular parenchymal infiltrates. What is the permeability; mechanism of edema in this case, and what is Exudate the kind of effusion?

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TOPNOTCH MEDICAL BOARD PREP PATHO SUPPLEMENT HANDOUT by KEVIN ELOMINA, MD For inquiries visit www.topnotchboardprep.com.ph or https://www.facebook.com/topnotchmedicalboardprep/ 57/M, chronic alcoholic, presented with Decreased oncotic increase in abdominal girth. Chemistry pressure showed low serum albumin and elevated ALT and AST. Abdominal UTZ showed moderate ascites. What is the mechanism of edema in this case? 34/F, known case of breast cancer stage 2 Lymphatic (T2N0M0), s/p MRM, left, developed left arm obstruction swelling. What is the mechanism of edema in this case? TYPES OF EFFUSIONS Parameter Transudate Exudate Pathophysiology Abnormalities in Increased vascular Starling forces permeability Vascular permeability Normal Increased Plasma protein leak Absent Present Protein content of Low High fluid Specific gravity < 1.012 > 1.012 Fibrin Absent Present Inflammatory cells Absent Present HYPEREMIA AND CONGESTION It is an active process resulting from augmented blood Hyperemia flow due to arteriolar dilation or increased oxygen demand; affected tissue is redder than normal, because of engorgement with oxygenated blood It is a passive process resulting from impaired venous Congestion return out of a tissue; tissue has a blue-red color due to accumulation of deoxygenated blood in the affected tissue PRACTICE CASES 24/M, with a large left atrial myxoma that obstructed Acute flow of blood into the left atrium, subsequently died. pulmonary Autopsy of the lung showed engorged alveolar congestion capillaries, alveolar septal edema, and focal intraalveolar hemorrhage. What is the diagnosis? 34/F, died from acute right-sided heart failure Acute secondary to saddle embolus. Autopsy of the liver hepatic showed distended central vein and sinusoids, congestion centrilobular ischemic necrosis, and periportal fatty change. What is the diagnosis? 55/M, died of complications from congestive heart Chronic failure. Autopsy of the lung showed thickened and passive fibrotic alveolar septa, and hemosiderin-laden congestion, macrophages. What is the diagnosis? lung 60/M, died of complications from heart failure. On Chronic autopsy, liver is heavier than normal and has a nutmegpassive like appearance. Sections show centrilobular congestion, hemorrhage, hemosiderin-laden macrophages, and liver hepatocyte loss of variable degrees. What is the diagnosis? THROMBOSIS Components of Virchow triad Endothelial injury, (abnormalities that lead to thrombus Stasis, formation) Hypercoagulability It is a major contributor to the development Turbulence or of arterial thrombi endothelial injury It is a major contributor to the development Stasis of venous thrombi Any alteration of the coagulation pathway Hypercoagulability that predisposes to thrombosis; can be primary (e.g. Factor V Leiden, Protein C and S deficiency) or secondary (e.g. Cancer, atrial fibrillation, and prolonged immobilization) Laminations composed of pale platelet and Lines of Zahn fibrin deposits alternating with darker red cell-rich layers; signify formation of thrombus in flowing blood; present in antemortem thrombosis Most common site of arterial thrombosis Coronary > cerebral > femoral Most common site of venous thrombosis Superficial or deep veins of the leg Note: Thrombi in superficial leg veins rarely embolize, while thrombi in deep leg veins are the most common sources of venous emboli

Dissolution Organization and recanalization

Rapid shrinkage and total disappearance of recent thrombi Thrombi becomes incorporated in the vessel wall with formation of new capillary channels that restore blood flow

EMBOLISM Most common and most dreaded sequela of deep Pulmonary venous thrombosis embolism Embolus occluding the bifurcation of the pulmonary Saddle trunk; associated with sudden death due to acute rightembolus sided heart failure PRACTICE CASES 65/F, known case of DVT, came from a 17-hour Pulmonary flight, developed respiratory distress with right embolism ventricular wall dysfunction on 2D-Echo. What is the diagnosis? 45/F, known case of thyrotoxic heart disease Systemic and chronic atrial fibrillation, developed thromboembolism sudden left-sided weakness and loss of (from mural sensation. What is the type of embolism thrombus) observed in the patient? 38/M, known case of Non-Hodgkin lymphoma, Paradoxical developed sudden right-sided weakness. Patient embolism (Cardiac has had a recent admission for a month, and has pathology is PFO) a history of a cardiac pathology that the cardiologist deemed benign. What is the phenomenon observed in the patient? 32/M, involved in a motorcycle accident, and Fat embolism sustained a mid-shaft right femoral fracture, without any blunt or penetrating head and chest trauma. Patient developed progressive respiratory distress, and died. Autopsy showed fat globules in pulmonary vasculature. What is the diagnosis? 25 G1P1(1001) developed respiratory distress, Amniotic fluid seizures, and refractory bleeding post-partum, embolism and died. Autopsy showed fetal skin and lanugo in pulmonary vasculature. What is the diagnosis? 30/M, diver, developed respiratory distress and Air embolism joint pain after rapid ascent. Work-up showed (Decompression gas bubbles in pulmonary vasculature and sickness) joints. What is the diagnosis? INFARCT Infarcts that tend to occur in loose tissues and in Red those with dual circulations, previously congested (hemorrhagic) tissues, or when flow is reestablished after an infarct infarction (i.e. after angioplasty of obstructed artery); examples: Pulmonary and Bowel infarcts Infarcts that tend to occur in solid organs with endWhite arterial circulations; examples: Myocardial and (anemic) Splenic infarcts infarct SHOCK 55/M, known case of massive MI, developed Cardiogenic shock ventricular fibrillation, and died. What kind of shock did the patient suffer from? 65/M, with ruptured abdominal aortic Hypovolemic aneurysm, died. What kind of shock did the shock patient suffer from? 23/M, college student and dormer, developed Meningococcemia; cough and colds for 2 days, followed by Septic shock remittent high-grade fever, with dusky ecchymoses on the lower extremities. At ER, patient was stuporous with BP = 50 palpatory. What is the diagnosis, and the kind of shock did the patient suffer from? 25/F, suffered from a bee sting, developed Anaphylactic generalized wheals, periorbital edema, and shock respiratory distress. At ER, BP = 70/50. What kind of shock did the patient suffer from? 28/F, suffered from a blunt trauma of the back Neurogenic shock after a vehicular accident, was hypotensive for several days, and was started on vasopressors for management. What kind of shock did the patient suffer from?

Fate Propagation Embolization

FATES OF THROMBUS Definition Thrombi accumulate additional platelets and fibrin Thrombi dislodge and travel to other sites in the vasculature

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4. GENETIC DISORDERS QUESTION MENDELIAN DISORDERS One dominant allele is enough to produce phenotype (heterozygous); diseases with mutations in key structural proteins/receptors are usually inherited in this manner; examples: Huntington disease, Neurofibromatosis, Myotonic dystrophy, Tuberous sclerosis complex, ADPKD, Familial polyposis coli, Hereditary spherocytosis, von Willebrand disease, Marfan syndrome, Ehler-Danlos Syndrome (some types), Osteogenesis imperfecta, Achondroplasia, Familial hypercholesterolemia, Acute intermittent porphyria Two recessive alleles produce phenotype; enzyme deficiencies are usually inherited in this manner: examples: Cystic fibrosis, Phenylketonuria, Galactosemia, Homocystinuria, Lysosomal storage diseases, α-1-antitrypsin deficiency, Wilson disease, Hemochromatosis, Glycogen storage diseases, Sickle cell anemia, Thalassemias, Congenital adrenal hyperplasia, Ehler-Danlos Syndrome (some types), Alkaptonuria, Neurogenic muscular atrophies, Freidrich ataxia, Spinal muscular atrophy In this pattern of inheritance, males are usually affected due to hemizygosity of the allele, but females may express phenotype due to random activation of one X chromosome; examples: Duchenne Muscular Dystrophy, Hemophilia A and B, Chronic granulomatous disease, G6PD deficiency, Agammaglobulinemia, Wiskott-Aldrich syndrome, Diabetes insipidus, LeschNyhan syndrome, Fragile X syndrome In this pattern of inheritance, females in general are more affected than males (in any scenario), because one allele in a female is enough to manifest the trait; examples: Alport syndrome and Vitamin D-resistant rickets CHROMOSOMAL DISORDERS DISORDERS OF AUTOSOMES Most common of the chromosomal disorders; leading cause of MR; most common cause: nondisjunction of Ch21 during meiosis; diagnostic clinical features: flat facial profile, oblique palpebral fissures, and epicanthal folds Prominent occiput, mental retardation, micrognathia, low-set ears, short neck, overlapping fingers, cardiac defects, renal malformations, limited hip abduction, and rocker-bottom feet are features of this syndrome Microcephaly and mental retardation, microphathalmia, cleft lip and palate, polydactyly, cardiac defects, umbilical hernias, renal defects, and rocker-bottom feet are features of this syndrome

ANSWER Autosomal dominant

Autosomal recessive

TRINUCLEOTIDE REPEAT DISORDERS Most common cause of MR following Trisomy

DISORDERS OF GENOMIC IMPRINTING Deletion in paternally derived Chromosome 15; clinical features include: mental retardation, hypotonia, profound hyperphagia, obesity, small hands and feet, and hypogonadism Deletion in maternally derived Chromosome 15; clinical features include: mental retardation, ataxic gait, seizure, and inappropriate laughter “happy puppet”

syndrome Huntington disease

Prader-Willi syndrome Angelman syndrome

5. DISEASES OF THE IMMUNE SYSTEM

X-linked recessive disorders

X-linked dominant disorders

Trisomy 21 (Down syndrome)

Trisomy 18 (Edward syndrome) Trisomy 13 (Patau syndrome)

Note: Italicized features would help differentiate it from Edward syndrome

Syndrome consisting of cardiac anomalies, abnormal facies, thymic hypoplasia, cleft palate, hypocalcemia, due to deletion in the long arm of Chromosome 22 (part of Ch22q11.2 deletion syndrome, together with velocardiofacial syndrome) DISORDERS OF SEX CHROMOSOMES Condition characterized by ≥ 2 X chromosomes and ≥ 1 Y chromosomes; most common karyotype is 47XXY; important cause of reduced spermatogenesis and male infertility; clinical features include: eunuchoid body habitus, testicular atrophy, micropenis, absence of secondary sex characteristics, etc. Complete or partial monosomy of X chromosome; female hypogonadism in phenotypic females; Most common abnormality is lack of entire X chromosome (45XO); single most important cause of primary amenorrhea; clinical features include: ovarian streaks, absence of secondary sex characteristics, short stature, cystic hygromas of head neck, preductal CoA, etc. Type of hermaphrodism characterized by presence of both ovarian and testicular tissue Type of hermaphrodism characterized by disagreement between phenotypic and gonadal sex; examples: MRKH syndrome and androgenital syndromes

21; involves CGG expansion in FMR1 gene in Xchromosome; most distinctive feature is macroorchidism Autosomal dominant neurodegenerative disorder; CAG expansion on HTT gene on Ch4; relentlessly progressive and uniformly fatal

DiGeorge syndrome

Klinefelter syndrome

Turner syndrome

True hermaphrodism Pseudohermaphro dism

QUESTION ANSWER GELL AND COOMBS CLASSIFICATION OF HYPERSENSITIVITY Caused by activation of TH2 CD4+ helper T cells by Type I environmental antigens, leading to the production of (Immediate, IgE antibodies, which become attached to mast cells; IgEexamples: Anaphylaxis, Bronchial asthma, Allergic mediated) rhinitis, sinusitis (Hay fever), Food allergies Vascular dilation, edema, smooth muscle contraction, mucus production, tissue injury, and inflammation are characteristic of this type of hypersensitivity Caused by antibodies that bind to fixed tissue and cell Type II antigens and promote phagocytosis and destruction of (Antibodythe coated cells or trigger pathologic inflammation in mediated) tissues; examples: Autoimmune hemolytic anemia, Immune thrombocytopenic purpura, Pemphigus vulgaris, ANCA-vasculitis, Goodpasture syndrome, Acute rheumatic fever, Myasthenia gravis, Graves disease, Insulin-resistant diabetes, Pernicious anemia Phagocytosis and lysis of cells, inflammation, and functional derangements without evidence of cell or tissue injury (in some diseases) are characteristic of this type of hypersensitivity Caused by antibodies binding to antigens to form Type III complexes that circulate and may deposit in vascular (Immunebeds and stimulate inflammation secondary to complex complement activation; examples: SLE, PSAGN, mediated) Polyarteritis nodosa, Reactive arthritis, Serum sickness, Arthus reaction Inflammation and necrotizing vasculitis (fibrinoid necrosis) are characteristic of this type of hypersensitivity Cell-mediated immune responses in which T Type IV (Tlymphocytes cause tissue injury, either by producing cellcytokines that induce inflammation and activate mediated/del macrophages, or by directly killing cells; examples: ayed) Rheumatoid arthritis, Multiple sclerosis, Type I Diabetes Mellitus, Inflammatory bowel disease, Psoriasis, Contact sensitivity Perivascular cellular infiltrates, edema, granuloma formation, and cell destruction are characteristic of this type of hypersensitivity AUTOIMMUNE DISEASES 32/F, with difficulty in breathing, Systemic lupus bilateral elbow joint pains, and rash erythematosus (SLE) after sun exposure. CBC showed low hemoglobin and reticulocytosis. ANA titer is positive. What is the diagnosis? Note: Table 6-9 in Robbins and Cotran Pathologic Basis of Disease, 9th ed. p. 218; or Page 11 in Main handout is an important table, as it allows you to diagnose SLE clinically. Make sure you know this by heart. Mechanisms of organ damage in SLE Type III (most); Type II (opsonization and phagocytosis, hematologic manifestations) Most common autoantibody in SLE ANA Most specific autoantibodies for SLE anti-Sm (Smith), anti-dsDNA (anti-dsDNA correlates with disease activity) Histopathologic findings in SLE with LM: Liquefactive skin involvement degeneration of basal layer, edema at DEJ, mononuclear infiltrates around blood vessels and skin appendages IF: Deposition of Ig and complement at DEJ

Fragile X-

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TOPNOTCH MEDICAL BOARD PREP PATHO SUPPLEMENT HANDOUT by KEVIN ELOMINA, MD For inquiries visit www.topnotchboardprep.com.ph or https://www.facebook.com/topnotchmedicalboardprep/ Type of LE that associated with Drug-induced lupus Hydralazine, INH, Procainamide, and D-Penicillamine intake; rarely involves kidneys and brain; rarely associated with anti-dsDNA; associated with anti-histone antibodies CLASSES OF LUPUS NEPHRITIDES Class LM IF Minimal Normal ICs in mesangium mesangial (Class I) Mesangial Mesangial cell Granular mesangial Ig proliferative proliferation; often with and complement without (Class II) mesangial matrix involvement of accumulation glomerular capillaries Focal Swelling and Subendothelial IC (Class III) hypercellularity; capillary deposits necrosis and hyaline thrombi; <50% of glomeruli Diffuse Type III with ≥50% of (Class IV) glomeruli; Wire-loop appearance of capillaries Membranous Diffuse capillary Subepithelial IC deposits (Class V) thickening Advance Sclerosis of >90% - sclerosing glomeruli (Class VI) 34/F, with dry eyes and dry mouth. Lip Sjogren syndrome (late) (Please also study the early biopsy showed acinar atrophy, fibrosis, histologic findings in Sjogren and hyalinization of the minor salivary syndrome) glands. What is the diagnosis? Most common and most important Anti-Ro (SS-A) and anti-La autoantibody detected in Sjogren (SS-B) syndrome 45/F, with chronic GERD, history of Systemic sclerosis progressive dyspnea, and chronic kidney disease, with note of thickening of the skin. What is the diagnosis? Most common autoantibody associated Anti-DNA topoisomerase I with diffuse cutaneous systemic sclerosis (anti-Scl 70) Common autoantibody associated with Anti-centromere limited scleroderma (limited cutaneous antibodies systemic sclerosis) TRANSPLANTATION IMMUNOLOGY RENAL TRANSPLANT REJECTION 48/M, s/p kidney transplant, suddenly Hyperacute rejection developed bloody urine few hours after the procedure. Nephrectomy revealed a cyanotic, mottled, and flaccid kidney with necrotic cortex. Biopsy showed thrombotic occlusion of the capillaries and fibrinoid necrosis of arterial walls. What is the diagnosis? 45/F, with signs of renal failure 2 Acute cellular (T-cell months after her renal transplant. mediated) rejection, Biopsy showed extensive interstitial tubulointerstitial type mononuclear infiltrate with edema and (tubulitis) mild interstitial hemorrhage. Immunohistochemical stains for CD3, CD4 and CD8 are positive. What is the diagnosis? 30/M, developed oliguria and Acute antibody-mediated subsequent renal failure 3 weeks after rejection an uneventful kidney transplant. Biopsy showed inflammation of glomeruli and peritubular capillaries with focal thrombosis of small vessels. What is the diagnosis? 24/F, diagnosed with renal failure, Chronic rejection underwent renal transplant. Four years later, increasing level of creatinine was noted. Biopsy showed interstitial fibrosis and tubular atrophy. What is the diagnosis? HEMATOPOIETIC STEM CELL TRANSPLANTATION 66/M, known case of multiple Acute graft vs. host disease myeloma, underwent HSC (GVHD) transplantation, presented with bloody diarrhea and generalized morbilliform rash few weeks after the procedure. What is the diagnosis?

