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Pathology_Robbins. Fig. 12.12 Atypicallymphocytesininfectiousmononucleosis. EBV is a potent transforming virus that plays a role in the pathogenesis of a number of human malignancies, including several types of B cell lymphoma (Chapter 6). A serious complication in those lacking T cell immunity is unimpeded EBV-driven B cell proliferation. This process can be initiated by an acute infection or by the reactivation of a latent B cell infection and generally begins as a polyclonal proliferation that transforms to overt monoclonal B cell lymphoma over time. Reconstitution of immunity (e.g., by cessation of immunosuppressive drugs) is sometimes sufficient to cause complete regression of the B cell proliferation, which is uniformly fatal if left untreated.


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Pathology_Robbins. The importance of the cellular immune response in controlling EBV infection also is driven home by X-linked lymphoproliferative syndrome (XLP), a rare inherited immunodeficiency characterized by an ineffective response to EBV. Most affected boys have mutations in the SH2D1A gene, which encodes a signaling protein that participates in the activation of T and NK cells. In more than 50% of cases, EBV causes an acute overwhelming infection, often complicated by hemophagocytic lymphohistiocytosis (HLH, described later), whereas other patients succumb to EBV-driven lymphoma or secondary infections related to hypogammaglobulinemia, the basis of which is not understood.


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Pathology_Robbins. Infections and nonmicrobial inflammatory stimuli often activate immune cells residing in lymph nodes, which act as defensive barriers. Any immune response against foreign antigens can lead to lymph node enlargement (lymphadenopathy). Infections causing lymphadenitis are varied and numerous, and may be acute or chronic. In most instances the histologic appearance of the lymph node reaction is nonspecific. A somewhat distinctive form of lymphadenitis that occurs with cat-scratch disease is described separately later. This form of lymphadenitis may be isolated to a group of nodes draining a local infection, or be generalized, as in systemic infectious and inflammatory conditions.


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Pathology_Robbins. This form of lymphadenitis may be isolated to a group of nodes draining a local infection, or be generalized, as in systemic infectious and inflammatory conditions. MORPHOLOGYInflamednodesinacutenonspecificlymphadenitisareswollen,gray-red,andengorged.Histologically,therearelarge germinal centers containingnumerousmitoticfigures.Whenthecauseisapyogenicorganism,aneutrophilicinfiltrateisseenaroundthefolliclesandwithinthelymphoidsinuses.Withsevereinfections,thecentersoffolliclescanundergonecrosis,leadingtotheformationofanabscess. http://ebooksmedicine.net Affectednodesaretenderandmaybecomefluctuantifabscessformationisextensive.Theoverlyingskinisfrequentlyredandmaydevelopdrainingsinuses.Withcontroloftheinfectionthelymphnodesmayreverttoanormal“resting”appearanceor,ifdamaged,undergoscarring. Depending on the causative agent, chronic nonspecific lymphadenitis can assume one of three patterns: follicular hyperplasia, paracortical hyperplasia, or sinus histiocytosis.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Paracortical Hyperplasia. ThispatterniscausedbyimmunereactionsinvolvingtheT cell regions ofthelymphnode.Whenactivated,parafollicularTcellstransformintolargeproliferatingimmunoblaststhatcaneffacetheBcellfollicles.Paracorticalhyperplasiaisencounteredinviral infections (suchasEBV),aftercertainvaccinations (e.g.,smallpox),andinimmunereactionsinducedbydrugs (especiallyphenytoin). Sinus Histiocytosis. Thisreactivepatternischaracterizedbydistentionandprominenceofthelymphaticsinusoids,owingtoamarkedhypertrophy of lining endothelial cells andaninfiltrate of macrophages (histiocytes). Itoftenisencounteredinlymphnodesdrainingcancersandmayrepresentanimmuneresponsetothetumororitsproducts


Pathology_Robbins

Pathology_Robbins. Cat-scratch disease is a self-limited lymphadenitis caused by the bacterium Bartonella henselae. It is primarily a disease of childhood; 90% of the patients are younger than 18 years of age. It manifests with regional lymphadenopathy, most frequently in the axilla and the neck. The nodal enlargement appears approximately 2 weeks after a feline scratch or, less commonly, after a splinter or thorn injury. An inflammatory nodule, vesicle, or eschar is sometimes visible at the site of the skin injury. In most patients the lymph node enlargement regresses during a period of 2 to 4 months. Rarely, encephalitis, osteomyelitis, or thrombocytopenia may develop in patients.


Pathology_Robbins

Pathology_Robbins. HLH is an uncommon disorder in which a viral infection or other proinflammatory exposures trigger activation of macrophages throughout the body, leading to phagocytosis of blood cells and their precursors, cytopenias, and symptoms related to systemic inflammation and organ dysfunction. Inherited defects in several genes that regulate the function of immune cells are associated with a greatly elevated risk of HLH. The involved genes and proteins are diverse, but they share a common feature in that they are required for the cytolytic function of CD8+ T cells and NK cells. Owing to this defect in “killer lymphocytes,” cytotoxic lymphocytes are unable to kill their targets (e.g. virus infected cells) and remain engaged with targeted cells for longer than normal periods of time, leading to excessive release of cytokines, such as interferon gamma, that activate macrophages. The unbridled macrophage activation results in the release of toxic levels of additional pro-inflammatory cytokines,


Pathology_Robbins

Pathology_Robbins. release of cytokines, such as interferon gamma, that activate macrophages. The unbridled macrophage activation results in the release of toxic levels of additional pro-inflammatory cytokines, such as TNF and IL-6, producing signs and symptoms that closely resemble those associated with sepsis and other conditions that lead to the systemic inflammatory response syndrome (SIRS) (Chapter 4).


Pathology_Robbins

Pathology_Robbins. HLH occurs in several distinct settings. It is most common in infants and young children with homozygous defects in genes that are required for cytotoxic lymphocyte function, such the gene PRF1, which encodes perforin, an essential component of cytotoxic granules. In this setting the trigger may be some normally trivial childhood viral infection. Other times, HLH arises in older male children and adolescents with X-linked lymphoproliferative disorder, in which the trigger is EBV infection. In those affected, inherited defects in a signaling molecule called SLAM-associated protein (SAP) leads to inefficient killing of EBV-infected B cells. HLH also may complicate other systemic inflammatory disorders, such as rheumatologic conditions. At least a subset of these individuals have heterozygous defects in genes required for cytotoxic lymphocyte function, creating a genetic background that increases the likelihood of HLH. Finally, HLH may be seen as a secondary phenomenon in patients with


Pathology_Robbins

Pathology_Robbins. defects in genes required for cytotoxic lymphocyte function, creating a genetic background that increases the likelihood of HLH. Finally, HLH may be seen as a secondary phenomenon in patients with peripheral T cell lymphomas. The precise mechanism in this context is uncertain; aberrant cytokine production by malignant T cells leading to dysregulation of non-neoplastic cytotoxic lymphocytes is suspected.


Pathology_Robbins

Pathology_Robbins. Regardless of cause, patients with HLH typically present with fever, splenomegaly, and pancytopenia. In severe cases, DIC and organ failure may supervene. An examination of the bone marrow shows macrophages phagocytosing red cells, platelets, and nucleated marrow cells. Laboratory abnormalities typically include a very high ferritin level (>10,000 µg/L), hypertriglyceridemia, high serum levels of soluble IL2 receptor, and low levels of circulating NK cells and cytotoxic T lymphocytes. In concert, these findings are quite sensitive and specific for HLH. Treatment varies depending on the underlying cause, but it is generally poor. In those with HLH stemming from inherited defects, hematopoietic stem cell transplantation offers a chance for cure. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net The most important disorders of white cells are neoplasms. Virtually all of these tumors are considered to be malignant, but they demonstrate a wide range of behaviors, ranging from some of the most aggressive cancers of man to tumors that are so indolent that they were only recognized recently as true neoplasms. Hematologic malignancies occur at all ages and include disorders that preferentially affect infants, children, and young adults, as well as the very old. As a group they are quite common; in aggregate, there are about 150,000 new hematologic malignancies diagnosed each year in the United States. Current systems of classifying white cell neoplasms rely on a mixture of morphologic and molecular criteria, including lineage-specific protein markers and genetic findings. We will organize our discussion by dividing the white cell neoplasms into four broad categories based on the origin and differentiation state of the tumor cells, as follows:


Pathology_Robbins

Pathology_Robbins. Lymphoid neoplasms, which include certain leukemias and the non-Hodgkin and Hodgkin lymphomas. In many instances these tumors are composed of cells resembling some normal stage of lymphocyte differentiation, a feature that serves as one of the bases for their classification. A special group of lymphoid neoplasms are the plasma cell neoplasms and related entities, in which many of the clinical manifestations stem from abnormal immunoglobulins that are synthesized and secreted from the neoplastic cells. Myeloid neoplasms, which include certain leukemias, myelodysplastic syndromes (MDSs), and myeloproliferative neoplasms. These tumors have in common an origin from a hematopoietic stem cell or some other very early hematopoietic progenitor, and they typically involve the bone marrow. Histiocytic neoplasms, which include proliferative lesions of macrophages and dendritic cells. Of special interest is a spectrum of proliferations of Langerhans cells (Langerhans cell histiocytoses).


Pathology_Robbins

Pathology_Robbins. The numerous lymphoid neoplasms vary widely in their clinical presentation and behavior, and thus present challenges to students and clinicians alike. Some characteristically manifest as leukemias, with involvement of the bone marrow and the peripheral blood. Others tend to present as lymphomas, tumors that produce masses in lymph nodes or other tissues. Plasma cell tumors usually arise within the bones and manifest as discrete masses, causing systemic symptoms related to the production of a complete or partial monoclonal immunoglobulin. Although these tendencies are reflected in the names given to particular entities, in reality all lymphoid neoplasms have the potential to spread to lymph nodes and other tissues, especially the liver, spleen, bone marrow, and peripheral blood. Because of their overlapping clinical behavior, the diagnosis of lymphoid neoplasms is based on the morphologic and molecular characteristics of the tumor cells. Stated another way, for purposes of diagnosis


Pathology_Robbins

Pathology_Robbins. of their overlapping clinical behavior, the diagnosis of lymphoid neoplasms is based on the morphologic and molecular characteristics of the tumor cells. Stated another way, for purposes of diagnosis and prognostication, it is most important to focus on what kind of cell the tumor is made up of, not where the tumor resides in the patient.


Pathology_Robbins

Pathology_Robbins. Two groups of lymphomas are recognized: Hodgkin lymphomas and non-Hodgkin lymphomas. Although both arise most commonly in lymphoid tissues, Hodgkin lymphoma is set apart by the presence of distinctive neoplastic RS giant cells (see later), which usually are greatly outnumbered by nonneoplastic inflammatory cells. The biologic behavior and clinical treatment of Hodgkin lymphoma also are different from those of NHLs, making the distinction of practical importance. An international group of pathologists, molecular biologists, and clinicians working on behalf of the World Health Organization (WHO) has formulated a widely accepted classification scheme for lymphoid neoplasms and myeloid neoplasms (discussed later) that relies on a combination of morphologic, phenotypic, genotypic, and clinical features. As background for the subsequent discussion of this classification, certain important principles warrant consideration:


Pathology_Robbins

Pathology_Robbins. B and T cell tumors often are composed of cells that are arrested at or derived from a specific stage of normal lymphocyte differentiation ( Fig. 12.13 ). The diagnosis and classification of these tumors rely heavily on tests (either immunohistochemistry or flow cytometry) that detect lineage-specific antigens (e.g., B cell, T cell, and NK cell markers) and markers of maturity. By convention, many such markers are identified by their cluster of differentiation (CD) number.


