PATHOLOGIC
`BASIS of
`Third Edition DISEASE
`
`STANLEY L. ROBBINS, M.D.
`Visitlnq Professor of Pathology, Harvard Medical School;
`Ser:t::t PQthoiogist, Brigham ond Women's Hospital, Boston
`
`F. B. Ma!lor11 Professor of Potr;ology, Harva,cl ,;_.;.,
`. '·,oc:-!;
`Chairman, Department of Pathology, Brighcni :}:<.: ·. •'<nien's Hospital, Boston
`
`VINAY KUMAR, M.D.
`Charles T. Ashworth Professor of Pathology, University of Texas Health Science Center
`southwestern Medical School, Dallas
`
`NOVARTIS EXHIBIT 2095
`Breckenridge v. Novartis, IPR 2017-01592
`Page 1 of 54
`
`

`

`w. B. Saw1ders uimpauy;
`
`ri1il~d~iphia, PA 19105
`
`Library of Congress Cataloging in Publication Data
`
`Robbins, Stanley L.
`
`Pathologic basis of disease.
`
`Includes bibliographical references and index.
`
`1. Pathology.
`III. Title.
`
`II. Kumar' Vinay.
`I Cotran Ramzi S.
`[DNLM: 1'. Pathology. QZ 4 R363p)
`
`RB111.R62 1984
`ISBN 0-7216-7597-2
`
`616.07
`
`83-20403
`
`Listed here is the latest translated edition of this book together with the language of the translation and the publisher.
`
`Portuguese (3rd edition)-Discos CBS_ Industria e Comercio,
`Rio de Janeiro, Brazil
`
`Spanish (3rd f!dition)-N ueva Editorial Interamericana S. A.,
`Mexico City, Mexico
`
`Yug~slavian (1st edition)-Serbo-Croat, Skolska Knjiga, Zagreb, Yugoslavia
`
`Italian (3rd edition)-Piccin Nuova Libraria S.p.A., Padova, Italy
`
`Pathologic Basis of Disease
`
`ISBN 0-7216-7597-2
`
`· ht
`© 1984 by W. B. s,.nd,., Comp'."Y· Copy,ight 1974 ,nd 1979 by W. B. S,und.,, Comp,ny, Copy, lght on "
`.,,y b<
`e "' of
`,di,g, ~
`th Uniform Copyng
`.
`d
`Con"'ntwn. S,mult,neou,ly pubh,hed m C,n,d,. All ,lght, re,e,,ed. Th;, book i, proteoted by copynght. No P
`11
`repmdueed, ,tored ln ' ret,;-,~ ,y,tem, o, trnn,mltted in ,ny fo,m o, by any mean,, electronic, mech,nical, pbotocopymg, '':,., Co•·
`o~erwise, without written permission from the publisher. Made in the United States of America. Press of W. B. Saun
`pany. Library of Congress catalog card number 83-20403.
`
`Last digit is the print number:
`
`9
`
`8
`
`7
`
`6
`
`5
`
`NOVARTIS EXHIBIT 2095
`Breckenridge v. Novartis, IPR 2017-01592
`Page 2 of 54
`
`

`

`DISEASES OF WHITE CELLS,
`DI EASES OF WHITE CELLS,
`LYMPH NODES, AND SPLEEN*
`LYMPH NODES, AND SPLEEN*
`
`15
`
`White Cells and Lymph Nodes
`11s and Lymph Nod s
`----------Whit
`
`NOIIMAL
`p~n4()1.0QY
`PATHOLOGY
`Leukopenla
`Neuttopenlo—agtonuloeqosls
`~unopenl ogranulocytosl
`ReoctWe (Inflammatory) Proliferations of White
`~ (lnftammotoly) Proll,.fCltlON ol Whit•
`Cells and Nodes
`c.llaandNodM
`Leukocytosls
`ltu ocytOSls
`Acute nonspecific lymphadenitis
`N;1J nonspecific lymphodenllls
`Chronic nonspecific lymphadonltls
`ChrOfllc nonspectllc lymphod nllls
`Neopldstic Proliferations of White Cells
`Ntc)plaltlc Prol"9rotlont ol Whit. Cella
`Malignant lymphomas
`Mongnonl lymphomas
`Non-Hodgkin's lymphomas (NHL)
`Non-Hodgkin's lymphomas (NHL)
`
`Hodgkin's disoaso (Hodgkin's
`HOdgldn'1 dlaeo .. (HOdgkln'a
`lymphoma)
`lymphoma)
`(oukomlas
`L uk mloa
`Unusual typos of loukomlas and
`Unu uol type of leuk mto, ond
`lymphomas
`lymphoma,
`Agnogonlc myolold motaplasla
`Agnog nlc my lotd metoploslo
`(myolold motaplasla with
`(my lold metoplollo wtth
`myoloflbrosls)
`my loflblO&II)
`Plasma cell dyscraslas and related
`Plosmo c II dyscralloa and r lot~
`disorders
`dlSO!dOII
`Multiple myeloma (plasma cell
`Mulllple myeloma (plalt\'\CI cell
`myeloma)
`my loma)
`
`Solitary myeloma (plasrnocytorna)
`Waldenstrorn" moctogloWlnemia
`Heavy-chain disease
`Monoclonal gommopathy of
`undetermined Ogniflconce
`Histtocytosos
`Generalized Nstiocqosis (Letterer-Stwe
`syndrome)
`EoslnopNlic granuomo--unifocal and
`mutttfocd
`MgJolrnmunoblastic tyrnphadenopathy
`
`•With gratitude to Drs Jose Hernandez, Southwestern Medical School, Dallas, Texas, for a critical review of this chapter.