Based on the case above, the patient's Chronic GVHD symptoms resolved, but after a few years, he developed cutaneous sclerosis, jaundice, and dysphagia. Barium swallow showed esophageal strictures. What is the diagnosis? IMMUNODEFICIENCY SYNDROMES: PRACTICE CASES PRIMARY IMMUNODEFICIENCIES 6m/M, with morbilliform rash, recurrent Severe combined oral thrush, diaper rash, and failure to immunodeficiency thrive. PE: no cervical lymphoadenopathy. (SCID) CXR showed absence of thymic shadow. What is the diagnosis? 7m/M, with unremarkable first 6 months of X-linked life, developed recurrent pneumonia, and agammaglobulinemia steatorrheic diarrhea. Sputum culture (Bruton disease) revealed H. influenzae, and fecalysis revelaed Giardia lamblia trophozoites. PE: no cervical lymphadenopathy. Serum Igs are low. What is the diagnosis? 4m/M, with cyanosis since birth, associated DiGeorge syndrome with coarse facial features and cleft palate, presented with recurrent viral infections. PE: +3 reflexes. CXR showed a boot-shaped heart with absence of thymic shadow. FISH is positive for deletion in Ch22q11.2 locus. What is the diagnosis? 8m/M, with history of eczematous Wiskott-Aldrich dermatitis and recurrent infections. CBC syndrome (X-linked revealed low platelet. What is the most likely recessive) diagnosis? 16/F, with a history of viral URTI 3 weeks Isolated IgA deficiency prior, developed recurrent UTI and AGE. (acquired) Note: There are also Serum IgA is low. What is the diagnosis? familial forms of IgA deficiency

SECONDARY IMMUNODEFICIENCIES Most common secondary immunodeficiency; caused by HIV infection; hallmark is profound immune deficiency that leads to opportunistic infections, secondary neoplasms, and neurologic manifestations; the virus targets CD4+ T cells Most common fungal infection in patients with AIDS Most common type of lymphoma associated with HIV infection AIDS-defining sarcoma caused by Human herpesvirus 8 (HHV-8), clinically typified by appearance of purple patches, plaques or nodules on the skin

Acquired immune deficiency syndrome (AIDS)

Candidiasis B-cell lymphomas Kaposi sarcoma

6. NEOPLASIA

Note: Specific cancers will be discussed in their respective systems. QUESTION ANSWER NOMENCLATURE An abnormal mass of tissue with excessive and Neoplasm uncoordinated growth compared to that of normal tissues; its growth persists after cessation of the stimuli that evoked the growth; literally means "new growth" Localized neoplasms; usually end with –oma, EXCEPT Benign lymphoma, seminoma, dysgerminoma, hepatoma, neoplasms and melanoma (these are malignant neoplasms) Neoplasms that invade and destroy adjacent tissues Malignant neoplasms Malignant neoplasms of EPITHELIAL origin; usually Carcinomas spread by LYMPHATIC route; example: colorectal adenocarcinoma Malignant neoplasms of MESENCHYMAL origin; Sarcomas usually spread by HEMATOGENOUS route; example: uterine leiomyosarcoma Benign, but disorganized appearance of tissue Hamartoma indigenous to a particular organ; example: PeutzJegher polyp Cytologically and architecturally normal tissue in an Choristoma ectopic location; example: Ectopic gastric tissue in (basically, Meckel diverticulum Ectopia) CHARACTERISTICS OF BENIGN AND MALIGNANT NEOPLASMS Extent to which neoplastic cells resemble their Differentiation normal forebears morphologically and functionally Considered a hallmark of malignancy, which Anaplasia literally means "to form backward"; term used to describe cells with little or no differentiation

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TOPNOTCH MEDICAL BOARD PREP PATHO SUPPLEMENT HANDOUT by KEVIN ELOMINA, MD For inquiries visit www.topnotchboardprep.com.ph or https://www.facebook.com/topnotchmedicalboardprep/ Disorderly but non-neoplastic proliferation of cells; Dysplasia described as a loss in uniformity of individual cells and of their architectural orientation Fibrous tissue formation in response to neoplasm Desmoplasia Dysplastic changes that involve the entire thickness Carcinoma in of the epithelium, without violation of the basement situ membrane Development of secondary implants discontinuous Metastasis with the primary tumor, in remote tissues; more than any other attribute, this identifies a neoplasm as malignant Next to metastasis, this is the most reliable feature Local that distinguishes malignant from benign tumors invasiveness CANCER EPIDEMIOLOGY Top 3 common cancers in CHILDREN ALL > CNS tumors > Burkitt lymphoma Top 3 common cancers in MALES Prostate > Lung > Colorectal Top 3 common cancers in FEMALES Breast > Lung > Colorectal Top 3 common cancer mortalities in MALES Lung > Prostate > Colorectal Top 3 common cancer mortalities in Lung > Breast > FEMALES Colorectal MOLECULAR BIOLOGY OF CANCER Hallmarks of cancer • Self-sufficiency in growth signals • Insensitivity to growthinhibitory signals • Altered cellular metabolism • Evasion of apoptosis • Limitless replicative potential (immortality) • Sustained angiogenesis • Ability to invade and metastasize • Ability to evade the host immune response Normal cellular genes whose products Proto-oncogenes promote cell proliferation; examples: RAS (most commonly mutated protooncogene in human cancers) and ABL (in CML) Mutant or overexpressed versions of Oncogenes proto-oncogenes that function autonomously without a requirement for normal growth-promoting signals Genes whose products apply brakes to Tumor suppressor genes the cell proliferation; abnormalities in such genes lead to carcinogenesis “Governor of the cell cycle”; a tumor Rb suppressor gene that exerts antiproliferative effects by controlling G1-S checkpoint in the cell cycle; mutated in Retinoblastoma; key element in HPV tumorigenesis "Guardian of the genome"; a tumor p53 suppressor gene that regulates cell cycle progression, DNA repair, cellular senescence, and apoptosis; the most frequently mutated tumor-suppressor gene in human cancers; mutated in LiFraumeni syndrome CLINICAL ASPECTS OF NEOPLASIA Progressive loss of body fat and lean body mass, accompanied by profound weakness, anorexia, and anemia in cancer patients; main cytokine implicated is TNF Signs and symptoms not referable to the anatomic distribution of the tumor; usually due to ectopic hormone production by tumor cells examples: ectopic ACTH production (Cushing syndrome) in Small cell lung cancer; Hypercalcemia in squamous cell carcinoma (due to PTHrp expression) Term used to describe the degree of differentiation based on histologic appearance of the tumor; examples: Gleason scoring in Prostatic adenocarcinoma and FIGO grading for endometrioid endometrial carcinomas

Term used to describe the degree of localization/spread of the tumor; usual criteria: location and size of the primary tumor, nodal status, and presence of distant metastases; has more prognostic value than tumor grade; example: AJCC cancer staging system (TNM) Condition secondary to release of products of dying cancer cells during chemotherapy; characterized by hyperkalemia, hyperphosphatemia, hyperuricemia, and hypocalcemia

Tumor stage

Tumor lysis syndrome

7. INFECTIOUS DISEASES QUESTION ANSWER GENERAL PATTERN OF RESPONSE TO INFECTIONS Usual pattern of inflammation observed in Suppurative infections with extracellular Gram-positive cocci, and Gram-negative rods (pyogenic organisms) Usual pattern of inflammation observed in Mononuclear chronic, acute viral, and parasitic infections, and infections involving intracellular bacteria Usual pattern of inflammation observed in Granulomatous tuberculosis, fungal infections, and schistosome eggs; response to infectious agents that are not easily eliminated Usual response to viral infections that involves Cytopathic/ cytopathic changes in cells (inclusion bodies and Cytoproliferative multinucleated giant cells) or proliferation of host cells Usual response to clostridial infections, Tissue necrosis Entamoeba histolytica, HBV in liver, and Herpesviruses in brain Usually a sequela of chronic inflammation, seen Chronic in chronic HBV infection (cirrhosis), and inflammation and Schistosoma (pipestem fibrosis) scarring

Cancer cachexia

VIRAL DISEASES 10/F, incomplete EPI, presented with cough, colds, and conjunctivitis for 3 days with associated cervical lymphadenopathy, followed by eruption of rash from the head down, accompanied by high-grade fever. Lymph node biopsy revealed multinucleated giant cells with eosinophilic nuclear and cytoplasmic inclusions (Warthin-Finkeldey cells). What is the diagnosis? 30/M, sexually active, with painful perioral blisters. Biopsy of the blister revealed cells with pink to purple intranuclear inclusion bodies (Cowdry Type A inclusion bodies). What is the diagnosis? 23/F, with history of cough and colds for 3 days, followed by appearance of exquisitely pruritic vesicles resembling "dewdrops on a rose petal". Biopsy showed intraepithelial vesicles. What is the diagnosis? 25/M, sexually active, developed fever and lymphadenopathy. CBC showed lymphocytosis with a significant fraction of atypical lymphocytes. Lymph node biopsy revealed large, atypical cells with "Owl's eye" nuclei. Monospot test is negative. What is the diagnosis? 28/F, sexually active, developed fever and lymphadenopathy. CBC showed lymphocytosis with a significant fraction of atypical lymphocytes. Lymph node biopsy revealed paracortical hyperplasia, seen in a lot of viral infections. Monospot test is positive. What is the diagnosis?

Paraneoplastic syndromes

BACTERIAL DISEASES Main difference between staphylococcal and streptococcal infections

Tumor grade

10/F, incomplete EPI, developed low-grade fever and sore throat for 2 days, followed by inspiratory stridor and cyanosis. Patient was intubated, and suppuration with grayish pseudomembrane was noted on laryngoscopy. What is the diagnosis, and the causative organism?

Measles

Herpes labialis

Varicella

Cytomegalovirus (CMV) infection

Epstein-Barr virus (EBV)

More extensive tissue destruction in staphylococci Diphtheria, Corynebacterium diphtheriae

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TOPNOTCH MEDICAL BOARD PREP PATHO SUPPLEMENT HANDOUT by KEVIN ELOMINA, MD For inquiries visit www.topnotchboardprep.com.ph or https://www.facebook.com/topnotchmedicalboardprep/ LBB, delivered term via emergency CS for nonreassuring fetal status. PE: multiple pustular lesions. Patient eventually expired. CSF analysis showed intracellular, Gram-positive bacilli; Autopsy showed multiple granulomas in major organs. What is the diagnosis, and the causative organism? 25/M, sexually active, complaining of purulent penile discharge. GS/CS showed Gramnegative intracellular diplococci, and growth of glucose (+) and maltose (-) colonies on modified Thayer-Martin agar. What is the most likely etiologic agent? Based on the case above, if no organisms are seen on Gram-stain, what would be the most likely etiologic agent? 8/F, with cystic fibrosis and recurrent pneumonia. Lung biopsy showed fleur-de-lis pattern of necrotizing pneumonia and perivascular infiltration of organisms producing a "blue haze". What is the most likely etiology of pneumonia in this patient? 34/M, with a history of a painless nodule on the penis that spontaneously resolved, and flat, velvety, broad-based lesions in the perineum, now with an ulcerated nodule on the nose. Biopsy showed central coagulation necrosis, rimmed by palisading macrophages, and fibroblasts, plasma cell-rich infiltrate, and few organisms. RPR and TPPA are positive. What is the diagnosis, and what is the stage of the disease? FUNGAL DISEASES YEASTS 28/M, HIV-positive, with a whitish plaque on the buccal mucosa that can be scraped off, showed mucosal erythema. Examination of the plaque showed pseudohyphal structures. What is the diagnosis? Based on the case above, if the patient presented with neurologic manifestations and eventually died, and brain autopsy revealed soap bubble lesions, what is the etiologic agent? MOLDS 34/F, with a history of cavitary tuberculosis and breast cancer treated with alkylating agents, presented with hemoptysis and dyspnea. The patient eventually expired. Autopsy showed a mass occupying the cavity on the lung. Sections show septate hyphal elements, branching at acute angles (40°). What is the etiologic agent? 34/M, known case of Non-Hodgkin lymphoma treated with alkylating agents, presented with a necrotic lesion on the nose. Biopsy showed nonseptate hyphal elements, branching at right angles. What is the etiologic agent? PARASITIC DISEASES PROTOZOA 55/M, with history of travel to Angola, returned home with fever occurring every 72 hours. Giemsa-stained smears show numerous ring forms in erythrocytes. Methylene blue-stained smear show hemozoin pigment. What is etiologic agent and the diagnosis? Based on the case above, if the patient presents with fever, and Giemsa-stained smears show numerous forms resembling a Maltese cross, and Methylene blue-stained smears are negative for hemozoin pigment, what is the etiologic agent and the diagnosis? 35/M, with history of travel to Sudan, presented with anemia and hepatosplenomegaly. Biopsy showed macrophages filled with organisms. What is the etiologic agent, and the diagnosis? 38/F, with history of travel to Africa, presented with increased sleeping time, and frequent tendencies of fall. PBS showed flagellated organisms with undulating membrane. CSF showed the same organisms. What is the diagnosis, the stage, and the etiologic agent?

Granulomatosis infantiseptica, Listeria monocytogenes

Neisseria gonorrheae

Chlamydia trachomatis Pseudomonas aeruginosa

Syphilitic gumma, Tertiary syphilis

Oropharyngeal candidiasis (Thrush) Cryptococcus neoformans

Aspergillus

Mucor

Plasmodium sp., Malaria

Babesia sp., Babesiosis

Leishmania sp., Visceral leishmaniasis

African sleeping sickness, meningoencephalitic stage, Trypanosoma brucei

37/M, without any coronary risk factors, Chagas disease with remote history of travel to several (Trypanosoma cruzi) countries in South America, presented with syncope, and eventual death. Autopsy showed an enlarged colon and esophagus. Sections of the heart show C-shaped, curved, trypanosomes infiltrating the myocardium. What is the diagnosis and the etiologic agent? Metazoans are better studied in Microbiology.

8. ENVIRONMENTAL AND NUTRITIONAL PATHOLOGY

Note: The chapter concerns many topics, but are discussed across different subjects, and for the interest of time, recurring concepts, as well as low-yield topics, are omitted. Please refer to the main handout for a more detailed discussion. ENVIRONMENTAL PATHOLOGY QUESTION ANSWER AIR POLLUTION 34/M, history of sleeping in the car with windows CO closed, presented with decrease in sensorium, and poisoning cherry red discoloration of the skin and mucosal membranes. What is the most likely diagnosis? HEAVY METAL POISONING 6/M, with pica, presented with poorly localized Lead abdominal pain, poor school performance, and poisoning decreased play activity. CBC and PBS showed microcytic hypochromic anemia, with basophilic stippling. X-ray showed opacities occupying the epiphyseal plates. What is the diagnosis? NUTRITIONAL DISORDERS PROTEIN-ENERGY MALNUTRITION Parameter Marasmus Kwashiorkor Definition Weight <60% of normal Protein > caloric deprivation Protein • Somatic: Emaciated • Somatic: relatively component extremities (atrophy) spared affectation • Visceral: minimally • Visceral: depleted (normal hypoalbuminemia à albumin) generalized edema Subcutaneous Affected Relatively spared fat Growth failure Present Anemia Yes (mainly due to decreased precursors) Immune and Present (thymic and lymphoid atrophy more marked vitamin in kwashiorkor) deficiencies Other findings Head relatively larger • Liver: steatosis than body • Small bowel: atrophy, loss of microvilli • Brain: cerebral atrophy, ↓ neurons, impaired myelinization VITAMIN DISORDERS (DEFICIENCIES) Note: Other vitamin disorders are discussed in Biochemistry

34/M, known case of Crohn disease, presented with chronic steatorrhea and weight loss, was involved in a vehicular accident that happened at night. He reported that he experienced difficulty in seeing things at night. What is the most likely vitamin deficient in this patient? 26/F, complaining of gum bleeding with minor trauma. CBC and bleeding parameters are unremarkable. What is the most likely vitamin deficient in this patient? 7/M, with difficulty in ambulating. X-ray showed bowing of legs and lumbar lordosis. What is the most likely vitamin deficient in this patient?

Vitamin A

Vitamin C Vitamin D

9. DISEASES OF INFANCY AND CHILDHOOD QUESTION COMPLICATIONS OF PREMATURITY LBB, born preterm at 27 weeks AOG via VSD, was observed to be tachypneic a few minutes after birth, with associated grunting, alar flaring, and intercostal retractions. CXR showed ground-glass appearance of lung fields with air bronchograms. The patient eventually expired 2 days after, despite appropriate treatment measures. Autopsy showed eosinophilic membranes lining the alveolar walls. What is the diagnosis?

ANSWER Respiratory distress syndrome of the newborn (Hyaline membrane disease)

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TOPNOTCH MEDICAL BOARD PREP PATHO SUPPLEMENT HANDOUT by KEVIN ELOMINA, MD For inquiries visit www.topnotchboardprep.com.ph or https://www.facebook.com/topnotchmedicalboardprep/ Based on the case above, if the patient had lived Retinopathy of because of aggressive management, including prematurity excessive oxygen administration, and (ROP)/Retrolental funduscopy showed retinal fibroplasia neovascularization, what is the diagnosis? Based on the first case, if the patient had lived, Bronchopulmonary and was admitted at the NICU for 7 weeks dysplasia (BPD) maintained on >21% FiO2, but was assessed to (Moderate) require the same FiO2 at discharge, but then several days after, he eventually expired, and autopsy showed decrease in alveolar septation, what is the diagnosis? LBG, born preterm at 29 weeks AOG via VSD, Necrotizing was observed to have hematochezia and enterocolitis (NEC) abdominal distention. Babygram showed (Severe) pneumoperitoneum. The patient eventually expired after a few days. Autopsy showed transmural coagulative necrosis, ulceration, and submucosal gas bubbles in the colon. What is the diagnosis? FEATL HYDROPS IMMUNE HYDROPS Parameter Rh incompatibility ABO incompatibility Setup • Mother: Rh(-) • Mother: O • Fetus: Rh(+) • Fetus: A or B • Subsequent pregnancy Signficant: >1cc Rh(+) fetal RBCs Severity Protection Consequence

More severe Less severe RhIg in 28 weeks and No known protection within 72 hours prior to delivery 1. Hemolysis à Anemia à Cardiac failure (increased hydrostatic pressure) and liver failure (decreased protein synthesis à decreased colloid oncotic pressure) à Edema 2. Hemolysis à Jaundice and Kernicterus

CYSTIC FIBROSIS 7/F, with salty sweat, and history of Cystic fibrosis recurrent pulmonary infections, presented (CF)/Mucoviscidosis; with dyspnea, and cyanosis, and was Bronchiectasis intubated. ETA CS showed Pseudomonas aeruginosa. The patient eventually expired. Autopsy showed no diagnostic abnormality on the skin, but sections from the lung show dilation of the airways with intense acute and chronic inflammation, and granulation tissue formation. What is the underlying cause of death, and what is the diagnosis for the pulmonary findings? TUMORS 6/M, with an enlarging abdominal mass that Neuroblastoma crosses the midline, and generalized, dusky macules, resembling the surface of a blueberry muffin. The patient eventually expired. Autopsy showed a mass in the adrenal gland. Sections show sheets of small, round, blue cells, with occasional formation of Homer-Wright rosettes. What is the diagnosis? 5/F, with hematuria, and a large abdominal mass, Wilms tumor mainly located on the right, but appears to cross the midline. Biopsy of the mass showed a mixture of glandular structures, sheets of spindle cells, and small, round, blue cells. What is the diagnosis?

PART II: SYSTEMIC PATHOLOGY 10. BLOOD VESSELS QUESTION HYPERTENSION 54/F, known hypertensive with rising BUN and creatinine. Impression was hypertensive nephrosclerosis. Renal biopsy showed homogenous, pink, hyaline material on the walls of arterioles, with narrowing of the lumen. What is the vascular pathology seen? 55/M, presented with sudden onset of oliguria and a BP of 220/110 mmHg. The patient eventually died. Autopsy of the kidney showed "onion-skin", concentric, laminated thickening of the walls of arterioles with luminal narrowing, and necrotizing arteriolitis. What is the vascular pathology seen?

ANSWER Hyaline arteriolosclerosis

Hyperplastic artieriolosclerosis

ATHEROSCLEROSIS 67/M, known hypertensive and diabetic, presented with exertional retrosternal chest heaviness lasting for 5 minutes, relieved by rest and sublingual nitroglycerin. Angiography revealed 75% stenosis of the LAD. What is the diagnosis, and the pathologic consequence of atherosclerosis that led to the disease in this case? Based on the case above, the patient instead presented with retrosternal chest heaviness lasting for 30 minutes at rest, not relieved by sublingual nitroglycerin. ECG showed STelevation in leads II, III, and aVf. He had several episodes of refractory hypotension and eventually expired. Autopsy of the coronary vessels showed a large, intraplaque hemorrhage that occluded the whole vessel lumen. What is the diagnosis, and the pathologic consequence of atherosclerosis that led to the disease in this case? ANEURYSMS AND DISSECTION 34/F, known case of autosomal dominant polycystic kidney disease, presented with severe headache and eventual collapse. She was admitted comatose, and eventually died. Antemortem plain cranial CT showed enhancement of the sulci. Autopsy showed multiple saccular dilatations along the vessels of the Circle of Willis, with a ruptured one on the ACA-ACoA junction. What is the diagnosis? 55/M, known hypertensive, with previous CXR and plain abdominal films only showing atheromatous aorta, presented with a pulsating abdominal mass. An inexperienced doctor vigorously palpated the abdomen, and the patient complained of pain, and became hypotensive, and eventually died. Autospy revealed a fusiform dilation of the abdominal aorta with a point of rupture. What is the diagnosis? 34/M, 6'5" with long fingers, presented with chronic nonproductive cough. PE: BP: 120/10. The patient suddenly went overtly hypotensive with muffled heart sounds and neck vein distention. The patient eventually expired. Autopsy showed 200 cc of blood in the pericardial cavity, with a fusiform dilation of the aortic root with a point of rupture. What is the diagnosis? Based on the case above, if the patient presented with sudden onset of exquisite chest pain, tearing in character, radiating to the back, with sudden cardiovascular collapse, and eventual death, and autopsy showed a secondary lumen in the thoracic aorta with point of tear noted proximal to the formation of the secondary lumen, what is the diagnosis? VASCULITIDES 65/F, known case of polymyalgia rheumatica, presented with severe headache and diplopia associated with fever and fatigue. PE: tenderness over the course of the superficial temporal artery was painful to palpation. Biopsy showed intimal thickening of the artery, granulomatous inflammation of the internal elastic lamina with infiltrate of T cells and macrophages. What is the diagnosis? 38/F, with fatigue, weight loss and fever, and reduced blood pressure, weak pulses in the carotids and upper extremities, ocular disturbances, and neurologic deficits. Morphological findings same as above. What is the diagnosis?

