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https://kickass.to/user/tahir99/ AN ORIGINAL VRG RELEASE H ISTOLOGY for PATHOLOGISTS F O U R T H E D IT IO N https://kickass.to/user/tahir99/ AN ORIGINAL VRG RELEASE https://kickass.to/user/tahir99/ AN ORIGINAL VRG RELEASE H ISTOLOGY for PATHOLOGISTS F O U R T H E D IT IO N Editor Stacey E Mills, MD W.S Royster Professor of Pathology Director of Surgical Pathology and Cytopathology University of Virginia Health System Charlottesville, Virginia Senior Executive Editor: Jonathan W Pine, Jr Product Manager: Marian A Bellus Vendor Manager: Bridgett Dougherty Marketing Manager: Caroline Foote Senior Manufacturing Manager: Benjamin Rivera Creative Director: Doug Smock Production Service: Aptara, Inc © 2012, 2007 by LIPPINCOTT WILLIAMS & WILKINS, a WOLTERS KLUWER Business; © 1997 Lippincott-Raven Publishers; © 1992 Raven Press Two Commerce Square 2001 Market Street Philadelphia, PA 19103 USA LWW.com All rights reserved This book is protected by copyright No part o this book may be reproduced in any orm by any means, including photocopying, or utilized by any in ormation storage and retrieval system without written permission rom the copyright owner, except or brie quotations embodied in critical articles and reviews Materials appearing in this book prepared by individuals as part o their o f cial duties as U.S government employees are not covered by the above-mentioned copyright Printed in the People’s Republic o China Library of Congress Cataloging-in-Publication Data Histology or pathologists 4th ed / editor, Stacey E Mills p ; cm In cludes bibliograph ical re eren ces an d in dex ISBN 978-1-4511-1303-7 ( h ardback) I Mills, Stacey E [ DNLM: H istology Path ology QS 504] 611′.018 dc23 2012011114 Care has been taken to conf rm the accuracy o the in ormation presented and to describe generally accepted practices However, the authors, editors, and publisher are not responsible or errors or omissions or or any consequences rom application o the in ormation in this book and make no warranty, expressed or implied, with respect to the currency, completen ess, or accuracy o th e ten ts o th e publication Application o the in ormation in a particular situation remains the pro essional responsibility o the practitioner The authors, editors, and publisher have exerted every e ort to ensure that drug selection and dosage set orth in this text are in accordance with current recommendations and practice at the time o publication However, in view o ongoing research, changes in government regulations, and the constant ow o in ormation relating to drug therapy and drug reaction s, th e reader is urged to ch eck th e package in sert or each drug or an y ch an ge in indications and dosage and or added warnings and precautions This is particularly important when the recommended agent is a new or in requently employed drug Some drugs and medical devices presented in the publication have Food and Drug Administration ( FDA) clearance or limited use in restricted research settings It is the respon sibility o th e h ealth care provider to ascertain th e FDA status o each drug or device planned or use in their clinical practice To purchase additional copies o this book, call our customer service department at ( 800) 638-3030 or ax orders to ( 301) 223-2320 International customers should call ( 301) 2232300 Visit Lippincott Williams & Wilkins on the Internet: at LWW.com Lippincott Williams & Wilkin s customer service represen tatives are available rom 8:30 am to pm, EST 10 Contributors Graziella Abu-Jawdeh, MD Gerald J Berry, MD Associate Pathologist Pathology Department North Shore Medical Center Salem, Massachusetts Professor of Pathology Department of Pathology Stanford University Director of Cardiac Pathology Co-Director of Surgical Pathology Department of Pathology Stanford University Medical Center Stanford, California Hikmat Al-Ahmadie, MD Assistant Attending Department of Pathology Memorial Sloan-Kettering Cancer Center New York, New York Jacques Bosq, MD Pathologist, Chief of Pathology Unit Department of Pathology and Laboratory Medicine Institut Gustave Roussy Villejuif, France Kristen A Atkins, MD Associate Professor of Pathology Director, Residency Training Department of Pathology University of Virginia School of Medicine Charlottesville, Virginia John S J Brooks, MD Professor and Vice Chair Pathology and Laboratory Medicine University of Pennsylvania Medical School José E Barreto, MD Pathologist Pathology Department National University Chair and Director, Ayer Laboratory Pathology Department Pennsylvania Hospital of UPHS Philadelphia, Pennsylvania Pathologist Pathology Department Instituto de Patología e Investigación Asunción, Paraguay Peter G Bullough, MD, ChB Assistant Professor of Pathology Department of Pathology Duke University Medical Center Durham, North Carolina Professor Emeritus Director of Laboratories Emeritus Department of Pathology Cornell University Medical School Hospital for Special Surgery New York, New York Kurt Benirschke, MD Peter C Burger, MD Sarah M Bean, MD Professor Emeritus Emeritus Director of Autopsy Service Pathology Department University of California–San Diego Medical Center San Diego, California Professor of Pathology Department of Pathology The John Hopkins University School of Medicine Baltimore, Maryland Rex C Bentley, MD Chief, Pathology A Diagnostic Pathology and Laboratory Fondazione IRCCS Istituto Nazionale dei Tumori Milan, Italy Associate Professor Department of Pathology Duke University Medical Center Durham, North Carolina Maria Luisa Carcangiu, MD https://kickass.to/user/tahir99/ AN ORIGINAL VRG RELEASE v vi Co n trib u to rs J Aidan Carney, MD, PhD, FRCP Lola Conejo-Mir, MD Emeritus Professor of Pathology Department of Laboratory and Pathology Mayo Clinic Rochester, Minnesota Dermatologist Dermatology Department Virgen Del Rocio University Hospital Seville, Spain Darryl Carter, MD Byron P Croker, MD, PhD Professor Emeritus Pathology Department Yale University New Haven, Connecticut Professor Department of Pathology, Immunology, and Laboratory Medicine University of Florida Odile Casiraghi, MD Chief Pathology and Laboratory Medicine Service North Florida/South Georgia Veterans Health System Gainesville, Florida Department of Biology and Medical Pathology Gustave-Roussy Cancer Institute Villejuif, France William L Clapp, MD Associate Professor Department of Pathology, Immunology and Laboratory Medicine University of Florida College of Medicine Antonio L Cubilla, MD Chief, Anatomic Pathology Pathology and Laboratory Medicine Service North Florida/South Georgia Veterans Health System Gainesville, Florida Director Pathology Department Instituto de Patología e Investigación Asunción, Paraguay Philip B Clement, MD Thomas J Cummings, MD Professor Emeritus Pathology