`I •clic,11 · hoot, Dnll
`, T x , for critical r view of this chap r.
`
`NORMAL
`NORMAL
`The origin and differentiation of white cells (gran-
`Th origin and diffi r ntiation of whit c l\s (gran(cid:173)
`ulocytes, monocytes, and lymphocytes) were briefly
`ulocyt
`, monoc te , and lympho yt ) w r bri By
`discussed in Chapter 14 along with the other formed
`discus d in Chapter 14 along with the other formed
`elements of blood. Lymphocytes and monocytes not
`elem nts of blood. Lymphocyt
`and monocyt s not
`only circulate in the blood and lymph, but also accu-
`only circulate in the blood and lymph, but al o accu(cid:173)
`mulate in discrete and organized masses, the so-called
`mulat
`in di cret and organiz d mas es, th so-called
`lymphoreticular system. Components of this system
`lymphor ticular syst m. Components of this system
`include lymph nodes, thymus, spleen, tonsils, adenoids,
`includ lymph node , thymus, spl en, tonsils, adenoids,
`and Peyer's patches. Less discrete collections of lym-
`and P yer's patches. Less discr t coll ctions of lym(cid:173)
`phoid cells also occur in the bone marrow, lungs, and
`phoid cells also occur in the bon marrow, lungs, and
`gastrointestinal tract and other tissues. Lymph nodes
`gnstroint
`tinal tract and other ti su s. Lymph nodes
`are the most widely distributed and easily accessible
`are the mo t wid ly di tributed and easily accessible
`component of the lymphoid tissue and are therefore
`compon nt of the lymphoid tissue and are therefore
`frequently examined for the diagnosis of lymphoreticular
`frequ ntly examin d for the diagnosis oflymphoretic~lar
`disorders. It would therefore be advantageous to review
`di ord r . It would th refor b advantageous to reV1ew
`the normal morphology of lymph nodes.
`the normal morphology of lymph nod s.
`Lymph nodes, in general, are discrete structures,
`Lymph nod
`, in g neral, nre discrete structures,
`Ovoid in shape, that vary from a few millimeters to 1 to
`ovoid in hape, that vary from a fi w millimeters t~ l to
`2 cm in length. Their consistency is soft and their cut
`2 cm in l ngth. Th ir consist ncy is soft and their cut
`surface is gray-white. They are surrounded by a capsule
`surface i gray-whit . Th y ar urrounded by ~ cap ~le
`composed of connective tissue and a few elastic fibrils,
`compos cl of conn , tiv
`ti su and a fi w ela tic fibnl ,
`Pelforated at various points by afferent lymphatics that
`perforat d at variou points by affi r nt lymphatics that
`empty into the peripheral sinus subjacent to the capsule.
`mpty into th p riph rul sinu subjacent to th capsule.
`Branches of the sinus extend into the nodes and termi-
`Branche of th
`inu
`t nd into th nod s and t rmi(cid:173)
`nate at the hilus, where the efferent lymphatics emerge.
`nat at the hilu wh r, th
`ffi r nt lymphatics m rge.
`All lymphatics are lined with reticuloendothelial cells.
`All lymphatic ;re Jin d with r ticulo ndoth lial cell .