Chronic stable angina pectoris, Atherosclerotic stenosis

Inferior wall STEMI, Acute plaque change (Hemorrhage)

Subarachnoid hemorrhage secondary to ruptured intracranial berry aneurysm

Ruptured abdominal aortic aneurysm

Ruptured thoracic aortic aneurysm; Marfan syndrome

Aortic dissection

Giant cell arteritis (Large arteries)

Takayasu arteritis (Large arteries)

Note: Both vasculitides affect large arteries and exhibit granulomatous type of inflammation. In fact, they have the same histologic appearance. It depends on the clinical data to differentiate both diseases.

56/M, known case of chronic active hepatitis B, presented with rapidly accelerating hypertension, abdominal pain, bloody stool, and myalgia, and eventually expired. Biopsy showed segmental transmural necrotizing inflammation with extensive fibrinoid necrosis and temporal heterogeneity of lesions. What is the diagnosis?

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Polyarteritis nodosa

TOPNOTCH MEDICAL BOARD PREP PATHO SUPPLEMENT HANDOUT by KEVIN ELOMINA, MD For inquiries visit www.topnotchboardprep.com.ph or https://www.facebook.com/topnotchmedicalboardprep/ 4/F presented with fever and maculopapular rash on her trunk and extremities. This is associated with conjunctival erythema, and cervical lymph node enlargement. Biopsy showed segmental transmural necrotizing inflammation with less fibrinoid necrosis. What is the diagnosis?

Kawasaki disease

Note: Both vasculitides that affect medium-sized arteries have the same histologic appearance; only Kawasaki disease has less fibrinoid necrosis. It depends on the clinical data to differentiate both diseases.

45/M, presented with hemoptysis and hematuria. Serology: p-ANCA/MPO-ANCA (+). Biopsy showed a vasculitis pattern similar to PAN, but lesions are of the same stage, and with fragmented PMNs in post-capillary venules (leukocytoclasia). What is the diagnosis? 34/F, known case of bronchial asthma. CBC: 62% eosinophils, without blasts; Serology: pANCA/MPO-ANCA (+). Biopsy showed granulomatous inflammation involving the respiratory tract and necrotizing vasculitis. What is the diagnosis? 54/M, with hemoptysis and hematuria with increasing BUN and creatinine. Serology: c-ANCA (PR3-ANCA) (+). Biopsy showed necrotizing granulomas of the respiratory tract, necrotizing vasculitis, and crescentic glomerulonephritis with negative findings on immunofluorescence. What is the diagnosis? 30/M, smoker, with intermittent claudication with the right leg. Biopsy showed segmental thrombosing acute and chronic vasculitis with microabscesses. What is the diagnosis? TUMORS AND TUMOR-LIKE CONDITIONS 45/M, chronic alcoholic, known case of liver cirrhosis, presented with multiple, radial, pulsatile arrays of dilated submucosal arteries that blanch with pressure. What is the diagnosis? 4/M, with seizures, mental retardation, and hemiplegia. PE: port-wine stain on the left; CTscan: extraaxial hyperdense lesion on the left parietal convexity. Biopsy showed dilated venous vessels. What is the most likely diagnosis? 4/F, with a pinkish exophytic lesion on the lip since birth. Biopsy showed small, endotheliallined spaces, filled with red blood cells. What is the diagnosis? Based on the third case, if the patient reports that the lesion only appeared 3 months prior, after history of trauma, and biopsy showed additional granulating acute and chronic inflammation, what is the diagnosis? 43/F, with a liver mass. Biopsy showed dilated vascular spaces filled with blood. What is the diagnosis? 15/F, with short stature and amenorrhea, presented with a mass on the neck, measuring 10 cm in widest dimension. Biopsy showed dilated endothelial lined space without red blood cells. What is the diagnosis, and what syndrome is observed in this case? 29/M, known case of HIV, developed purple plaques on bilateral lower extremities. Biopsy showed dermal accumulations of jagged vascular channels lined and surrounded by plump spindle cells. What is the diagnosis? 46/M, exposed to vinyl chloride, presented with a liver mass. Biopsy showed sheets of spindle cells with occasional vessel formation. Immunohistochemistry: CD31, vWF (+). What is the diagnosis?

Microscopic polyangiitis

Churg-Strauss syndrome

Granulomatosis with angiitis (Wegener granulomatosis)

Thromboangiitis obliterans (Buerger disease)

Spider telangiectasia Sturge-Weber syndrome

Capillary hemangiomas Pyogenic granuloma

Cavernous hemangioma Cavernous lymphagngioma; Turner syndrome

Kaposi sarcoma

Hepatic angiosarcoma

CONGENITAL HEART DISEASES 30/M, with occasional episodes of chest ASD heaviness, dyspnea, and syncope. Cardiac examination: (+) systolic murmur at the 2nd LICS. CXR: increased pulmonary vascular markings with RVH. What is the diagnosis? 5/M, apparently asymptomatic, with an VSD incidental finding of a holosystolic murmur best heard at the left lower sternal border, radiating to the right lower sternal border. CXR: increased pulmonary vascular markings, BVH, and normal aortic knob size. What is the diagnosis? 16/M, apparently asymptomatic, with an PDA incidental finding of a heart murmur (continuous, "machinery like") best heard at the 2nd LICS. CXR: increased pulmonary vascular markings, LVH/BVH, and enlarged aortic knob. What is the diagnosis? 4/M, cyanotic with failure to thrive. CXR: Tetralogy of Fallot decreased pulmonary vascular markings and (TOF) RVH, with a characteristic boot-shaped heart. What is the diagnosis? 3d/M, cyanotic, with history of maternal GDM. Transposition of CXR: Increased pulmonary vascular markings the Great Arteries and RVH, with a characteristic egg on the side (TGA) appearance. What is the diagnosis? COARCTATION OF THE AORTA Feature Infantile Adult Obstruction Tubular hypoplasia of Coarctation opposite the aortic arch proximal to ligamentum arteriosum the PDA distal to the arch vessels Associations Turner syndrome - Clinical findings Lower extremity • Upper extremity cyanosis hypertension • Rib notching on CXR: increased blood flow to intercostal vessels Chamber RVH (or biventricular) LVH hypertrophy ISCHEMIC HEART DISEASE 48/M, known hypertensive, presented with Chronic stable exertional retrosternal chest heaviness <2 minutes angina in duration that improves with rest. Exercise ECG pectoris shows non-specific ST wave changes. Cardiac markers are negative. What is the diagnosis? Based on the case above, if he presented with chest Unstable heaviness at rest lasting for 15 minutes, without angina improvement with ISDN sublingual tablets, and ECG showed ST wave depression in contiguous leads, but cardiac biomarkers are negative, what is the diagnosis? Based on the second case, if the chest pain lasts for NSTEMI 30 minutes, and cardiac biomarkers are positive, what is the specific diagnosis? Based on the third case, if the patient died 2 hours Waviness of after the onset of chest pain, what would be the fibers at expected morphologic finding on autopsy? border of infarct Based on the third case, if the patient died after 2 Coagulation days, what would be the expected morphologic necrosis with finding on autopsy? neutrophilic infiltration Note: Please study this part well in the main handout, because ischemic heart disease is one of the most common diseases that you will encounter as a physician, and therefore the examiners will never fail to include this in the board examination, across all subjects.

11. HEART QUESTION HEART FAILURE 67/M, presented with easy fatigability, paroxysmal nocturnal dyspnea, and 3-pillow orthopnea. Known case of hypertension, poorly controlled, for 20 years. What is the type of heart failure seen in this case? 45/M, known case of COPD, presented with decreased sensorium, increased liver span, and lower extremity edema. What is the type of heart failure seen in this case?

ANSWER Left-sided heart failure

Right-sided heart failure

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•

Findings

•

• •

HYPERTENSIVE HEART DISEASE Left-sided HHD Right-sided HHD More common Less common Systemic hypertension • Pulmonary hypertension (if secondary to pulmonary disease: cor pulmonale) • Most common cause: LSHD Concentric LVH usually • Acute cor pulmonale: RV accompanied by dilation interstitial fibrosis • Chronic cor pulmonale: (impaired filling) à LA RV hypertrophy, enlargement dilation and possible History/evidence of RSHF hypertension in other organs Earliest change: increased transverse diameter of myocytes àà variable cell/nuclear enlargement with interstitial fibrosis

VALVULAR HEART DISEASES 12/F, presented with dyspnea and knee pain (with Acute rheumatic an antecedent history of ankle pain that fever; Type II spontaneously improved). History revealed previous sore throat 4 weeks prior to the onset of symptoms. ASO titer is high. PE: systolic murmur at apex. Patient eventually expired. Autopsy of the heart shows Aschoff bodies in the epicardium, myocardium and endocardium layers. What is the diagnosis, and the type of hypersensitivity that this disease exhibits? Based on the case above, suppose that the patient Rheumatic lived, and was lost to follow up, and came back after heart disease 12 years, now with dyspnea. PE: diastolic murmur at apex. Patient eventually expired. Autopsy of the heart shows a fish-mouth deformity of the mitral valve. What is the diagnosis? Based on the second case, suppose that the patient Subacute survived, but presented with high-grade fever as Infective well. Blood CS turned positive for viridans endocarditis streptococci. Despite appropriate management, she died. Autopsy of the heart shows large, irregular masses on the valve cusps that may extend into chordae. What is the specific diagnosis? CARDIOMYOPATHIES 14/M, with a history of viral URTI, then Dilated developed progressive dyspnea, and died. cardiomyopathy Autopsy showed enlarged, heavy, flabby secondary to diffuse heart with dilated chambers. Sections interstitial myocarditis from the myocardium show lymphocytic infiltration. What is the complete diagnosis 25/M, was playing basketball, when he Hypertrophic suddenly collapsed, and died. Autopsy cardiomyopathy showed hypertrophic myocardium, particularly the interventricular septum. Sections show myofiber disarray, and interstitial fibrosis. What is the diagnosis? CARDIAC TUMORS Parameter Myxoma Rhabdomyoma Epidemiologic Most common primary Most common notes cardiac tumor in adults primary cardiac tumor in children Location Atria; LA > RA Ventricles Associations • McCune-Albright Tuberous sclerosis syndrome complex • Carney complex Clinical Ball-valve obstruction, Obstruction presentation embolization, constitutional symptoms Gross Usually solitary, sessile or Usually multiple, pedunculated masses gray-white masses mottled with hemorrhage Histology Stellate/globular myxoma Thin strands of cells embedded within cytoplasm that stretch acid mucopolysaccharide from the nucleus to matrix with vessel or the surface membrane gland like projections “spider cells”

PERICARDIAL DISEASES 55/M, with a thoracic aortic aneurysm, near the Pericardial aortic root, presented with sudden prostration, tamponade hypotension, with neck vein distention, and distant secondary to heart sounds on cardiac auscultation. The patient ruptured eventually expired. Autopsy showed a ruptured thoracic thoracic aneurysm, and a blood-filled pericardial aneurysm cavity. What is the diagnosis? PERICARDITIDES Feature Acute pericarditis Chronic pericarditis Forms • Fibrinous/serofibrinous • Usually, consequence of (most common); purulent pericarditis common causes: AMI • Adhesive (Dressler syndrome), mediastinopericarditis: uremia, radiation, RF, parietal pericardium SLE, trauma adheres with mediastinal • Purulent: infections structures • Hemorrhagic: most • Constrictive pericarditis: common cause: heart enclosed in a dense neoplasms fibrocalcific scar • Caseous: most common cause: TB Clinical • Chest pain, relieved • Adhesive findings when leaning forward mediastinopericarditis: • Pericardial friction rub Systolic retraction of the (most striking clinical rib cage and diaphragm, finding) pulsus paradoxus • Constrictive pericarditis: diastolic dysfunction

12. WHITE BLOOD CELLS, LYMPH NODES, SPLEEN, AND THYMUS

Note: The chapter focuses on the COMMON white cell disorders. For the diseases of the spleen and the thymus, please refer to the main handout. QUESTION ANSWER NON-NEOPLASTIC WHITE CELL DISORDERS Decreased number of circulating Leukopenia leukocytes; most commonly involves neutrophils (neutropenia); deficiency of lymphocytes (lymphopenia) is less common, and is commonly seen in advanced HIV and other diseases

Clinically significant neutropenia (<500/mm3); high susceptibility to infections (Candida and Aspergillus); most common cause is drug toxicity An increase in the number of white cells in the blood in a variety of inflammatory states caused by microbial and nonmicrobial stimuli that may mimic leukemia

Agranulocytosis

Reactive leukocytosis, Leukemoid reaction (high leukocyte alkaline phosphatase (LAP): a product of normal WBCs; used to differentiate it from leukemias i.e. CML (low LAP))

Enlargement of a lymph node as Reactive lymphadenitis immune response to foreign antigens; histology usually nonspecific; depends on duration of disease and type of offending agent REACTIVE LYMPHADENITIS: PRACTICE CASES 7/F, with obstructive sleep apnea secondary to chronic Follicular hypertrophic tonsils, Grade 3; underwent bilateral hyperplasia tonsillectomy and adenoidectomy. Biopsy of the adenoids shows increase in the number of germinal centers (secondary follicles) per unit area. What is the diagnosis for the adenoids? 27/F, developed fever and lymphadenopathy. Paracortical Serology: heretophil antibodies (+). Diagnosis was hyperplasia infectious mononucleosis. Lymph node biopsy shows expansion of the paracortical zones imparting a mottled appearance (because of the heterogeneous population of T-cells, immunoblasts, histiocytes, and plasmacytoid dendritic cells). What is the diagnosis? 59/F, known case of breast cancer, underwent sentinel Sinusoidal lymph node biopsy. Lymph node biopsy shows no hyperplasia evidence of metastases, but with distention of /Sinus lymphatic sinusoids by histiocytes. What is the histiocytosis diagnosis? NEOPLASTIC WHITE CELL DISORDERS Neoplastic proliferation of white cells wherein the Leukemia neoplastic white cells populate the peripheral blood and bone marrow, which leads to peripheral blood cytopenias. Clinical manifestations depend on the cell line/s affected. Neoplastic proliferation of white cells that presents as Lymphoma discrete tissue masses

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TOPNOTCH MEDICAL BOARD PREP PATHO SUPPLEMENT HANDOUT by KEVIN ELOMINA, MD For inquiries visit www.topnotchboardprep.com.ph or https://www.facebook.com/topnotchmedicalboardprep/ LEUKEMIAS Parameter Acute leukemia Chronic leukemia Age Usually younger Usually older Morphological Usually more Usually more matureappearance of cells primitive looking Clinical course and Usually aggressive; Usually indolent; presentation severe symptoms subtle symptoms Amenability to Usually amenable Usually resistant treatment ACUTE LEUKEMIAS 4/F presents with pallor, recurrent URTI, and Acute epistaxis. lymphoblastic PE: increased liver span and obliterated Traube leukemia (ALL) space (precursor BCBC: 35% Blast count with lymphocytic cell ALL) background BM trephine: Hypercellular marrow with diffuse infiltration of blast cells Flow cytometry: 89% Bone marrow blasts Myeloid markers: MPO, CD117, CD33 (-) Lymphoid markers: Tdt (+) B-cell lineage marker: CD79a, CD19 (+) T-cell lineage markers: CD3, CD7 (-) What is the diagnosis? 12/M presents with mediastinal mass. Precursor TCT: Multiple mass in the abdomen and mediastinum cell ALL CBC: 40% Blast count with lymphocytic background BM trephine: Hypercellular marrow with diffuse infiltration of blast cells. Flow cytometry: 78% BM Blasts Myeloid markers: MPO, CD117, CD33 (-) Lymphoid markers: Tdt (+) B-cell lineage marker: CD79a, CD19 (-) T-cell lineage markers: CD3, CD7 (+) What is the diagnosis? 40/M, presents with bleeding. Acute CBC: thrombocytopenia, 15% Blast count, with promyelocytic 40% nucleolated WBCs with Auer rods obscuring leukemia the supposed perinuclear clearing (Golgi zone) of a (WHO Class I) Note: in cases of promyelocyte t(15;17) AML, Coags: Elevated PT/PTT 20% blast count FISH: (+) t(15;17) PML-RARA requirement is not What is the diagnosis? needed for diagnosis

36/M, known case of Hodgkin lymphoma Stage Acute myeloid IIIB, underwent chemotherapy with alkylating leukemia agents, developed recurrent epistaxis. (AML) PE: increased liver span and obliterated Traube (Therapyspace related AML) CBC: Anemia, thrombocytopenia, Leukocytosis (WHO Class II) (200,000/mm3) with 40% Blast count BM trephine: Hypercellular marrow with diffuse infiltration of blast cells Flow cytometry: 92% BM Blasts Myeloid markers: MPO, CD117, CD33 (+) Lymphoid markers: Tdt (-) B-cell lineage marker: CD79a, CD19 (-) T-cell lineage markers: CD3, CD7 (-) What is the diagnosis? DIFFERENCE BETWEEN AML and ALL Parameter AML ALL Age of onset Adults Children Presentation Bone marrow failure CNS spread Rare Common Prognosis Generally difficult to treat Generally responsive to chemotherapy CHRONIC LEUKEMIAS 68/M, with multiple lymphadenopathy. Chronic CBC: 300,000/mm3 with 95% lymphocytes lymphocytic (285,000/mm3) leukemia PBS: Lymphocytosis with smudge cells. (CLL) BM trephine: Hypercellular marrow with nodular lymphoid aggregates. LN biopsy: Diffuse but vaguely nodular infiltration of small lymphocytes with proliferation centers (pseudofollicular pattern) IHC: CD3(-), CD20, CD5, CD23(+) What is the diagnosis?