Pathology_Robbins

Pathology_Robbins. Class switching and somatic hypermutation are mistake-prone forms of regulated genomic instability that place germinal center B cells at relatively high risk for potentially transforming mutations. The most common lymphomas are derived from B cells that have migrated into germinal centers following antigen stimulation. This conclusion is drawn from analyses showing that most B cell lymphomas have undergone somatic hypermutation, an event confined to germinal center B cells. Normal germinal center B cells also undergo immunoglobulin class switching, which allows B cells to express immunoglobulins other than IgM. Many of the recurrent chromosomal translocations found in mature B cell malignancies involve the immunoglobulin loci and appear to stem from “accidents” during attempted diversification of the immunoglobulin genes. By contrast, mature T cells, which are genomically stable, give rise to lymphoma infrequently and only very rarely have chromosomal translocations involving the T


Pathology_Robbins

Pathology_Robbins. of the immunoglobulin genes. By contrast, mature T cells, which are genomically stable, give rise to lymphoma infrequently and only very rarely have chromosomal translocations involving the T cell receptor loci.


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Pathology_Robbins. http://ebooksmedicine.net • Like other cancers, lymphoid neoplasms are derived from a single transformed cell and are therefore clonal. As described in Chapter 5, precursor B and T cells rearrange their antigen receptor genes through a mechanism that ensures that each lymphocyte makes a single, unique antigen receptor. Because antigen receptor gene rearrangement virtually always precedes transformation, the daughter cells derived from a given malignant progenitor share the same antigen receptor gene configuration and synthesize identical antigen receptor proteins (either immunoglobulins or T cell receptors). Thus, analyses of antigen receptor genes and their protein products can be used to differentiate lymphoid neoplasms (which are clonal) from immune reactions (which are polyclonal).


Pathology_Robbins

Pathology_Robbins. • Lymphoid neoplasms often disrupt normal immune function. Both immunodeficiency (made evident by increased susceptibility to infection) and autoimmunity may be seen, sometimes in the same patient. Ironically, patients with inherited or acquired immunodeficiencies are at high risk for the development of certain lymphoid neoplasms, particularly those associated with EBV infection. • Although NHLs often manifest at a particular tissue site, sensitive molecular assays usually show that the tumor is widely disseminated at diagnosis. As a result, with few exceptions, only systemic therapies are curative for those with NHL. By contrast, Hodgkin lymphoma often arises at a single site and spreads in a predictable fashion to contiguous lymph node groups.


Pathology_Robbins

Pathology_Robbins. The WHO classification of lymphoid neoplasms ( 12.7 ) considers the morphology, cell of origin (determined by immunophenotyping), clinical features, and genotype (e.g., karyotype, presence of viral genomes) of each entity. As is evident, the diagnostic entities are numerous. We will focus our discussion on a subset that are particularly clinically important or pathogenically illustrative: Table 12.7 WHO Classification of Lymphoid Neoplasms Mycosis fungoides/Sézary syndrome Peripheral T cell lymphoma, unspecified NK, Naturalkiller;WHO, WorldHealthOrganization.aEntriesinitalics areamongthemostcommonlymphoidtumors. Together these neoplasms constitute more than 90% of the lymphoid tumors seen in the United States. The salient features of the more common lymphoid leukemias, non-Hodgkin lymphomas, and plasma cell tumors are summarized in


Pathology_Robbins

Pathology_Robbins. The salient features of the more common lymphoid leukemias, non-Hodgkin lymphomas, and plasma cell tumors are summarized in Table 12.8 and are discussed in the following sections. We will then cover Hodgkin lymphoma and finish by briefly mentioning a few uncommon entities with distinctive clinicopathologic features. Acute lymphoblastic leukemia/lymphomas (ALLs) are neoplasms composed of immature B (pre-B) or T (pre-T) cells, which are referred to as lymphoblasts. About 85% are B-ALLs, which typically manifest as childhood acute “leukemias.” The less common T-ALLs tend to present in adolescent males as thymic “lymphomas.” There is, however, considerable overlap in the clinical behavior of Band T-ALL; for example, many T-ALLs present with or evolve to a leukemic picture. Because of their morphologic and clinical similarities, the various forms of ALL will be considered here together.


Pathology_Robbins

Pathology_Robbins. ALL is the most common cancer of children. Approximately 2500 new cases are diagnosed each year in the United States, most occurring in individuals younger than 15 years of age. ALL is almost three times as common in whites as in blacks and is slightly more frequent in boys than in girls. Hispanics have the highest incidence of any ethnic group. B-ALL peaks in incidence at about the age of 3, perhaps because the number of normal bone marrow pre-B cells (the cell of origin) is greatest very early in life. Similarly the peak incidence of T-ALL is in adolescence, the age when the thymus reaches its maximum size.


Pathology_Robbins

Pathology_Robbins. Many chromosomal aberrations seen in ALL dysregulate the expression and function of transcription factors that are required for the normal differentiation of B and T cell progenitors. Up to 70% of T-ALLs have gain-offunction mutations in NOTCH1, a gene that is essential for T cell differentiation, whereas a high fraction of B-ALLs has loss-of-function mutations in genes that are required for B cell differentiation, such as PAX5. These varied mutations appear to promote maturation arrest and increased self-renewal, a feature of immortalized cells, which, as mentioned, is one of the hallmarks of cancers.


Pathology_Robbins

Pathology_Robbins. In keeping with the multistep origins of cancer, mutations in transcription factor genes are not sufficient to produce ALL, and aberrations that drive cell growth, such as mutations that increase tyrosine kinase activity and RAS signaling, also are common. Ongoing deep sequencing of ALL genomes is rapidly filling in the remaining gaps. Early returns suggest that fewer than 10 mutations are sufficient to produce full-blown ALL; hence, compared to solid tumors, ALL is a genetically simple tumor. MORPHOLOGYInleukemicpresentations,the marrow is hypercellular and packed with lymphoblasts, whichreplacenormalmarrowelements.Mediastinal masses occurin50%to70%ofT-ALLs,whicharealsomorelikelytobeassociatedwithlymphadenopathyandsplenomegaly.InbothB-andT-ALL,thetumorcellshavescantbasophiliccytoplasmandnucleiwithdelicate,finelystippledchromatinandsmallnucleoli(


Pathology_Robbins

Pathology_Robbins. Fig.12.14A ).Inkeepingwiththeaggressiveclinicalbehavior,themitoticrateishigh.Theappearanceoftheblastsisidenticalinpre-Bandpre-TALLsandisnotsufficientlycharacteristictoexcludetheothermajorsubtypeofacuteleukemia,acutemyeloidleukemia(AML,discussedlater).Forthisreason,definitivediagnosisreliesonstainsperformedwithantibodiesspecificforBandTcellantigens( Fig. 12.14B–C ).Histochemicalstainsarealsohelpful,inthat(incontrasttomyeloblasts)lymphoblastsaremyeloperoxidase-negativeandoftencontainperiodicacid-Schiff–positiveglycogengranules. http://ebooksmedicine.net Table 12.8 Characteristics of the More Common Lymphoid Leukemias, Non-Hodgkin Lymphomas, and Plasma Cell Tumors Clinical Entity Frequency Salient Morphology Cell of Origin Comments


Pathology_Robbins

Pathology_Robbins. Table 12.8 Characteristics of the More Common Lymphoid Leukemias, Non-Hodgkin Lymphomas, and Plasma Cell Tumors Clinical Entity Frequency Salient Morphology Cell of Origin Comments Theperipheralbloodfindingsarehighlyvariable.Thewhitecellcountmaybegreaterthan100,000cells/µLbutinabouthalfofthepatientsislessthan10,000cells/µL.Afewpatientshavenocirculatingblasts(aleukemicleukemia).Anemiaalmostalwaysispresent,andtheplateletcountusuallyisbelow100,000/µL.Neutropeniaisanothercommonfinding.


Pathology_Robbins

Pathology_Robbins. Genetics. Approximately 90% of ALLs have nonrandom karyotypic abnormalities. Most common in childhood pre–B cell tumors are hyperdiploidy (more than 50 chromosomes/cell) and a (12;21) translocation involving the ETV6 and RUNX1 genes, creating a fusion gene encoding an aberrant transcription factor, whereas about 25% of adult pre–B cell tumors have a (9;22) translocation involving the ABL and BCR genes. Pre–T cell tumors are associated with diverse chromosomal aberrations, including frequent translocations involving the T cell receptor loci and certain transcription factor genes, as well as mutations that inactivate tumors suppressor genes such as PTEN (leading to increased pro-growth signaling) and CDKN2A, which encodes a negative regulator of the cell cycle and a positive regulator of p53.


Pathology_Robbins

Pathology_Robbins. Immunophenotype. As mentioned, immunophenotyping is very useful in subtyping ALLs and distinguishing them from AML. Terminal deoxynucleotidyl transferase (TdT), an enzyme specifically expressed in pre–B and pre–T cells, is present in more than 95% of cases. Further subtyping of ALL into pre–B and pre–T cell types relies on stains for lineage-specific markers, such as the B cell marker CD19 and the T cell marker CD3. Clinical Features. ALL is an aggressive disease, and most patients present within a few weeks of the onset of symptoms. Among the most important signs and symptoms are the following: Symptoms related to depression of marrow function, including fatigue resulting from anemia; fever, reflecting infections secondary to neutropenia; and bleeding due to thrombocytopenia


Pathology_Robbins

Pathology_Robbins. Symptoms related to depression of marrow function, including fatigue resulting from anemia; fever, reflecting infections secondary to neutropenia; and bleeding due to thrombocytopenia Mass effects caused by neoplastic infiltration, including bone pain resulting from marrow expansion and infiltration of the subperiosteum; generalized lymphadenopathy, splenomegaly, and hepatomegaly; and in T-ALL, complications related to compression of large vessels and airways in the mediastinum Central nervous system manifestations resulting from meningeal spread, such as headache, vomiting, and nerve palsies Despite its highly malignant natural history, pediatric ALL is one of the great success stories of oncology. With aggressive chemotherapy, about 95% of children with ALL obtain a remission, and 75% to 85% are cured. It is sobering http://ebooksmedicine.net Fig. 12.14 Acutelymphoblasticleukemia(ALL).(A)Lymphoblastswithcondensednuclearchromatin,smallnucleoli,andscantagranularcytoplasm.


Pathology_Robbins

Pathology_Robbins. Fig. 12.14 Acutelymphoblasticleukemia(ALL).(A)Lymphoblastswithcondensednuclearchromatin,smallnucleoli,andscantagranularcytoplasm. (B)and(C)showflowcytometryresultsfortheALLshownin(A).ThetumorcellsarepositivefortheBcellmarkersCD19andCD22;CD10(amarkerexpressedonasubsetofALLs),andTdT(aspecializedDNApolymerasethatisexpressedinpre-Bandpre-Tcells).(A,Courtesy of Dr. Robert


Pathology_Robbins

Pathology_Robbins. W. McKenna, Department of Pathology, University of Texas Southwestern Medical School, Dallas,Texas. BandC,Courtesy of Dr. Louis Picker, Oregon Health Science Center, Portland, Oregon.) to consider, however, that ALL remains the leading cause of cancer deaths in children, and that only 35% to 40% of affected adults are cured. Several factors are associated with a worse prognosis: (1) age younger than 2 years, largely because these tumors are genetically distinct, often being associated with translocations involving the MLL gene; (2) presentation in adolescence or adulthood; and (3) peripheral blood blast counts greater than 100,000. Favorable prognostic markers include (1) age between 2 and 10 years, (2) a low white cell count, and (3) hyperdiploidy. The molecular detection of residual disease after therapy also is predictive of a worse outcome in both Band T-ALL and is being used to guide therapy.


