DISEASE OF BLOOD
Anaemia is a blood disease of erythrocytes quantity or their hemoglobin saturation per unit blood volume. At the same time in the circulating blood there can appear erythrocytes of different sizes (poikilocytosias, poikilocythemia), different shapes (anisocytosis), different levels of colouring (hyperchromatism and hypochromatism), erythrocytes with inclusions (Jolly’s corpuscles, Kabo’s rings), nuclear erythrocytes (erythroblasts, normoblasts, megaloblasts).
Fig.1 This is the appearance of normal bone marrow at medium magnification. Note the presence of megakaryocytes, erythroid islands, and granulocytic precursors. This marrow is taken from the posterior iliac crest in a middle aged person, so it is about 50% cellular, with steatocytes admixed with the marrow elements.
Fig.2 This is the appearance of normal bone marrow at high magnification. Note the presence of megakaryocytes, erythroid islands, and granulocytic precursors. This marrow is taken from the posterior iliac crest in a middle aged person, so it is about 50% cellular, with steatocytes admixed with the marrow elements.
Fig. 3.This is the appearance of normal bone marrow smear at high magnification. Note the presence of erythroid precursors and granulocytic precursors.
Fig. 4 This is the appearance of normal bone marrow smear at high magnification. Note the presence of an eosinophilic myelocyte, a basophilic myelocyte, and a plasma cell.
Fig.5. This is the appearance of normal bone marrow smear at high magnification. Note the presence of megakaryocytes, erythroid precursors, and granulocytic precursors.
To define the peculiarities of anaemia, morphogenesis and other blood diseases, biopsy of the sternal bone marrow puncture is widely used. In breast bone (sternum) punctate it is possible to diagnose the bone marrow regeneration level in anaemia as well as the type of erythropoiesis (erythroblastic, normoblastic, megaloblastic).
Fig.6 The red blood cells here are normal, happy RBC’s. They have a zone of central pallor about 1/3 the size of the RBC. The RBC’s demonstrate minimal variation in size (anisocytosis) and shape (poikilocytosis). A few small fuzzy blue platelets are seen. In the center of the field are a band neutrophil on the left and a segmented neutrophil on the right.
Fig.7. A normal mature lymphocyte is seen on the left compared to a segmented PMN on the right. An RBC is seen to be about 2/3 the size of a normal lymphocyte.
Fig. 7. Here is a monocyte. It is slightly larger than a lymphocyte and has a folded nucleus. Monocytes can migrate out of the bloodstream and become tissue macrophages under the influence of cytokines. Note the many small smudgy blue platelets between the RBC’s.
Fig.8. In the center of the field is an eosinophil with a bilobed nucleus and numerous reddish granules in the cytoplasm. Just underneath it is a small lymphocyte. Eosinophils can increase with allergic reactions and with parasitic infestations.
Fig.9. There is a basophil in the center of the field which has a lobed nucleus (like PMN’s) and numerous coarse, dark blue granules in the cytoplasm. They are infrequent in a normal peripheral blood smear, and their significance is uncertain. A band neutrophil is seen on the left, and a large, activated lymphocyte on the right.
Fif.10 The RBC’s in the background appear normal. The important finding here is the presence of many PMN’s. An elevated WBC count with mainly neutrophils suggests inflammation or infection. A very high WBC count (>50,000) that is not a leukemia is known as a “leukemoid reaction”. This reaction can be distinguished from malignant WBC’s by the presence of large amounts of leukocyte alkaline phosphatase (LAP) in the normal neutrophils.
Classification of anaemias: According to the etiology and pathogenesis, there are three groups of anaemias: posthemorrhagic anaemia (as a result of blood loss), anaemia as a result of erythropoiesis disturbance, and hemolytic anaemia (as a result of increased haemolysis). According to the clinical course anaemia can be acute and chronic.