`Situated in the cortex or peripheral portion of the node
`ituat d in th cort x or p riph ral portion of th nod
`are spherical aggregates of lymphoid tissue, the so-
`are ph rical aggr gat s of lymphoid tis u , the ·o(cid:173)
`called primary follicles, which represent the B-cell
`call <l primary follicl s, which r prese~t th B~cell
`areas. Upon antigenic stimulation, the primary follicles
`ar as. Upon nntig ni
`timulation, th pnmary folhcl
`enlarge and develop pale-staining germinal centers com-
`nlarg and d v ·lop pal _ taining g ~rminul c 1~t r co_m(cid:173)
`Posed of follicular center cells (lymphocytes in varying
`po cd of follicular c nt r
`ll (lymphocyt · m v~~ng
`stages of activation, described on p, 663). Surrounding
`st ge of activation d s rib d on p. 663). urroun mg
`these germinal centers are mantles of small unchal-
`th
`g rminul
`~t rs ar mantl 'S of smnll unchal-
`
`lenged B cells. The T cells occupy the parafollicular
`I nged B cells. The T cells occupy the paraf~llicular
`regions (p. 158). The medullary cords, occupying the
`regions (p. 158). The medullary cord , occupymg the
`central portion of the node, contain predominantly
`central portion of the node, contain predominantly
`plasma cells and some lymphocytes. A delicate reticulin
`plasma cells and some lymphocytes. A delicate reticulin
`that connects peripherally with the capsule is the pre-
`that connects peripherally with the capsule is the pre(cid:173)
`dominant supporting structure within the lymph nodes.
`dominant supporting structure within the lymph nodes.
`The morphologic description of the lymph node
`The morphologic description of the lymph node
`just given is highly idealized and falsely static. The size
`just given is highly idealized and falsely static. The size
`and morphology of lymph nodes are modified by stress,
`and morphology of lymph nodes are modified by stress,
`thyroid and adrenal function, and immune responses.
`thyroid and adrenal function, and immune responses.
`As secondary lines of defense, they are constantly re-
`As secondary lines of defense, they are constantly re(cid:173)
`sponding to stimuli, even in the absence of clinical
`sponding to stimuli, even in the absence of clinical
`disease. Trivial injuries and infections effect subtle
`disease. Trivial injuries and infections effect subtle
`changes in lymph node histology. More significant bac-
`changes in lymph node histology. More significant bac(cid:173)
`terial infections inevitably produce enlargement of
`terial infections inevitably produce enlargement of
`nodes and sometimes leave residual scarring. For this
`nodes and sometimes leave residual scarring. For this
`reason, lymph nodes in the adult are almost never
`reason, lymph nodes in the adult are almost never
`normal," since they usually bear the scars of previous
`"normal," since they usually bear the scars of previous
`events, rendering the inguinal nodes particularly inap-
`events, rendering the inguinal nodes particularly inap(cid:173)
`propriate for evaluative biopsies. Except in the child, it
`propriate for evaluative biopsies. Except in the child it
`is diffcult to find a "normal" node, and in histologic
`is diffi~ult t? ~nd a "normal" node, and in histologic
`evaluations it is often necessary to distinguish changes
`evaluations 1t 1s often necessary to distinguish changes
`secondary to past experience from those related to
`secondary to past experience from those related to
`present disease.
`present disease.
`
`PATHOLOGY
`PATHOLOGY
`Disorders of white cells may be classified into two
`Disord rs of white c Us may be classified into h
`broad categories, proliferative and those characterized
`broad cat~gories, proliferative and those characteriz~
`by a deficiency of leukocytes, i.e., leukopenias. Prolif-
`by ~ deflc1enc~ of leukocytes, i.e., leukopenias. Prolif-
`erations of white cells and lymph nodes miy be reactive
`rations of wlute cells and l mph nodes
`.,_ he
`· s ·
`.
`or neoplastic. Since their major function is host defense,
`l
`mu.
`or n ?P astic. me th ir major function is h
`reactive
`t d fe
`reactive proliferation in response to an underlying pri-
`r active prolifi ration in response to an u do l _e ns~,
`mary, often microbial disease is fairly common. Neo-
`mary, often microbial disease is fairly n
`r ymg pn-
`eo-
`common.
`653
`
`NOVARTIS EXHIBIT 2095
`Breckenridge v. Novartis, IPR 2017-01592
`Page 3 of 54
`
`

`

`654 DISEASES OF WHITE CELLS, LYMPH NODES. AND SPLEEN
`654 DISEASES OF WHITE CELLS, LYMPH NODES, ANO SPLEEN
`plastic disorders, although less frequent, are much more
`important. In the following discussion, we will describe
`first the leukopenic states and summarize the common
`reactive disorders, and then consider in some detail
`malignant proliferations of the white cells that in many
`instances arise in the nodes.