University of British Columbia Consultant Pathologist Pathology Department Vancouver General Hospital Vancouver, Canada Thomas V Colby, MD Professor Mayo Clinic of Medicine–Arizona Scottsdale, Arizona Laura C Collins, MD Associate Professor of Pathology Harvard Medical School Associate Director of Anatomic Pathology Pathology Department Beth Israel Deaconess Medical Center Boston, Massachusetts Julian Conejo-Mir, MD, PhD Head Professor Dermatology Department Faculty of Medicine Chairman Dermatology Department Virgen Del Rocio University Hospital Seville, Spain Professor Emeritus Pathology National University Professor of Pathology Department of Pathology Duke University Medical Center Durham, North Carolina Julia Dahl, MD Chief Medical Of cer and Director of Surgical Pathology Mosaic Pathology Consultants The Regional Medical Center at Memphis Memphis, Tennessee Yogeshwar Dayal, MD Clinical Professor Department of Pathology University of Massachusetts Medical School Worcester, Massachusetts Ronald A DeLellis, MD Professor Pathology and Laboratory Medicine Brown University/Warren Alpert Medical School Pathologist Pathology Department Rhode Island Hospital Providence, Rhode Island Co n trib u to rs Hala El-Zimaity, MD Nancy S Hardt, MD Associate Professor of Pathology Pathology Department University of Toronto University Health Network Toronto, Ontario Professor, Pathology and Ob-Gyn Pathology, Immunology and Laboratory Medicine University of Florida College of Medicine Gainesville, Florida Claus Fenger, MD, Dr M.Sc Department of Clinical Pathology University of Southern Denmark Odense, Denmark Chair Department of Pathology and Anatomical Sciences University at Buffalo School of Medicine Buffalo, New York Samson W Fine, MD Michael R Hendrickson, MD Assistant Attending Pathologist Department of Pathology Memorial Sloan-Kettering Cancer Center New York, New York Professor Emeritus of Pathology Department of Pathology Stanford University Medical Center Stanford, California Henry F Frierson, Jr., MD Boris Hinz, PhD Professor Department of Pathology University of Virginia Health System Charlottesville, Virginia Associate Professor Matrix Dynamics Group, Faculty of Dentistry University of Toronto Toronto, Ontario Gregory N Fuller, MD, PhD Seung-Mo Hong, MD, PhD Professor, Department of Pathology Chief, Section of Neuropathology The University of Texas M D Anderson Cancer Center Houston, Texas Associate Professor Department of Pathology Asan Medical Center University of Ulsan College of Medicine Seoul, Korea Reid R Heffner Jr., MD Giulio Gabbiani, MD, PhD Eva Horvath, PhD Professor of Pathology Faculty of Medicine University of Geneva Geneva, Switzerland Patrick J Gallagher, MD, PhD, FRCPath Senior Clinical Lecturer Centre for Medical Education University of Bristol Bristol, United Kingdom Ralph H Hruban, MD Professor Pathology Department The Johns Hopkins School of Medicine C Blake Gilks, MD, FRCP(C) Professor Department of Pathology and Laboratory Medicine University of British Columbia Consultant Pathologist Department of Anatomic Pathology Vancouver General Hospital Vancouver, British Columbia Joel Kasle Greenson, MD Professor Gastrointestinal and Hepatic Pathologist Pathology Department University of Michigan Health Center Ann Arbor, Michigan Associate Professor Laboratory Medicine St Michael’s Hospital University of Toronto Toronto, Ontario Attending Pathologist Pathology Department The Johns Hopkins Hospital Baltimore, Maryland Nicole Belsley Johnson, MD Instructor Pathology Department Harvard Medical School Staff Pathologist Pathology Department Beth Israel Deaconess Medical Center Boston, Massachusetts https://kickass.to/user/tahir99/ AN ORIGINAL VRG RELEASE vii viii Co n trib u to rs Andrew Kanik, MD Steven H Lewis, MD, FCAP, FACOG Director of Dermatopathology CBLPath Rye Brook, New York Clinical Professor of Pathology University of Colorado School of Medicine, Denver Chairman, Public Programs The Given Institute Aspen, Colorado Richard L Kempson, MD Professor of Pathology, Emeritus Pathology Department Stanford University School of Medicine Stanford, California Min Li, MD, PhD Attending Pathologist/Dermatopathologist St Luke’s Hospital and Health Network Bethlehem, Pennsylvania David S Klimstra, MD Professor Pathology and Laboratory Medicine Weill Medical College of Cornell University M Beatriz S Lopes, MD Professor of Pathology & Neurologic Surgery Department of Pathology University of Virginia Chief, Surgical Pathology Service Department of Pathology Memorial Sloan-Kettering Cancer Center New York, New York Division Chief Division of Neuropathology University of Virginia Health System Charlottesville, Virginia Gordon K Klintworth, MD, PhD Joseph A C Wadsworth Professor of Ophthalmology and Professor of Pathology Duke University Medical Center Durham, North Carolina Fernando Martínez-Madrigal, MD Kalman Kovacs, MD, PhD Pathologist Pathology Department Hospital Regional de Zona No del Instituto Mexicano del Seguro Social Morelia, Michoacán, Mexico Emeritus Professor and Scientist Laboratory Medicine St Michael’s Hospital University of Toronto Toronto, Ontario J Han J M van Krieken, MD, PhD Head of Pathology Radboud University Nijmegen Medical Centre Nijmegen, The Netherlands Steven H Kroft, MD Professor and Vice Chair for Education and Academic Affairs Professor Pathology and Histology Department Universidad Michoacana de San Nicolas de Hidalgo Jesse K McKenney, MD Associate Professor Pathology and Urology Stanford University Director of Urologic Pathology Pathology Department Stanford University Medical Center Stanford, California Director of Hematopathology Department of Pathology Medical College of Wisconsin Milwaukee, Wisconsin Leslie Michaels, MD Kevin O Leslie, MD Visiting Professor of ENTpathology Department of Histopathology Imperial College London Charing Cross Hospital Campus London, England Professor Emeritus Department of Histopathology University College London Medical School Professor Laboratory Medicine and Pathology Mayo Clinic of Medicine Rochester, Minnesota Chair, Division of Anatomic Pathology Department of Laboratory Medicine and Pathology Mayo Clinic of Medicine–Arizona Scottsdale, Arizona https://kickass.to/user/tahir99/ AN ORIGINAL VRG RELEASE 570 S E C TIO N VI: Th o x a n d Se ro u s Me m b n e s down to end in the moderator muscle The papillary muscles of the right ventricle are relatively constant, with an anterior papillary muscle located on the anterior wall near its junction with the septum and a small posterior papillary muscle arising under the crista superventricularis at the inferior border of the right ventricular out ow tract In addition, there is an inconstant group of posterior papillary muscles that can arise from the diaphragmatic wall of the right ventricle The histology of the right ventricle