Posthemorrhagic anaemia develops as a result of massive hemorrhage of the stomach or intestinal vessels due to ulcer or tumor effects, uterine tube rupture in extrauterine pregnancy, rupture of the aorta, pulmonary vessels disturbance in tuberculosis, etc. Because of the bleeding of large vessels the acute posthemorrhagic anaemia occurs and death occurs faster than morphologic manifestations of anaemia. Because of the prolonged bleeding of small vessels the chronic posthemorrhagic anaemia develops and its manifestation can be pallor of the skin, mucous tunics, and viscera. Hyperplasia of the red bone marrow of flat bones and epiphysial plates turning intense and succulent. Metaplasia of yellow bone marrow occurs, turning red, the centres of extramedullary erythropoiesis in the spleen, thymus, lymph nodes and other tissues occurs. As a result of hypoxia (oxygen starvation) dystrophic changes occurs in the viscera, small hemorrhages in mucous and serous tunics may develop.
Posthemorrhagic anaemia
Posthemorrhagic anaemia
Posthemorrhagic anaemia
Anaemia as a result of erythropoiesis disturbance develops due to the deficiency of iron, vitamin B-12 and folic acid. Examples of this are hypoplastic and aplastic anaemiae. Asiderotic (iron-deficiency) anaemia is always hypochromic and develops as a result of low intake of iron into the organism with food. Such anaemiae are common among children, and also under intense need of iron during pregnancy, female maturation(from puberty to about 30 years) or chlorosis. This anaemia can appear in stomach and intestinal diseases, especially after their resection. Vitamin B12 and folic acid deficiency anaemias (megaloblastic hyperchromatism, pernicious (Biermer’s, Biermer-Ehrlich) anaemia) are characterized by erythropoiesis disturbance and appear in disturbance of tha absorbtion of exogenous vitamin B-12 in the stomach, in diseases of the stomach, with decreased secretion of gastromucoprotein.
Vitamin B12 and folic acid deficiency anaemias
Such changes can be of hereditary origin or autoimmune genesis.At lymphogranulomatosis, polyposis, syphilis, corrosive (necrotic, (toxico-chemical) gastritis, malignant growths of stomach, after the ulcer of the stomach, intestinal resections pernicious anaemia can appear. The cause of such anaemia can be deficiency of exogenous vitamin B-12 or folic acid of children fed with goat’s milk. As a result of this the erythropoiesis is realized by the megaloblastic type and the hemolysis exceeds the erythropoiesis. The pathomorphologic manifestations of this anaemia are as follows: liver, spleen, kidney hemosiderosis, fatty degeneration of parenchymatous organs, general obesity, bleach lemon-tinged skin, small hemorrhages in mucous and serous tunics and in the skin. In the gastrointestinal tract, there are atrophic and sclerotic changes, the bone marrow turns raspberry-red with the predominance of erythroblasts, normoblasts, and megakaryoblasts. In lateral and posterior (dorsal) columns of spinal cord there is funicular myelosis and in the brain there are the centres of encephalomalacia and ischemia. Hypoplastic and aplastic anaemias can be endogenous or inherited (familial aplastic anaemia of Fanconi and Ehrlich’s hypoplastic anaemia), and exogenous or acquired (radiation, toxic, medicamentosis anaemias).
Iron deficiency anemia – children
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Anemia is a condition in which the body does not have enough healthy red blood cells. Red blood cells bring oxygen to body tissues.
There are many types of anemia. Iron deficiency anemia is a decrease in the number of red blood cells in the blood due to a lack of iron.
This article focuses on iron deficiency anemia in children.
Causes
Iron deficiency anemia is the most common form of anemia. You get iron through certain foods, and your body also reuses iron from old red blood cells.
Iron deficiency (too little iron) may be caused by:
An iron-poor diet (this is the most common cause)
Body not being able to absorb iron very well, even though you’re eating enough iron
Long-term, slow blood loss — usually through menstrual periods or bleeding in the digestive tract
Rapid growth (in the first year of life and in adolescence), when more iron is needed
Babies are born with iron stored in their bodies. Because they grow rapidly, infants and childreeed to absorb an average of 1 mg of iron per day.
Since children only absorb about 10% of the iron they eat, most children need to receive 8-10 mg of iron per day. Breastfed babies need less, because iron is absorbed 3 times better when it is in breast milk.