Pathology_Robbins

Pathology_Robbins. Although most chromosomal aberrations in ALL alter the function of transcription factors, the t(9;22) instead creates a fusion gene encoding a constitutively active BCR-ABL tyrosine kinase (described later under chronic myeloid leukemia). Treatment of t(9;22)-positive ALLs with BCR-ABL kinase inhibitors in combination with conventional chemotherapy is highly effective and has improved the outcome for this subtype of B-ALL in both children and adults. Tests to identify other “targetable” mutated tyrosine kinases in ALLs lacking BCR-ABL are under development. The outlook for adults with ALL remains guarded, in part because of differences in the molecular pathogenesis of adult and childhood ALL, and also because older adults cannot tolerate the intensive chemotherapy regimens that are curative in children.


Pathology_Robbins

Pathology_Robbins. Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are essentially identical, differing only in the extent of peripheral blood involvement. Somewhat arbitrarily, if the peripheral blood lymphocyte count exceeds 5000 cells/µL, the patient is diagnosed with CLL. Most cases fit the diagnostic criteria for CLL, which is the most common leukemia of adults in the Western world. By contrast, SLL constitutes only 4% of NHLs. For unclear reasons, CLL/SLL is much less common in Asia.


Pathology_Robbins

Pathology_Robbins. CLL/SLL is an indolent, slowly growing tumor in which increased tumor cell survival appears to be more important than tumor cell proliferation per se. In line with this idea, CLL/SLL cells contain high levels of BCL2, a protein that inhibits apoptosis (Chapters 1 and 6). One mechanism of BCL2 overexpression appears to be chromosomal deletions that lead to the loss of genes encoding micro-RNAs that are negative regulators of BCL2. Also of critical importance are signals generated by surface immunoglobulin (the so-called B cell receptor, or BCR). BCR signals flow through an intermediary called Bruton tyrosine kinase (BTK) that ultimately contributes to the expression of genes that promote the survival of CLL/SLL cells.


Pathology_Robbins

Pathology_Robbins. CLL/SLL also causes immune dysregulation, particularly of normal B cells. Through unclear mechanisms, the accumulation of CLL/SLL cells suppresses normal B cell function, often resulting in hypogammaglobulinemia. Paradoxically, approximately 15% of patients develop auto-antibodies against their own red cells or platelets. When present, the autoantibodies are made by nonmalignant bystander B cells, indicating that CLL/SLL cells somehow impair immune tolerance. MORPHOLOGYInvolvedlymphnodesareeffacedbysheetsofsmalllymphocytesandbyscatteredill-definedfocioflarger,activelydividingcells( Fig.12.15A ).Thepredominantcellsaresmall,restinglymphocyteswithdark,round nuclei,andscantycytoplasm(Fig.


Pathology_Robbins

Pathology_Robbins. Fig.12.15A ).Thepredominantcellsaresmall,restinglymphocyteswithdark,round nuclei,andscantycytoplasm(Fig. 12.15B ).Thefociofmitoticallyactivecellsarecalledproliferation centers, whicharepathognomonicforCLL/SLL.Inadditiontothelymphnodes,thebonemarrow,spleen,andliverareinvolvedinalmostallcases.Inmostpatientsthereisanabsolutelymphocytosis featuringsmall,mature-lookinglymphocytes.Thesecirculatingcellsarefragileandduringthepreparationofsmearsmanyaredisrupted,producingcharacteristicsmudge cells. Variablenumbersoflargeractivatedlymphocytesalsoareusuallypresentinbloodsmears. Immunophenotype and Genetics. CLL/SLL is a neoplasm of mature B cells expressing the CD20 and surface immunoglobulins. The tumor cells also express CD5. This http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Immunophenotype and Genetics. CLL/SLL is a neoplasm of mature B cells expressing the CD20 and surface immunoglobulins. The tumor cells also express CD5. This http://ebooksmedicine.net Fig. 12.15 Smalllymphocyticlymphoma/chroniclymphocyticleukemia—lymphnode.(A)Low-powerviewshowsdiffuseeffacementofnodalarchitecture.(B)Athighpower,amajorityofthetumorcellshavetheappearanceofsmall,roundlymphocytes.A“prolymphocyte,”alargercellwithacentrallyplacednucleolus,alsoispresentinthisfield(arrow).(A,Courtesy of Dr. José Hernandez, Department of Pathology, University of Texas Southwestern Medical School, Dallas,Texas.) is a helpful diagnostic clue, since among B cell lymphomas only CLL/SLL and mantle cell lymphoma (discussed later) commonly express CD5. Approximately 50% of tumors have karyotypic abnormalities, the most common of which are trisomy 12 and deletions involving portions of chromosomes 11, 13, and 17. Unlike in other B cell neoplasms, chromosomal translocations are rare.


Pathology_Robbins

Pathology_Robbins. Clinical Features. When first detected, CLL/SLL often is asymptomatic. The most common signs and symptoms are nonspecific and include easy fatigability, weight loss, and anorexia. Generalized lymphadenopathy and hepatosplenomegaly are present in 50% to 60% of patients. The leukocyte count may be increased only slightly (in SLL) or may exceed 200,000 cells/µL. Hypogammaglobulinemia develops in more than 50% of the patients, usually late in the course, and leads to an increased susceptibility to bacterial infections. Less commonly, autoimmune hemolytic anemia and thrombocytopenia are seen.


Pathology_Robbins

Pathology_Robbins. The course and prognosis of CLL/SLL are highly variable and depend on the disease stage and genetic findings. For example, the presence of abnormalities in the TP53 tumor suppressor gene is associated with an overall survival of less than 30% at 10 years, whereas isolated abnormalities of chromosome 13q are associated with an overall survival that is not significantly different from that of the matched general population. Insights into the molecular pathogenesis of CLL/SLL has led to development of effective new drugs that variously inhibit BCR signaling (e.g., by targeting BTK) or BCL2 function. However, cure may only be achieved with hematopoietic stem cell transplantation, which is reserved for relatively young patients who fail conventional therapies. A small fraction of tumors transform to aggressive tumors resembling diffuse large B cell lymphoma (Richter transformation); after transformation occurs, the median survival is less than 1 year.


Pathology_Robbins

Pathology_Robbins. This relatively common tumor constitutes 40% of the adult NHLs in the United States. Like CLL/SLL, it occurs much less frequently in Asian populations. Greater than 85% of follicular lymphomas have a characteristic (14;18) translocation that fuses the BCL2 gene on chromosome 18 to the IgH locus on chromosome 14. This chromosomal rearrangement results in the inappropriate “overexpression” of BCL2 protein, which you will recall is an inhibitor of apoptosis that contributes to cell survival (Chapters 1 and 6). Whole genome sequencing of follicular lymphomas has identified additional mutations in genes encoding histone-modifying proteins in about one-third of cases, suggesting that epigenetic changes also contribute to the genesis of these tumors. Fig.12.16A ).Mostcommonly,thepredominantneoplasticcellsareso-called“centrocytes”,cellsslightlylargerthanrestinglymphocytesthathaveangular“cleaved”nucleiwithprominentindentationsandlinearinfoldings(


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Immunophenotype. These tumors express B cell markers such as CD20 and the germinal center B cell markers CD10 and BCL6; of note, BCL6 is a transcription factor that is required for the generation of germinal center B cells.


Pathology_Robbins

Pathology_Robbins. Clinical Features. Follicular lymphoma mainly occurs in adults older than 50 years of age and affects males and females equally. It usually manifests as painless, generalized lymphadenopathy. The bone marrow is involved at diagnosis in approximately 80% of cases. Although the natural history is prolonged (overall median survival, approximately 10 years), follicular lymphoma is not curable, an unfortunate feature shared with most other relatively indolent lymphoid malignancies. As a result, therapy with cytotoxic drugs and rituximab (anti-CD20 antibody) is reserved for those with bulky, symptomatic disease. BTK and BCL2 inhibitors are also active in this disease and are being evaluated in clinical trials. In about 30% to 40% of patients, follicular lymphoma progresses to diffuse large B cell lymphoma. This transformation is an ominous event, as tumors arising from such conversions are much less curable than de novo diffuse large B cell lymphomas, described later.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Fig. 12.16 Follicularlymphoma—lymphnode.(A)Nodularaggregatesoflymphomacellsarepresentthroughout.(B)Athighmagnification,smalllymphoidcellswithcondensedchromatinandirregularorcleavednuclearoutlines(centrocytes)aremixedwithapopulationoflargercellswithnucleoli(centroblasts).(A,Courtesy of Dr. Robert W. McKenna,Department of Pathology,University of Texas Southwestern Medical School,Dallas,Texas.) Mantle cell lymphoma is composed of cells resembling the naive B cells found in the mantle zones of normal lymphoid follicles. It constitutes approximately 6% of all NHLs and occurs mainly in men older than 50 years of age. Almost all tumors have an (11;14) translocation that fuses the cyclin D1 gene to the IgH locus. This translocation leads to overexpression of cyclin D1, which you will recall stimulates growth by promoting the progression of cells from the G1 phase to the S phase of the cell cycle (Chapter 6).


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYMantlecelllymphomamayinvolvelymphnodesinadiffuseorvaguelynodularpattern.Proliferationcentersareabsent,afeaturethathelpstodistinguishmantlecelllymphomafromCLL/SLL.Thetumorcellsusuallyareslightlylargerthannormallymphocytesandhaveanirregularnucleus,inconspicuousnucleoli,andscantcytoplasm.Lesscommonly,thecellsarelargerandmorphologicallyresemblelymphoblasts.Thebonemarrowisinvolvedinmostcasesandtheperipheralbloodinabout20%ofcases.Thetumorsometimesarisesinthegastrointestinaltract,oftenmanifestingasmultifocalsubmucosalnodulesthatgrosslyresemblepolyps(lymphomatoidpolyposis). Immunophenotype. The tumor cells express surface IgM and IgD, the B cell antigen CD20, and CD5, and they contain high levels of cyclin D1 protein.


Pathology_Robbins

Pathology_Robbins. Immunophenotype. The tumor cells express surface IgM and IgD, the B cell antigen CD20, and CD5, and they contain high levels of cyclin D1 protein. Clinical Features. Most patients present with fatigue and lymphadenopathy and are found to have generalized disease involving the bone marrow, spleen, liver, and (often) the gastrointestinal tract. These tumors are moderately aggressive and incurable. The median survival is 4 to 6 years. Like CLL/SLL cells, mantle cell lymphoma cells depend on signals generated through BTK for survival, and it is hoped that newly available BTK inhibitors will improve clinical outcomes. This indolent B cell tumor arises most commonly in epithelial tissues such as the stomach, salivary glands, small and large bowel, lungs, orbit, and breast.


Pathology_Robbins

Pathology_Robbins. Extranodal marginal zone lymphoma is an example of a cancer that arises within and is sustained by chronic inflammation. It tends to develop within tissues that are involved by chronic inflammation triggered by autoimmune disorders (such as the salivary gland in Sjögren syndrome and the thyroid gland in Hashimoto thyroiditis) or that are the sites of chronic infection (such as H. pylori gastritis). In the case of H. pylori–associated gastric marginal zone lymphoma, eradication of H. pylori with antibiotic therapy often leads to regression of the tumor cells, which depend on inflammatory cytokines secreted by H. pylori–specific T cells for their growth and survival. Based on these observations, it is supposed that the disease is initiated within the context of a polyclonal immune reaction. With the acquisition of still-unknown initiating mutations, a B cell clone emerges that depends on antigen-stimulated T-helper cells for signals that drive growth and survival. At this stage,


Pathology_Robbins

Pathology_Robbins. With the acquisition of still-unknown initiating mutations, a B cell clone emerges that depends on antigen-stimulated T-helper cells for signals that drive growth and survival. At this stage, withdrawal of the responsible antigen causes tumor involution. As further clonal evolution leads to greater tumor cell autonomy, spread to distant sites may occur. This theme of polyclonal to monoclonal transition during lymphomagenesis is also applicable to the pathogenesis of EBV-induced lymphoma (discussed in Chapter 6).