45/F, apparently asymptomatic. Chronic CBC: 300,000/mm3 with neutrophilia, left shift myelogenous (myelocytes and metamyelocytes), and 2% blast leukemia count (CML) LAP score: Low FISH studies: (+) BCR-ABL1 t(9;22). What is the diagnosis? LYMPHOMAS Parameter HL NHL Lymph node Single, axial group of Multiple, peripheral involvement nodes (cervical, nodes mediastinal, paraaortic) Spread Contiguous Non-contiguous Mesenteric nodes and Rare Common Waldeyer ring involvement Extranodal Rare Common presentation HODGKIN LYMPHOMA 23/F, Filipino, with long-standing solitary left lateral Mixed neck mass, with fever and night sweats. PPD is cellularity positive. HL LN biopsy: mixed infiltrate of inflammatory cells with large cells with multiple nuclei, each of which has a nucleolus ("Owl-eye" nuclei); fibrous nodules are not observed IHC: Large cells are positive for CD15 and CD30. What is the diagnosis? Based on the case above, if at least one fibrous nodule Nodular is observed, with scattered RS cells, and no observable sclerosis HL necrosis, what would be the histologic diagnosis? (Grade I) Based on the first case, if histology showed scant Lymphocyte lymphocytic infiltrate with predominance of large, -depleted HL pleomorphic cells; some of which look like RS cells, and IHC: CD30, PAX5 (+), ALK, CD45(-), what is the histologic diagnosis? SUBTYPES OF HL Association Immuno- Subtype Morphological pearls with EBV phenotype Nodular Reactive T-cells with (-) CD15(+) sclerosis (NS) fibrous bands forming CD30(+) nodules Mixed Mixed leukocytic 70% CD15(+) cellularity (MC) infiltrate without CD30(+) fibrous nodules Lymphocyte Rich reactive T-cell 40% CD15(+) rich (LR) infiltrate CD30(+) Lymphocyte Rare reactive Most (+) CD15(+) depleted lymphocytes CD30(+) (LD) Lymphocyte Reactive B cells; (-) CD15(-) predominant lymphohistiocytic CD30(-) (LP) “popcorn” RS cells CD20(+) NON-HODGKIN LYMPHOMA 60/M, with multiple lymphadenopathy. Small CBC: 5,000/mm3 with 80% lymphocytes (4,000/mm3) lymphocytic PBS: lymphocytosis with smudge cells lymphoma LN biopsy: Diffuse but vaguely nodular infiltration of (SLL) small lymphocytes with proliferation centers (pseudofollicular pattern) IHC: CD3(-), CD20, CD5, CD23(+) What is the diagnosis? 70/F, with multiple cervical lymphadenopathy. Follicular CBC: WBC 20,000, with 80% lymphocytes lymphoma (15,000/mm3). LN biopsy: Nodular pattern (Follicular) of infiltration of small lymphocytes with follicle formation in perinodal fat BM trephine: Hypercellular marrow with paratrabecular lymphoid aggregates IHC: CD3, CD5(-), CD20, CD10, BCL2 (+) What is the diagnosis? 47/M, with an enlarging mass on the ankle and Diffuse Large profound weight loss. B-cell Incision biopsy: sheets of large, pleomorphic cells lymphoma Initial diagnosis: Malignant round cell neoplasm (DLBCL), IHC: CK, vimentin (-), CD45, CD10, BCL6, MUM1(+), high-grade, Ki-67=80% non-germinal What is the diagnosis? center type

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TOPNOTCH MEDICAL BOARD PREP PATHO SUPPLEMENT HANDOUT by KEVIN ELOMINA, MD For inquiries visit www.topnotchboardprep.com.ph or https://www.facebook.com/topnotchmedicalboardprep/ 12/M, with a rapidly enlarging mandibular mass. Burkitt Incision biopsy: sheets of medium-sized lymphocytes lymphoma with several macrophages resembling a "starry sky" pattern. IHC: Ki67=100%, MYC(+) FISH: (+) t(8:14) cMYC What is the diagnosis? 45/F, with history of Sjogren syndrome, developed a Marginal right parotid mass. zone Incision biopsy: sheets of small lymphocytes lymphoma IHC: CD3, CD5, CD10 (-), CD20 (+) What is the most likely diagnosis? 67/M, with generalized brown-tan scaly, plaques, Mycosis and was managed as a case of psoriasis for several fungoides months with no relief. (Cutaneous TSkin biopsy: Collections of cells with cerebriform cell nuclei (Sezary cells) in the epidermis (Pautrier lymphoma) microabscesses) IHC: CD4 (+) What is the diagnosis? Based on the third case under Hodgkin lymphoma Anaplastic (diagnosis is lymphocyte-depleted HL), if IHC: CD30, large cell ALK (+), CD45(-), PAX5(-), what is the histologic lymphoma, diagnosis? ALK-positive PLASMA CELL NEOPLASMS 78/M, with enlarging mass on the mandible. Initial Multiple impression was ameloblastoma. myeloma Biopsy: Sheets of plasmacytoid cells IHC: CD138 and Kappa chain (+), Lambda chain (-) BM trephine: Hypercellular marrow with plasmacytoid cells Flow cytometry: Similar results as IHC CBC: Low hemoglobin Chemistry: Elevated serum Ca and creatinine What is the most likely diagnosis? MYELODYSPLASTIC SYNDROME 60/M, with long-standing anemia and Myelodysplastic thrombocytopenia. syndrome BM trephine: Hypercellular marrow BM smear: Ringed sideroblasts >20% of erythroids, hypogranular PMNs, Pseudo-Pelger Huet cells, and dwarf, hypolobated, and Pawn ball megakaryocytes. (Dysplastic forms make up more than 10% of each respective population) What is the most likely diagnosis? CHRONIC MYELOPROLIFERATIVE DISORDERS (Technically, CML belongs to this group, but for the sake of easier presentation of concepts, it was discussed under Leukemias)

Common features of chronic myeloproliferative disorders

Increase in all cell lines, but erythroid lines are more increased; associated with JAK2 mutations in most cases; 2% chance of transformation to AML Increase in megakaryocytic lines; associated with JAK2 mutations in 50% of cases; transformation to AML is uncommon Extensive deposition of collagen in marrow by non-neoplastic fibroblasts; associated with JAK2 mutations in 5060% of cases; 5-20% chance of transformation to AML

• Increased proliferative drive in bone marrow • Extramedullary hematopoiesis • Spent phase • Variable transformation to AML Polycythemia vera (PV)

Essential thrombocytosis (ET) Primary myelofibrosis (PM)

13. RED BLOOD CELL AND BLEEDING DISORDERS RED CELL DISORDERS Note: The chapter focuses on the COMMON anemias (excluding anemia of acute blood loss). For polycythemia, please refer to the main handout. QUESTION ANSWER HEMOLYTIC ANEMIAS Common features: 1. Shortened red cell life span (<120 days) 2. ↑ EPO levels à ↑ Erythropoiesis (compensatory) 3. Accumulation of hemoglobin degradation products 3/M, CBC: increased MCHC; PBS: mostly spherical Hereditary cells without central pallor; Osmotic fragility spherocytosis testing (+). What is the diagnosis?

1m/M, No newborn screening done, with pyuria treated with Co-trimoxazole. Days later, presented with jaundice. PBS: mostly schistocytes (Bite cells). What is the diagnosis? 6/M, African, presented with relapsing excruciating pain on the leg and recurrent pneumonia; Sputum culture revealed: Streptococcus pneumonia; PBS: Sickle-shaped erythrocytes. What is the diagnosis?

Glucose-6phosphate dehydrogenase deficiency (G6PD deficiency) Sickle cell anemia (with autosplenecto my as complication) Thalassemia (β-thalassemia minor)

25/F, chronically anemic, otherwise unremarkable; PBS: microcytic, hypochromic erythrocytes with several target cells; Gap PCR showed deletion in 1 β-globin gene. What is the diagnosis? THALASSEMIA SYNDROMES # Affected Clinical syndrome Clinical manifestations gene β-thalassemia β-thalassemia major 2 Severe; blood transfusion required β-thalassemia Variable Severe; regular transfusions intermedia not required β-thalassemia minor 1 Asymptomatic with mild or absent anemia; (+) red cell abnormalities α-thalassemia Silent carrier 1 Asymptomatic; no red cell abnormality α-thalassemia trait 2 Asymptomatic; like βthalassemia minor HbH disease 3 Severe; like β-thalassemia intermedia Hydrops fetalis 4 Lethal in utero without transfusions 39/M, with cola-colored urine upon first Paroxysmal morning voiding; Urinalysis: 0-1 RBC/HPF. Flow nocturnal cytometry: (-) CD55 and CD59 in almost 100% hemoglobinuria of red cells. What is the diagnosis? 17/F, with history of productive cough with Cold agglutinin whitish sputum for 5 days that spontaneously immunohemolytic resolved, developed anemia 5 days after; CBC: anemia Increased MCV; PBS: agglutinated erythrocytes with schistocytes. Coombs test is positive. What is the diagnosis? 68/F, known case of CLL, presents with chronic Warm agglutinin anemia. PBS: agglutinated erythrocytes with immunohemolytic schistocytes. Coombs test is positive. What is the anemia diagnosis? 34/M, documented case of thrombotic Microangiopathic thrombocytopenic purpura (TTP), presents hemolytic anemia with anemia. PBS: several schistocytes. What is the most likely diagnosis? HEMOLYTIC ANEMIAS: SUMMARY Disease Type of hemolysis Site of hemolysis Hereditary Intrinsic Extravascular spherocytosis (HS) G6PD deficiency Intrinsic BOTH Sickle cell anemia Intrinsic Extravascular (SCA) Thalassemia Intrinsic Extravascular Paroxysmal nocturnal Intrinsic Intravascular hemoglobinuria (PNH) Immunohemolytic Extrinsic BOTH (depending on anemias type)* Microangiopathic Extrinsic Intravascular hemolytic anemia Macroangiopathic Extrinsic Intravascular hemolytic anemia * - Major types of immunohemolytic anemias usually exhibit EXTRAVASCULAR hemolysis (see main handout) HYPOPROLIFERATIVE ANEMIAS 35/M, strict vegan for 2 years, developed loss of Megaloblastic proprioception and anemia. PBS: macro-ovalocytes anemia and hypersegmented PMNs. BM trephine biopsy: (Vitamin B12 Hypercellular marrow. What is the diagnosis, and deficiency) what is the vitamin deficient in the following case? 6/F, with chronic malaise and pallor. CBC: Iron deficiency microcytic, hypochromic erythrocytes; low serum anemia Fe, high TIBC, low ferritin. What is the diagnosis?

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TOPNOTCH MEDICAL BOARD PREP PATHO SUPPLEMENT HANDOUT by KEVIN ELOMINA, MD For inquiries visit www.topnotchboardprep.com.ph or https://www.facebook.com/topnotchmedicalboardprep/ 35/F with breast carcinoma; CBC: normocytic erythrocytes with moderate hypochromia; low serum Fe, low TIBC, high ferritin. What is the diagnosis? 12/F, with bacterial URTI and complete course of Chloramphenicol for treatment, developed anemia and epistaxis; PE: no organomegaly; CBC: pancytopenia; BM trephine: Hypocellular marrow. What is the diagnosis? 35/F with a mediastinal mass and anemia. Biopsy of the mass showed thymoma; CBC: normal WBC and platelet counts; BM trephine: hypo- to normocellular marrow with marked decreased only in erythroid precursors. What is the diagnosis? 46/F with pallor and epistaxis. PE: hepatosplenomegaly; CBC: WBC=400,000 with 40% Blasts; PBS: several dacrocytes; BM trephine: Hypercellular marrow with 35% Blasts. What is the most appropriate diagnosis for the anemia?

Anemia of chronic disease Aplastic anemia

Pure red cell aplasia (PRCA)

Myelophthisic anemia

BLEEDING DISORDERS Note: The chapter focuses on the common bleeding disorders. For transfusion reactions, please refer to the main handout. Bleeding Bleeding Bleeding Clinical function disorder parameters manifestations determined category Platelet count Platelet Disorders of Superficial (skin (PC) number platelet and mucosal) number bleeding, petechiae Bleeding time Platelet Defects of (BT) function platelet function Prothrombin Coagulation: Disorders of Deep-seated time (PT) extrinsic coagulation bleeding, pathway Hemarthroses Activated partial Coagulation: thromboplastin intrinsic time (aPTT) pathway DISORDERS OF PLATELET NUMBER (Common laboratory abnormality: THROMBOCYTOPENIA AND PROLONGED BLEEDING TIME) 26/F, with SLE. Presents with epistaxis and mild Chronic ITP splenomegaly. PBS: large platelets; BM trephine biopsy: Increased megakaryocytes with dysplasia <10% of population (allowable). What is the diagnosis? 11/M, post-viral URTI, presented with epistaxis. Acute ITP PBS: large platelets; BM trephine biopsy: Increased megakaryocytes with dysplasia <10% of population (allowable) 54/M, known case of MI, maintained on Heparin-induced heparin, presented with claudication with his thrombocytopenia left leg. Angiography: thrombotic occlusion of (HIT) the posterior tibial artery. What is the diagnosis? 34/M, with fever, pallor, epistaxis, and seizures. Thrombotic CBC: anemia and thrombocytopenia; PBS: thrombocytopenic numerous schistocytes; Elevated serum purpura (TTP) creatinine. What is the diagnosis? 26/M, with history of beef consumption from a Hemolytic Uremic grill offering "unlimited beef", developed pallor Syndrome (HUS) and epistaxis with dysentery. CBC: anemia and thrombocytopenia; PBS: numerous schistocytes; Elevated serum creatinine. What is the diagnosis? DISORDERS OF PLATELET FUNCTION (Common laboratory abnormality: PROLONGED BLEEDING TIME) 23/M, with epistaxis; CBC: decreased platelet Bernard-Soulier count; normal PT/PTT. What is the diagnosis? syndrome 24/F, with gum bleeding on minor trauma; Glanzmann CBC: normal platelet count; normal PT/PTT. thrombasthenia What is the diagnosis? DISORDERS OF COAGULATION (Common laboratory abnormality: PROLONGED COAGULATION PARAMETERS, depending on the pathway involved 34/M, with easy bruising. CBC: normal Von Willebrand platelet count; prolonged BT and PTT; disease (vWD) normal PT. What is the diagnosis? 12/M, with hemarthrosis of the right knee. Hemophilia CBC: normal platelet count, BT and PT; (Hemophilia A – prolonged PTT. What is the diagnosis, and Factor VIII what factors are missing for the major types of deficiency; the disease? Hemophilia B (Christmas disease) – Factor IX deficiency

LBB born term with a hilot, developed Vitamin K deficiency hematochezia. CBC: normal platelet count and BT; prolonged PT and PTT. What is the diagnosis? 34 G1P1 postpartum with excessive bleeding. Disseminated CBC: low platelet; prolonged bleeding intravascular parameters. Patient eventually expired, and coagulation (DIC) was found to have suffered from amniotic fluid embolism on autopsy. What is the most likely bleeding disorder did the patient suffer from? BLEEDING DISORDERS: SUMMARY Disease PC BT PT PTT Ehler-Danlos syndrome N N N N Immune thrombocytopenic ↓ ↑ N N purpura Thrombotic ↓ ↑ N N thrombocytopenic purpura Bernard-Soulier disease ↓ ↑ N N Glanzmann thrombasthenia N ↑ N N Von Willebrand disease N ↑ N ↑ Hemophilia N N N ↑ Vitamin K deficiency N N ↑ ↑ DIC ↓ ↑ ↑ ↑

14. LUNG AND PLEURA OBSTRUCTIVE AND RESTRICTIVE LUNG DISEASES Parameter Obstructive Restrictive Fundamental ↑ Airway resistance Reduced expansion of Pathology due to obstruction the lung parenchyma with ↓ TLC Examples Bronchial asthma, Pulmonary fibrosing Emphysema*, Chronic diseases, and chest bronchitis*, wall disorders Bronchiectasis Lung volumes ↑ ↓ FEV1 ↓↓ ↓ FVC ↓ ↓↓ FEV1/FVC ratio ↓ (<0.7) Normal to ↑ QUESTION ANSWER OBSTRUCTIVE LUNG DISEASES 70/M, smoker, presented with dyspnea. PE: Emphysema, barrel-chested, in tripod position, and centriacinar type moderate distress. Patient eventually expired, (Pink puffers) despite appropriate management. Autopsy showed destruction of air spaces distal to terminal bronchioles, leading to their enlargement, without obvious fibrosis; the process mainly involves respiratory bronchioles, with sparing of the alveoli. What is the diagnosis? 35/M, non-smoker, with family history of Emphysema, multiple deaths either due to liver cancer or a panacinar type pulmonary disease, presented with respiratory distress, and eventually died. Autopsy showed destruction of air spaces distal to terminal bronchioles, leading to their enlargement, without obvious fibrosis; the process involves the respiratory bronchioles and the alveoli. What is the diagnosis? 50/M, smoker, with history cough with sputum Chronic bronchitis production for at least 3 months for at least 2 (Blue bloaters) consecutive years, presented with dyspnea, and eventually expired. Autopsy showed enlargement of mucous-secreting glands and chronic inflammation with bronchiolar wall fibrosis. What is the diagnosis? 15/M, with a history of viral URTI, presented Bronchial asthma with dyspnea. PE: wheezes all over. Salbutamol (Status nebulization offered partial relief, however, asthmaticus) after a few hours, patient arrested and expired. Autopsy showed bronchoconstriction and obstruction of small airways by thick tenacious mucus plugs. What is the diagnosis? 13/F, known case of cystic fibrosis, with a Bronchiectasis chronic history of cough with copious amount of foul-smelling sputum, presented with dyspnea and eventually expired. Autopsy showed grossly dilated airways, with intense acute and chronic inflammatory exudation within the walls of the bronchi and bronchioles, fibrosis of the bronchial and bronchiolar walls, and peribronchiolar fibrosis. What is the diagnosis? For restrictive lung diseases, please refer to the main handout.

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TOPNOTCH MEDICAL BOARD PREP PATHO SUPPLEMENT HANDOUT by KEVIN ELOMINA, MD For inquiries visit www.topnotchboardprep.com.ph or https://www.facebook.com/topnotchmedicalboardprep/ BASIC PATTERNS OF PULMONARY INFECTIONS BronchoParameter Lobar pneumonia pneumonia Consolidation Patchy Lobar or large portion of lobe Gross Consolidated • Congestion: red, heavy, boggy areas of acute • Red hepatization: red, firm, suppurative airless inflammation • Gray hepatization: grayishbrown • Resolution: resorption of exudates; or organization (fibrosis) Histology Neutrophil• Congestion: vascular rich exudate engorgement with intra-alveolar that fills the fluid, few PMNs, and numerous airways bacteria • Red hepatization: PMNs, RBCs, and fibrin • Gray hepatization: RBCs disintegrate, fibrinosuppurative exudate • Resolution: exudates resorbed or ingested by macrophages; or fibrosis OTHER PNEUMONIA SYNDROMES 18/M, in a dormitory, exposed to roommates that have productive cough with whitish sputum without fever, presented with the same symptoms. CXR: interstitial infiltrates. What is the diagnosis? 34/M, from an intense alcohol drinking session, developed productive cough with copious, yellowish, foul-smelling sputum and high-grade fever. CXR showed a cavity with air-fluid level on the right lower lung field. What is the diagnosis? TUBERCULOSIS 35/M, presented with productive cough for 2 weeks duration with no relief of symptoms after a 1-week course of CoAmoxiclav, with associated cervical lymphadenopathy. CXR: apical opacities; Sputum AFB: 3+; Lymph node biopsy showed caseating granulomas with Langhans type giant cells. What is the diagnosis? Formation of granulomas in a patient with tuberculosis signifies an intact

Atypical pneumonia (probably Mycoplasma in origin)

Lung abscess

LUNG CARCINOMAS Note: Remember that most lung tumors are carcinomas (95%), so a lung mass can be considered to be malignant unless proven otherwise. Clinically, patients usually have a history of chronic smoking, and usually present with chronic cough with profound weight loss.