consists of a thin endocardial layer The thickness of myocardial wall in normal human adults is about one-third the left ventricle and measures up to mm The endocardium is similar to the other chambers except it has more variability from region to region, with the thickest area found in the septum The subendocardial space includes a fenestrated elastic membrane and, on occasion, bundles of smooth muscle, particularly in the interventricular septum (Figure 20.7) The interventricular septum also contains blood vessels, nerves, and the left bundle branch of the conduction system The ventricular free wall has numerous vascular channels consisting of intertrabecular channels that lead into myocardial sinusoids and thebesian veins Myocardial sinusoids are also found within the trabeculae Arterioluminal vessels, leading directly from the systemic coronary circulation into the capillary beds, empty into the myocardial sinusoids The myocardium is richly supplied with small vascular channels that form an intramural circulation (42) There is an FIGURE 20.15 Diagrammatic representation o the various intramural vascular channels (Reprinted with permission rom: Barry A, Patten B The structure o the adult heart In: Gould SE, ed Pathology of the Heart and Blood Vessels Springf eld, IL: Charles C Thomas; 1968:104–105.) Endoca rdium extensive web of capillaries that course among the cardiac muscle bers, are fed by branches of the coronary arteries, and are drained, in part, by the coronary veins They are also directed to the intramyocardial sinusoids and thence into the lumen of the heart Deep within the myocardial musculature is found, in addition to the capillary bed, a richly anastomosing network of irregular channels that have been called myocardial sinusoids These sinusoids receive vessels from the coronary arteries and the capillaries and communicate with coronary veins The connections between the coronary arteries and the cardiac chambers are called arterioluminal vessels (Figure 20.15) Within the myocardium, variable amounts of adipose tissue can be found, particularly in the outer half of the free wall When extensive, it is called fatty in ltration of the right ventricle and represents a metaplastic change It should not be confused with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/CMP) Applied Anatomy The importance of recognizing the presence of myocyte disarray and adipose tissue as common ndings within the trabeculated musculature of the right ventricle of the normal adult heart has been discussed The distinction of “physiologic adipose tissue” from ARVD/CMP is problematic and clinical, molecular and morphologic criteria have been enumerated (43,44) Currently, CT and MR imaging are being evaluated to aid in this distinction (45) The apical Myoca rdium Epica rdium Arte rio–lumina l ve s s e l Myoca rdia l s inus oid Inte rtra be cula r s pa ce Ana s tomos is be twe e n myoca rdia l s inus oids Corona ry a rte ry Ana s tomos e s be twe e n corona ry a rte rie s Arte rio–s inus oida l ve s s e l Tra be cula e ca rne a e Arte rio–ve nous a na s tomos is Ca pilla ry be d Myoca rdia l s inus oid Ve no–ve nous a na s tomos is Ca pilla rie s e mptying into myoca rdia l s inus oids The be s ia n ve in Ana s tomos is be twe e n The be s ia n ve ins Corona ry ve in CH AP TER : No rm a l He a rt trabecular region is also the site of pacemaker wire placement and endomyocardial biopsy sampling LEFTVENTRICLE The left ventricle receives blood from the left atrium during ventricular diastole and ejects blood into the systemic arterial circulation across the aortic valve during ventricular systole The left ventricle is somewhat bullet shaped, with the blunt tip directed anteriorly and inferiorly and to the left (46) Like the right ventricle, it is composed of in ow, septal or apical, and out ow components It lacks the moderator band and septomarginal trabeculations of the right ventricle (32) The left ventricular chamber is surrounded by a thick muscular wall measuring up to 15 mm in thickness (note: The papillary muscles are not included in the measurement) The medial wall of the left ventricle is the interventricular septum, which is shared with the right ventricle The septum is roughly triangular in shape, with the base of the triangle at the level of the aortic cusps; it is entirely muscular, except for the small membranous septum located just below the right coronary and posterior cusps The upper third of the septum, or out ow tract, is lined by smooth endocardium The inferior two-thirds of the septum and the remaining ventricular walls are composed of the criss-crossing trabeculae carneae, which are thinner and less prominent than in the right ventricle The free wall of the left ventricle is that portion that is exclusive of the septum The histology of the left ventricle is similar to that of the right side, although the endocardium is slightly thicker as a result of higher hemodynamic pressures The small arterioles subadjacent to the endocardium have slightly thicker walls than those of the right ventricle, most likely because of the higher pressure in the left ventricle The myocardium of the left ventricle is arranged in such a way that it appears to spiral inward from the super cial layers The super cial layers run at right angles to the layers deeper within the wall These layers are intimately interdigitated to prevent dissection into lamina structures The attachment of the muscular layers is from the brous skeleton at the base of the heart The deeper muscle layers of the interventricular septum are composed of the deep bulbospiral muscle in the center of the septum originating from the septal portion of the atrioventricular annulus The fascicles of the deep bulbospiral and sinospiral muscles interdigitate within the muscular interventricular septum The spiral muscle pulls the base of the ventricle toward the apex during systolic contraction The blood supply is similar to that of the right ventricle In cut sections, the LV displays three planes or “layers” of myocardium that represent planes of orientation rather than distinct subdivisions of myocardium (47) 571 asymmetric type of hypertrophic cardiomyopathy Portions of the left ventricular free wall may be removed as aneurysmectomy specimens or during VAD placement The intermediate bulbospiral muscle of the interventricular septum is primarily involved in idiopathic hypertrophic subaortic stenosis (IHSS) Since it lies deep within the septum, the disarray associated with IHSS may not always be seen in the super cial myomectomy specimen The mechanisms of myocyte replacement, senescence and apoptosis, in the normal aging heart and the role of human cardiac stem cells are currently under investigation (48) CARDIACVALVES Semilunar Valves The semilunar valves consist of the pulmonic and aortic valves