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net MORPHOLOGYTheclonalBcellscharacteristicallyinfiltratetheepitheliumofinvolvedtissues,oftencollectinginsmallaggregatesthatarecalledlymphoepithelial lesions. Insometumorsthetumorcellsaccumulateabundantpalecytoplasmorexhibitplasmacelldifferentiation,featuresthatarecharacteristicbutnotpathognomonic. Immunophenotype. This is a tumor of mature B cells expressing CD20 and surface immunoglobulin, usually IgM. Clinical Features. These tumors often present as swelling of the salivary gland, thyroid or orbit or are discovered incidentally in the setting of H. pylori–induced gastritis or an imaging procedure. When localized, they are often cured by simple excision followed by radiotherapy. Diffuse large B cell lymphoma is the most common type of lymphoma in adults, accounting for approximately 35% of adult NHLs. It includes several subtypes that share an aggressive natural history.


Pathology_Robbins

Pathology_Robbins. Diffuse large B cell lymphoma is the most common type of lymphoma in adults, accounting for approximately 35% of adult NHLs. It includes several subtypes that share an aggressive natural history. About one-third of diffuse large B cell lymphomas have rearrangements of the BCL6 gene, located on 3q27, and an even higher fraction of tumors have activating point mutations in the BCL6 promoter. Both aberrations result in increased levels of BCL6 protein, an important transcriptional regulator of gene expression in germinal center B cells. Another 30% of tumors have a (14;18) translocation involving the BCL2 gene that results in overexpression of BCL2 protein. Some of these tumors may represent “transformed” follicular lymphomas. The remaining tumors have other diverse driver mutations, such as translocations involving the MYC gene.


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYTheneoplasticBcellsarelarge(atleastthreetofourtimesthesizeofrestinglymphocytes)andvaryinappearancefromtumortotumor.Inmanytumors,cellswithroundorovalnuclearcontours,dispersedchromatin,severaldistinctnucleoli,andmodestamountsofpalecytoplasmpredominate( Fig.12.17 ).Inothertumorsthecellshavearoundormultilobatevesicularnucleus,oneortwoprominentcentrallyplacednucleoli,andabundantpaleorbasophiliccytoplasm.Occasionally,thetumorcellsarehighlyanaplasticandincludetumorgiantcellsresemblingRScells,themalignantcellsofHodgkinlymphoma. Immunophenotype. These tumors express the B cell antigen CD20. Many also express surface IgM and/or IgG. Other antigens (e.g., CD10, BCL2) are variably expressed. Fig. 12.17 DiffuselargeBcelllymphoma—lymphnode.Thetumorcellshavelargenucleiwithopenchromatinandprominentnucleoli.(Courtesy of Dr.Robert W.McKenna,Department of Pathology,University of Texas Southwestern Medical School, Dallas,Texas.)


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Pathology_Robbins. Special Subtypes. Several distinctive clinicopathologic subtypes are included in the category of diffuse large B cell lymphoma. EBV-associated diffuse large B cell lymphomas arise in the setting of AIDS, iatrogenic immunosuppression (e.g., in transplant recipients), and the elderly. In the posttransplantation setting, these tumors often begin as EBV-driven polyclonal B cell proliferations that may regress if immune function is restored. Kaposi sarcoma herpesvirus (KSHV), also called human herpesvirus type 8 (HHV-8), is associated with rare primary effusion lymphomas, which may arise within the pleural cavity, pericardium, or peritoneum. These tumors are latently infected with KSHV, which encodes proteins homologous to several known oncoproteins, including cyclin D1. As with EBV-related lymphomas, most affected patients are immunosuppressed.


Pathology_Robbins

Pathology_Robbins. Mediastinal large B cell lymphoma occurs most often in young women and shows a predilection for spread to abdominal viscera and the central nervous system. Clinical Features. Although the median age at presentation is about 60 years, diffuse large B cell lymphoma can occur at any age; it constitutes about 15% of childhood lymphomas. Patients typically present with a rapidly enlarging, often symptomatic mass at one or several sites. Extranodal presentations are common. The gastrointestinal tract is the most common extranodal site, but tumors can appear in virtually any organ or tissue. Unlike the more indolent lymphomas (e.g., follicular lymphoma), involvement of the liver, spleen, and bone marrow is not common at diagnosis.


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Pathology_Robbins. Without treatment, diffuse large cell B cell lymphomas are aggressive and rapidly fatal. With intensive combination chemotherapy and anti-CD20 immunotherapy, complete remissions are achieved in 60% to 80% of the patients; of these, approximately 50% remain free of disease and appear to be cured. For those not so fortunate, other aggressive treatments (e.g., high-dose chemotherapy and hematopoietic stem cell transplantation) offer some hope. http://ebooksmedicine.net Burkitt lymphoma is endemic in parts of Africa and occurs sporadically in other geographic areas, including the United States. Histologically, the African and nonendemic diseases are identical, although there are clinical and virologic differences. Burkitt lymphoma is highly associated with translocations involving the MYC gene on chromosome 8 that result in overexpression of the MYC transcription factor.


Pathology_Robbins

Pathology_Robbins. Burkitt lymphoma is highly associated with translocations involving the MYC gene on chromosome 8 that result in overexpression of the MYC transcription factor. As mentioned in Chapter 6, MYC is a master regulator of Warburg metabolism (aerobic glycolysis), a cancer hallmark that is associated with rapid cell growth. In keeping with this association, Burkitt lymphoma is said to be the fastest growing human tumor. Most translocations fuse MYC with the IgH gene on chromosome 14, but variant translocations involving the κ or λ light chain loci also are observed. The net result of each is the same—the dysregulation and overexpression of MYC. In most endemic cases and about 20% of sporadic cases, the tumor cells are latently infected with EBV, a relationship also discussed in Chapter 6.


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Pathology_Robbins. Fig.12.18).There isamoderateamountofbasophilicoramphophiliccytoplasmthatoftencontainssmall,lipid-filledvacuoles(afeatureappreciatedonsmears).Veryhighratesofproliferationandapoptosisarecharacteristic,thelatteraccountingforthepresenceofnumeroustissuemacrophagescontainingingestednucleardebris.Thesebenignmacrophagesoftenaresurroundedbyaclearspace,creatinga“starry sky” pattern. Fig. 12.18 Burkittlymphoma—lymphnode.Thetumorcellsandtheirnucleiarefairlyuniform,givingamonotonousappearance.Notethehighlevelofmitoticactivity(arrowheads) andprominentnucleoli.The“starrysky”patternproducedbyinterspersed,lightlystaining,normalmacrophagesisbetterappreciatedatalowermagnification.(Courtesy of Dr. Robert W. McKenna, Department of Pathology, University of Texas Southwestern Medical School, Dallas,Texas.) Immunophenotype. These tumors express surface IgM, the B cell marker CD20, and the germinal center B cell markers CD10 and BCL6.


Pathology_Robbins

Pathology_Robbins. Immunophenotype. These tumors express surface IgM, the B cell marker CD20, and the germinal center B cell markers CD10 and BCL6. Clinical Features. Both the endemic and nonendemic sporadic forms affect mainly children and young adults. Burkitt lymphoma accounts for approximately 30% of childhood NHLs in the United States. The disease usually arises at extranodal sites. Endemic tumors often manifest as maxillary or mandibular masses, whereas abdominal tumors involving the bowel, retroperitoneum, and ovaries are more common in North America. Leukemic presentations sometimes occur and must be distinguished from ALL, which is treated with different drug regimens. Burkitt lymphoma is highly aggressive; however, with very intensive chemotherapy regimens, a majority of patients can be cured.


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Pathology_Robbins. These B cell proliferations contain neoplastic plasma cells that virtually always secrete a monoclonal immunoglobulin or immunoglobulin fragment, which serve as tumor markers and often have pathologic consequences. Collectively, plasma cell neoplasms and related disorders account for about 15% of the deaths caused by lymphoid neoplasms. The most common and deadly of these neoplasms is multiple myeloma, of which there are about 15,000 new cases per year in the United States.


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Pathology_Robbins. A monoclonal immunoglobulin identified in the blood is referred to as an M protein, in reference to myeloma. Because complete M proteins have molecular weights of 160,000 or higher, they are restricted to the plasma and extracellular fluid and excluded from the urine in the absence of glomerular damage. However, neoplastic plasma cells often synthesize excess immunoglobulin light chains along with complete immunoglobulins. In unusual cases, tumors may produce only light chains, which are detected and quantified in the blood and the urine by highly sensitive tests. Terms used to describe the abnormal immunoglobulins associated with plasma cell neoplasms include monoclonal gammopathy, dysproteinemia, and paraproteinemia. These abnormal proteins are associated with several clinicopathologic entities:


Pathology_Robbins

Pathology_Robbins. Multiple myeloma (plasma cell myeloma), the most important plasma cell neoplasm, usually presents as tumorous masses scattered throughout the skeletal system. Solitary plasmacytoma is an infrequent variant that presents as a single mass in bone or soft tissue. Smoldering myeloma is another uncommon variant defined by a lack of symptoms and a high plasma M component. Monoclonal gammopathy of undetermined significance (MGUS) is applied to patients without signs or symptoms who have small to moderately large M components in their blood. MGUS is very common in older adults and has a low but constant rate of transformation to a symptomatic monoclonal gammopathy, most often multiple myeloma. Primary or immunocyte-associated amyloidosis results from a monoclonal proliferation of plasma cells secreting light chains that are deposited as amyloid. Some http://ebooksmedicine.net patients have overt multiple myeloma, but others have only a minor clonal population of plasma cells in the marrow.


Pathology_Robbins

Pathology_Robbins. • Waldenström macroglobulinemia is a syndrome in which high levels of IgM lead to symptoms related to hyper-viscosity of the blood. It occurs in older adults, most commonly in association with lymphoplasmacytic lymphoma (described later). With this background, we now turn to some of the specific clinicopathologic entities. Primary amyloidosis was discussed along with other disorders of the immune system in Chapter 5. Multiple myeloma is one of the most common lymphoid malignancies; approximately 20,000 new cases are diagnosed in the United States each year. The median age at diagnosis is 70 years, and it is more common in males and in people of African origin. It principally involves the bone marrow and usually is associated with lytic lesions throughout the skeletal system.


Pathology_Robbins

Pathology_Robbins. The most frequent M protein produced by myeloma cells is IgG (60%), followed by IgA (20%–25%); only rarely are IgM, IgD, or IgE M proteins observed. In the remaining cases, the plasma cells produce only κ or λ light chains. Because free light chains are small in size, they are also excreted in the urine, where they are referred to as Bence Jones proteins. In many cases, the malignant plasma cells secrete both complete immunoglobulins and free light chains and thus produce both M proteins and Bence Jones proteins. As described later, the excess light chains have important pathogenic effects.