`
`LEUKOPENIA
`LEUKOPENIA
`The number of circulating white cells may be
`ma h
`markedly decreased in a variety of disorders. An abnor-
`mally low white cell count (leukopenia) may occur
`because of decreased numbers of any one of the specific
`types of leukocytes, but most often involves the neutro-
`phils (neutropenia, granulocytopenia). Lymphopenias
`are much less common, and in addition to the congenital
`immunodeficiency diseases (p. 205) they are associated
`with specific clinical syndromes (e. g. , Hodgkin's disease,
`nonlymphocytic
`leukemias,
`following corticosteroid
`therapy, and occasionally in chronic diseases). Only the
`more common leukopenias involving granulocytes will
`be discussed here.
`
`Neutropenia—Agranulocytosis
`Neutropenla-Agranulocytosls
`Reduction in the number of granulocytes in the
`R duction in the numb r of granulocyte
`in th
`peripheral blood—neutropenia—may be seen in a wide
`peripheral blood-neritropenia-may be seen in a wid
`variety of circumstances. Frequently it is transient and
`variety of circumstances. Frequently it i tran i nt and
`of trivial significance. Sometimes the reduction in cir-
`of trivial significance. Sometim s the r duction in cir(cid:173)
`culating neutrophils is marked and has serious conse-
`is marked and has
`riou cons -
`culating neutrophil
`quences by predisposing to infections. When of this
`quences by predisposing to infection . When of thi
`magnitude, it is referred to as agranulocytosis. The
`magnitude, it is referred to a agranulocyto i . Th
`lymphocytes are not affected, so the percentage of
`lymphocytes are not affected, o th p re ntage of
`lymphocytes is increased (relative lymphocytosis).
`lymphocytes i increa ed (relative lymphocyto i ).
`PATHOGENESIS. Considering first the broad topic
`PATHOGENESIS. Considering fir t the broad topic
`of neutropenia, whatever its severity, a reduction in
`of neutropenia, whatever it s v rity, a reduction in
`circulating granulocytes will occur if (1) granulopoiesis
`circulating granulocytes will occur if (1) granulopoi si
`fails to keep pace with the normal tumov r rate of
`neutrophils or (2) there is accelerated removal of neu-
`neutrophils or (2) there is accelerated removal of n u(cid:173)
`trophils from the circulating blood. You recall that the
`trophils from the circulating blood. You recall that th
`neutrophil is a very short-lived cell having a half-life of
`neutrophil is a very short-lived cell having a half-life of
`only six to seven hours. Any impairment of granulo-
`only six to seven hours. Any impairment of granulo(cid:173)
`poiesis can therefore induce a neutropenia within hours
`poiesis can therefore induce a neutrop nia within hours
`to a few days.
`to a few days.
`Inadequate or ineffective granulopoiesis may be
`Inadequate or ineffective granulopoiesis may b
`encountered with (l) suppression of pluripotent myeloid
`encountered with (1) suppr ssion of pluripotent m eloid
`stem cells, as occurs in aplastic anemia (p. 638) and a
`stem cells, as occur
`in aplastic an mia (p. 63 ) and a
`variety of leukemias and lymphomas (p. 683)-—in these
`variety of leukemias and lymphoma (p. 683)-in th s
`conditions, granulocytopenia is accompanied by anemia
`conditions, granulocytop nia is accompanied by an mia
`and thrombocytopenia; (2) suppression of the committed
`and thrombocytop nia; (2) suppr ssion of th committed
`granulocytic precursors, which occurs after exposure to
`to
`granulocytic pr cursors, which occurs aft r exposur
`certain drugs, o discussed below; (3) megnloblastic
`anemias, due to vitamin 1312 or folate deficiency (p. 630),
`anemias, due to vitamin 8 12 or folat d fici ncy (p, 630),
`in which defective DNA synthesis produces abnormal
`in which cl •fectiv D A ynth sis produc s abnormal
`granulocytic precursors, rendering them susceptible to
`granulocytic pr cursors, r nd ring th m susc ptibl
`to
`intramedullary death (ineffective granulopoiesis). Mar-
`intramcdullary death (in ffi
`tiv granulopoi •is). Mar(cid:173)
`row granulopoiesis is increased but the number of
`row granulopolesis is incr a cl hut the numb r of
`mature neutrophils entering the blood is decreased.
`mature ne~1trophils ent ring the blood i deer used.