The normal valve circumference for the aortic valve is 5.7 to 7.9 cm for women and 6.0 to 8.5 cm for men The normal pulmonic valve circumference is 5.7 to 7.4 cm for women and 9.2 to 9.9 cm for men (49) Interestingly, when adjusted for body surface area, the valves in women are slightly larger than in men (10) Each semilunar valve consists of three semicircular cusps (50), each of which is attached by its semicircular border, or annulus, to the aortic or pulmonic ring The three points of lateral attachment of adjacent cusps are the commissures (Figure 20.16) The lines of cusp apposition are not at the free margin but are angulated lines extending from well below the point of attachment in the commissure to just below the midpoint of the free edge In the aortic valve, these lines (the linea alba) and the central nodules (the noduli arenti) can be seen (50) In the pulmonic valve, these landmarks are less obvious because of the lower right-sided pressures The lunulae are thin, delicate areas of cusp between the linear alba and the free edge The semilunar aortic and pulmonic valves are similar in guration, except that the aortic cusps are slightly Applied Anatomy Portions of the left ventricular subaortic out ow tract may be submitted as myomectomy specimens in patients with FIGURE 20.16 Aortic valve rom normal heart showing the cusps and the coronary ostia 572 S E C TIO N VI: Th o x a n d Se ro u s Me m b n e s thicker and contain coronary ostia They are situated at the summit at the out ow tract of their corresponding ventricle, the pulmonic valve being anterior, superior, and slightly to the left of the aortic valve in the normal heart The cusps, which are often slightly unequal in width, circle the inside of the respective vessel root (eg, pulmonary artery trunk or aortic root) Behind each cusp, the vessel wall bulges outward, creating a pouch-like dilatation known as the sinus of Valsalva The portion of the cusp adjacent to the rim is thin and may contain small perforations in the normal situation The noduli arenti meet in the center and contribute to the support of the lea ets Since the plane of the aortic valve is oblique with the right posterior side lower than the left anterior side, the origin of the left coronary artery is slightly superior to that of the right coronary artery The ostia of coronary arteries are located in the upper third of their respective sinuses The right coronary artery passes anteriorly and to the left In some hearts, there is a separate ostium in the right coronary sinus for the conus artery, sometimes called the third coronary artery (46) The molecular mechanisms of valvular development during embryogenesis have been further clari ed in recent studies (51) The histology of the semilunar valves is that of a well-de ned multilayered structure Three distinct layers are recognizable: The brosa, the spongiosa, and the ventricularis The brosa is a layer of dense collagen that constitutes the major structural component of the cusp and extends to its free edge (52) The densely packed collagen bundles blend into the collagen of the valvular ring in the region of the commissures Some broblasts are present in this layer, as are some very ne elastic bers The spongiosa is subadjacent to the brosa and occupies a central position in the thickness of the cusp (Figure 20.17) It is best devel- A B FIGURE 20.17 High- (A) and low-power (B) views o a section o the aortic cusp showing the three distinct layers as described in the text oped in the basal third of the cusp It does not extend to the free edge, which is composed only of brosa and ventricularis layers The spongiosa is composed of large amounts of proteoglycans and glycosaminoglycans, loosely arranged collagen brils, scattered broblasts, and mesenchymal cells (52) The ventricularis is subadjacent to the spongiosa and is in direct contact with the endothelial layer of the in ow surface of the cusp (ie, closest to the ventricular surface) It is distinguished from the brosa by its abundance of elastic bers This feature is often helpful in orienting and identifying the layers of excised aortic valvular cusps The surface lining of the cusps consists of a single layer of endothelial cells The surface topography of the aortic cusp varies according to its state of stress The bundles are wavy and the in ow surface is smoother in the stressed state and rougher in the relaxed state (52) Atrioventricular Valves The atrioventricular valves consist of the mitral valve and the tricuspid valve The normal circumference of the tricuspid valve is 10 to 11.1 cm in women and 11.2 to 11.8 cm in men The normal circumference of the mitral valve is 8.2 to 9.1 cm in women and 9.2 to 9.9 cm in men (49) The valvular apparatus is made up of the annulus, commissures, lea ets, chordae tendineae, and papillary muscles The annulus is composed of a ring of circumferentially oriented collagen and elastic bers with extensions into the ventricle and the atrium Currently, a number of different descriptors are used in clinical practice to distinguish the two lea ets of the mitral valve (53) The smaller but broader lea et is designated as the anterior or aortic lea et and comprises a third of the circumference It is arbitrarily divided into three segments (A1, A2, A3) The posterior or mural lea et is likewise separated into three segments beginning near the anterolateral commissure (P1) and ending near the posteromedial commissure (P3) The central segment (P2) can vary considerably in size (54) The atrioventricular valves have four histologic layers (atrialis, spongiosum, brosa, and ventricularis) (Figure 20.18) There is an abundance of collagen bers and the different types include type I (74%), type III (24%) and type V (2%) (54) The collagen bundles of the annulus spread down into the majority of the cusps of the mitral valve (except at the free edge of the lea et) and are known as the brosa They continue into the chordae tendineae and nally spread out into a network that covers the tip of the papillary muscles (Figure 20.19) Adjacent to the brosa layer on the ventricular side of the valve is the ventricularis The ventricularis contains many elastic and collagen bers and is covered by endothelium Some of the elastic bers extend into the chordae tendineae; but, in general, this layer is incomplete, as it does not extend to the free edge of the lea et The spongiosa is situated on the atrial side of the brosa layer Like the semilunar valves, it has a rich matrix of proteoglycans and glycosaminoglycans and a few elastic bers, collagen brils, and connective tissue cells such as CH AP TER : No rm a l He a rt 573 FIGURE 20.19 A normal mitral valve with chordae tendineae inserting into the papillary muscles A B FIGURE 20.18 High- (A) and low-power (B) views o a section o the mitral lea et showing the three