Cow’s milk is a common cause of iron deficiency. It contains less iron than many other foods and also makes it more difficult for the body to absorb iron from other foods. Cow’s milk also can cause the intestines to lose small amounts of blood.
The risk of developing iron deficiency anemia is increased in:
Infants younger than 12 months who drink cow’s milk rather than breast milk or iron-fortified formula
Young children who drink a lot of cow’s milk rather than eating foods that supply the body with more iron
Iron deficiency anemia most commonly affects babies 9 – 24 months old. All babies should have a screening test for iron deficiency at this age. Babies born prematurely may need to be tested earlier.
Iron deficiency in children also can be related to lead poisoning.
Symptoms
Blue-tinged or very pale whites of eyes
Blood in the stools
Brittle nails
Decreased appetite (especially in children)
Fatigue
Headache
Irritability
Pale skin color (pallor)
Shortness of breath
Sore tongue
Unusual food cravings (called pica)
Weakness
Note: There may be no symptoms if anemia is mild.
Exams and Tests
The health care provider will perform a physical exam. A blood sample is taken and sent to a laboratory for examination. Iron-poor red blood cells appear small and pale when looked at under a microscope.
Tests that may be done include:
Hematocrit
Serum ferritin
Serum iron
Total iron binding capacity (TIBC)
A measurement called iron saturation (serum iron/TIBC) often can show whether you have enough iron in your body.
Hemolytic anaemia is characterized by the increased haemolysis which can be intravascular and extravascular. Intravascular anaemia appears when hemolytic poisons get into the organism, in bad burns (toxic anaemia), in malaria, sepsis and other infections (infectious anaemia), blood transfusion of incompatible blood group or Rhesus factor (posttransfusion anaemia), at immune pathologic processes (immune, isoimmune and autoimmune anaemias (hemolytic disease of newborns, chronic lympholeukemia, bone marrow carcinomatosis, systemic lupus erythematosus, medicamentosis immune hemolysis, thermal hemoglobinuria and other). Extravascular (intracellular) anaemia is mostly of inherited origin and is divided into erythrocytopathy, erythrocyte-enzymopathy and hemoglobinopathy. Diseases such as microspherocytosis, inherited ovalocytosis, etc result in hemolytic anaemia due to their deviation from normal structures of the erythrocytes’ membrane. Erythrocyte-enzymopathic hemolytic anaemia appears due to deficiency of enzymes of pentose-phosphate cycle – glucose 6-phosphate dehydrogenase and pyruvate kinase. This anaemia grows progressively worse in viral infections, usage of some medicaments. Hemoglobinopathic hemolytic anaemia develops in disturbance of haemoglobin synthesis – a and b-thalassemia or in appearance of anomalous haemoglobin – S, C, D, E. Falciform cellular anaemia can include hemoglobinopathies.
1. The most common cause for a hypochromic microcytic anemia is iron deficiency. The most commoutritional deficiency is lack of dietary iron. Thus, iron deficiency anemia is common. Persons most at risk are children and women in reproductive years (from menstrual blood loss and from pregnancy).
2. Here is a hypersegmented neutrophil that is present with megaloblastic anemias. There are 8 lobes instead of the usual 3 or 4. Such anemias can be due to folate or to B12 deficiency. The size of the RBC’s is also increased (macrocytosis, which is hard to appreciate in a blood smear).
This hypersegmented neutrophil is present along with macro-ovalocytes in a case of pernicious anemia. Compare the size of the RBC’s to the lymphocyte at the lower left center.
3. There are numerous fragmented RBC’s seen here. Some of the irregular shapes appear as “helmet” cells. Such fragmented RBC’s are known as “schistocytes” and they are indicative of a microangiopathic hemolytic anemia (MAHA) or other cause for intravascular hemolysis. This finding is typical for disseminated intravascular coagulopathy (DIC).
4. The sinusoids are packed with RBC’s in this case of hereditary spherocytosis. The osmotic fragility of spherocytes is increased, because the RBC’s have decreased surface area per unit volume. The major clinical features are anemia, splenomegaly, and jaundice. An aplastic crisis may occur with parvovirus infection.