45/M, smoker. Mass location: central (left Squamous cell primary bronchus). CT guided biopsy (core): carcinoma Sheets of anaplastic cells with eosinophilic cytoplasm with intercellular bridges and dyskeratotic cells. Immunohistochemistry: p63, p40 (+). What is the diagnosis? 39/F non-smoker. Mass location: peripheral. CT Adenocarcinoma guided biopsy (core): Anaplastic cells forming glandular structures; some of which contain mucin. Immunohistochemistry: TTF-1, napsin A (+). What is the diagnosis? 60/M, smoker. Mass location: central. CT-guided Small cell (Oat biopsy: sheets of small, round, blue cells with cell) carcinoma crushing artifact on a markedly necrotic background. Immunohistochemistry: CD57, Chromogranin (+). What is the diagnosis? 56/M, smoker. Mass location: central. CT-guided Large cell biopsy: sheets of large, anaplastic cells. carcinoma Immunohistochemistry: p63, p40, TTF-1, napsin (Undifferentiated) A (-). What is the diagnosis? DISEASES OF THE PLEURA 60/F, staying at an old ancestral house, Malignant presented with sudden dyspnea. CXR mesothelioma, revealed massive left pleural effusion. epithelioid type (Note: Malignant CTT was inserted draining 8L of mesothelioma is commonly serosanguinous fluid. CXR: ill-defined associated with asbestos, but mass occupying the left lobe. CT-guided the most common cancer biopsy core: Anaplastic cells forming asbestos causes is still lung glandular structures. cancer) Immunohistochemistry: TTF-1, napsin A (), Calretinin, CK5,6 (+). What is the diagnosis?

15. HEAD AND NECK Tuberculosis, pulmonary; Tuberculous lymphadenitis

Cell-mediated immunity (Granuloma is a T-cell response) Macrophages filled with acid fast bacilli

Based on the case above, if the patient is positive for HIV, and has a profoundly depressed CD4 count, what would be the expected morphologic finding? What is the cytokine secreted by TH1 cells IFN-γ that leads to formation of granulomas? TUBERCULOSIS: CLINICAL FORMS Form Lesions Sequelae Primary • Ghon focus • Healing by fibrosis (consolidation): (generally happens in subpleural, (lower part immunocompetent of upper lobe or upper individuals, and with part of lower lobe) anti-TB therapy) • Ghon complex: GF + pulmonary hilar node involvement Secondary • Simmon focus • Healing by fibrosis (consolidation): apical • Localized caseating destructive lesions • Progressive secondary Progressive • Erosion into bronchi or • Miliary pulmonary TB pulmonary vessels • Spread into adjacent parenchyma • Pleural involvement: effusions, empyema, obliterative fibrous pleuritis Miliary • Scattered small foci of • Disseminated TB pulmonary consolidation (Miliary pattern in other throughout lung organs) parenchyma

QUESTION ORAL CAVITY 46/M, smoker, with a white plaque on the lateral aspect of the tongue that cannot be scraped off. Punch biopsy showed acanthosis, hyperkeratosis, and atypical squamous cells, and an intact basement membrane. What is the diagnosis? Based on the case above, the patient was lost to follow-up, and after 5 years, presented with an ulcerating necrotic mass on the site where the plaque used to be. Biopsy showed nests of anaplastic cells with eosinophilic cytoplasm and several keratin pearls. What is the diagnosis? 39/F, with an enlarging mandibular mass. Panoramic X-ray: Soap bubble lesions with well-defined borders. Hemimandibulectomy was performed. Biopsy of the mass showed nests with an outer layer of columnar cells with reverse polarity of nuclei, and an inner layer, resembling stellate reticulum. What is the diagnosis? UPPER AIRWAYS 35/M, smoker, with chronic nasal congestion and cervical lymphadenopathy. Endoscopy: friable, cream-white mass obstructing the nasopharynx. Punch biopsy of the mass, and lymph node biopsy were performed, and showed sheets and nests of highly anaplastic cells with dense lymphocytic infiltrate in the stroma. What is the diagnosis? 4/M, with a history of hoarseness and stridor. Neonatal history: born via VSD to a mother with condyloma acuminata via a hilot in the province. Laryngoscopy: multiple, fleshy, papillary excrescences on the larynx. What is the diagnosis?

ANSWER Leukoplakia

Squamous cell carcinoma

Ameloblastoma

Nasopharyngeal carcinoma (Undifferentiated, Lymphoepithelial carcinoma)

Laryngeal papilloma (Juvenile respiratory papillomatosis)

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TOPNOTCH MEDICAL BOARD PREP PATHO SUPPLEMENT HANDOUT by KEVIN ELOMINA, MD For inquiries visit www.topnotchboardprep.com.ph or https://www.facebook.com/topnotchmedicalboardprep/ 70/M, smoker, presented with persistent hoarseness. Laryngoscopy: pale-tan exophytic mass on the on the larynx with friable excrescences. Biopsy shows nests of anaplastic cells with eosinophilic cytoplasm and several keratin pearls. What is the diagnosis? EARS 35/F with a chronic history of aural fullness and yellowish aural discharge, presented with unilateral hearing loss. Otoscopy revealed an "earwax-like" mass in the middle ear space. Mastoidectomy was done: Biopsy showed stratified cytologically benign squamous cells and keratinous material. What is the diagnosis? NECK 5/M, with a left lateral neck mass along the SCM. Excision biopsy was done, and showed a unilocular cystic space lined by stratified squamous epithelium with lymphoid aggregates on the cyst wall. What is the diagnosis? 6/F, with an anterior neck mass at the midline that moves with deglutition. Sistrunk procedure was performed, and biopsy showed a unilocular cystic space lined by respiratory epithelium with few islands of thyroid follicles on the cyst wall. What is the diagnosis? SALIVARY GLAND TUMORS 32/F, with a parotid mass. Excision biopsy was done, and showed nests of benign looking epithelial cells, occasionally forming duct-like structures, embedded in a myxoid stroma. What is the diagnosis? 36/F, with a parotid mass. Excision biopsy was done, and showed sheets of anaplastic squamous and mucussecreting cells. What is the diagnosis? 37/M, smoker, with a submandibular mass. Excision biopsy was done, and showed, double-layer of oncocytic epithelial cells with a dense lymphocytic infiltrate in the stroma. What is the diagnosis? 30/F, with a mass on the inner side of the upper lip. Excision biopsy was done, and showed gland-like structures; some showing cribriform pattern; lined by small cells with scant cytoplasm and hyperchromatic compact nuclei. What is the diagnosis?

Laryngeal squamous cell carcinoma

Chronic suppurative otitis media with cholesteatoma

Branchial cleft cyst

Thyroglossal duct cyst

Pleomorphic adenoma

Mucoepidermoid carcinoma Warthin tumor (Papillary cystadenoma lymphomatosum)

Adenoid cystic carcinoma

16. GASTROINTESTINAL TRACT

ESOPHAGUS NON-NEOPLASTIC LESIONS 23/M, with burning epigastric pain, heartburn and Reflux water brash. Endoscopy revealed mucosal breaks and esophagitis erythema. Biopsy show eosinophils in mucosa with basal zone hyperplasia exceeding 20% of total epithelial thickness. What is the diagnosis? Based on the case above, patient was lost to follow up, Barrett and came back after 5 years, without clinical esophagus improvement. Endoscopy revealed pinkish/reddish areas. Biopsy show intestinal metaplasia. What is the diagnosis? 47/M, chronic alcoholic, diagnosed with cirrhosis, Esophageal presents with hemoptysis and underwent shock, and varices eventually expired. Autopsy of the esophagus showed dilated submucosal vessels. What is the diagnosis? ESOPHAGEAL CARCINOMA Common presentation: Progressive dysphagia and/or odynophagia with constitutional symptoms e.g. weight loss 34/M, smoker, with a history of suicide attempt Squamous cell through caustic ingestion. Biopsy showed nests of carcinoma atypical squamous cells invading the stroma. What is the diagnosis? 34/M, smoker, with chronic untreated GERD. Adenocarcinoma Biopsy showed glands lined by dysplastic epithelial cells, invading the stroma. What is the diagnosis?

STOMACH GASTRITIDES Common presentation: Epigastric pain Endoscopy: predominantly antral erythema H. pylori Serology: anti H. pylori antibodies (+) gastritis Biopsy: Mononuclear infiltrate in lamina propria with intestinal metaplasia What is the diagnosis? Endoscopy: erythema pronounced at the corpus Autoimmune Serology: anti IF and proton pump antibodies (+) gastritis Biopsy: Chief cell loss with mononuclear infiltrate concentrated on the glands What is the diagnosis? PEPTIC ULCER DISEASE Common presentation: Epigastric pain with/without hematemesis Common morphology: NIGS: N: necrosis, I: acute inflammation, G: granulation tissue, S: fibrous scar (from superficial to deep) 34/F, with pain felt shortly after meals, without Gastric ulcer nocturnal awakening from pain. Gastric pH: increased Endoscopy: Ulcer located at the corpus 34/M, with pain felt hours after meals, with nocturnal Duodenal awakening from pain. Gastric pH: decreased ulcer Endoscopy: Ulcer located at the antrum NEOPLASMS 45/M, with progressive early satiety and Gastric carcinoma, profound weight loss. Endoscopy revealed an intestinal type ulcerated lesion with heaped-up borders. Biopsy showed structures resembling intestinal glands, lined by dysplastic epithelial cells invading the stroma. What is the diagnosis? Based on the case above, if biopsy revealed Gastric poorly cohesive cells with signet ring cells, adenocarcinoma, what is the diagnosis? diffuse type Based on the case above, if endoscopy revealed a Gastric MALT large, exophytic, cream-white, ovoid, fleshy lymphoma mass, and biopsy revealed sheets of uniform, small lymphocytes, what is the diagnosis? Based on the case above, if the patient presented Gastric carcinoid with diarrhea, flushing, and episodic dyspnea, and endoscopy revealed a small, exophytic, fleshy, ovoid, fleshy mass, and biopsy showed sheets and nests of uniform cells with scant cytoplasm and stippled nuclei, and immunohistochemistry: Chromgranin and Synaptophysin (+), what is the diagnosis? Based on the case above, if endoscopy revealed a Gastrointestinal large, fleshy, ovoid mass, and biopsy showed stromal tumor spindle cells, and immunohistochemistry: (GIST) CD117(+), what is the diagnosis? SMALL AND LARGE INTESTINES INFLAMMATORY BOWEL DISEASE Feature Crohn disease Ulcerative colitis Macroscopic Bowel region Ileum + colon Colon only Distribution Ski lesions Diffuse Stricture Yes Rare Wall appearance Thick Thin Microscopic Inflammation Transmural Limited to mucosa Pseudopolyps Moderate Marked Ulcers Deep, knife-like Superficial, broadbased Lymphoid reaction Marked Moderate Fibrosis Marked Mild to none Serositis Marked Mild to none Granulomas Yes (~35%) No Fistulous/sinuses Yes No Clinical Perianal fistula Yes (in colonic No disease) Fat/vitamin Yes No malabsorption Malignant potential With colonic Yes involvement Recurrence after Common No surgery Toxic megacolon No Yes

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TOPNOTCH MEDICAL BOARD PREP PATHO SUPPLEMENT HANDOUT by KEVIN ELOMINA, MD For inquiries visit www.topnotchboardprep.com.ph or https://www.facebook.com/topnotchmedicalboardprep/ NEOPLASMS 56/M, with pallor and weakness. CBC and PBS: Colonic microcytic hypochromic anemia; low serum Fe, adenocarcinoma high TIBC. Colonoscopy was done, showing a bulky, fleshy, exophytic mass in the ascending colon. Biopsy revealed irregular glands lined by dysplastic epithelial cells, invading the stroma. What is the diagnosis? FAMILIAL TUMOR SYNDROMES Parameter Familial adenomatous Hereditary nonpolyposis polyposis (FAP) colon cancer (HNPCC) (Lynch syndrome) Syndrome Multiple colorectal Familial clustering of adenomas as teenagers colorectum, endometrium, stomach, ovary, ureters, brain, small bowel, hepatobiliary tract, pancreas, and skin Mutations APC (Ch5) MSH2, MLH1 Diagnosis 100 polyps Amsterdam criteria Clinical Colonic adenocarcinoma significance develops in 100% of untreated patients often before 30 and nearly always by age 50 Associations Gardner syndrome: Osteomas, thyroid and desmoid tumors, skin cysts Turcot syndrome: Medulloblastoma, Glioblastoma APPENDIX 28/M, with initial periumbilical pain shifting to the Acute RLQ, with associated fever, anorexia, and vomiting. suppurative Appendectomy was performed. Biopsy showed PMNs in appendicitis muscularis layer. What is the diagnosis? 28/F, clinically diagnosed with acute appendicitis, Carcinoid, underwent appendectomy. Sections of the appendix appendix showed congestion, but an incidental finding of sheets and nests of uniform cells with scant cytoplasm and stippled nuclei. Immunohistochemistry: Chromogranin and Synaptophysin (+). What is the diagnosis?

17. LIVER AND GALLBLADDER LIVER QUESTION VIRAL HEPATITIDES 25/M, with history of eating street foods, presented with right upper quadrant pain and jaundice. ALT and AST were elevated; Serology: anti HAV (+); Liver biopsy showed scant portal mononuclear infiltrate, predominantly plasma cells, and hepatocyte necrosis and apoptosis. What is the diagnosis? 43/M, with positive HBsAg 7 months prior, still has (+) HBsAg, (-) anti HBs, and (+) HBeAg. ALT and AST were elevated; Liver biopsy showed dense portal mononuclear infiltrate, and ground-glass hepatocytes. What is the diagnosis? 43/M, with anti-HCV (+) for 8 months, underwent HCV RNA testing, which turned out to be positive. ALT and AST were elevated; Liver biopsy showed dense portal mononuclear infiltrate, lymphoid follicles, bile duct injury, and steatosis. What is the diagnosis? ALCOHOLIC LIVER DISEASE 56/M, chronic alcoholic, prefers hard drinks, and is usually out for drinking sessions at least 4x a week. Liver biopsy showed lipid droplets in hepatocytes. What is the diagnosis? Based on the case above, if liver biopsy showed hepatocyte swelling (ballooning) and necrosis, Mallory-Denk bodies, and neutrophilic infiltration, what is the diagnosis? Based on the case above, if liver biopsy showed perisinusoidal chicken-wire fence pattern of fibrosis, what is the diagnosis?

ANSWER Acute Hepatitis A infection

Chronic active Hepatitis B infection

Chronic Hepatitis C infection

METABOLIC LIVER DISEASE 45/M, known hypertensive and diabetic, nonalcoholic. Liver biopsy showed lipid droplets in hepatocytes. What is the diagnosis? Based on the case above, if liver biopsy showed predominantly mononuclear infiltrates, periportal fibrosis, and less Mallory-Denk bodies, what is the diagnosis? 27/M, known diabetic, with skin hyperpigmentation, and liver cirrhosis. Liver biopsy with Prussian blue revealed hemosiderin deposition in hepatocytes. What is the diagnosis? 34/M, came in the neurology clinic for dysarthria. On assessment of pupillary light reflex, (+) Kayser-Fleisher rings. Chemistry: low serum ceruloplasmin and high urinary Cu. What is the diagnosis? 21/F, presenting with exertional dyspnea and jaundice, with family history of lung disease. Liver biopsy showed PAS (+) hyaline globules. What is the diagnosis?

NAFLD NASH

Hereditary Hemochromatosis

Wilson disease (Hepatolenticular degeneration) α-1-antitrypsin deficiency

CHOLESTATIC LIVER DISEASE 44/F, known case of gallstones, presented with Ascending fever, jaundice and RUQ pain. Patient was cholangitis started on IV antibiotics and underwent ERCP with sphincterotomy, What is the diagnosis? 1w/M, with jaundice and bilirubinuria. TB and Extrahepatic DB were elevated. If liver biopsy showed biliary atresia inflammation and fibrosing stricture of the hepatic bile ducts, what is the diagnosis? GALLBLADDER NON-NEOPLASTIC CONDITIONS 45/F, obese, presented with colicky Chronic calculous epigastric pain after eating. cholecystitis Cholecystectomy was performed. Grossly, (Xanthogranulomatous the gallbladder is filled with stones and cholecystitis) the mucosal surface is ridden with multiple yellow pinpoint excrescences. Biopsy showed mononuclear infiltrates in the mucosa with lipid-laden macrophages (cholesterolosis), and prominent Rokitansky-Aschoff sinuses. What is the diagnosis? TUMORS 45/F, managed as a case of chronic calculous cholecystitis is undergoing laparoscopic cholecystectomy, but gallbladder was found to be large, needing conversion to open cholecystectomy. Biopsy showed irregular glands lined by dysplastic epithelial cells, invading the stroma. What is the diagnosis? 50/F, presenting with signs of obstructive jaundice, with dyspnea. CXR: multiple cannon-ball lesions; Abdominal UTZ: multiple hepatic nodules. Patient eventually expired. Biopsy of the bile duct showed glands lined by dysplastic epithelial cells that invade the stroma. What is the diagnosis?

Gallbladder adenocarcinoma

Cholangiocarcinoma

Hepatocellular steatosis Alcoholic steatohepatitis Alcoholic Steatofibrosis

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TOPNOTCH MEDICAL BOARD PREP PATHO SUPPLEMENT HANDOUT by KEVIN ELOMINA, MD For inquiries visit www.topnotchboardprep.com.ph or https://www.facebook.com/topnotchmedicalboardprep/ Features Age Gender Clinical course Associated conditions

Serology

Radiology

Inflammation Bile ducts involved Histologic pearls

Diagnosis Others

AUTOIMMUNE CHOLANGIOPATHIES Primary sclerosing Primary biliary cirrhosis cholangitis Median age 50 years (30-70) Median age 30 90% Female 70% Male Progressive Unpredictable but progressive Sjogren syndrome (70%) IBD (70%) Scleroderma (5%) Pancreatitis (≤25%) Thyroid disease (20%) Idiopathic fibrosing diseases (retroperitoneal fibrosis 95% AMA(+) 0-5% AMA(+) (low 50% ANA(+) titer) 40% ANCA(+) 6% ANA(+) 65% ANCA(+) Normal Strictures and beading of large bile ducts; pruning of smaller ducts Often granulomatous Sclerosing Small to medium-sized, All sizes, Intrahepatic Intrahepatic and Extrahepatic • Active destruction of • Large duct: interlobular bile ducts by Neutrophilic lymphoplasmacytic infiltration on a infiltration with or without background of granulomas (Florid duct chronic lesion) inflammation • (+) Mallory-Denk bodies • Small duct: onion• Ductular reaction skin fibrosis • Micronodular cirrhosis with hepatomegaly (vs. other forms of cirrhosis) Liver biopsy Radiologic imaging of biliary tree (beading of contrast medium) - Increased risk of cholangiocarcinoma

STRUCTURAL ABNORMALITIES IN THE BILIARY TREE 20/M, with jaundice, RUQ pain, and an Choledochal cyst abdominal mass. Exploratory laparotomy was performed, which showed cystic dilatation of the common bile duct. What is the diagnosis? TUMORS 43/F, asymptomatic, underwent abdominal UTZ, with an incidental finding of a well-demarcated, hyperechoic nodule that she wants to be removed. Biopsy showed large, dilated blood-filled spaces lined by endothelial cells. What is the diagnosis? 40/F, asymptomatic with an incidental finding of a liver nodule with a central scar on CT. Angiography: hypervascular lesion, with normal to increased uptake in liver scan. Biopsy showed nodules with large arteries not accompanied by veins or bile ducts. What is the diagnosis? Based on the case above, if CT findings did not show any central scar, and angiography showed a hypovascular lesion with no uptake on liver scan, and biopsy showed sheets of normal-looking hepatocytes without portal tracts, what is the diagnosis? 47/M, known case of chronic hepatitis B with cirrhosis, presented with dyspnea and jaundice. CXR: multiple cannon ball lesions; elevated serum AFP. CT scan showed a lesion in the liver with early arterial enchancement and early washout of contrast. Biopsy showed sheets of anaplastic hepatocytes; some of which form pseudoglandular structures. What is the diagnosis?