distinct layers with muscle in the central portion near the base o the valve interstitial broblasts (52,54) This layer, along with the brosa layer, extends throughout the entire length of the lea et The spongiosa in the anterior and posterior mitral lea ets can contain cardiac myocytes that are a direct extension of the left atrial myocardium but not in continuity (Figure 20.18) In the anterior mitral lea et, this layer extends into the middle third, whereas in the posterior lea et it only extends into its proximal third Neural elements and lymphatics can be found in the lea ets The atrial aspect of the spongiosa (ie, layer closest to the atrium) is covered by the atrialis or auricularis, which in turn has a continuous endothelial lining The auricularis contains collagen and elastic bers and smooth muscle cells It is prominent near the annulus but thins out in the distal third of the lea et such that the most distal aspect of the valves is composed only of spongiosa and brosa The endothelial cells on the atrial aspect of the atrioventricular valves are plump and have irregular nuclei compared to the atter endothelial cells on the ventricular aspect The architecture of the tricuspid valve apparatus and the layered arrangements of its lea ets are similar to those in the mitral valve; however, the individual layers are thinner in the tricuspid valve Cardiac muscle bundles insert fairly low into the base of the tricuspid lea ets but not extend into the lea et substance In the posterior and septal lea ets, the auricularis is thicker and contains more abundant smooth muscle cells Chordae Tendineae The chordae tendineae in the normal state are thin brous cords that emanate in a fanlike manner from the broad lea ets of the atrioventricular valves and insert into the papillary muscles (Figure 20.19) The central cores of the chordae are composed of longitudinally oriented collagen brils The core is surrounded more peripherally by loosely arranged collagen brils and elastic bers and is embedded in proteoglycan-rich matrix (52,54) (Figure 20.20) Some chordae contain a small central core of muscle known as chordae muscularis (Figure 20.21), although others contain blood vessels and collagen in variable amounts and appear eshier in color (Figure 20.22) The endothelial cells on the chordae resemble the attened ovoid nuclei of the ventricular surface of the lea ets Applied Anatomy of Intracardiac Valves Semilunar and atrioventricular valves are frequently encountered in the surgical pathology laboratory Indications for valvular replacement or repair include a variety of congenital, infectious, in ammatory, degenerative, and paraneoplastic causes In many cases, the chordae and portions of papillary muscle may be attached In the setting of FIGURE 20.20 Longitudinal section o chordae tendineae showing the relationships o elastic f bers on the sur ace and collagen in the center (elastic van Giesen) 574 S E C TIO N VI: Th o x a n d Se ro u s Me m b n e s may become calci ed with age The valvular circumferences increase with age (10) PAPILLARYMUSCLES FIGURE 20.21 Transverse section o chordae tendineae showing central core o muscle (H&E) myocardial infarction, infection, or valvular prolapse, ruptured papillary muscles may become surgical specimens Lambl’s excrescences and brous nodules are papillary projections along the lines of closure or free edge of the valve, respectively Aging Changes of Intracardiac Valves With age, all the cardiac valves become thicker, more opaque, and less pliable The increase in collagen content may account for the loss of plasticity, and calci cations may occur The posterior lea et of the mitral valve often shows yellow atheromatous alteration The mitral valve annulus FIGURE 20.22 Transverse section o a muscular chorda showing f brous tissue, muscle, and small vessel within the chorda (Masson’s trichrome) The two papillary muscles of the right ventricle (anterior and conal) are relatively constant There is also a group of inconstant posterior papillary muscles on the inferior wall In the left ventricle there are two constant papillary muscles: The anterolateral and posteromedial The papillary muscles receive the chordae They are variable in shape and width and on occasion may have multiple heads (Figure 20.19) The histology of the papillary muscles includes the brous cap, into which the chordae insert (Figure 20.23) The small arteries and arterioles in the papillary muscle are notable for their wall thickness and irregularity in comparison to other intracardiac small vessels (Figure 20.24) The myocardium and the endocardial covering are similar to their counterparts described elsewhere In marked ventricular dilatation, the papillary muscles may become thinned and attened CONDUCTIONSYSTEM Myocardial bers are delineated along two functional pathways in humans: (a) contractile bers and (b) myocardial bers specialized for the initiation and propagation of an impulse for contraction The conduction system is recognized FIGURE 20.23 Longitudinal section o papillary muscle showing the f brous cap o the insertion o the chordae tendineae (Masson’s trichrome) CH AP TER : No rm a l He a rt 575 abundant collagen and elastic bers, respectively (Figure 20.25) Abundant nerve bers run into the node The exact pathway(s) carrying the electrical impulse from the SA node to the AV node remains controversial Some investigators think that several specialized bundles of conducting system cells (eg, anterior, middle, and posterior internodal tracts) conduct the impulse around the atrium Others argue that the arrangement of myocardial bers within the atrium and interatrial septum serves to propagate the impulse (16) Atrioventricular Node FIGURE 20.24 Section o abnormally thickened arteriole within a papillary muscle (elastic van Gieson) to be myogenic in origin, with nerves playing only a subsidiary controlling function For most pathologists, examining the conduction system is often regarded as a daunting exercise This is due in large part to the fact that the number of cases requiring detailed morphologic analysis is infrequent and is often limited to speci c requests from clinicians In addition to detailing the microscopic features of the sinoatrial (SA) and atrioventricular (AV) nodes, we will present our practical approach to the dissection of these structures We recommend careful attention to key anatomic landmarks to ensure successful retrieval of these structures Sinoatrial Node The SA node has the highest intrinsic rate and is recognized as the primary pacemaker of the heart This node is situated within the terminal groove at the junction of the SVC and the lateral border of the right atrium (Figure 20.25) Its position is constant and is marked by the apex of the crest of the atrial appendage It is ovoid or cigar shaped in most hearts, but cases of