`
`Accelerated removal or destruction of neutrophdt
`(l) immunologiGilly mediated
`is encountered
`to the neutrophils, which may be idiopathic with n;
`other abnormality, associated with a well-defined im-
`munologic disorder (e.g.. Felty•s syndrome. p. 1.135),
`or produced by exposure to drugs; (2) splenic seques_
`tration in which excessive destruction o«urs
`to cnlargcmcnt of the spleen (p, 6!h)), associated also
`with excessive destruction of red o•lls and platelets.
`Among the many associations mentioned, the most
`significant neutropenias (agranulocytoscs) are produced
`by drugs.' Certain drugs, such as alkylating ak'onts am]
`antimctabolites used in cancer treatment. produce
`agranulocytosis in a predictable, dose-related
`They cause a generalized suppression of the iFjne mar.
`row, and therefore other cells are also affected Laplastic
`anemia). Agranulocytosis may also be encount€'5Ul as an
`idiosyncratic reaction to a large variety of agents.
`roster of implicated drugs includes aminopyllte, chlor-
`amphenicol, sulfonamides, chlorpromazine, thiouracd,
`and phenylbutazone. Although the mechanism of agran-
`ulocytosis here 'is obscure, both decreased production
`and increased destruction have been implicated. The
`neutropenia induced by chlorpromazine and related
`phenothiazines is of slow onset and is believed to result
`from the suppression of granulocytic precursors in the
`bone marrow. Chlorpromazine can inhibit DNA synthe-
`sis of marrow cells in vitro, and therefore it is postulated
`that certain individuals unusually sensitive to this effect
`develop agranulocytosis. Neutrophil production gradu-
`ally becomes normal after the cessation of drug therapy.
`Agranulocytosis following administration of aminopyr-
`ine, thiouracils, and certain sulfonamides is believed to
`result from immunologically mediated destruction of
`mature neutrophils. Antibodies reactive against a com-
`plex between the drug or its metabolite (acting as the
`hapten) and leukocyte proteins may evoke a Tvpe Il
`hypersensitivity reaction. Alternatively, neutrophils
`may be damaged as innocent bystanders by the adsorp-
`tion of drug-antibody complexes on the sufface and the
`subsequent activation of complement. In many cases,
`no antecedent cause of neutropenia can be detected but
`autoimmunity is suspected, since serum antibodies di-
`rected against neutrophil-specific antigens can be de-
`
`MORPHOLOGY. The anatomic alterations in the bone
`.
`MORPHOLOGY Th
`e anat?m,c alterations in the ~e
`marrow de end
`•
`When it is caused by excessive destruction of the mature
`When it is Pcaus: the underl¥ing basis of the neutropenia.
`neutrophils, the marrow may be hypercellular with increased
`by excessive destruction of the mature
`neutrophils th
`numbers of immature granulocytic precursors. HypercellU•
`numbers of i~mrr:i~rrow may be hypercellular with increased
`larity is also seen with ineffective granulopoiesis, as occurs
`larity Is also seen ure granulocytic precursors. Hypercellu(cid:173)
`in megaloblastic anemias. Agranulocytosis caused by agents
`ln megaloblastlc an~lt~ ineffective granulopoiesis, as occurs
`that affect the committed granulocytic precursors are under-
`that affect the comm~'~· Agranulocytosis caused by agents
`standably associated with hypocellular marrow, resulting
`standably associat I e granulocytic precursors are under(cid:173)
`from greatly decreased leukopoietic elements. Erythropoie-
`from greatly decreaed d~lth hypocellular marrow, result!~
`sis and megakaryocytes usually remain at normal levels, but
`sis and megaka oc se eukopofetic elements. Erythrop01e·
`with certain myelotoxic drugs all marrow elements may be
`with certain myZotf ~s dusually remain at normal levels, but
`affected. Occasionally, increased numbers of plasma cells
`affected. Occasional~ c
`rugs all marrow elements may b8
`and lymphocytes are found in the marrow, particularly as
`and lymphocyt
`Y, Increased numbers of plasma cells
`the marrow becomes acellular.
`the marrow b~;maere found in the marrow particularly as
`s acellular.
`'
`
`NOVARTIS EXHIBIT 2095
`Breckenridge v. Novartis, IPR 2017-01592
`Page 4 of 54
`
`

`

`Infections are a characteristic feature of agranulo.