5. Though in early childhood the spleen may be enlarged with sickle cell anemia, continual stasis and trapping of abnormal RBC’s leads to infarctions that eventually reduce the size of the spleen tremendously by adolescence. This is sometimes called “autosplenectomy”. Seen here is the small remnant of spleen in a patient with sickle cell anemia.
Fig. Severe, chronic anemias (such as thalassemias and sickle cell anemia) can increase the bone marrow response to form RBC’s. This drive for erythropoiesis may increase the mass of marrow and lead to increase in marrow in places, such as the skull seen here, that is not normally found. Such an increase in marrow in skull may lead to “frontal bossing” or forehead prominence because of the skull shape change.
Morphologic manifestations of hemolytic anaemias are very specific: general hemosiderosis, hemolytic jaundice in serious cases with hemoglobinuric nephrosis, splenomegaly in inherited hemolytic anaemias, the presence of centres of extramedullar erythropoiesis.
Fig. Hematopoietic elements in this bone marrow biopsy are markedly reduced. This is a case of aplastic anemia. Of course, besides, RBC’s the platelets and granulocytes will often be diminished. Sometimes a drug or toxin is the cause and sometimes infection. Wheo known cause can be found, it is termed idiopathic aplastic anemia.
In contrast to aplastic anemia, leukemia results in a highly cellular marrow. The marrow between the pink bone trabeculae seen here is nearly 100% cellular, and it consists of leukemic cells of acute lymphocytic leukemia (ALL) that have virtually replaced or suppressed normal hematopoiesis. Thus, though the marrow is quite cellular, there can be peripheral cytopenias. This explains the complications of infection (lack of normal leukocytes), hemorrhage (lack of platelets), and anemia (lack of red blood cells) that often appear with leukemia.
Thrombocyte diseases. Diseases which manifest themselves in reduced quantity of platelets in circulating blood as a result of their increased destruction or decreased production are called thrombocytopenias. They can be inherited or acquired. Inherited thrombocytopenias are divided into immune and non-immune. Immune thrombocytopenia appears in incompatibility of blood in any system, in the disturbance of antigenic thrombocytes structure (heteroimmune), in production of antybodies against their own thrombocytes (autoimmune). Non-immune thrombocytopenia appears in case of mechanic injuries of thrombocytes, impaired proliferation of bone marrow cells because of toxic agents, radiation, metastases of malignant growths, hemoblastosis, vitamin B-12 or folic acid deficiency, disseminated intravascular coagulation (DIC), etc. Morphologic manifestation of thrombocytopenia is the presence of hemorrhagic syndrome on the skin, mucous tunics, and parenchyma of internal organs.
Tthrombocytopenia.
Thrombocytopathies are diseases in which morphologic, functional, biochemical thrombocytes impairments is observed, which causes the hemorrhagic syndrome development in the vessels of microcirculatory channels. Thrombocytopathies can be congenital or acquired. They are characterized by the disturbance of the formation of hemostatic thrombocyte plug including adhesion, secretion, and aggregation. Inherited variants of pathology mostly accompany other inherited defects. In their essence there is autosomal recessive disturbance of membrane glycoprotein synthesis and thrombocytes secretion. As an example we can observe Glanzmann –Negeli(Glanzmann’s thrombasthenia) disease with lack of thrombocytes aggregation, the disturbance of binding with fibrinogen and prolonged bleedings. The other example is Bernard-Soulier syndrome with large thrombocytes and reduction of their adhesion. Acquired thrombocytopathies appear in many diseases: hemoblastosis, vitamin B-12 deficiency anaemia, cirrhosis, tumour diseases of the liver, uraemia, radiation sickness, scorbutus (scurvy), massive hemotransfusion, DIC syndrome, hormonal disturbance, medicamentosis and toxic infections of the organism, etc. Thrombocytopathies can occur with more or less apparent thrombocytopenia.
The WBC’s seen here are lymphocytes, but they are blastsvery immature cells with larger nuclei that contaiucleoli. Such lymphocytes are indicative of acute lymphocytic leukemia (ALL). ALL is more common in children than adults. Many cases of ALL in children respond well to treatment, and many are curable.