Pathology_Robbins

Pathology_Robbins. As with most other B cell malignancies, myeloma often has chromosomal translocations that fuse the IgH locus on chromosome 14 to oncogenes such as the cyclin D1 and cyclin D3 genes. As might be surmised from this, dysregulation of D cyclins is common in multiple myeloma and is believed to contribute to increases in cell proliferation. Proliferation of myeloma cells also is supported by the cytokine interleukin 6 (IL-6), which is produced by fibroblasts and macrophages in the bone marrow stroma. Late in the course, translocations involving MYC are sometimes observed, particularly in patients with aggressive disease. Multiple myeloma has a number of untoward effects on the skeleton, the immune system, and the kidney, all of which contribute to morbidity and mortality:


Pathology_Robbins

Pathology_Robbins. Multiple myeloma has a number of untoward effects on the skeleton, the immune system, and the kidney, all of which contribute to morbidity and mortality: Factors produced by neoplastic plasma cells mediate bone destruction, the major pathologic feature of multiple myeloma. Of particular importance, myelomaderived factors upregulate the expression of the receptor activator of NF-κB ligand (RANKL) by bone marrow stromal cells, which in turn activate osteoclasts. Other factors released from tumor cells are potent inhibitors of osteoblast function. The net effect is increased bone resorption, leading to hypercalcemia and pathologic fractures.


Pathology_Robbins

Pathology_Robbins. Myeloma causes defects in humoral immunity. Through still-uncertain mechanisms, myeloma cells compromise the function of normal B cells. Ironically, although the plasma has elevated levels of immunoglobulin owing to the presence of an M protein, the production of functional antibodies often is profoundly depressed. As a result, patients are at high risk for bacterial infections.


Pathology_Robbins

Pathology_Robbins. • Renal dysfunction stems from several pathologic effects of myeloma that may occur alone or in combination. Most important are obstructive proteinaceous casts, which often form in the distal convoluted tubules and the collecting ducts. The casts consist mostly of Bence Jones proteins along with variable amounts of complete immunoglobulin, Tamm-Horsfall protein, and albumin. Light chain deposition in the glomeruli or the interstitium, either as amyloid or linear deposits, also may contribute to renal damage. Completing the assault is hypercalcemia, which may lead to dehydration and renal stones, and frequent bouts of bacterial pyelonephritis, which stem in part from the hypogammaglobulinemia.


Pathology_Robbins


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Pathology_Robbins. Fig.12.19B ).Withdiseaseprogression,myelomacellsmayspreadtothevisceraandothersofttissuesites,andinterminalstagesaleukemicpicturemayemerge. Renalinvolvement(myeloma nephrosis) isassociatedwithproteinaceouscastsconsistingmostlyofBenceJonesproteinsthatobstructthedistalconvolutedtubulesandthecollectingducts.Multinucleategiantcellsderivedfrommacrophagesusuallysurroundthecasts.Veryoftentheepithelial cells adjacent to the casts become necrotic or atrophic owingtothetoxiceffectsofBenceJonesproteins.Othercommonpathologicprocessesinvolvingthekidneyincludemetastatic calcification,stemmingfromboneresorptionandhypercalcemia;light chain (AL) amyloidosis,involvingtherenalglomeruliandvesselwalls;andbacterial pyelonephritis, secondarytotheincreasedsusceptibilitytobacterialinfections.Rarely,infiltratesofneoplasticplasmacellsareseenintherenalinterstitium.


Pathology_Robbins

Pathology_Robbins. Clinical Features. Clinical findings stem mainly from (1) the effects of plasma cells on the skeleton; (2) the production of excessive immunoglobulins, which often have abnormal physicochemical properties; and (3) the suppression of humoral immunity.


Pathology_Robbins

Pathology_Robbins. Bone resorption often leads to pathologic fractures and chronic pain. The attendant hypercalcemia can give rise to neurologic manifestations, such as confusion, weakness, and lethargy, and contributes to renal dysfunction. Decreased production of normal immunoglobulins sets the stage for recurrent bacterial infections. Of great significance is renal insufficiency, which trails only infections as a cause of death. Renal failure occurs in up to 50% of patients and is associated strongly with the presence and level of Bence Jones proteinuria, highlighting the importance of free light chains in renal disease. Certain light chains also are prone to cause amyloidosis of the AL type (Chapter 5), which can exacerbate renal dysfunction and deposit in other tissues as well. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Fig. 12.19 Multiplemyeloma.(A)Radiographoftheskull,lateralview.Thesharplypunched-outbonedefectsaremostobviousinthecalvaria.(B)Bonemarrowaspirate.Normalmarrowcellsarelargelyreplacedbyplasmacells,includingatypicalformswithmultiplenuclei,prominentnucleoli,andcyto-plasmicdropletscontainingimmunoglobulin. Laboratory analyses typically show increased levels of immunoglobulins in the blood and/or Bence Jones proteins in the urine. Free light chains and an M protein component are observed together in 60% to 70% of cases, whereas in about 20% of patients only free light chains are present. Around 1% of myelomas are nonsecretory; hence, the absence of detectable M component does not completely exclude the diagnosis.


Pathology_Robbins

Pathology_Robbins. The diagnosis rests on radiologic and laboratory findings. It can be strongly suspected when imaging studies show typical bone lesions, but definitive diagnosis requires a bone marrow examination. Marrow involvement often gives rise to a normocytic normochromic anemia, sometimes accompanied by moderate leukopenia and thrombocytopenia.


Pathology_Robbins

Pathology_Robbins. The prognosis is variable. Patients with multiple bony lesions, if untreated, rarely survive for more than 6 to 12 months, whereas patients with “smoldering myeloma” may be asymptomatic for many years. The median survival is 4 to 7 years. Although cures have yet to be achieved, new therapies offer hope. Myeloma cells are sensitive to inhibitors of the proteasome, a cellular organelle that degrades unwanted and misfolded proteins. As discussed in Chapter 2, misfolded proteins activate apoptotic pathways, and myeloma cells are prone to the accumulation of misfolded, unpaired immunoglobulin chains. Proteasome inhibitors likely induce myeloma cell death by exacerbating this inherent tendency. The thalidomide-like compound lenalidomide also is effective in treating myeloma, but through a different mechanism that involves its ability to stimulate the degradation of specific proteins with oncogenic activities. Biphosphonates, drugs that inhibit bone resorption, reduce pathologic fractures


Pathology_Robbins

Pathology_Robbins. mechanism that involves its ability to stimulate the degradation of specific proteins with oncogenic activities. Biphosphonates, drugs that inhibit bone resorption, reduce pathologic fractures and limit the hypercalcemia. Hematopoietic stem cell transplantation prolongs life but has not yet proven to be curative.


Pathology_Robbins

Pathology_Robbins. Lymphoplasmacytic lymphoma is a B cell neoplasm of older adults that usually presents in the sixth or seventh decade of life. Although bearing a superficial resemblance to CLL/SLL, it differs in that a substantial fraction of the tumor cells undergo terminal differentiation to plasma cells. Most commonly, the plasma cell component secretes monoclonal IgM, often in amounts sufficient to cause a hyperviscosity syndrome known as Waldenström macroglobulinemia. Unlike multiple myeloma, complications stemming from the secretion of free light chains (e.g., renal failure and amyloidosis) are relatively rare and bone destruction does not occur. Virtually all cases of lymphoplasmacytic lymphoma are associated with acquired mutations in MYD88. The MYD88 gene encodes an adaptor protein that participates in signaling events that activate NF-κB and also augment signals downstream of the BCR (Ig) complex, both of which may promote the growth and survival of the tumor cells.


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYTypically,themarrowcontainsaninfiltrateoflymphocytes,plasmacells,andplasmacytoidlymphocytesinvaryingproportions,oftenaccompaniedbymastcellhyperplasia.Sometumorsalsocontainapopulationoflargerlymphoidcellswithmorevesicularnuclearchromatinandprominentnucleoli.Periodicacid-Schiff-positiveinclusionscontainingimmunoglobulinarefrequentlyseeninthecytoplasm(Russell bodies) orthenucleus(Dutcher bodies) ofsomeoftheplasmacells.Atdiagnosisthetumorhasusuallydisseminatedtothelymphnodes,spleen,andliver.Infiltrationofthenerveroots,meninges,andmorerarelythebraincanalsooccurwithdiseaseprogression. http://ebooksmedicine.net Immunophenotype. The lymphoid component expresses B cell markers such as CD20 and surface immunoglobulin, whereas the plasma cell component secretes the same immunoglobulin that is expressed on the surface of the lymphoid cells. In almost all tumors, the secreted immunoglobulin is an IgM.


Pathology_Robbins

Pathology_Robbins. Clinical Features. The dominant presenting complaints are nonspecific and include weakness, fatigue, and weight loss. Approximately half the patients have lymphadenopathy, hepatomegaly, and splenomegaly. Anemia caused by marrow infiltration is common. About 10% of patients have autoimmune hemolysis caused by cold agglutinins, IgM antibodies that bind to red cells at temperatures of less than 37°C. Patients with IgM-secreting tumors have additional signs and symptoms stemming from the physicochemical properties of IgM. Because of its large size, at high concentrations IgM greatly increases the viscosity of the blood, giving rise to a hyperviscosity syndrome characterized by the following: Visual impairment associated with venous congestion, which is reflected by striking tortuosity and distention of retinal veins; retinal hemorrhages and exudates may also contribute to problems with vision


Pathology_Robbins

Pathology_Robbins. Neurologic problems such as headaches, dizziness, deafness, and stupor, all stemming from sluggish venous blood flow Bleeding related to the formation of complexes between macroglobulins and clotting factors as well as interference with platelet function Cryoglobulinemia resulting from the precipitation of macroglobulins at low temperatures, which produces symptoms such as Raynaud phenomenon and cold urticaria Lymphoplasmacytic lymphoma is an incurable progressive disease. Because most IgM is intravascular, symptoms caused by the high IgM levels (e.g., hyperviscosity and hemolysis) can be alleviated temporarily by plasmapheresis. Tumor growth can be controlled with low doses of chemotherapeutic drugs and immunotherapy with anti-CD20 antibody, and recent work has shown that BTK inhibitors are also effective. Transformation to large-cell lymphoma occurs but is uncommon. Median survival is about 4 years.


Pathology_Robbins

Pathology_Robbins. Hodgkin lymphoma encompasses a distinctive group of neoplasms that are characterized by the presence of a tumor giant cell, the RS cell. Unlike most NHLs, Hodgkin lymphomas arise in a single lymph node or chain of lymph nodes and typically spread in a stepwise fashion to anatomically contiguous nodes. Although the Hodgkin lymphomas are now understood to be unusual tumors of B cell origin, they are distinguished from the NHLs by their unusual pathologic and clinical features. Fig. 12.20 Hodgkinlymphoma—lymphnode.AbinucleateReed-Sternbergcellwithlarge,inclusion-likenucleoliandabundantcytoplasmissurroundedbylymphocytes,macrophages,andaneosinophil.(Courtesy of Dr. Robert W. McKenna, Department of Pathology, University of Texas Southwestern Medical School, Dallas,Texas.)


Pathology_Robbins

Pathology_Robbins. Classification. Five subtypes of Hodgkin lymphoma are recognized: (1) nodular sclerosis, (2) mixed cellularity, (3) lymphocyte rich, (4) lymphocyte depletion, and (5) lymphocyte predominant. In the first four subtypes the RS cells share certain morphologic and immunophenotypic features (described later), leading some researchers to lump together these entities under the rubric classical Hodgkin lymphoma. The lymphocyte predominant type is set apart by the expression of germinal center B cell markers by the RS cells. This subtype and the two most common forms of classical Hodgkin lymphoma, the nodular sclerosis and mixed-cellularity types, are discussed next.