Cavernous hemangioma

Focal nodular hyperplasia

Hepatic adenoma

Hepatocellular carcinoma

18. PANCREAS QUESTION PANCREATITIDES 55/M, alcoholic, with history of gallstones, but refused to be operated on, presented with severe epigastric pain, boring in character, radiating to the back, with associated jaundice, acholic stools, and tea-colored urine. Despite appropriate management, he expired. Autopsy of the pancreas shows microvascular leak and edema, enzymatic fat necrosis, acute inflammation, destruction of pancreatic parenchyma, and destruction of blood vessels, and interstitial hemorrhage. What is the diagnosis? 59/M, alcoholic, complaining of recurrent epigastric pain with food intake, with consequent anorexia and weight loss, coupled with chronic steatorrhea. He was admitted for pneumonia for several days, and eventually expired. Autopsy of the pancreas shows fibrosis, atrophy, dropout of acini, variable dilation of pancreatic ducts, and chronic inflammation. What is the diagnosis? NEOPLASMS 68/M, smoker, presents with jaundice, acholic stools, tea-colored urine, with associated cough. Chemistry: Elevated TB and DB; Serology: (+) CA 19-9. Imaging showed a mass on the pancreatic head, with multiple nodules on the liver and the lungs. Biopsy showed glands lined by dysplastic epithelial cells accompanied by intensely desmoplastic stroma. What is the diagnosis?

ANSWER Acute pancreatitis (Biliary pancreatitis)

Chronic pancreatitis

Pancreatic adenocarcinoma with metastases to the liver and lungs

19. KIDNEY QUESTION ANSWER GLOMERULAR DISEASES Nephritic syndrome: 1. Hematuria (with dysmorphic RBCs and red cell casts indicating glomerular pathology); 2. Oliguria and azotemia; and 3. Hypertension 15/M, with history of sore throat 4 weeks prior to onset of PSAGN symptoms, with an increased ASO titer, and decreased C3. LM: diffuse hypercellularity (almost, if not all glomeruli) EM: subepithelial humps on GBM IF: granular deposits of IgG and complement within the capillary walls mesangium Rapidly progressing glomerulonephritis: syndrome of progressive loss of renal function, characterized by nephritic syndrome often with severe oliguria; histologic hallmark is presence of “crescents”, thus crescentic GN 25/M, smoker, with history of hemoptysis and oliguria RPGN EM: ruptures in the GBM Type I IF: linear IgG and C3 deposits along the GBM 15/M, with a history of PSAGN RPGN EM: “lumpy bumpy” appearance of GBM (due to deposits) Type II IF: granular deposition of Ig and complement in GBM 30/M, known case of microscopic polyangiitis RPGN EM: no detectable deposits Type III IF: negative for Ig and complement 19/F with ESRD. Grossly, kidneys are symmetrically contracted, surfaces are red-brown and diffusely granular; histologically, glomeruli are obliterated with marked interstitial fibrosis. What is the diagnosis?

Chronic GN

Nephrotic syndrome: 1. Massive proteinuria (≥3.5g/dL; 2. Hypoalbuminemia (<3g/dL); 3. Generalized edema; 4. Hyperlipidemia and lipiduria 7/M, with puffy eyelids and scrotal edema Minimal change LM: none disease/Lipoid EM: uniform and diffuse effacement of foot nephrosis processes of the podocytes 29/M, MSM, HIV (+) with a history of heroin abuse. Focal segmental LM: increased mesangial matrix, obliterated glomerulosclero capillary lumina, and deposition effacement of foot sis (FSGS) processes of hyaline masses (hyalinosis) and lipid droplets. EM: Effacement of foot processes IF: nonspecific trapping of immunoglobulins, usually IgM, and complement in the areas of hyalinosis 25/F with Lung carcinoma. Membranous LM: diffuse thickening of the capillary wall nephropathy EM: subepithelial deposits along the GBM (spike and dome appearance); effacement of foot processes IF: granular deposits of immunoglobulins and complement along the GBM

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TOPNOTCH MEDICAL BOARD PREP PATHO SUPPLEMENT HANDOUT by KEVIN ELOMINA, MD For inquiries visit www.topnotchboardprep.com.ph or https://www.facebook.com/topnotchmedicalboardprep/ 29/F with SLE. LM: Thickened split GBM (Tram track appearance) EM: subendothelial electron-dense deposits IF: Irregular granular C3 deposits, with IgG and early complement components (C1q and C4) 32/F with a complement defect i.e. persistent activation. LM: Thickened split GBM (Tram track appearance) EM: lamina densa and glomerular capillary wall transformed into irregular, ribbon-like, extremely electron-dense structure IF: Irregular chunky and segmental linear foci of C3 deposits in GBM and mesangium, without IgG and early complement components (C1q and C4) ISOLATED GLOMERULAR ABNORMALITIES 26/F, with history of viral URTI, developed hematuria LM: mesangial widening and segmental inflammation EM: mesangial electron-dense deposits IF: mesangial deposition of IgA, often with C3 and properdin and smaller amounts of IgG or IgM 8/M, with palpable purpura in both lower extremities, abdominal pain, and hematuria Morphologic findings same as above. 11/M, with anterior lenticonus, sensorineural hearing loss, and hematuria with proteinuria LM: glomerulosclerosis, vascular sclerosis, tubular atrophy, and interstitial fibrosis EM: thin GBM (early); irregular foci of GBM thickening or attenuation (late); “basket-weave” appearance TUBULES AND INTERSTITIUM 25/M, victim of hazing, with multiple ecchymoses on both thighs, presents with cola-colored urine and increased BUN and creatinine. LM: Extensive necrosis of tubules primarily involving the proximal tubules 26/F, with fever, chills and left flank pain. Urinalysis: WBC: 50-60/HPF with several WBC casts. LM: Patchy, interstitial suppurative inflammation, intratubular aggregates of neutrophils, neutrophilic tubulitis and tubular necrosis 35/F, with history of recurrent acute pyelonephritis, presents with increased BUN and creatinine. LM: Thyroidization and tubular atrophy; vascular sclerosis in scarred areas 25/F, with increased BUN and creatinine, and a history of Methicillin intake. LM: interstitial inflammation, with abundant eosinophils with several eosinophils and edema

MPGN Type I

Dense deposit disease

IgA nephropathy (Berger disease)

HenochSchonlein purpura Alport syndrome

Acute tubular necrosis (Toxic ATN) Note: Ischemic ATN has a different distribution of necrosis

Acute pyelonephritis

Chronic pyelonephritis

Drug-induced interstitial nephritis

VASCULAR DISEASES 56/M, known diabetic, with increasing BUN and Nephrosclerosis creatinine. Impression was diabetic nephropathy. Blood vessels show hyaline arteriolosclerosis. What is the diagnosis? 50/M, known diabetic, with treatment resistant Renal artery hypertension that started 2 months ago. Renal stenosis vein sampling: right: normal renin, left: elevated renin. What is the most likely diagnosis? CYSTIC DISEASES OF THE KIDNEY Parameter Autosomal dominant Autosomal recessive (Adult) (Childhood) Mutation • PKD1 (polycystin-1, PKHD1 (fibrocystin, Ch6; Ch16; distal nephron) fetal kidney, liver and (85%; more severe) pancreas) • PKD2 (polycystin-2, Ch4; all segments of tubules) (15%; less severe) Renal failure Yes Associated • Liver cysts Periportal fibrosis (if anomalies • Intracranial berry patients survive infancy) aneurysms • Mitral valve prolapse Most common Coronary or hypertensive Renal failure (in infancy) cause of death heart disease (40%)

NEPHROLITHIASES Common presentation: Painful hematuria TYPES OF NEPHROLITHS Stone Urine Radiologic pH appearance Calcium oxalate Acidic Opaque Magnesium Basic Opaque ammonium phosphate/ Triple phosphate/ Struvite Uric acid Acidic Lucent Cystine

Acidic

Opaque, but difficult to visualize than Ca stones

TUMORS 62/M, smoker, with hematuria, left flank pain and a palpable left flank mass. CT-scan showed a renal mass suspicious of malignancy, and nephrectomy was done. What is the most likely diagnosis? Biopsy shows rounded or polygonal cells with abundant clear or granular cytoplasm. What is the diagnosis? Biopsy shows cuboidal or low columnar cells arranged in papillary formation with Psammoma bodies. What is the diagnosis? Biopsy shows pale eosinophilic cells, often with a perinuclear halo, arranged in solid sheets with a concentration of the largest cells around blood vessels. What is the diagnosis?

Associated conditions Various Proteus infections Large stones occupying renal calyces: Staghorn calculi Hyperuricemia/Hy peruricosuria Cystinuria

Renal cell carcinoma (RCC)

Clear cell RCC Papillary RCC Chromophobe RCC

20. LOWER URINARY TRACT AND MALE GENITAL TRACT QUESTION LOWER URINARY TRACT URINARY BLADDER 49/M, smoker, with painless hematuria, without any palpable flank or abdominal mass. Cystoscopy showed multiple hemorrhagic papillary excrescences. Biopsy was done, which showed a papillary architecture lined by highly atypical cells with high mitotic index, invading the muscularis propria. What is the diagnosis, and what is the prognosis? 49/M, with painless hematuria, and history of multiple urinalysis results with a finding of parasitic ova with prominent terminal spine. Cystoscopy showed ulcerations with heaped-up borders with friable excrescences. Biospy showed sheets of anaplastic cells with eosinophilic cytoplasm and prominent intercellular bridges. What is the diagnosis, and the parasitic infection that led its development? TESTIS NON-NEOPLASTIC CONDITIONS 12/M, with an incidental finding of an absent left testicle, and a left inguinal mass. Diagnosis was indirect inguinal hernia, left and the herniated testicle was removed. Biopsy of the testis showed arrest in germ cell development, hyalinization and thickening of BM, increase in interstitial stroma, and prominent Leydig cells. What is the diagnosis? 15/M, biker, complained of pain on the right testicle 12 hours prior to consult. Doppler ultrasound showed absent blood flow on the left testicle. The patient was operated immediately, but the testis was grossly hemorrhagic intraoperatively, and was consequently removed. Biopsy of the testis showed hemorrhagic infarction. What is the diagnosis?

ANSWER

Muscle-invasive urothelial carcinoma (from high-grade urothelial carcinoma); Poor prognosis compared to superficial invasive and non-invasive Squamous cell carcinoma, Schistosoma haematobium

Cryptorchidism

Hemorrhagic infarction secondary to testicular torsion

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TOPNOTCH MEDICAL BOARD PREP PATHO SUPPLEMENT HANDOUT by KEVIN ELOMINA, MD For inquiries visit www.topnotchboardprep.com.ph or https://www.facebook.com/topnotchmedicalboardprep/ TESTICULAR NEOPLASMS Common presentation: testicular mass; always take note of the age of the patient when attempting to diagnose a testicular neoplasm. Note: the most common cause of painless testicular enlargement is a testicular tumor; so a testicular mass is considered neoplastic, unless proven otherwise 35/M, biopsy showed sheets of large, Seminoma (Classic) uniform cells with clear cytoplasm and round nuclei with conspicuous nucleoli, Note: Female and intervening fibrous septae infiltrated counterpart is with lymphocytes; Immunohistochemistry: Dysgerminoma CD117 (c-kit) and PLAP (+). What is the diagnosis 30/M, biopsy showed large, anaplastic cells Embryonal carcinoma with indistinct borders, tumor giant cells, and frequent mitosis. Immunohistochemistry: CD117, PLAP (-), CD30 (+). What is the diagnosis? 3/M, biopsy showed glomeruloid structures Yolk sac (Schiller-Duval) bodies and PAS-positive tumor/Endodermal hyaline globules. Immunohistochemistry: sinus tumor/Infantile AFP (+). What is the diagnosis? embryonal carcinoma 40/M, with multiple cannon-ball lesions on Choriocarcinoma CXR, without a palpable testicular mass, and an elevated serum HCG. VATS was done to get a biopsy of the nodules, which showed sheets of anaplastic cytotrophoblasts and synctiotrophoblasts without villus formation. What is the diagnosis? 5/M, biopsy showed haphazardly arranged Teratoma (Benign) neural tissue, cartilage, adipose tissue, bone, and epithelial elements. What is the diagnosis, and what is the expected biological behavior of the tumor? Based on the case above, if the same tumor Malignant was observed in a 16-year old, what would be the expected biologic behavior of the tumor? 65/M, with rapidly enlarging testicular Testicular lymphoma mass. Biopsy of the testis showed sheets of (Diffuse Large B-cell large, anaplastic cells. lymphoma) Immunohistochemistry: CK and vimentin (-), LCA/CD45, CD79a (+). What is the diagnosis? PROSTATE 78/M, with nocturia. KUB-Prostate UTZ: enlarged prostate with estimated weight of 60 grams. Free PSA is elevated. TURP was performed. Biopsy showed epithelial and stromal hyperplasia with fibrous septae forming multiple nodules. What is the diagnosis? 80/M, with nocturia. KUB-Prostate UTZ: enlarged prostate with estimated weight of 60 grams. Complexed PSA is elevated. TURP was performed. Biopsy showed small, predominantly discrete and confluent glandular structures, with several areas showeding cribriform pattern invading the fibromuscular stroma. What is the diagnosis?

Nodular prostatic hyperplasia

Prostatic adenocarcinoma (Gleason 3+4), WHO group grade 2

21. FEMALE GENITAL TRACT Note: The chapter focuses on highly recurring concepts on the female genital tract. Please refer to the main handout for a more detailed discussion. QUESTION ANSWER CERVIX 32 G0, complaining of post-coital bleeding with Endocervical minimal dyspareunia. Speculum exam revealed a polyp fleshy polypoid mass on the cervix. Polypectomy was done, showing a polypoid tissue with endocervical lining and an edematous stroma with mild chronic inflammation. What is the diagnosis? 45 G5P5 (5005), came for a routine gynecologic Low-grade checkup. Pap smear revealed atypical squamous squamous cells of undetermined significance (ASCUS). intraepithelial Repeat Pap smear revealed atypical squamous lesion (LSIL) cells. Raising suspicion, colposcopy was performed and punch biopsy was done on the suspicious area. Biopsy showed atypical squamous cells occupying the lower 1/3 of the epithelial thickness. What is the diagnosis?

Based on the case above, if the atypical squamous cells occupy the lower full-thickness of the epithelium, What is the diagnosis?

High-grade squamous intraepithelial lesion (HSIL), Carcinoma in situ Cervical squamous cell carcinoma

32 G4P4 (4004), presented with foul-smelling discharge per vagina, and vaginal bleeding. IE: ~ 4 cm mass on the cervix at the 9 o'clock position, Bilateral parametria were unremarkable. Speculum examination revealed pale-tan, exophytic mass with friable excrescences. Punch biopsy was done showing sheets of anaplastic squamous cells. What is the diagnosis? BODY OF THE UTERUS ENDOMETRIOSIS AND ADENOMYOSIS 43 G0 complaining of intense dysmenorrhea and Endometriosis dyspareunia. Ultrasound revealed a cystic mass (Pelvic on the right ovary. Right oophorocystectomy was endometriosis, perfomed. Incidental finding of multiple severe; peritoneal implants was noted, and samples were endomteriotic taken for biopsy. Grossly, the mass consists of a cyst, right ovary) unilocular cystic space containing chocolate brown material. Sections show endometrial lining of the cyst wall. Biopsy of the implants showed endometrial glands and stroma surrounded by a fibrotic stroma with chronic inflammation. What is the diagnosis? 44 G3P3 (3003) complaining of chronic Adenomyosis dysmenorrhea and menorrhagia. Corpus size is compatible with that of 16 weeks AOG. TAHBSO was performed and showing thickened myometria with blood lakes. Biopsy revealed endometrial stroma with glands in the myometrium found ~ 5mm from the decidua basalis layer. What is the diagnosis? ENDOMETRIAL DISORDERS Common presentation: abnormal uterine bleeding 44 G2P2 (2002). UTZ: polypoid mass on the Endometrial endometrial canal. UTZ-guided endometrial polyp biopsy was done. Biopsy showed proliferative phase endometrial glands in a fibrous stroma. What is the diagnosis? 47 G0. Diagnostic curettage was performed Endometrial yielding curettings with an aggregate diameter of hyperplasia 7.0 cm. Biopsy show back-to-back glands; some (Complex of the cells lining the glands exhibit nuclear hyperplasia with rounding (normal is cigar-shaped). What is the atypia) diagnosis? 45 G0. Diagnostic curettage was performed Endometrioid yielding curettings with an aggregate diameter of carcinoma (Type 5.0 cm. Biopsy showed haphazardly-arranged, I) irregular, discrete and confluent glands lined by cells with minimal atypia; some showing cribriform pattern. Areas of squamous differentiation are also noted. What is the diagnosis? 65 G0, with palpable hypogastric mass. Serous carcinoma Diagnostic curettage was performed yielding (Type II) curettings with an aggregate diameter of 12.0 cm. Biopsy showed papillary fronds lined by highly anaplastic cells with high mitotic rate, some of which exhibit detachment and hobnail pattern. Areas of necrosis are also noted. What is the diagnosis? MYOMETRIAL TUMORS 45 G4P4 (4004), apparently asymptomatic, came Leiomyoma in for a routine gynecologic check-up. UTZ: multiple myoma uteri. TAHBSO was performed. Grossly, multple, cream-white, wellcircumscribed, non-encapsulated, firm masses are noted within the myometrium. Sections show benign-looking smooth muscle cells arranged in whorling pattern. What is the diagnosis? 45 G5P5 (5005), with abdominal enlargement Leiomyosarcoma and profound weight loss. UTZ: Solitary myometrial mass suspicious of malignancy. TAHBSO was performed. The mass was noted to be grossly necrotic and hemorrhagic. Sections show sheets of highly atypical cells with necrosis and high mitotic index. IHC: Smooth muscle actin (+). What is the diagnosis? OVARIES OVARIAN TUMORS Common presentation: Ovarian mass, with abdominal fullness and pain (if large); pain is more pronounced if torsion occurs

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TOPNOTCH MEDICAL BOARD PREP PATHO SUPPLEMENT HANDOUT by KEVIN ELOMINA, MD For inquiries visit www.topnotchboardprep.com.ph or https://www.facebook.com/topnotchmedicalboardprep/ Surface epithelial (Mullerian) tumors Note: Remember that there are benign, borderline, and malignant classifications of these tumors, depending on the cytologic atypia, architectural complexity, and stromal invasion. The details of which are beyond the scope of being a general practitioner. Histologically characterized by tubal-like Serous tumors epithelial lining Histologically characterized by either intestinal or Mucinous tumor endocervical epithelial lining (mucincontaining) Histologically characterized by glandular Endometrioid structures resembling endometrial glands tumors Germ cell tumors Note: Other germ cell tumors are discussed in Male genital tract Cystic, lined by skin-like structures (dermoid Mature cystic cyst); usually occur in reproductive age women; teratoma histologically, derivatives from more than one germ layer can be seen; generally benign Solid masses that usually occur in younger Immature women and children; histologically composed of teratoma neuroepithelium; generally malignant Sex-cord stromal tumors Note: Aside from the presence of ovarian mass, depending on the capability of the tumor to produce hormones, additional clinical manifestations referable to sex hormone excess may help you clinch the diagnosis May clinically present as precocious puberty (in Granulosa cell premenarcheal) or abnormal uterine bleeding (in tumor menstruating and postmenopausal), due to its estrogen secretion; histologically characterized by sheets of cuboidal granulosa cells; some of the cells recapitulate ovarian follicle as Call-Exner bodies May clinically present with virilization, due to its Sertoli-Leydig androgen secretion; histologically, the tumor cell tumor recapitulates Tubules formed by Sertoli cells, or Leydig cells interspersed in stroma Usually associated with hydrothorax and ascites Thecoma(Meig syndrome); histologically composed of fibroma sheets of fibrous cells or (lipid-laden) plump thecal cells, or in combination DISEASES OF PREGNANCY 31 G1P0 12 weeks AOG, with passage of grapelike vesicles per vagina and bleeding. Corpus size is 16 weeks AOG. UTZ: snowstorm appearance. Suction curettage was done. Biopsy revealed DIFFUSE villus edema and trophoblastic proliferation with several atypical trophoblasts. What is the diagnosis? 31 G1P0 12 weeks AOG, with passage of meaty material per vagina and bleeding. Diagnosis was incomplete abortion, and completion curettage was performed. Biopsy revealed FOCAL villus edema and trophoblastic proliferation with few atypical trophoblasts. What is the diagnosis? 31 G1P0 (0010) with a history of complete hydatidiform mole with a persistently elevated HCG after post-curettage surveillance, presented with hemoptysis. CXR: cannon-ball lesions. Biopsy of the lesions showed sheets of atypical cytotrophoblasts and syncytiotrophoblasts WITHOUT villus formation. What is the diagnosis?