`Infection• tal re a chatrl a1cterl tic f ature of agranulo(cid:173)
`cytosis. Ulcerating necrotizing lesions of the gingiva, floor
`cyto•I•· Ulcers ng necro z ng leslon of the glnglva, floor
`of the mouth, buccal mucosa, pharynx, or anywhere within
`of the mouth, buccal mucosa, pharynx, or anywh re within
`the oral cavity (agranulocytic angina) are quite characteristic
`tt,e oral cavity (agranulocytlc angina) aro quit character! tic
`of agranulocytosis (Fig. 15—1). These ulcers are typically
`typlcall
`r
`of agranulocytosls (Fig. 15-1 ). These ulc rs
`deep, undermined, and covered by gray to green-black
`de8P, undermined, and cover d by gray to gre n-blac~
`necrotic membranes from which numbers of bacteria or fungi
`necrotic membranes from which numbers of bacteria or fun 1
`can be isolated. Similar ulcerations may occur in the skin,
`can be Isolated. Slmllar ulcerations may occur In the ski~
`vagina, anus, or gastrointestinal tract, but these sites are
`vagina, anus, or gastrolntestlnal tract, but these sites ar~
`much less frequently involved. Severe necrotizing infections
`much less frequently Involved. Severe necrotlzlng Infections
`are also encountered, but less prominently, in the lungs,
`are also encountered, but less prominently, In the lungs,
`urinary tract, and kidneys. All these sites of infection are
`urinary tract, and kidneys. All these sites of infection are
`characterized by massive growth of bacteria (or other
`characterized by massive growth of bacteria (or other
`agents) with relatively poor leukocytic response. In many
`agents) with relatively poor leukocytic response. In many
`instances, the bacteria grow in colony formation (botryomy-
`instances, the bacteria grow in colony formation (botryomy(cid:173)
`cosis) as though they were cultured on nutrient media. The
`cosis) as though they were cultured on nutrient media. The
`regional lymph nodes draining these infections are enlarged
`regional lymph nodes draining these infections are enlarged
`and inflamed. The spleen and liver are rarely enlarged.
`and inflamed. The spleen and liver are rarely enlarged.
`CLINICAL COURSE. Agranulocytosis tends to follow
`to foll ow
`t nd
`tosi
`CLINICAL COURSE. granulo
`a fairly characteristic clinical pattern. The initial symp-
`initial symp(cid:173)
`a fairly charact ri tic clinical patt rn . Th
`toms are often malaise, chills, and fever, followed in
`toms are often malais , chill , and fi
`r, foll owed in
`sequence by marked weakness and fatigability, symp-
`sequence by marked weakn s and fatigabili ty, ymp(cid:173)
`toms that stem from the severe infections characteristic
`infection characte ri tic
`r
`toms that stem from the s
`of this disorder. In severe agranulocytosis with virtual
`, ith virtual
`of this disorder. In severe agranuloc to i
`absence of neutrophils, these infections may become so
`absence of neutrophil , these in.Fi ctions may become o
`overwhelming as to cause death within a few days. Less
`overwhelming as to cau e death within a few day . Le s
`extreme depression of the marrow may appear insidi-
`extreme depression of the marrow may appear insidi(cid:173)
`ously and come to light only during the investigation of
`ligation of
`ously and come to light only during the inv
`frequent and persistent minor infections.
`frequent and persistent minor infections .
`Characteristically, the total white cell count is
`the total white cell count i
`Characteristically,
`reduced to 1000 cells per mm3 of blood and, in certain
`reduced to 1000 cells per mm 3 of blood and, in certain
`instances, to levels as low as 200 to 300 cells. Usually
`instances, to levels as low as 200 to 300 cells. U ually
`there is no associated anemia, save that caused by the
`there is no associated anemia, save that caused by the
`infections, nor is there thrombocytopenia.
`infections, nor is there throm bocytope nia.
`The prognosis is very unpredictable. Before the
`The prognosis is very unpredictable. B fore th
`advent of antibiotics, the mortality rate ranged between
`advent of antibiotics, the mortality rate ranged betw~en
`70 and 90%. At present the antibiotics and supportive
`70 and 90%. At present the antibiotics and supportive
`measures such as neutrophil transfusions allow better
`fu ·ons aJlow bette r
`h .1
`Hi
`f
`trans si
`survival since, in many instances, the adverse effects of
`measures such as neutrop 1
`survival since, in many instances, the adverse e ects o
`
`...... /i;_;~. .
`? ,·, . •.
`;,✓--· • a .~ ..
`..
`... .,,
`.. ,~· .'1,.
`-
`•· -
`·•t:rar1;.,
`t
`
`. ...
`-
`
`•
`
`:tit '
`
`.
`
`.
`. . ...
`'
`-.•
`. J
`
`. ...
`0
`
`'.:.j ~ ili.1
`f"
`./
`"
`.
`I.