These mature lymphocytes are increased markedly iumber. They are indicative of chronic lymphocytic leukemia, a disease most often seen in older adults. This disease responds poorly to treatment, but it is indolent.
Coagulopathies is a group of diseases connected with the disturbance of blood coagulation system. Prolonged deficiency of any coagulation factor causes hemorrhagic syndrome in organism: prolonged bleeding, spontaneous petechia, large posttraumatic haematomas, hemorrhages into gastroiintestinal tract, joints, etc.
Coagulation disturbances can be congenital and acquired. Acquired coagulopathies appear under K vitamin deficiency, when the factors of coagulation: II, VII, IX, X and C protein are oppressed. Such conditions are common in liver diseases since almost all coagulation factors are synthesized in the liver; and at DIC syndrome. DIC syndrome is a coagulopathy with the activation of coagulation which leads to the formation of microthrombs in the microcircular canal. As a result of thrombophilia, the deficiency of thrombocytes, the coagulation factors and the secondary activation fibrinolysis mechanisms appears, which increases the hemorrhagic diathesis.
Coagulopathies
Coagulopathies
Inherited coagulopathies appear as a deficiency of one coagulation factor. They are often met in family marriages (rulers dynasties in Europe, Russia). Examples are haemophilia-A at factor VIII deficiency, and haemophilia-B in factor IX deficiency. For the most coagulopathies autosomal transfer is typical. Hemostasic disturbance is expressed through such coagulation changes as: prolonged bleeding, prolonged prothrombin time (duration in seconds of formation of blood plasma clot with the presence of thromboplastin and calcareous salt), and prolonged thromboplastin time (formation period of thromboplastin- factor III of thrombocytes which helps to transform prothrombin into thrombin).
The sideroblastic anemias are a heterogeneous group of disorders characterized by amorphous iron deposits in erythroblast mitochondria that are housed within a distinct, mitochondrial ferritin . The iron-glutted mitochondria account for the so-called ring sideroblast, an erythroblast in which numerous Prussian blue–positive granules often appear in a perinuclear distribution, particularly in the later stages of its maturation .
The basis for the mitochondrial iron accumulation in the various sideroblastic anemias can be regarded as either insufficient generation of heme as a result of certain enzyme defects in the heme biosynthetic pathway or from faults in mitochondrial functions that involve iron pathways, creating an imbalance between mitochondrial iron import and its utilization (. Iron delivery to the erythroid cell is not down-regulated in the face of the diminished heme synthesis, and iron continues to be transported normally to mitochondria, where it accumulates (). Globin synthesis is also reduced, but this effect is secondary as it can be corrected in vitro by the addition of heme).
Kinetically, the sideroblastic anemias are characterized by ineffective erythropoiesis, like other erythroid disorders with defective cytoplasmic or nuclear maturation. Erythroid hyperplasia of the bone marrow is accompanied by a normal or only slightly increased reticulocyte count. The plasma iron turnover rate is increased, but iron incorporation into circulating red cells is reduced. Red cell survival, as measured with the usual random labels), tends to be normal or slightly reduced. Slight hyperbilirubinemia may be noted, as well as an increase in urobilinogen excretion, as a result of a raised erythropoietic component of the “early-label” bilirubin peak (Thus, it can be inferred that a substantial proportion of the developing ring sideroblasts are nonviable, and their expiration through enhanced apoptotic mechanisms within the marrow () accounts for the kinetic abnormalities.