Complete hydatidiform mole

Incomplete (Partial) hydatidiform mole Gestational choriocarcinoma

22. BREAST

In practice, the common complaint of patients with breast disease, which warrants histologic evaluation, is the presence of a mass. Other lesions may have clinical findings that are suggestive of a particular lesion. QUESTION ANSWER NON-PROLIFERATIVE BREAST CHANGES 32/F. Biopsy showed fibrosis, increase in the Fibrocystic number of acini per lobule, and cystic dilatation change of the acini; some which show apocrine metaplasia. What is the diagnosis? PROLIFERATIVE BREAST DISEASES WITHOUT ATYPIA 34/F. Biopsy showed fibrocystic changes and Epithelial areas showing ducts lined by more than 2 layers hyperplasia of cells with slit-like lumina at the periphery, and an intact myoepithelial layer. What is the diagnosis? 37/F. Biopsy showed cords and sheets of cells Sclerosing within a sclerotic stroma, with dilated ducts at adenosis the periphery. Immunohistochemistry: p63, CK5,6 (+). What is the diagnosis?

27/F with bloody nipple discharge. Biopsy Intraductal showed papillary fronds within a duct. papilloma Immunohistochemistry: p63, CK 5,6 (+). What is the diagnosis? 35/F. Biopsy showed central nidus of entrapped Complex glands within a hyalinized stroma, with sclerosing fibrocystic changes and epithelial hyperplasia lesion/Radial on adjacent areas. What is the diagnosis? scar PROLIFERATIVE BREAST DISEASES WITH ATYPIA AND CARCINOMA IN SITU 46/F. Biopsy showed nests of monomorphic cells, Atypical ductal and ducts filled with the same cells, showing hyperplasia cribriform pattern. The changes do not involve the (ADH) whole duct. What is the diagnosis? Based on the case above, if the change involves the Ductal whole duct, what would be the diagnosis? carcinoma in situ (DCIS) Based on the second case, if there are dilated ducts Comedo DCIS lined by cells with high-grade nuclear atypia and central necrosis, what would be the specific diagnosis? Based on the first case, if biopsy revealed Atypical lobular monomorphic cells proliferating within the lobule hyperplasia of the acini, but the change is evident in only 10% (ALH) of the acini in a lobule, what would be the diagnosis? Based on the fourth case, if the change involves all Lobular of the acini in a lobule, what is the diagnosis? carcinoma in situ (LCIS) CARCINOMAS 45/F, with a rash on the nipple area. PE: (+) firm Paget disease of mass, on the upper outer quadrant of the breast. the nipple Biopsy of the rash showed large cells with mild nuclear atypia in the epidermis. Immunohistochemistry: Epithelial membrane antigen (EMA) (+). What is the diagnosis? Based on the case above, mastectomy was Invasive performed. Grossly, there is a cream-tan, firm mass (ductal) with irregular borders. Sections show cells with carcinoma (No moderate pleomorphism, forming tubule-like special type) structures (>80%) with occasional solid nests Welland sheets. Mitosis is 1-3/10 HPF. What is the differentiated diagnosis and what is the histologic grade? (Elston score: 4 = 1+2+1) Based on the second case, if biopsy showed cords of Invasive lobular medium-sized cells showing an Indian filing carcinoma pattern, and cords of cells encircling a duct (targetoid pattern), and IHC for E-cadherin turned out to be negative, what is the diagnosis? Based on the second case, if biopsy showed nests of Pure mucinous atypical cells, floating in pools of mucin, carcinoma comprising 95% of the tumor, what is the diagnosis? 65/F, with breast pain, and a firm mass at the Inflammatory upper outer quadrant. PE: erythematous, (+) carcinoma orange peel appearance of skin, tender breast. Biopsy showed solid sheets and nests of cells with high-grade nuclear atypia, and numerous mitotic figures. What is the diagnosis? 60/F, with a firm mass on the upper outer Medullary quadrant. Biopsy showed syncytium-like solid carcinoma sheets of large cells with pleomorphic nuclei and prominent nucleoli, with high mitotic index, dense lymphoplasmacytic infiltrate, and pushing borders. Immunohistochemistry: ER, and HER-2 (-). what is the diagnosis? MOLECULAR SUBTYPES OF BREAST CANCER Luminal HER-2 Feature Basal enriched A B Phenotype ER(+), HER2(-) HER2(+) ER(-), ER, PR (+/-) HER2(-) Frequency 40-55% ~10% ~20% ~15% Proliferation Low High N/A index (Ki-67) Treatment Hormonal therapies HER-2 In study (Tamoxifen) targeted therapy (Trastuzumab) STROMAL TUMORS 25/F, with 2.0 cm mass. Biopsy showed Fibroadenoma proliferation of intralobular stroma that surrounds and compresses the ducts. What is the diagnosis?

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TOPNOTCH MEDICAL BOARD PREP PATHO SUPPLEMENT HANDOUT by KEVIN ELOMINA, MD For inquiries visit www.topnotchboardprep.com.ph or https://www.facebook.com/topnotchmedicalboardprep/ 50/F, with 6.0 cm mass. Biopsy showed intense proliferation of intralobular stroma with leaf-like processes lined by ductal epithelium; there is stromal hypercellularity, cellular atypia, and increaed mitotic index. What is the diagnosis? DISEASES OF THE MALE BREAST 24/M, with bilateral areolar swelling. Excision was performed, and biopsy showed increase in connective tissue and epithelial hyperplasia of the ducts, without lobule formation. What is the diagnosis?

Phyllodes tumor

Gynecomastia

23. ENDOCRINE SYSTEM PITUITARY GLAND QUESTION ANSWER 34/F, with galactorrhea and amenorrhea. Pituitary adenoma Imaging showed a pituitary mass, (Prolactin cell measuring 2.0 cm. Transsphenoidal adenoma) resection was done. Biopsy showed sheets of benign-looking pituicytes with sparse reticulin network. What is the diagnosis? Based on the case above, if metastases Pituitary carcinoma were found in other sites, what would be the diagnosis? 15/M, with a cranial mass. Biopsy showed Craniopharyngioma a lesion that looks like an ameloblastoma. (Adamantinomatous) What is the most likely diagnosis? THYROID GLAND HYPOTHYROIDISM 6/M, with mental retardation, short stature, Cretinism coarse facial features, protruding tongue, umbilical hernia, and history of maternal hypothyroidism. What is the diagnosis? 34/F, with profound weight gain, deepening of Myxedema voice, and nonpitting edema. Skin biopsy showed accumulation of matrix substances, such as glycosaminoglycans and hyaluronic acid. What is the diagnosis? THYROIDITIDES 35/F, with thyroid enlargement. Total Hashimoto thyroidectomy was done. Biopsy showed thyroiditis lymphoid follicles scattered throughout the parenchyma with Hurthle cell change. What is the most likely diagnosis? 35/F, with a history of viral URTI, complained of De Quervain anterior neck pain and sudden thyroid thyroiditis enlargement. Total thyroidectomy was done. Biopsy showed granulomatous inflammation. What is the diagnosis? GRAVES DISEASE 36/F, with proptosis, pretibial myxedema, and Graves Disease modest thyroid enlargement. TSH is low and FT4 is high. Total thyroidectomy was done. Biopsy showed diffuse hyperplasia with pseudopapillary structures and moth-eaten colloid. What is the diagnosis? GOITERS 45/F, with an anterior neck mass. Total Colloid goiter thyroidectomy was done. Cut sections show a single nodule. Biopsy showed follicles distended by abundant amount of colloid. What is the diagnosis? Based on the case above, if cut sections show Multinodular multiple nodules, and biopsy showed multiple goiter nodules distended by colloid, as well as nodules forming pseudopapillary structures, what is the diagnosis? Based on the case above, if the patient presented Plummer with hyperthyroidism, and the histologic syndrome diagnosis is still multinodular goiter, what is the clinical diagnosis? TUMORS 38/F, with an anterior neck mass. Total Papillary thyroidectomy was done. Biopsy showed carcinoma papillary fronds lined with atypical thyrocytes with Orphan Annie nuclei and Psammoma bodies. What is the diagnosis? Based on the case above, if grossly there is only Follicular one nodule observed, and biopsy showed sheets adenoma of benign-looking thyrocytes without capsular or vascular invasion, what is the diagnosis? Based on the second case, if capsular and Follicular vascular invasion were observed, what would carcinoma be diagnostic?

67/M, with a history of multinodular goiter, Anaplastic presented with sudden, massive enlargement of (undifferentiated) the thyroid gland with profound weight loss. carcinoma Total thyroidectomy was done. Biopsy showed sheets of highly anaplastic cells. Immunohistochemistry: CK (+), thyroglobulin (). What is the diagnosis? 25/M, with strong history of MEN2A in the Medullary family, underwent total thyroidectomy. Cut carcinoma sections show bilateral thyroid masses. Biopsy showed sheets of polygonal cells with amyloid deposition. What is the diagnosis? ENDOCRINE PANCREAS DIABETES MELLITUS 15/M, with polyuria, polydipsia, and polyphagia, Type 1 DM forgot his insulin for a week, presented with weakness and increased sleeping time at the ER, and eventually expired. Autopsy of the pancreas showed lymphocytic infiltration of the islets (insulitis). What is the diagnosis? 44/F, with polyuria, polydipsia, and polyphagia, Type 2 DM presented with a gangrenous foot and high-grade fever. Patient eventually died of septic shock. Autopsy of the pancreas showed amyloid deposition. What is the diagnosis? Based on the case above, if the patient lived longer, but Diabetic presented with rising BUN and creatinine, and then nephropathy eventually died of uremia, and autopsy of the kidney showed hyaline arteriolosclerosis and nodular glomerulosclerosis (Kimmelsteil-Wilson lesion), what is the diagnosis? Based on the second case, if the patient lived, but Diabetic presented with progressive deterioration of visual retinopathy acuity, and retinal workup showed neovascularization and cotton-wool exudates, what is the diagnosis? PANCREATIC NEUROENDOCRINE TUMORS Parameter Insulinoma Gastrinoma Clinical Hyperinsulinism Hypergastrinemia syndrome Whipple Triad Zollinger-Ellison 1. Hypoglycemia (<50 syndrome mg/dL) 1. Pancreatic islet 2. Neuroglycopenic cell tumor symptoms 2. Hypersecretion of 3. Relief upon parenteral gastric acid glucose administration 3. Severe peptic ulceration (may occur in jejunum) Location Pancreas Gastrinoma triangle Biologic Usually benign Usually malignant behavior Gross and May recapitulate normal pancreatic islets; even histology malignant tumors can be encapsulated; amyloid deposition (in insulinomas) ADRENAL GLANDS ADRENAL CORTEX 34/M, obese with moon facies, purple Cushing syndrome abdominal striae, and dorsocervical secondary to cortisolfullness (buffalo hump). 24-hour urine secreting adrenal cortisol is increased. Plasma ACTH is adenoma decreased. Imaging showed a right adrenal mass. Biopsy showed cells resembling normal zona fasciculata. What is the diagnosis? Based on the case above, if plasma ACTH is Cushing disease increased, and imaging showed bilateral (Cushing syndrome adrenal hyperplasia, and cranial MRI secondary to ACTHshowed a pituitary mass, what is the secreting pituitary diagnosis? adenoma) 45/F, presented with weakness and Conn syndrome treatment-resistant hypertension. Plasma (Primary aldosterone is elevated. Plasma renin is hyperaldosteronism decreased. Imaging showed a left adrenal secondary to mass. Biopsy showed cells resembling aldosterone-secreting normal zona fasciculata with adrenal adenoma) spironolactone bodies. What is the diagnosis? 6/F, with ambiguous genitalia, presented Congenital adrenal with fever, cough and colds, with hyperplasia, salthypotension and hypoglycemia. Cortisol wasting type and aldosterone levels are decreased. Plasma renin is increased. Serum sodium is low, and potassium is high. Imaging showed bilateral adrenal hyperplasia. What is the diagnosis?

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TOPNOTCH MEDICAL BOARD PREP PATHO SUPPLEMENT HANDOUT by KEVIN ELOMINA, MD For inquiries visit www.topnotchboardprep.com.ph or https://www.facebook.com/topnotchmedicalboardprep/ 34/F, with skin hyperpigmentation, hypotension, hypoglycemia, hyponatremia and hyperkalemia. Imaging showed irregularly shrunken adrenal glands. Biopsy showed lymphocytic infiltrates. What is the diagnosis?

Addison disease secondary to autoimmune adrenalitis

ADRENAL MEDULLA 30/M, with paroxysms of severe hypertension Pheochromocytoma and elevated plasma metanephrines. Imaging showed an adrenal mass, and after appropriate preoperative evaluation, adrenalectomy was performed with resolution of the hypertension. Biopsy showed nests of cells surrounded by sustentacular cells (zellballen); the nuclei of the cells exhibit a salt and pepper chromatin pattern. What is the diagnosis? MULTIPLE ENDOCRINE NEOPLASIA SYNDROMES MEN2A MEN1 Parameter Sipple MEN2B Wermer syndrome syndrome Mutation MEN1 RET (2A and 2B have distinct mutations) Syndrome • Pituitary: Prolactinomas Common: (MC) Pheochromocytoma, • Parathyroid: Primary MTC** (MEN2B-associated hyperparathyroidism are more aggressive than (MC; either adenoma or MEN2A-associated) hyperplasia) • MEN2A: Parathyroid • Pancreas: PP (MC), hyperplasia Insulinoma or • MEN2B: Neuromas, gastrinoma* (MC types ganglioneuromas, that produce Marfanoid habitus hypersecretory states) Genetic Importance not wellImportant due to MTC screening established (mortality prevented by early thyroidectomy)

24. SKIN Note: Please familiarize yourselves with the dermatologic and dermatopathologic lexicon before proceeding. QUESTION ANSWER DISORDERS OF PIGMENTATION AND MELANOCYTES 34/F, with a pigmented lesion on the nasolabial fold. Melanocytic Biopsy showed nests of uniform, cytologically benign nevus cells, with extracellular pigment, that are entirely in (Pigmented the dermis, with neurotization underneath. What is intradermal the specific diagnosis? nevus) 45/F, with a variegated pigmented lesion on the arm Melanoma with irregular borders, measuring 5.0 cm in widest dimension. Wide excision was done, and biopsy showed nests of highly anaplastic cells with abundant extracellular pigment deposition. What is the diagnosis? BENIGN AND PREMALIGNANT EPITHELIAL LESIONS 70/M, with a pigmented plaque on the face. Lens Seborrheic examination showed multiple ostia on the lesion's keratosis surface. Biopsy was done, showing multiple horn cysts. What is the diagnosis? 50/M, with an exophytic, gray-tan mass on the face. Actinic Biopsy showed basal layer atypia with intercellular keratosis bridges, blue-gray elastic fibers (solar elastosis), and dermal chronic inflammation. What is the diagnosis? MALIGNANT EPITHELIAL TUMORS 46/M, with an ulcerated lesion on the cheek. Biopsy Squamous showed nests of atypical squamous cells invading a cell desmoplastic stroma, with occasional keratin pearl carcinoma formation. What is the diagnosis? 34/F, with a pearly, telangiectatic papule on the face. Basal cell Biopsy showed nests of basaloid cells with peripheral carcinoma palisading and stromal retraction, invading the dermis. What is the diagnosis? ACUTE INFLAMMATORY DERMATOSES 26/M, known case of bronchial asthma, and allergic Urticaria rhinitis, presented with multiple wheals. Biopsy showed superficial dermal edema, and sparse superficial perivenular mononuclear infiltrate. What is the diagnosis? 29/M, with a history of penicillin intake, developed Acute erythematous patches with vesicles. Biopsy showed eczematous thickening of the epidermis and the horny cell layer, dermatitis with epidermal intercellular edema. What is the (drugdiagnosis? related)

45/F, known case of Non-Hodgkin lymphoma, developed multiple target lesions. Biopsy showed superficial perivascular, lymphocytic infiltrate, dermal edema, and lymphocytes at DEJ associated with necrotic keratinocytes. What is the diagnosis? CHRONIC INFLAMMATORY DERMATOSIS 36/F, with salmon pink scaly plaques on the legs with punctate bleeding on removal of the plaque (Auspitz sign). Biopsy of the plaque showed acanthosis with elongation of rete ridges, resembling test tubes in a rack, with neutrophils in the parakeratotic stratum corneum (Munro microabscesses). What is the diagnosis? BLISTERING DISORDERS 48/M, with multiple skin bullae. PE: (+) Nikolsky sign. Serology: IgG against desmoglein (+). Biopsy showed acanthloysis, and suprabasilar blister with lace-like pattern of immunofluorescence. What is the diagnosis? Based on the case above, if PE: (-) Nikolsky sign. Serology: IgG against BPAG (+); and biopsy showed basal layer vacuolization, and subepidermal blister with linear pattern of immunofluorescence, what is the diagnosis? 38/F, known case of celiac disease, with multiple skin bullae. Biopsy showed PMNs at tips of dermal papillae, and subepidermal blister with granular pattern of immunofluorescnece. What is the diagnosis? INFECTIOUS DERMATOSES 8/F, with multiple honey-colored crusts. Biopsy showed accumulation of PMNs beneath the stratum corneum. What is the diagnosis? 32/M, with a grayish-tan papule on the neck. Biopsy showed papillomatous epithelial hyperplasia, with koilocytic change. What is the diagnosis?