`• .
`Ji·
`• ... - ~
`•
`•xy,, .. •
`.
`·•
`t
`
`..
`• · .
`
`Figure 15-1. Granulocytopenia. Gingival margins show chronic
`Qppurative necrotizing infection due to loss of protective white cells
`
`h w chronic
`. . I margins s o
`ells
`Flgu
`i
`11 .... " 15-1 . Granulocytopenla . Gingiva of protective wh te c
`;;wurauve necrotizing infection due to loss
`Circu1a11on.
`circulation.
`
`655
`White Cells and Lymph Nodes
`655
`White Cells and Lymph Nod s
`the toxic drug are discovered early and the depression
`r >d arl and th • d •pr•
`io n
`:o
`th • toxi · drug ar • di
`of Whitc cells eventually remits. The idiopathic form,
`•vcn tu ll y r •mil . lb• idiopathic form ,
`•II
`of whit •
`too, may spontaneously remit or may progressively
`too, muy ponlan •ou ·ly r mit or may progr • siv ly
`worsen, leading to death.
`wor •n, lt•udl11g lo cJ •ttth.
`
`REACTIVE (INFLAMMATORY)
`REACTIVE (INFLAMMATORY)
`PROLIFERATIONS OF WHITE CELLS
`PROLIFERATIONS OF WHITE CELLS
`Leukocytosis
`Leukocytosls
`Leukocytosis is a common reaction in a variety of
`vari ·tv of
`L uko ytosis is a common Paction in
`inflammatory states. The particular white cell series
`;ri
`•JI
`•. Th particu lar whit,
`·t t
`inflammatory
`affected varies with the underlying cause. In Chapter 2
`affi •cted varies with th• underlying cau e . ln hapt ·r 2
`we discussed polymorphonuclear leukocytosis (granulo-
`w discus ed polymorphonuclear leukoctJlosis (granulo-
`cytosis), which accompanies acute inflammation. Pyo-
`to is), which accompanie acu te inflammation . Pyo(cid:173)
`genic infections are common causes of neutrophilic
`of n utrophilic
`gen ie infi ctions are common cau
`leukocytosis, but it may also result from nonmicrobial
`le ukocytosi , but it may al o result from nonmicrobial
`stimuli such as tissue necrosis caused by burns or
`tissue necro is caused by burn or
`timuli such as
`myocardial infarction. In patients with severe, life-
`infarction . In patie nts with evere, life(cid:173)
`myocardial
`threatening sepsis, in addition to leukocytosis there may
`threatening sepsis, in addition to le ukocytosis there may
`be morphologic changes in the neutrophils such as toxic
`be morphologic changes in the neutrophils such as toxic
`granulations, Döhle bodies, and cytoplasmic vacuoles.
`granulations, Dohle bodies, and cytoplasmic vacuoles.
`Toxic granules are coarse and darker than the normal
`Toxic granules are coarse and darker than the normaJ
`neutrophilic granules. Although their precise origin is
`neutrophilic granules. Although their precise origin is
`not entirely clear, they are believed to represent ab-
`not entirely clear, they are believed to repre ent ab(cid:173)
`normal forms of azurophilic granules. Döhle bodies are
`normal forms of azurophilic granuJes. Dohle bodies are
`pale blue, round or oval inclusions that represent ag-
`pale blue, round or oval inclusions that represent ag(cid:173)
`gregates of the rough endoplasmic reticulum.
`gregates of the rough endoplasmic reticulum .
`Eosinophilic leukocytosis is characteristic of allergic
`Eosinophilic leukocytosis is characteristic of aUergic
`disorders such as bronchial asthma, hay fever (p. 727),
`disorders such as bronchial asthma, hay fever (p. 727),
`parasitic infections, and some diseases of the skin. The
`parasitic infections, and some diseases of the skin. The
`latter include pemphigus, eczema, and dermatitis her-
`latter include pemphigus, eczema, and dermatiti her(cid:173)
`petiformis, all of which are probably immunologic in
`pe tifonnis, all of which ar probably immunologic in
`origin. Elevations in monocyte count may be seen in
`origin. Elevations in monocyte count may be seen in
`several chronic infections including tuberculosis, bac-
`several chronic infections including tuberculosis, bac(cid:173)
`terial endocarditis, brucellosis, rickettsiosis, and ma-
`terial endocarditis, brucellosis, rickettsio is, and ma(cid:173)
`laria. Certain collagen vascular diseases such as systemic
`laria. Certain collagen vascular diseases such as sy temic
`lupus erythematosus (SLE) and rheumatoid arthritis are
`lupus erythematosus (SLE) and rheumatoid arthriti are
`also associated with monocytosis. Lymphocytosis may
`also associated with monocytosis. Lymphocytosis may
`accompany monocytosis in chronic inflammatory states
`tat
`accompany monocytosis in chronic inflammatory
`such as brucellosis and tuberculosis, representing in
`such as brucellosis and tuberculo i , repre enting in
`these instances a sustained activation of the immune
`these instances a sustain d activation of th
`immune
`response. The lymphocyte count may also be increased
`response. The lymphocyte count may al o be increased
`in acute viral infections such as viral hepatitis, in cyto-
`in acute viral infections such as viral hepatitis, in c to(cid:173)
`megalovirus infections, and particularly in infectious
`megaJovirus infections, and particuJarly in infectious
`mononucleosis (p. 288).