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Pathology_Robbins. Fig.12.20 ),averylargecell(15to45µmindiameter)withanenormousmultilobatenucleus,exceptionallyprominentnucleoli,andabundant,usuallyslightlyeosinophilic,cytoplasm.Particularlycharacteristicarecellswithtwo mirror-image nuclei or nuclear lobes, each containing a large (inclusion-like) acidophilic nucleolus surrounded by a clear zone,featuresthatimpartanowl-eyeappearance.TypicalRScellsandvariantshaveacharacteristicimmunophenotype,astheyexpressCD15andCD30andfailtoexpressCD45(leukocytecommonantigen),Bcellantigens,andTcellantigens.Asweshallsee,“classic”RScellsarecommoninthemixed-cellularitysubtype,uncommoninthenodularsclerosissubtype,andrareinthelymphocyte-predominancesubtype;intheselattertwosubtypes,othercharacteristicRScellvariantspredominate. Nodular sclerosis Hodgkin lymphoma isthemostcommonform.Itisequallyfrequentinmenandinwomenandhasastrikingpropensitytoinvolvethelowercervical,supraclavicular,andmediastinallymphnodes.Mostpatientsare http://ebooksmedicine.net


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Pathology_Robbins. Fig. 12.22 Hodgkinlymphoma,nodularsclerosistype—lymphnode.Alow-powerviewshowswell-definedbandsofpink,acellularcollagenthathavesubdividedthetumorcellsintonodules.(Courtesy of Dr. Robert W. McKenna, Department of Pathology, University of Texas Southwestern Medical School, Dallas,Texas.) Fig. 12.21 Hodgkinlymphoma,nodularsclerosistype—lymphnode.Adistinctive“lacunarcell”withamultilobednucleuscontainingmanysmallnucleoliisseenlyingwithinaclearspacecreatedbyretractionofitscytoplasm.Itissurroundedbylymphocytes.(Courtesy of Dr. Robert W. McKenna, Department of Pathology, University of Texas Southwestern Medical School, Dallas,Texas.) adolescentsoryoungadults,andtheoverallprognosisisexcellent.Itischaracterizedmorphologicallybythefollowing:


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Pathology_Robbins. Fig.12.21 ),aparticularRScellvariantthathasasinglemultilobatenucleus,multiplesmallnucleoli,andabundant,pale-stainingcytoplasm.Insectionsofformalin-fixedtissue,thecytoplasmoftenistornaway,leavingthenucleuslyinginanemptyspace(alacune).TheimmunophenotypeoflacunarvariantsisidenticaltothatofotherRScellsfoundinclassicalsubtypes. Collagen bands,whichdividetheinvolvedlymphoidtissueintocircumscribednodules( Fig.12.22 ).Thefibrosismaybescantorabundantandthecellularinfiltratecontainsvaryingproportionsoflymphocytes,eosinophils,histiocytes,andlacunarcells. Mixed-cellularity Hodgkin lymphoma isthemostcommonformofHodgkinlymphomainpatientsolderthan50yearsofageandcomprisesabout25%ofcasesoverall.Thereisamalepredominance.Classic RS cells are plentiful withinaheterogeneousinflammatoryinfiltratecontainingsmalllymphocytes,eosinophils,plasmacells,andmacrophages( Fig.12.23 ).Thissubtypeismorelikelytobedisseminatedandtobeassociatedwithsystemicmanifestationsthanthenodularsclerosissubtype.


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Pathology_Robbins. ItisapparentthatHodgkinlymphomaspansawiderangeofhistologicpatternsthatoftensimulateareactiveinflammatoryprocess.Regardlessofsubtype,the diagnosis rests on the definitive identification of RS cells or variants in the appropriate background of reactive cells. ImmunophenotypingplaysanimportantroleindistinguishingHodgkinlymphomafromreactiveconditionsandotherformsoflymphoma.Inallsubtypes,involvementofthespleen,liver,bonemarrow,andotherorgansmayappearinduecourseandtakestheformofirregularnodulescomposedofamixtureofRScellsandreactivecells,similartowhatisobservedinlymphnodes. Fig. 12.23 Hodgkinlymphoma,mixed-cellularitytype—lymphnode.Adiag-nostic,binucleateReed-Sternbergcellissurroundedbyeosinophils,lympho-cytes,andhistiocytes.(Courtesy of Dr. Robert W. McKenna, Department of Pathology,University of Texas Southwestern Medical School,Dallas,Texas.)


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Pathology_Robbins. Fig. 12.24 Hodgkinlymphoma,nodularlymphocyte-predominanttype—lymphnode.Numerousmature-lookinglymphocytessurroundscattered,large,pale-staininglymphocyticandhistiocyticvariants(“popcorn”cells). (Courtesy of Dr. Robert W. McKenna, Department of Pathology, University of Texas Southwestern Medical School, Dallas,Texas.) http://ebooksmedicine.net The origin of RS cells remained mysterious through most of the 20th century, but was finally solved by elegant studies performed on single microdissected RS cells. These showed that every RS cell from any given case possesses the same immunoglobulin gene rearrangements and that these rearranged immunoglobulin genes have undergone somatic hypermutation. As a result, it is now agreed that Hodgkin lymphoma is a neoplasm that arises from germinal center B cells.


Pathology_Robbins

Pathology_Robbins. Hodgkin lymphoma is a neoplasm that arises from germinal center B cells. Another clue into the etiology of Hodgkin lymphoma stems from the frequent involvement of EBV. EBV is present in the RS cells in as many as 70% of cases of the mixed-cellularity subtype and a smaller fraction of other “classical” forms of Hodgkin lymphoma. The structure of the EBV genome is identical in all RS cells in a given case, indicating that infection precedes (and therefore may be related to) transformation and clonal expansion. Thus, EBV infection probably is one of several steps contributing to tumor development, particularly of the mixed-cellularity subtype.


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Pathology_Robbins. The characteristic nonneoplastic, inflammatory cell infiltrate is generated by a number of cytokines. Some of these are secreted by RS cells, including IL-5, a chemoattractant for eosinophils; transforming growth factor-β, a fibrogenic factor; and IL-13, which may stimulate RS cell growth through an autocrine mechanism. Conversely, the responding inflammatory cells, rather than being innocent bystanders, produce additional factors that aid the growth and survival of RS cells and contribute further to the tissue reaction.


Pathology_Robbins

Pathology_Robbins. Hodgkin lymphoma is a cardinal example of a tumor that escapes from the host immune response by expressing proteins that inhibit T cell function. The RS cells of classical Hodgkin lymphoma express high levels of PD ligands, factors that antagonize T cell responses. In many tumors the region on chromosome 9 containing the genes encoding the two PD ligands, PD-L1 and PD-L2, is amplified, an alteration that appears to contribute to their overexpression. The importance of PD ligand expression has been proven in clinical trials of antibodies that block PD-1, which is the T cell receptor for PD ligands (Chapter 6). Most tumors, even those that are resistant to all other therapies, are responsive to PD-1 antibodies, presumably because of the reactivation of a latent host response that was stifled by the PD ligand/ PD-1 signaling axis. Clinical Features. Hodgkin lymphoma, like NHL, usually manifests as painless lymphadenopathy. Although a definitive distinction from NHL can be made only by


Pathology_Robbins

Pathology_Robbins. Clinical Features. Hodgkin lymphoma, like NHL, usually manifests as painless lymphadenopathy. Although a definitive distinction from NHL can be made only by Table 12.9 Clinical Differences Between Hodgkin and Non-Hodgkin Lymphomas MoreoftenlocalizedtoasingleMorefrequentinvolvementofaxialgroupofnodes(cervical,multipleperipheralnodesmediastinal,paraaortic) examination of a tissue biopsy, several clinical features favor the diagnosis of Hodgkin lymphoma ( Table 12.9 ). After the diagnosis is established, staging is used to guide therapy and determine prognosis (


Pathology_Robbins

Pathology_Robbins. Table 12.9 ). After the diagnosis is established, staging is used to guide therapy and determine prognosis ( Table 12.10 ). Younger patients with more favorable subtypes tend to present with stage I or stage II disease and usually are free of so-called “B symptoms” (fever, weight loss, night sweats). Patients with advanced disease (stages III and IV) are more likely to exhibit B symptoms as well as pruritus and anemia. Because of the long-term complications of radiotherapy, even patients with stage I disease are now treated with systemic chemotherapy. More advanced disease is generally also treated with chemotherapy, sometimes together with involved field radiotherapy.


Pathology_Robbins

Pathology_Robbins. The outlook, even for those with advanced disease, is very good. The 5-year survival rate for patients with stage I-A or II-A disease is more than 90%. Even with advanced disease (stage IV-A or IV-B), the overall 5-year disease-free survival rate is around 50%. Among long-term survivors treated with radiotherapy, a higher risk of certain malignancies, including lung cancer and breast cancer, as well as cardiovascular disease, has been reported. These sobering results have spurred development of new regimens that minimize the use of radiotherapy and use less toxic chemotherapy. As already mentioned, anti-PD-1 antibodies have produced excellent responses in patients with relapsed, Table 12.10 Clinical Staging of Hodgkin and Non-Hodgkin Lymphomas (Ann Arbor Classification) Stage Distribution of Disease


Pathology_Robbins

Pathology_Robbins. Table 12.10 Clinical Staging of Hodgkin and Non-Hodgkin Lymphomas (Ann Arbor Classification) Stage Distribution of Disease IIIInvolvementoflymphnoderegionsonbothsidesofthediaphragm(III),whichmayincludethespleen(IIIS),limitedcontiguousextralymphaticorganorsite(IIIE),orboth(IIIES) aAllstagesarefurtherdividedbasedontheabsence(A)orpresence(B)ofthefollowingsystemicsymptomsandsigns:significantfever,nightsweats,unexplainedlossofmorethan10%ofnormalbodyweight.FromCarbonePT,etal:Symposium(AnnArbor):staginginHodgkindisease.Cancer Res 31:1707,1971. http://ebooksmedicine.net refractory disease and represent a promising immune-based therapy. Among the many other forms of lymphoid neoplasia in the WHO classification, several with distinctive or clinically important features merit brief discussion.


Pathology_Robbins

Pathology_Robbins. Among the many other forms of lymphoid neoplasia in the WHO classification, several with distinctive or clinically important features merit brief discussion. Hairy Cell Leukemia. Hairy cell leukemia is an uncommon, indolent B cell neoplasm characterized by the presence of fine, hairlike cytoplasmic projections. The tumor cells express B cell markers (CD20), surface immunoglobulin, and CD11c and CD103; the latter two antigens are not present on most other B cell tumors, making them diagnostically useful. Virtually all cases are associated with activating mutations in the serine/threonine kinase BRAF, which is also mutated in diverse other cancers (Chapter 6).


Pathology_Robbins

Pathology_Robbins. Hairy cell leukemia occurs mainly in older males, and its manifestations result from infiltration of bone marrow and spleen. Splenomegaly, often massive, is the most common and sometimes only physical finding. Pancytopenia, resulting from marrow infiltration and splenic sequestration, is seen in more than half of cases. Lymph node involvement is rare. Leukocytosis is uncommon, being present only in 15% to 20% of patients, but scattered “hairy cells” can be identified in the peripheral blood smear in most cases. The disease is indolent but progressive if untreated; pancytopenia and infections are the major clinical problems. Unlike most other indolent lymphoid neoplasms, hairy cell leukemia is extremely sensitive to chemotherapeutic agents, particularly purine nucleosides. Complete durable responses are the rule and the overall prognosis is excellent. Tumors that fail conventional therapy have excellent responses to BRAF inhibitors, which ultimately may become the treatment of choice.