Erytherma multiforme

Psoriasis

Pemphigus vulgaris

Bullous pemphigoid

Dermatitis herpetiformis

Impetigo contagiosa Verruca vulgaris

25. BONES, JOINTS, AND SOFT TISSUES Note: The chapter only includes bones and joints. For soft tissues, please refer to the main handout. BONES QUESTION ANSWER ACQUIRED DISEASES 60/F, with shortening of stature and lower Osteoporosis, back pain. Lumbar X-ray showed compression decreased bone fracture of the L1 vertebra. Lumbar spine mass BMD T-score <-2.5 SD. What is the diagnosis, and what is the fundamental abnormality? 56/M, with chronic lower back pain and pain Paget disease of on the left lower extremity. Lumbar MRI bone (Osteitis showed a lesion on L2 vertebra with deformans) compression of the left nerve root. Biopsy showed mosaic pattern of lamellar bone with cement lines “jigsaw puzzle”. What is the diagnosis? OSTEOMYELITIS 32/M, with a history of neglected cellulitis on Pyogenic the ankle area, now presented with loss of osteomyelitis range of motion of the ankle joint, associated with high-grade fever. Debridement was performed, and samples were taken for biopsy, which showed bone necrosis with brisk neutrophilic infiltrate and reactive bone formation. What is the diagnosis? 34/F, known case of pulmonary TB and did Pott disease not complete her 6 months treatment, presented with severe back pain on the lumbar area, with difficulty in maintaining an erect posture. MRI showed destruction of L2 and L3 with abscess formation. Biopsy showed chronic granulomatous inflammation with caseation necrosis and Langhans type giant cells. What is the diagnosis? TUMORS 25/M, asymptomatic, with an incidental Osteoid osteoma finding of a mass on the knee, measuring 1.5 cm. Biopsy showed interlacing bony trabeculae with osteoblastic rimming. What is the diagnosis? Based on the case above, if the patient Osteoblastoma presented with pain, and the lesion measures 3.0 cm, with the same histologic findings, what is the diagnosis?

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TOPNOTCH MEDICAL BOARD PREP PATHO SUPPLEMENT HANDOUT by KEVIN ELOMINA, MD For inquiries visit www.topnotchboardprep.com.ph or https://www.facebook.com/topnotchmedicalboardprep/ Based on the case above, if osteoblastic Fibrous dysplasia rimming is absent, what would be the most likely diagnosis? 25/M, gymnast, presented with limping, on the Osteosarcoma right, with pain referred on the knee. X-ray showed a lesion on the distal femur, (+) Codman triangle and sunburst appearance. Biopsy showed lace-like pattern of bone deposition by anaplastic tumor cells. What is the diagnosis? 34/F, with a mass on the left index finger. Chondroma Biopsy showed sheets of cytologically benign chondrocytes. What is the diagnosis? 27/M, with an incidental finding of a knee Osteochondroma mass. Biopsy showed a bone with an underlying marrow cavity, covered a cartilage cap. What is the diagnosis? 67/M, with a right scapular mass. Biopsy Chondrosarcoma showed sheets of anaplastic cartilage-forming cells with high mitotic rate. What is the diagnosis? 12/M, with a mass on the humerus, with Ewing sarcoma associated intermittent low-grade fever. Biopsy showed sheets of small, round, blue cells? Immunohistochemistry: vimentin, CD99 (+). What is the diagnosis? 35/F, with a left knee mass. Biopsy showed Giant cell tumor of mononuclear cells with abundance of bone multinucleated giant cells. What is the (Osteoclastoma) diagnosis? JOINTS DEGENERATIVE BONE DISEASE 62/M, with pain on the right knee that Osteoarthritis worsens with activity. PE: (+) nodules on DIP (Heberden) and PIP (Bouchard nodes). Osseous ankylosis is not seen on imaging. What is the most likely diagnosis? 34/F, with morning stiffness and pain on both Rheumatoid hands that improve with activity. Patient is arthritis (RA) positive for HLA-DRB1; Serology: RF and antiCCP (+). Imaging showed pannus with osseous ankylosis. What is the most likely diagnosis? 50/M with chronic back pain and stiffness Ankylosing that improve with activity. X-ray of the spine spondylitis showed a bamboo-stick appearance. Patient is positive for HLA-B27. What is the diagnosis? CRYSTAL-INDUCED ARTHROPATHIES Parameter Gout Pseudogout Types and • Most common: • Sporadic (idiopathic), characteristics primary, most hereditary and common: unknown secondary gene defects • AD: germline • Hyperuricemia (>6.8 mutations in mg/dL): from pyrophosphate increased production transport channel or impaired excretion Clinical • Usually • Monoarticular or monoarticular, acute polyarticular, from (most common: 1st acute to chronic (most MTPJ) common: knee) Crystals Monosodium urate, Calcium pyrophosphate, needle-shaped, rhomboid-shaped, negatively birefringent positively birefringent Inflammation Intense (neutrophilic) If present, usually milder than gout Treatment NSAIDs and colchicine No known treatment (acute), uric acid lowering agents

26. PERIPHERAL NERVOUS SYSTEM AND SKELETAL MUSCLE QUESTION DISORDERS OF PERIPHERAL NERVES 43/M, with history of fever and nonproductive cough a week prior, presented with bilateral weakness involving first the lower extremities until the lower trunk. CSF analysis: mild lymphocytic pleocytosis and moderately elevated protein. Biopsy of muscle revealed mononuclear, perivenular and perineurial infiltrate, with segmental demyelination of nerve. What is the diagnosis, and the pattern of neuropathy observed in this case?

ANSWER Guillain-Barre syndrome, Symmetric ascending demyelinating polyradiculoneuropa thy

55/M, with polyphagia, polyuria, and polydipsia, with FBS = 130 mg/dL, presented with numbness on both fingers and toes, resembling a "glove and stocking pattern" of sensory deficit. What is the diagnosis, and the pattern of neuropathy observed in this case? DISORDERS OF NEUROMUSCULAR JUNCTION 32/F, with mediastinal mass; biopsy revealed thymoma, presented with ptosis and dysarthria late in the afternoon, with improvement after rest. Edrophonium test was positive. What is the diagnosis, and the autoantibodies present? 45/M, heavy smoker, with small cell lung carcinoma, presented with ptosis and difficulty in moving his hips and thighs. Associated symptoms include dry mouth and impotence. PE: 0 reflexes on patellar and ankle. What is the diagnosis, and the autoantibodies present?

Diabetic neuropathy, Axonal neuropathy

Myasthenia gravis; Autoantibodies to ACH receptor

Lambert-Eaton myasthenic syndrome (LEMS); Autoantibodies to presynaptic Ca channel

ACQUIRED DISORDERS OF SKELETAL MUSCLE 13/F, presented with difficulty in shoulder Dermatomyositis abduction, followed by weakness of the forearm and hand muscles. PE: periorbital lilac discoloration (Heliotrope rash) and dusky red patches over knuckles (Gottron papules). Muscle biopsy: Perifascicular atrophy with perimysial and perivascular mononuclear infiltrates. What is the diagnosis? 48/M, presented with difficulty in shoulder Polymyositis abduction, followed by weakness of the forearm and hand muscles; otherwise unremarkable. Muscle biopsy: Random, patchy areas of atrophy with endomysial mononuclear infiltrates. What is the diagnosis? MUSCULAR DYSTROPHIES 5/M, complained of being called "lampa" by his playmates. History revealed frequent episodes of fall. Patient uses his hands to get up (Gower sign). Muscle biopsy: segmental myofiber degeneration and regeneration with preserved fascicular architecture. IHC: Dystrophin (-) Difference in dystrophin immunohistochemistry between DMD and BMD

Duchenne Muscular Dystrophy (DMD) (early) Note: Histologic findings for late DMD is different

DMD: Dystrophin(-) BMD: Dystrophin(+) but reduced

PERIPHERAL NERVE SHEATH TUMORS 23/M, with an arm mass. Biopsy showed Schwannoma/ alternating hypercellular (Antoni A) and Neurilemmoma hypocellular (Antoni B) areas, composed of benignlooking spindle cells with palisading nuclei, and nucleus-less areas (Verocay bodies). IHC: S-100 (+). What is the diagnosis? 23/M, with an arm mass. Biopsy showed benignNeurofibroma looking spindle cells with collagen bundles resembling "shredded carrot" appearance. IHC: CD34 (+). What is the diagnosis? NEUROFIBROMATOSES Parameter NF Type 1 NF Type 2 Inheritance AD; NF1 (Ch17) AD; NF2 (Ch22) and gene Incidence Components

More common Neurofibromas MPNSTs Optic nerve gliomas Other glial tumors and hamartomatous lesions • Pheochromocytomas • Pigmented iris nodules (Lisch nodules) • Cutaneous hyperpigmented macules (Café au lait spots) • • • •

Less common • Bilateral eight nerve schwannomas • Multiple meningiomas • Ependymomas (commonly intraspinal)

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27. CENTRAL NERVOUS SYSTEM Note: Congenital anomalies are omitted because of low yield; for completion, you may refer to the parent handout. Also, some common CNS anomalies are discussed in anatomy (under embryology). CNS infections are covered in Microbiology, and lumbar tap findings for meningitides are covered in IM and Pediatrics. QUESTION ANSWER 37/M, diagnosed case of glioblastoma, presents Focal vasogenic with headache and projectile vomiting. CTcerebral edema scan showed intense hypodensity around an ill- secondary to defined mass, with flattened gyri and glioblastoma attenuated sulci. What is the specific diagnosis? Based on the case above, the patient eventually Tonsillar arrested and expired. Autopsy showed herniation cerebellar tonsils passing through the foramen magnum, compressing the brainstem. What is the type of herniation seen in this case? 2m/M with presented with enlargement of the Nonhead and sunsetting of eyes. Imaging showed communicating aqueductal stenosis and dilation of the lateral hydrocephalus ventricles. What is the specific diagnosis? TRAUMATIC VASCULAR DISEASES Parameter Epidural hematoma Subdural hematoma Age/Onset Middle age Extremes of age Clinical Rapidly evolving Slowly evolving picture neurologic symptoms neurologic symptoms; with lucid intervals often delayed onset Blood source Arterial: most common: Venous: bridging veins middle meningeal artery (from pterion fracture) Plain CT-scan Lentiform density Crescent-shaped density appearance CEREBROVASCULAR DISEASES 45/M, known hypertensive, presented with left Focal cerebral upper extremity weakness and loss of sensation. ischemia Motor strength grading is 2/5 at left upper extremity, and sensation is about 40%. Plain cranial CT-scan showed a hypodense area on the region of the right MCA. What is the diagnosis? Based on the case above, if the patient had an Hypertensive antecedent history of a high BP (200/100 mmHg), intracerebral and presented with decrease in sensorium, and plain hemorrhage cranial CT-scan showed a hyperdense lesion with perilesional edema on the region of the right MCA, what is the diagnosis? 41/F, after a heated argument with a store clerk, Subarachnoid presented with an intense headache and syncope. hemorrhage Patient went into comatose for several days and died. Antemortem CT showed hyperdense material filling the sulci. What is the diagnosis? 15/F, collapsed after an exam week. CT-scan showed Arteriovenous an irregular hyperdense lesion. CT angiography malformation showed a bag of worms appearance. Removal of the lesion was done. Biopsy showed large vessels with intervening brain tissue. What is the diagnosis? DEMYELINATING DISORDERS 32/F, with history of diplopia for 2 weeks, 2 years Multiple prior, now presented with bilateral facial sclerosis weakness for 3 weeks. Lumbar tap was done showing moderate pleocytosis, mildly elevated protein, and increased oligoclonal IgG. What is the most likely diagnosis? NEURODEGENERATIVE DISEASES 72/M with progressive dementia and Alzheimer dysautonomia, eventually succumbed to disease (AD) pneumonia. Brain autopsy showed cortical atrophy with neuritic plaques, and neurofibrillary tangles. What is the diagnosis? 43/F, with tremor, rigidity, and bradykinesia, Parkinson which became progressive, precluding her to disease (PD) ambulate properly. She eventually expired due to pneumonia. Brain autopsy showed pallor of substantia nigra and multiple, intracytoplasmic, eosinophilic, round to elongated inclusions that often have a dense core surrounded by a pale halo (Lewy bodies). What is the diagnosis? 45/M, with increased incidence of fall and tendency Amytropic to drop things, without any sensory deficit. He fell lateral from the stairs and died to traumatic brain injury. sclerosis (ALS) Autopsy showed thinned-out anterior horn neurons, cranial nerve motor nuclei, and corticospinal tract degeneration. What is the

diagnosis? ACQUIRED METABOLIC AND TOXIC DISTURBANCES 32/F, known case of pernicious anemia, presented Subacute with ataxia and numbness of the lower extremities combined that led to spastic paralysis and paraplegia, and degeneration eventual demise from pneumonia. What is the most likely diagnosis? WERNICE-KORSAKOFF SYNDROME Wernicke Parameter Korsakoff syndrome encephalopathy Syndrome Psychotic symptoms or Short-term memory ophthalmoplegia disturbances and Memory device: ataxia, confabulation confusion, Memory device: ophthalmoplegia (ACO) confabulation, hallucinations, amnesia (CHA) Duration Acute Chronic Reversibility Yes No with thiamine Morphology Hemorrhage and necrosis Cystic space with of the mammillary bodies hemosiderin-laden and the walls of the third macrophages in and fourth ventricles dorsomedial nucleus of the thalamus TUMORS 65/M, with a cranial mass. Biopsy showed Glioblastoma pseudopalisading to tumor cells around areas (WHO IV/IV) of necrosis with accompanying microvascular proliferation proliferation. What is the diagnosis? Based on the case above (65/M), if thorough Anaplastic examination of the sections did not show any astrocytoma (WHO necrosis or microvascular proliferation, what III/IV) would be the more appropriate diagnosis? Based on the case above (65/M), if biopsy Oligodendroglioma showed sheets of round cells with cytoplasmic (WHO II/IV) halos, resembling a fried-egg appearance, what is the diagnosis? Based on the case above, if the mass is located on Intraspinal the spinal cord, and biopsy showed Ependymoma perivascular pseudorosettes, what is the (WHO II/IV) Note: location of diagnosis? ependymomas is different depending on the age

12/M, with cerebellar mass. Biopsy showed bipolar cells with thin, hair-like processes and Rosenthal fibers. What is the diagnosis? Based on the case above (12/M), if biopsy showed sheets of small, round, blue cells with Homer-Wright rosettes, what is the diagnosis? 35/F, presented with progressive headache, and an intracranial extra-axial mass. Biopsy showed syncytial nests of bland-looking cells and several Psammoma bodies. What is the diagnosis?

Pilocytic astrocytoma (WHO I/IV) Medulloblastoma (WHO IV/IV) Meningothelial meningioma (WHO I/IV)

28. EYE QUESTION ORBIT Forward displacement of the eye; has two forms: axial and positional Most common primary tumor of the orbit

EYELID Most common malignancy of the eyelid CONJUNCTIVA Etiologic agent of conjunctivitis that leads to significant conjunctival scarring Most common site of conjunctival neoplasms Histology of common conjunctival malignancies

ANSWER Proptosis Vascular tumors (Infancy and early childhood: capillary hemangioma, lymphangioma; adults: cavernous hemangioma)

Basal cell carcinoma

Chlamydia trachomatis Limbus Squamous cell carcinomas, Melanomas



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TOPNOTCH MEDICAL BOARD PREP PATHO SUPPLEMENT HANDOUT by KEVIN ELOMINA, MD For inquiries visit www.topnotchboardprep.com.ph or https://www.facebook.com/topnotchmedicalboardprep/ ANTERIOR SEGMENT Inflammation within the vitreous humor Endophthalmitis Inflammation involving the retina, uvea, Panophthalmitis sclera, and orbit Opacification of the lens Cataract Submucosal fibrovascular connective tissue Pinguecula that does not invade the cornea Submucosal fibrovascular connective tissue Pterygium that invades the cornea; associated with visual problems (astigmatism) Diseases characterized by distinctive changes Glaucoma in visual field and optic nerve cup; most are associated with increased intraocular pressure TYPES OF GLAUCOMA Normal Parameter Open-angle Angle-closure pressure Trabecular Yes No Yes meshwork access Pathogenesis Increased Peripheral Characteristic resistance to zone of the iris optic nerve aqueous outflow adheres to the and visual field in open angle of trabecular changes the anterior meshwork without segment (hyperopics, increased IOP shallow anterior chambers) Increased IOP Yes Yes No Acute/Chronic Chronic Acute Chronic UVEA Inflammation of the tissues that comprise the Uveitis uvea (iris, ciliary body and choroid) Most common intraocular malignancy Metastases to uvea Most common primary intraocular Melanoma malignancy in adults RETINA AND VITREOUS TYPES OF RETINAL DETACHMENT Parameter Rhegmatogenous Non-rhegmatogenous Full-thickness Yes No retinal defect Pathogenesis Unclean vitreous Any condition that detachment tears the damages the RPE and retina; liquefied permits fluid to leak vitreous accumulates from the choroidal between RPE and circulation under the neurosensory retina retina Photoreceptor Present in chronic; absent in acute atrophy Clinical Ophthalmologic emergency significance RETINAL OCCLUSION SYNDROMES Central retinal artery Central retinal vein Parameter occlusion occlusion Ischemia • Occurs in ischemia • May occur with or without ischemia Histologic • Fragments of • Retinal hemorrhages, findings atherosclerotic plaque dilated tortuous lodged in retinal circulation retinal veins, cotton(Hollenhorst plaques) wool spots, macular • Cherry-red spot in macula edema, and optic disc (fovea and foveola) with edema retinal pallor Clinical Ophthalmologic emergency - significance Most common type of retinal lymphoma DLBCL 4/M, came for a routine check-up. On pupillary Retinoblastoma examination, (+) leukocoria, prompting referral to an ophthalmologist. The patient underwent operation and an intraocular mass was removed. Biopsy: small, round, blue cells, with some of cells encircling a lumen (Flexner-Wintersteiner rosettes and fleurettes). What is the diagnosis OPTIC NERVE Swelling of the optic nerve head; can be Optic nerve edema unilateral or bilateral (papilledema); usually caused by nerve compression (unilateral) and increased ICP (bilateral)

Loss of vision secondary to demyelination of the optic nerve; most important cause is multiple sclerosis Most common primary optic nerve tumors

Optic neuritis Pilocytic astrocytomas and meningiomas

---END OF PATHOLOGY SUPPLEMENT--- Edited by: Kevin A. Elomina, MD

These verses are included in my guiding verses in life, and during the boards. These speak of the power of persistence, and the providence of God to His children. Luke 11:5-13 New King James Version (NKJV) A Friend Comes at Midnight And He said to them, “Which of you shall have a friend, and go to him at midnight and say to him, ‘Friend, lend me three loaves; for a friend of mine has come to me on his journey, and I have nothing to set before him’; and he will answer from within and say, ‘Do not trouble me; the door is now shut, and my children are with me in bed; I cannot rise and give to you’? I say to you, though he will not rise and give to him because he is his friend, yet because of his persistence he will rise and give him as many as he needs. Keep Asking, Seeking, Knocking “So I say to you, ask, and it will be given to you; seek, and you will find; knock, and it will be opened to you. For everyone who asks receives, and he who seeks finds, and to him who knocks it will be opened. If a son asks for bread[a] from any father among you, will he give him a stone? Or if he asks for a fish, will he give him a serpent instead of a fish? Or if he asks for an egg, will he offer him a scorpion? If you then, being evil, know how to give good gifts to your children, how much more will your heavenly Father give the Holy Spirit to those who ask Him!"

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