`mononucleosis (p. 288).
`In most instances, reactive leukocytosis is easy to
`to
`to is i ea
`In most in tances, reactive I uko
`distinguish from neoplastic proliferation of the white
`di tinguish from neoplastic proliferation of th white
`cells (i.e., leukemias) by the rarity of immature cells in
`c lls (i. . , leuk mias) by the rarity of immatur c lls in
`the blood. However, in some inflammatory states, many
`inflammatory state , many
`th blood . How ver, in som
`immature white cells may appear in the blood and a
`immatur whit c II may app ar in the blood and a
`picture of leukemia may be simulated (leukemoid reac-
`pictur , of leuke mia ma b simuJat d (l ukemoid reac(cid:173)
`tion). The distinction from leukemias may then be
`tion ). Th di tinction from I uk mias may th n b
`difficult, as discussed on page 680.
`difficult, as discuss d on pag 680.
`Infections and other inflammatory stimuli may not
`Infi ctions and oth r inffammator stimuli may not
`only cause leukocytosis but also involve the lymph
`I mph
`th
`I ukocytosi but al o in ol
`on ly cau
`nodes, which act as defensive barriers. The infections
`tion
`inf(cid:141)
`nod, , which act a d fen ive barrier-. Th
`that lead to lymphadenitis (described below) are so
`o
`(d cribed b low) ar
`that ) ad to I mphnd niti
`numerous and varied that it is impossible to detail each,
`to d tai l ach,
`num rous and vari <l that It I impo sibl
`since it would be a virtual catalog of all systemic
`n virtual catalog of aJ I ystemic
`it wou ld b
`sine
`
`NOVARTIS EXHIBIT 2095
`Breckenridge v. Novartis, IPR 2017-01592
`Page 5 of 54
`
`

`

`656 DISEASES OF WHITE CELLS, LYMPH NODES, AND SPLEEN
`656 DISEASES OF WHITE CELLS, L VMPH NODES, AND SPLEEN
`microbiologic diseases. Moreover, in most instances the
`lymphadenitis is of a banal variety and is entirely
`nonspecific, designated acute or chronic nonspecific
`lymphadenitis.
`
`Acute Nonspecific Lymphadenltls
`Acute Nonspecific Lymphadenltls
`Lymph nodes undergo reactive changes whenever
`challenged by microbiologic agents or their toxic prod-
`ucts, or by cell debris and foreign matter introduced
`into wounds or into the circulation, as in drug addiction.
`Acutely inflamed nodes are most commonly caused
`by direct microbiologic drainage, and are seen most
`frequently in the cervical area in association with infec-
`tions of the teeth or tonsil, or in the axillary or inguinal
`regions secondary to infections in the extremities. Sim-
`ilarly, acute lymphadenitis is found in those nodes
`draining acute appendicitis, acute enteritis, or any other
`acute infections. Generalized acute lymphadenopathy is
`characteristic of viral infections and bacteremia, partic-
`ularly in children. The nodal reactions in the abdomen—
`mesenteric adenitis—may induce acute abdominal
`symptoms closely resembling acute appendicitis, a dif-
`ferential diagnosis that plagues the surgeon.
`Macroscopically, the nodes become swollen, gray-red,
`Macroscopically, the nodes become swollen, gray-red,
`and engorged. The capsules are generally intact, but per-
`and engorged. The capsules are generally intact, but per(cid:173)
`meation of infection may lead to inflammatory changes in
`meation of infection may lead to inflammatory changes In
`the perinodal tissues. Histologically there is prominence of
`the perinodal tissues. Histologically there is prominence of
`the lymphoid follicles and large germinal centers containing
`the lymphoid follicles and large germinal centers containing
`numerous mitotic figures. Histio