horseshoe-shaped SA nodes that extend into the interatrial groove are reported Removal of a rectangular block of tissue that includes the distal SVC and atrium on either side of the terminal groove is recommended Serial sectioning in a longitudinal plane parallel to the terminal groove at mm intervals is recommended, and all the tissue slices can be accommodated in two tissue cassettes Grossly identifying the SA nodal artery is also helpful in procuring the node (Figure 20.25) This is a branch of the right coronary artery that is found in slightly more than half of the general population Microscopically, the node is arranged around a central artery adjacent to the epicardial adipose tissue The node is composed of dense connective tissue within which the small muscle bers are embedded The muscle bers contain sparse myo brils, the striations are not prominent, and the whole mass has a pseudosyncytial appearance Connective tissue stains such as Masson’s trichrome and elastic van Gieson stains highlight the In our experience a heart opened along the lines of ow provides the optimum exposure for dissecting the AV node From a right-sided approach the interventricular septum is oriented with the tip of the apex pointing downward The important landmarks include the oval fossa, ostium of the coronary sinus, and tricuspid valve annulus and lea ets The AV node lies within the subendocardial tissues on the right side of the interatrial septum just anterior to the opening of the coronary sinus, posterior to the membranous interventricular septum (tendon of Todaro), and above the tricuspid valve annulus within the triangle of Koch (55) (Figure 20.26) A rectangular block of tissue, beginning with a vertical incision adjacent to the ostium of the coronary sinus and extending to cm below the annulus, is removed After careful trimming of valvular structures, the block will contain components of the tricuspid valve (septal lea et) and mitral and aortic valves (Figure 20.26) Serial sectioning at to mm intervals and sequential placement in tissue cassettes yields a total of to 10 cassettes In histologic sections, the AV node is attened against the central brous body and is composed of a network of muscle bers, with the super cial zone having bers arranged in a parallel manner These specialized bers retain their intercalated disks and striations but are characterized by their pale eosinophilic appearance (Figure 20.26) A small AV nodal artery is often identi ed adjacent to the AV node At the anterior end of the AV node, the muscle bers become arranged in parallel lines to form the main bundle of His or penetrating AV bundle To reach the ventricle, the AV bundle pierces the central brous body and runs forward on the upper margin of the muscular ventricular septum This penetrating portion of the main bundle is surrounded by dense connective tissue and anatomically is closely related to the aortic and mitral valve rings (Figure 20.26) Connective tissue stains can aid in the localization of the nodal tissue The bers of the main bundle are arranged in parallel The penetrating AV bundle terminates as the left and right bundle branches The left fascicle runs downward over the endocardial surface of the interventricular septum to the base of the anterior papillary muscle, and the right fascicle ends in the moderator band of the right ventricle Direct connection of both bundle branches to a complex ramifying system of subendocardial conduction bers can be demonstrated in mammalian hearts Light microscopy shows the bers in the bundle of His and the conduction bundles to be small and contain few myo brils (Figure 20.27) 576 S E C TIO N VI: Th o x a n d Se ro u s Me m b n e s A B C FIGURE 20.25 The SA node A The location o the SA node within the terminal groove at the junction o the superior vena cava (SVC) and crest o the atrial appendage (box) B Macroscopic and low-power magnif cation o serial sections o nodal tissue Note the nodal artery that is adjacent to the SA node C High-power magnif cation o the SA node showing the specialized f bers embedded within collagen and elastic tissue (H&E, trichrome, and elastic van Gieson stains) CH AP TER : No rm a l He a rt A 577 B C FIGURE 20.26 The AV nodal apparatus A The location o the AV node (box) viewed rom the right ventricle Important landmarks include the coronary sinus (CS), tricuspid valve annulus and lea et (TV), and ossa ovale (FO) B Serial sections o the rectangular block o tissue show the relationship o the nodal tissue to the tricuspid valve, mitral valve, atrioventricular valve, and f brous skeleton o the heart C The AV node (left), AV penetrating bundle (middle) and AV bundle with ascicle (right) are shown Aging Changes in the Human Conduction System With advancing age, the SA node displays progressive increase in brous tissue while the AV node remains relatively unchanged Similarly, brous tissue increases in the upper portion of the interventricular septum These changes are associated with a loss of conduction bers in the region of the left bundle branch Up to 50% of the left bundle origin may be lost in people over 60 years of age (56) CARDIACINNERVATION FIGURE 20.27 Section showing the pale cells o the mammalian conducting system These cells contain glycogen and only sparse myof brils (Masson’s trichrome) The nerve supply of the heart is autonomic, including both the sympathetic and parasympathetic supply via both the efferent and afferent bers Histologically, large nerves can be seen in the epicardium and adjacent to the coronary 578 S E C TIO N VI: Th o x a n d Se ro u s Me m b n e s FIGURE 20.29 Electron micrograph showing an intramyocardial lymphatic with thin walls and no basement membrane (original magnif cation ×20,000) FIGURE 20.28 Electron micrograph o sympathetic nerve showing dense-core granules in the myocardium (original magnif cation ×22,500) blood vessels Small nerves within the myocardium are hard to identify unless special stains are used Myocardial nerves are best viewed using electron microscopic examination, by which the autonomic nerves can be distinguished Cardiac ganglia (parasympathetic) can be found over the surface of the atria and in the AV groove (Figure 20.13) Autonomic Nerves Axonal varicosities occur at irregular intervals along autonomic bers, and their morphology is considered useful in determining whether the nerve is adrenergic or cholinergic (52) In cholinergic nerves, the varicosities contain accumulations of agranular vesicles and a few mitochondria In adrenergic nerves, the varicosities contain vesicles rich in electrondense cores Each of these cores is separated from the limiting membrane of the vesicle by an electron-lucent zone (Figure 20.28) Presumptive sensory nerve terminals have large diameters and contain numerous mitochondria They are located in perivascular regions