Pathology_Robbins

Pathology_Robbins. Mycosis Fungoides and Sézary Syndrome. These tumors of neoplastic CD4+ T cells home to the skin; as a result, they often are referred to as cutaneous T cell lymphoma. Mycosis fungoides usually manifests as a nonspecific erythrodermic rash that progresses with time to a plaque phase and then to a tumor phase. Histologically, neoplastic T cells, often with a cerebriform appearance produced by marked infolding of the nuclear membranes, infiltrate the epidermis and upper dermis. With disease progression, both nodal and visceral dissemination appear. Sézary syndrome is a clinical variant characterized by (1) a generalized exfoliative erythroderma and (2) tumor cells (Sézary cells) in the peripheral blood. Circulating tumor cells also are present in as many as 25% of cases of plaqueor tumor-phase mycosis fungoides. Patients diagnosed with early-phase mycosis fungoides often survive for many years, whereas patients with tumor-phase disease, visceral disease, or Sézary syndrome survive on


Pathology_Robbins

Pathology_Robbins. mycosis fungoides. Patients diagnosed with early-phase mycosis fungoides often survive for many years, whereas patients with tumor-phase disease, visceral disease, or Sézary syndrome survive on average for 1 to 3 years.


Pathology_Robbins

Pathology_Robbins. Adult T Cell Leukemia/Lymphoma. This neoplasm of CD4+ T cells is caused by a retrovirus, human T cell leukemia virus type 1 (HTLV-1). HTLV-1 infection is endemic in southern Japan, the Caribbean basin, and West Africa, and occurs sporadically elsewhere, including in the southeastern United States. The pathogenesis of this tumor is discussed in Chapter 6. In addition to lymphoid malignancies, HTLV-1 infection also can cause tropical spastic paraparesis, a progressive demyelinating disease affecting the central nervous system and the spinal cord. Adult T cell leukemia/lymphoma commonly is associated with skin lesions, lymphadenopathy, hepatosplenomegaly, hypercalcemia, and variable lymphocytosis. In addition to CD4, the leukemic cells express high levels of CD25, the IL-2 receptor α chain. In most cases the tumor is very aggressive and responds poorly to treatment. The median survival time is about 8 months.


Pathology_Robbins

Pathology_Robbins. Peripheral T Cell Lymphoma. This heterogeneous group of tumors makes up about 10% of adult NHLs. Although several rare distinctive subtypes fall under this heading, most tumors in this group are unclassifiable. In general, these are aggressive tumors that respond poorly to therapy. Moreover, because these are tumors of functional T cells, patients often suffer from symptoms related to tumor-derived inflammatory products, even when the tumor burden is relatively low. Before ending our review of lymphoid neoplasms, it is worthwhile pausing to summarize the manner in which common driver mutations in specific entities produce changes in cellular behavior that exemplify particular hallmarks of cancer ( Fig. 12.25 ). Such alterations not only highlight important pathogenic principles, but are increasingly the targets of effective therapies, such as antibodies that block PD-1 (Hodgkin lymphoma) and drugs that antagonize BCL2 (follicular lymphoma and other B cell tumors).


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Pathology_Robbins. Highlyaggressivetumorsthatmanifestwithsignsandsymptomsofbonemarrowfailure,orasrapidlygrowingmasses Tumorcellscontaingeneticlesionsthatblockdifferentiation,leadingtotheaccumulationofimmature,nonfunctionalblasts Indolentcourse,commonlyassociatedwithimmuneabnormalities,includinganincreasedsusceptibilitytoinfectionandautoimmunedisorders http://ebooksmedicine.net Mantle cell lymphoma Many examples Cyclin D1 translocations (e.g., loss of CDKN2A in ALL) Germinal center B cell lymphomas Class-switching, somatic hypermutation Relatively unimportant due to intrinsic ability of lymphoid cells to invade and circulate


Pathology_Robbins

Pathology_Robbins. Relatively unimportant due to intrinsic ability of lymphoid cells to invade and circulate Fig. 12.25 Cancerhallmarksexemplifiedbyparticularlymphoidneoplasms.Someofthebestcharacterizedpathogenicmechanismsinlymphoidmalignanciesaresummarizedhere,includingdysregulationofMYCinBurkittlymphoma(leadingtoWarburgmetabolismsandrapidcellgrowth);dysregulationofBCL2infollicularlymphoma(leadingtoresistancetoapoptosis);PD-1ligandgeneamplificationinHodgkinlymphoma(leadingtoevasionofhostimmunity);eventsleadingtolossofcellcyclecontrol(cyclinD1rearrangementsinmantlecelllymphomaandlossoftheCDKN2A geneinacutelymphoblasticleukemia[ALL]);mutationsinvarioustranscriptionfactors,particularlyinALL,thatblockdifferentiationandenhance“leukemiastemcell”self-renewal;andchronicimmunestimulation,inmarginalzonelymphoma.Bycontrast,becauselymphoidcellsnormallycirculatethroughoutthebody,thereisrelativelylittleselectivepressureinlymphoidmalignanciesforaberrationsthatincreaseangiogenesisoractivateinvasionandmetastasis.


Pathology_Robbins

Pathology_Robbins. MatureBcelltumorthatusuallymanifestswithadvanceddiseaseinvolvinglymphnodes,bonemarrow,andextranodalsitessuchasthegut Associatedwithan(11;14)translocationthatresultsinover-expressionofcyclinD1,aregulatorofcellcycleprogression MatureBcelltumorarisingatextranodalsitesinvolvedbychronicinflammationresultingfromautoimmunityorinfection(e.g.,H. pylori) UnusualBcelltumorconsistingmostlyofreactivelymphocytes,macrophages,andstromalcells MalignantRScellsmakeupaminorpartofthetumormass. Myeloid neoplasms arise from hematopoietic progenitors and typically give rise to proliferations that involve the bone marrow and replace normal marrow elements. There are three broad categories of myeloid neoplasia: • In acute myeloid leukemia (AML), the neoplastic cells are blocked at an early stage of myeloid cell development. Immature myeloid cells (blasts) accumulate in the marrow and replace normal elements, and frequently circulate in the peripheral blood. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net In myeloproliferative neoplasms, the neoplastic clone continues to undergo terminal differentiation but exhibits increased or dysregulated growth. Commonly, these are associated with an increase in one or more of the formed elements (red cells, platelets, and/or granulocytes) in the peripheral blood. In myelodysplastic syndromes (MDS), terminal differentiation occurs but in a disordered and ineffective fashion, leading to the appearance of dysplastic marrow precursors and peripheral blood cytopenias. Although these three categories provide a useful starting point, the divisions between the myeloid neoplasms sometimes blur. Both MDS and myeloproliferative neoplasms often transform to AML, and some neoplasms have features of both myelodysplasia and myeloproliferative neoplasms. Because all myeloid neoplasms arise from early multipotent progenitors, the close relationship among these disorders is not surprising.


Pathology_Robbins

Pathology_Robbins. It also is now recognized that AML and MDS often arise from an asymptomatic precursor referred to as clonal hematopoieis of indeterminant prognosis (CHIP) CHIP is characterized by normal blood counts despite the presence of one of more clonal acquired “driver” mutations in myeloid cells in the blood and the marrow. CHIP progresses to an overt white cell neoplasm at a frequency of about 1% per year and appears to be an important risk factor for cardiovascular disease (Chapter 10).


Pathology_Robbins

Pathology_Robbins. AML primarily affects older adults; the median age is 50 years. It is very heterogeneous, as discussed later. The clinical signs and symptoms closely resemble those produced by ALL and usually are related to the replacement of normal marrow elements by leukemic blasts. Fatigue, pallor, abnormal bleeding, and infections are common in newly diagnosed patients, who typically present within a few weeks of the onset of symptoms. Splenomegaly and lymphadenopathy generally are less prominent than in ALL, but on rare occasions AML mimics a lymphoma by manifesting as a discrete tissue mass (a so-called “granulocytic sarcoma”). The diagnosis and classification of AML are based on morphologic, histochemical, immunophenotypic, and karyotypic findings. Of these, the karyotype is most predictive of outcome.


Pathology_Robbins

Pathology_Robbins. Most AMLs harbor mutations in genes encoding transcription factors that are required for normal myeloid cell differentiation. These mutations interfere with the differentiation of early myeloid cells, leading to the accumulation of myeloid precursors (blasts) in the marrow. Of particular interest is the (15;17) translocation in acute promyelocytic leukemia, which results in the fusion of the retinoic acid receptor α (RARA) gene on chromosome 17 and the PML gene on chromosome 15. The chimeric gene produces a PML/RARA fusion protein that blocks myeloid differentiationat the promyelocyticstage, probablyinpart by inhibiting the function of normal retinoic acid receptors. Remarkably, pharmacologic doses of all-trans retinoic acid (ATRA), an analogue of vitamin A (Chapter 7), overcome this block and induce the neoplastic promyelocytes to differentiate into neutrophils rapidly. Because neutrophils die after an average life span of 6 hours, ATRA treatment rapidly clears the tumor. The effect


Pathology_Robbins

Pathology_Robbins. and induce the neoplastic promyelocytes to differentiate into neutrophils rapidly. Because neutrophils die after an average life span of 6 hours, ATRA treatment rapidly clears the tumor. The effect is very specific; AMLs without trans-locations involving RARA do not respond to ATRA. More recently, it has been noted that the combination of ATRA and arsenic trioxide, a salt that induces the degradation of the PML/RARA fusion protein, is even more effective than ATRA alone, producing cures in more than 80% of patients. This is an important example of a highly effective therapy targeted at a tumor-specific molecular defect.


Pathology_Robbins

Pathology_Robbins. Other work using mice has shown that the mutations in transcription factors found in AML are not sufficient to cause the disease. Putative collaborating mutations in several other tyrosine kinase genes and in the RAS gene have been detected. Sequencing of the AML genomes also has identified frequent mutations in genes that directly impact the epigenome, suggesting that epigenetic alterations have a central role in AML. For example, about 15% to 20% of AMLs are associated with mutations in isocitrate dehydrogenase (IDH). In such tumors, an “oncometabolite” synthesized by the mutated IDH protein blocks the function of enzymes that regulate the epigenome and interferes with myeloid cell differentiation (discussed in Chapter 6). Inhibitors of mutant IDH prevent the production of the oncometabolite and often produce remissions in this particular molecular subtype of AML.


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYBydefinition,inAMLmyeloidblastsorpromyelocytesmakeupmorethan20%ofthebonemarrowcellularity.Myeloblasts (precursorsofgranulocytes)havedelicatenuclearchromatin,threetofivenucleoli,andfineazurophiliccytoplasmicgranules( Fig.12.26 ).Auer rods, distinctivered-stainingrodlikestructures,maybepresentinmyeloblastsormoredifferentiatedcells;theyareparticularlynumerousinacutepromyelocyticleukemia( Fig.12.27 ).Auerrodsarespecificforneoplasticmyeloblastsandthusareahelpfuldiagnosticcluewhenpresent.InothersubtypesofAML,monoblasts,erythroblasts,ormegakaryoblastspredominate. Classification. AMLs are diverse in terms of genetics, cellular lineage, and degree of maturation. The WHO classification relies on all of these features to divide AML into four categories (


Pathology_Robbins

Pathology_Robbins. Classification. AMLs are diverse in terms of genetics, cellular lineage, and degree of maturation. The WHO classification relies on all of these features to divide AML into four categories ( Table 12.11 ): (1) AMLs associated with specific genetic aberrations, which are important because they predict outcome and they guide therapy; (2) AMLs with dysplasia, many of which arise from MDSs; (3) AMLs occurring after genotoxic chemotherapy; and (4) AMLs lacking any of the foregoing features. AMLs in the last category are subclassified based on the predominant line of differentiation that the tumor exhibits. Immunophenotype. The expression of immunologic markers is heterogeneous in AML. Most tumors express some combination of myeloid-associated antigens, such as CD13, CD14, CD15, CD64, or CD117 (KIT). CD34, a marker of hematopoietic stem cells, is often present on myeloblasts. Such markers are helpful in distinguishing AML http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Fig. 12.26 Acutemyeloidleukemia(AML).(A)Myeloblastswithdelicatenuclearchromatin,prominentnucleoli,andfineazurophiliccytoplasmicgranules.(B)and(C)showflowcytometryresultsfortheAMLshownin(A).ThetumorcellsarepositiveforthestemcellmarkerCD34andthemyeloidlineagespecificmarkersCD33andCD15(subset).(A,Courtesy of Dr. Robert W. McKenna, Department of Pathology, University of Texas Southwestern Medical School, Dallas,Texas. BandC,Courtesy of Dr. Louis Picker, Oregon Health Science Center, Portland, Oregon.) from ALL and in identifying AMLs with only minimal differentiation.