and are surrounded by Schwann cells A given Schwann cell may enclose adrenergic and cholinergic axons together with sensory axons (52) Autonomic ganglia are found in the subepicardial tissue of the atria and atria appendages and at the root of the great vessels, along the interatrial and AV grooves in the atrial septum and in the vicinity of the SA and AV nodes Large nerves can be seen in the subepicardial layer adjacent to the epicardial coronary arteries LYMPHATICS There are two networks of lymphatics in the heart: (a) in the endocardium and (b) in the epicardium The route of drainage of the endocardial network is through channels in the myocardium into the epicardial lymphatics The epicardial meshwork of channels, containing many valves, drains toward the AV sulcus by means of several longitudinal channels that run for the most part parallel to the coronary veins in the anterior and posterior longitudinal sulci of the ventricles (52) Lymphatics leave the pericardial cavity to empty into one of the pulmonary hilar lymph nodes and join the lymphatic drainage system of the mediastinum or into the thoracic duct Lymphatics are also found in the myocardial valves and lie within the grooves of the coronary blood vessels The lymph capillaries and larger lymphatic vessels accompany blood vessels in the myocardial interstitium The walls of the myocardial lymphatics consist of extremely thin endothelial cells, the nuclei of which bulge into the lumen (Figure 20.29) In contrast to endothelial cells of blood capillaries, those of the lymphatic capillaries not have a well-de ned external basal lamina The endothelial cells of lymphatic capillaries may have Weibel–Palade bodies and transplant vesicles (52) The larger lymphatics are ned to the outer third of the myocardial wall and occasionally contain valves These ap-like structures contain a core of collagen embedded in micro brils and are covered by endothelia SMALLINTRAMURALCORONARYARTERIES The structure of the intramural coronary arteries and the larger coronary arteries is similar and consists of the endothelium, smooth muscle, and adventitia (Figure 20.30) These smallest muscular arteries contain three or four layers of smooth muscles Arterioles have at, elongated endothelial cells that not protrude into the lumen Their internal elastic lamina is discontinuous Metarterioles are also known CH AP TER : No rm a l He a rt 579 the bioptome and the technique have undergone modi cations that now permit clinicians the opportunity to obtain cardiac tissue in a safe outpatient setting (57) The right internal jugular vein or femoral vein approaches are commonly used Complications are uncommon and include local problems (such as hematomas and nerve injury) and cardiac problems (such as arrhythmias, tricuspid valve apparatus damage, and ventricular perforation) Tissue Handling and Processing FIGURE 20.30 Transverse section o intramyocardial arteriole (elastic van Gieson) as precapillary sphincters The endothelial cells in metarterioles have numerous surface projections that bulge into the lumen (52) Although the medial smooth muscles form a single discontinuous layer, it gradually disappears as capillaries begin Capillaries are distinguished by the fact that their walls are composed of only a single layer of endothelial cells They not have smooth muscle cells but may have closely associated pericytes (52) Capillary endothelial cells may have microvilli and cytoplasmic processes ( lopodia) The myocardium has a rich network of capillaries These branches undergo anastomosis and eventually become thinwalled venules measuring up to 100 µ m in diameter VEINSANDVENULES Venules have thin, at endothelial cells and characteristically contain a large amount of connective tissue in the vicinity of their external surface; they contain collagen brils that approach the endothelial layer and are anchored on its outer surface (52) Venules gradually increase in size to become veins Veins have larger lumens but thinner walls than their arterial counterparts Veins have three layers: The intima, media, and adventitia The intima is thin, lacks smooth muscle cells and has a poorly de ned internal elastic lamina The media is also thin and contains few smooth muscle cells and elastic bers The adventitia is thick with abundant collagen and elastic bers Cardiac veins drain blood into either the coronary sinus or directly into the chambers (thebesian veins) THEENDOMYOCARDIALBIOPSY The transvenous endomyocardial biopsy is currently utilized for the diagnosis of allograft rejection and a variety of in ammatory, metabolic, and neoplastic conditions that affect the heart Originally introduced in the early 1960s, Proper tissue procurement and handling are essential for optimal diagnostic evaluation (58) Biopsy specimens should be gently extracted from the bioptome with a needle tip to limit crush artifactual distortion The clinical indications for the biopsy determine, in large part, the method of tissue handling For example, for standard light microscopy, the tissue should immediately be placed in a standard xative such as 10% neutral buffered formalin To demonstrate the type of amyloid bril in cardiac amyloidosis by immuno uorescence (eg, AL, AA, or transthyretin), one or two pieces should be received in saline or Zeus medium and then snap frozen in a plastic Beem capsule containing an embedding medium The diagnosis of chronic anthracycline cardiotoxicity requires that all the biopsy pieces (minimum of to pieces) be submitted in xative for transmission electron microscopy (eg, 2.5% glutaraldehyde with 2% paraformaldehyde in 0.1M sodium cacodylate buffer, pH 7.2) For routine diagnostic evaluation, overnight processing and paraf n embedding are suf cient For emergent cases, a 90-minute rapid (“ultra”) processing cycle is available, and microscopic slides can be prepared within three to four hours All the biopsy pieces should be embedded in the same block We recommend that a minimum of three slides be prepared, with each sectioned at to µ m thickness from various depths within the paraf n block Multiple fragments, or “ribbons,” are placed on each slide We routinely stain with hematoxylin and eosin (H&E) and use stains such as Masson’s trichrome to rm the presence of myocyte damage or brosis, Congo red stain for amyloid brils, and the Prussian blue stain for iron deposition Immunohistochemical, immuno uorescent, and molecular studies are utilized for speci c indications Paraf n section immunohistochemistry is used to evaluate for the presence of infectious myocarditis (eg, cytomegalovirus (CMV) or toxoplasmic myocarditis), post-transplant lymphoproliferative disorders (PTLD) [B-cell clonality, Epstein– Barr virus (EBV) latent membrane proteins, anomalous coexpression of B-cell and T-cell antigens] or acute antibody mediated rejection (intravascular collections of CD68+ histiocytes and deposition of C4d on the microvasculature) In situ hybridization is helpful to demonstrate the presence of EBV or other viral genome or light chain restriction in PTLD Biopsy Limitations and Tissue Artifacts Sampling error in the diagnosis of rejection, myocarditis, and infection remains a major consideration in the clinical A B C D E F G H FIGURE 20.31 Arti acts o endomyocardial biopsy specimens: A Contraction band arti act (H&E); note the normal appearance o myocyte nuclei B Contraction band necrosis with hyperchromatic pyknotic nuclei and eosinophilic cytoplasm The changes are contrasted with the common contraction band arti act in A C Telescoping o intramyocardial is highlighted by a trichrome stain D Intramyocardial adipose tissue The presence o at does not imply epicardial localization or per oration E Mesothelial cells admixed with f brin indicative o ventricular per oration F Thrombus without attached myocardial tissue G Bioptome-induced “Victorian waistband” arti act H Crush arti actual distortion o cells 580 CH AP TER : No rm a l He a rt management of patients and the evaluation of new noninvasive diagnostic modalities In general, the false-negative rate is low, particularly when four or more pieces of tissue are submitted The issue of how many lymphocytes are normally found in the myocardium has been addressed in a number of studies In an endomyocardial biopsy study, the mean number of lymphocytes reported is fewer than 5.0 per high-power eld (59) Tazelaar and Billingham reported foci of mononuclear in ammatory cells in 9.3% of cases in which biopsy samples were obtained from donor hearts just before transplant These foci ranged from six to at least 50 cells in number (60) In an autopsy study of young men who died from acute traumatic injury focal collections of at least 100 mononuclear cells were found in 5% of cases The study predated the Dallas criteria and the term “focal myocarditis” was utilized (61) These studies support the concept that small clusters of mononuclear cells including lymphocytes and macrophages are normal within the myocardium and should not be indiscriminately classi ed as myocarditis A variety of artifacts occur in endomyocardial biopsy specimens that may mimic pathologic lesions The surgical pathologist must be aware of these patterns to avoid a misdiagnosis that could lead to unnecessary therapeutic interventions These have been reviewed in detail in a recent publication and only selected topics will be brie y reviewed (62) The most common biopsy artifact is the presence of contraction bands in myocytes (Figure 20.31A) They are identical to the linear bands observed in acute ischemic necrosis and catecholamine (“pressor”) effect These changes are induced by the biopsy procedure itself and can be diminished by using xatives stored at room temperature In ischemic injury, the nuclei of surrounding myocytes are usually pyknotic (Figure 20.31B), while in artifactually induced contraction bands, the nuclei remain normal in appearance Another frequent artifact is intussusception, or “telescoping,” of small arteries that has been confused with luminal occlusion by thrombus and transplant-related arteriosclerosis Connective tissue stains such as Masson’s trichrome or elastic van Gieson highlight the internal elastic membranes of both vessel segments (Figure 20.31C) Intramyocardial accumulations of mature adipose tissue can simulate the epicardial tissue, especially if associated with vessels of relatively large caliber (Figure 20.31D) Both can be found in the right ventricular apical region, and adipose tissue is found not uncommonly in woman and elderly patients This should not be confused with arrhythmogenic right ventricular cardiomyopathy/dysplasia; clinical–pathologic correlation is essential for this purpose Ventricular perforation is identi ed by the presence of mesothelial cells (Figure 20.31E) Accumulations of fresh platelet- and brin-rich thrombus may be identi ed along the endocardial surface of biopsy fragments (Figure 20.31F) These form as a result of the repetitive placement of the bioptome along the endocardial surface and not 581 indicate chronic mural thrombi A number of patterns of bioptome-induced tissue distortion or crush artifact can be observed in biopsy samples The “hour-glass” or “Victorian waistband” effect is caused by central constriction of the tissue by the bioptome mechanism (Figure 20.31G) A more problematic artifact is the smearing of cytoplasmic and nuclear components of cells that yields strands of basophilic material (Figure 20.31H) In this setting, it may not be possible to distinguish the cell types (lymphocytes, endothelial cells, histiocytes, myocytes), and we not attempt to evaluate these foci for allograft rejection or myocarditis In some cases, procurement of additional leveled H&E-stained sections can provide less distorted foci in the deeper aspects of the biopsy sample In our experience, immunohistochemical stains have not been consistent or helpful SUMMARY Because of the structural–functional nature of cardiac disease, the surgical pathologist should have a working knowledge of both anatomy and histology Moreover, the alterations produced by the endomyocardial biopsy and the bioptome require familiarity with the myriad of tissue artifacts With a practical understanding of these points, the evaluation of specimens ranging from endomyocardial samples to explanted hearts will enhance the diagnostic information provided to clinicians and patients REFERENCES Stehlik J, Edwards LB, Kucheryavaya AY, et al The Registry of the International Society for Heart and Lung Transplantation: twenty-seventh of cial adult heart transplant report—2010 J Heart Lung Transplant 2010;29:1089–1103 Christie JD, Stehlik J, Edwards LB, et al The Registry of the International Society 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Am J Cardiovasc Pathol 1986;1:47–50 61 Stevens PJ, Ground KEU Occurrence and signi cance of myocarditis in trauma Aerosp Med 1970;41:776–780 62 Hauck AJ, Edwards WD Histopathologic examination of tissues obtained by endomyocardial biopsy In: Fowles RE, ed Cardiac Biopsy Mount Kisco, NY: Futura Publishing; 1992:95–153 ... 978 -1- 4 511 -13 03-7 ( h ardback) I Mills, Stacey E [ DNLM: H istology Path ology QS 504] 611 ′. 018 dc23 2 012 011 114 Care has been taken to conf rm the accuracy o the in ormation presented and to describe... Robboy 41 Normal Histology o the Uterus and Fallopian 30 Pancreas 777 S E C T IO N 40 Vagina 10 59 Tubes 10 71 Kristen A Atkins, Michael R Hendrickson, and Richard L Kempson 42 Ovary 11 19 C Blake... Muscle SPECIMEN HANDLING 21 ARTIFACTS 21 17 HISTOLOGIC DIFFERENCES OF SKIN WITH AGE 18 Newborns and Children 18 Elderly 18 INTRODUCTION The skin accounts for about 15 % of the total body weight