Pathology_Robbins

Pathology_Robbins. Clinical Features. Most patients present within weeks or a few months of the onset of symptoms with complaints related to anemia, neutropenia, and thrombocytopenia, most notably fatigue, fever, and spontaneous mucosal and cutaneous bleeding. As mentioned earlier, these findings are very similar to those produced by ALL. Thrombocytopenia results in a bleeding diathesis. Cutaneous petechiae and ecchymoses, serosal hemorrhages into the linings of the body cavities and viscera, and mucosal hemorrhages into the gingivae and urinary tract are common. Procoagulants and fibrinolytic factors released by leukemic cells, especially in AML with the t(15;17), exacerbate the bleeding tendency. Infections are frequent and are often caused by opportunists such as fungi, Pseudomonas, and commensals. Signs and symptoms related to the involvement of soft tissues are usually less striking in AML than in ALL, but tumors with monocytic differentiation often infiltrate the skin (leukemia cutis) and the


Pathology_Robbins

Pathology_Robbins. and symptoms related to the involvement of soft tissues are usually less striking in AML than in ALL, but tumors with monocytic differentiation often infiltrate the skin (leukemia cutis) and the gingiva. Central nervous system spread occurs but also is less common than in ALL.


Pathology_Robbins

Pathology_Robbins. AML remains a devastating disease. Tumors with “good-risk” karyotypic abnormalities (t[8;21], inv[16]) are associated with a 50% chance of long-term disease-free survival, but the overall survival in all patients is only 15% to 30% with conventional chemotherapy. AML associated with TP53 mutations has emerged as a subtype with a particularly poor prognosis. A bright spot is the improvement in outcomes in acute promyelocytic leukemia brought about by targeted treatment with ATRA and arsenic salts. IDH inhibitors also have produced encouraging results, apparently (like ATRA) by inducing the differentiation of AML blasts. An increasing number of patients with AML are being treated with more aggressive approaches, such as allogeneic hematopoietic stem cell transplantation, which can be curative in some patients.


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Pathology_Robbins. Fig. 12.27 Acutepromyelocyticleukemia—bonemarrowaspirate.Theneo-plasticpromyelocyteshaveabnormallycoarseandnumerousazurophilicgranules.OthercharacteristicfindingsincludeacellinthecenterofthefieldwithmultipleneedlelikeAuerrods.(Courtesy of Dr.Robert W.McKenna,Depart-ment of Pathology, University of Texas Southwestern Medical School, Dallas,Texas.) The term myelodysplastic syndrome (MDS) refers to a group of clonal stem cell disorders characterized by Table 12.11 WHO Classification of AML AMLwitht(15;17)(q22;q21.1);PML/RARA fusiongeneFavorable II. AML With Multilineage Dysplasia III. AML,Therapy-Related IV. AML, Not Otherwise Classified SubclassesdefinedbyextentandtypeofIntermediatedifferentiation(e.g.,myelocytic,monocytic) AML, Acutemyeloidleukemia;MDS, myelodysplasticsyndrome;NPM1, nucleophosmin1;WHO, WorldHealthOrganization. http://ebooksmedicine.net maturation defects that are associated with ineffective hematopoiesis and a high risk of transformation to AML.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net maturation defects that are associated with ineffective hematopoiesis and a high risk of transformation to AML. In MDSs, the bone marrow is partly or wholly replaced by the clonal progeny of a transformed multipotent stem cell that retains the capacity to differentiate into red cells, granulocytes, and platelets, but in a manner that is both ineffective and disordered. As a result, the marrow usually is hypercellular or normocellular, but the peripheral blood shows one or more cytopenias. The abnormal stem cell clone in the bone marrow is genetically unstable and prone to the acquisition of additional mutations and the eventual transformation to AML. Most cases are idiopathic, but some develop after chemotherapy with alkylating agents or exposure to ionizing radiation therapy.


Pathology_Robbins

Pathology_Robbins. Important new insights have come from deep sequencing of MDS genomes, which has identified a number of recurrently mutated genes. These genes can be lumped into three major functional categories, as follows: Epigenetic factors. Frequent mutations are seen involving many of the same epigenetic factors that are mutated in AML, including factors that regulate DNA methylation and histone modifications; thus, like AML, dysregulation of the epigenome appears to be important in the genesis of MDS. RNA splicing factors. A subset of tumors has mutations involving the RNA splicing machinery that are proposed to drive transformation by altering RNA processing, They are commonly associated with ring sideroblasts, a classic form of dysplasia that is seen in a subset of MDS. Transcription factors. These mutations affect transcription factors that are required for normal myelopoiesis and may contribute to the deranged differentiation that characterizes MDS.


Pathology_Robbins

Pathology_Robbins. Transcription factors. These mutations affect transcription factors that are required for normal myelopoiesis and may contribute to the deranged differentiation that characterizes MDS. In addition, roughly 10% of MDS cases have loss-offunction mutations in the tumor suppressor gene TP53, which correlate with the presence of a complex karyotype and particularly poor clinical outcomes. Both primary MDS and therapy-related MDS are associated with similar recurrent chromosomal abnormalities, including monosomies 5 and 7, deletions of 5q, 7q, and 20q, and trisomy 8. MORPHOLOGYInMDS,themarrowispopulatedbyabnormal-appearinghematopoieticprecursors.Someofthemorecommonabnormalitiesincludemegaloblastoid erythroid precursors resemblingthoseseeninthemegaloblasticanemias,erythroidformswithirondepositswithintheirmitochondria(ring sideroblasts),granulocyteprecursorswithabnormal granules ornuclearmaturation,andsmallmegakaryocyteswithsinglesmallnucleiormultipleseparatenuclei.


Pathology_Robbins

Pathology_Robbins. Clinical Features. MDS often is described as rare, but actually is about as common as AML, affecting up to 15,000 patients per year in the United States. Most patients present between the ages of 50 and 70. As a result of cytopenias, many suffer from infections, symptoms related to anemia, and hemorrhages. The response to conventional chemotherapy usually is poor, perhaps because MDS arises in a background of stem cell damage. Transformation to AML occurs in 10% to 40% of patients. The prognosis is variable; the median survival time ranges from 9 to 29 months and is worse in cases associated with increased marrow blasts, cytogenetic abnormalities, or TP53 mutations.


Pathology_Robbins

Pathology_Robbins. The common pathogenic feature of myeloproliferative neoplasms is the presence of mutated, constitutively activated tyrosine kinases or other acquired aberrations in signaling pathways that lead to growth factor independence. This insight provides a satisfying explanation for the observed overproduction of blood cells and is important therapeutically because of the availability of tyrosine kinase inhibitors. The neoplastic progenitors tend to seed secondary hematopoietic organs (the spleen, liver, and lymph nodes), resulting in hepatosplenomegaly (caused by neoplastic extramedullary hematopoiesis). Four major diagnostic entities are recognized: chronic myeloid leukemia (CML), polycythemia vera, primary myelofibrosis, and essential thrombocythemia. Their distinctive features are listed below: CML is separated from the others by its association with a characteristic abnormality, the BCR-ABL fusion gene, which produces a constitutively active BCR-ABL tyrosine kinase.


Pathology_Robbins

Pathology_Robbins. CML is separated from the others by its association with a characteristic abnormality, the BCR-ABL fusion gene, which produces a constitutively active BCR-ABL tyrosine kinase. The most common genetic abnormalities in the “BCRABL–negative” myeloproliferative neoplasms are activating mutations in the tyrosine kinase JAK2, which occur in virtually all cases of polycythemia vera and about 50% of cases of primary myelofibrosis and essential thrombocythemia Some rare myeloproliferative neoplasms are associated with activating mutations in other tyrosine kinases, such as platelet-derived growth factor receptor-α and platelet-derived growth factor receptor-β.


Pathology_Robbins

Pathology_Robbins. In addition, all myeloproliferative neoplasms have variable propensities to transform to a “spent phase” resembling primary myelofibrosis or to a “blast crisis” identical to acute leukemia, both presumably triggered by the acquisition of other somatic mutations. Only CML, polycythemia vera, and primary myelofibrosis are presented here, as other myeloproliferative neoplasms are too infrequent to merit discussion. CML principally affects adults between 25 and 60 years of age. The peak incidence is in the fourth and fifth decades of life. About 4500 new cases are diagnosed per year in the United States.


Pathology_Robbins

Pathology_Robbins. CML is distinguished from other myeloproliferative neoplasms by the presence of a chimeric BCR-ABL gene derived from portions of the BCR gene on chromosome 22 and the ABL gene on chromosome 9. In about 95% of cases, the BCR-ABL gene is the product of a balanced (9;22) translocation that moves ABL from chromosome 9 to a position on chromosome 22 adjacent to BCR. In the remaining http://ebooksmedicine.net 5% of cases, a BCR-ABL fusion gene is created by cytogenetically cryptic or complex rearrangements involving more than two chromosomes. The BCR-ABL fusion gene is present in granulocytic, erythroid, megakaryocytic, and B cell precursors, and in some cases T cell precursors as well, indicating that the tumor arises from a transformed hematopoietic stem cell. Although the Ph chromosome is highly characteristic of CML, it also is present in 25% of adult B cell–ALLs and a small subset of AMLs.


Pathology_Robbins

Pathology_Robbins. As described in Chapter 6, the BCR-ABL gene encodes a fusion protein consisting of portions of BCR and the tyrosine kinase domain of ABL. Normal myeloid progenitors depend on signals generated by growth factors and their receptors for growth and survival. The growth factor dependence of CML progenitors is greatly decreased by constitutive signals generated by BCR-ABL that mimic the effects of growth factor receptor activation. Importantly, because BCR-ABL does not inhibit differentiation, the early disease course is marked by excessive production of relatively normal blood cells, particularly granulocytes and platelets. MORPHOLOGYTheperipheralbloodfindingsarehighlycharacteristic.Theleukocytecountiselevated,oftenexceeding100,000cells/µL. The circulating cells are predominantly neutrophils, metamyelocytes, and myelocytes (


Pathology_Robbins

Pathology_Robbins. The circulating cells are predominantly neutrophils, metamyelocytes, and myelocytes ( Fig.12.28 ),butbasophils andeosinophils arealsoprominentandplateletsareusuallyincreased.Thebonemarrowishypercellularowingtoincreasednumbersofmaturinggranulocyticandmegakaryocyticprecursors.Theredpulpoftheenlargedspleenresemblesbonemarrowbecauseofthepresenceofextensiveextramedullary hematopoiesis. Thisburgeoningproliferationoftencompromisesthelocalbloodsupply,leadingtosplenic infarcts.