The progeny of surviving ring sideroblasts are hypochromic and microcytic erythrocytes, a finding that provides morphologic evidence of impaired hemoglobin production as well as an initial clue to the diagnosis. The degree of hypochromia and microcytosis varies considerably from one form of sideroblastic anemia to another). Often, dimorphism is pronounced, with a hypochromic/microcytic population of cells existing side by side with a normal or even a macrocytic one. The siderotic mitochondria of the developing cell may be retained in some circulating erythrocytes (Pappenheimer bodies) and are regularly found with concurrent hypofunction or absence of the spleen; these cells are the nearly pathognomonic siderocytes in the Wright-stained blood smear
An almost constant feature of those sideroblastic anemias that are not reversible is an excess of total body iron. The serum iron concentration is increased, often to the point of complete saturation of transferrin, and the level of serum ferritin roughly reflects the degree of iron overload. The ineffective erythropoiesis mediates increased intestinal absorption of iron most likely by suppressing hepcidin production The consequent iron overload state is called erythropoietic hemochromatosis, and its clinical and pathologic features and course can rival those of hereditary hemochromatosis. The occasional concomitant presence of alleles for hereditary hemochromatosis accentuates the iron overload , but their prevalence in patients with sideroblastic anemia does not appear to be greater than in the general population
Diverse mechanisms impairing erythroid heme synthesis are reflected in the various forms of sideroblastic anemia whether inherited or acquired. Within the hereditary group, X-linked transmission is the most frequent. In several kindreds, the disorder appeared to be inherited as an autosomal trait, and not infrequently sporadic congenital cases are encountered in children as well as in adults without other affected family members. Acquired sideroblastic anemia is considerably more common than the inherited forms and occurs as a clonal disorder manifesting only anemia or multilineage dysplasia or even myeloproliferative features. Several diverse factors, such as ethanol, certain drugs, copper deficiency, and hypothermia, produce the ring sideroblast abnormality that is fully reversible.
Acquired aplastic anemia can occur in any age group and is usually the consequence of an autoimmune attack against hematopoietic stem cells. Awareness of the less common inherited forms of bone marrow failure is critical in the assessment of any new patient with aplastic anemia. These inherited disorders can masquerade as acquired aplastic anemia, but rarely respond to immunosuppressive therapies; management usually consists of supportive care or bone marrow transplantation (BMT) in severe cases (3,4). Inherited forms of bone marrow failure generally pre-sent in the first decade of life and are often associated with physical anomalies (e.g., short stature, upper limb anomalies, hypogonadism, café-au-lait spots, etc.); however, inherited forms of bone marrow failure may present well into adulthood. Some patients have a positive family history of cytopenias, highlighting the importance of taking a careful family history when evaluating aplastic anemia patients.
Fanconi anemia, the most common form of inherited bone marrow failure, is usually an autosomal recessive disorder that is characterized by defects in DNA repair and a predisposition to leukemia and solid tumors. Recently, a rare, X-linked form of Fanconi anemia has been described ). Dyskeratosis congenita (DKC) is an inherited bone marrow failure syndrome that results from loss of function mutations of telomerase components and displays considerable clinical and genetic heterogeneity. Although DKC classically presents with the triad of abnormal skin pigmentation, nail dystrophy, and mucosal leukoplakia, these findings can be subtle ). X-linked recessive, autosomal dominant, and autosomal recessive forms of DKC are recognized. Telomerase reverse transcriptase (TERT) and the RNA component of telomerase (TERC) form the core of the active telomerase complex. Autosomal dominant DKC can result from mutations of TERC11 or TERT12. The X-linked recessive DKC results from mutations in the gene DKC1, whose gene product, dyskerin, is important for stabilizing the telomerase RNA–protein complex (13,14). Disruption of telomerase leads to accelerated telomere shortening, bone marrow failure, and premature aging.
Inherited amegakaryocytic thrombocytopenia is characterized by severe thrombocytopenia and megakaryocyte absence at birth. 0Missense or nonsense mutations in the c-mpl gene are present in most patients. A high percentage of these patients subsequently develop multilineage bone marrow failure in the second decade of life ().
Shwachman-Diamond syndrome is an autosomal recessive disorder characterized by pancreatic exocrine dysfunction, metaphyseal dysostosis, and bone marrow failure (16). Similar to Fanconi anemia, there is an increased risk of developing myelodysplasia or leukemia at an early age. No causative genetic lesion has been identified, but recently, a mutation in the gene SBDS, located on chromosome 7, has been associated with this disease ). The remainder of this chapter will focus on acquired aplastic anemia, hereafter referred to as aplastic anemia.
Aplastic anemia most commonly presents between the ages of 15 and 25, but there is a second smaller peak in incidence after age 60 . Similar to other autoimmune diseases, certain histocompatibility locus specificities, especially human leukocyte antigen (HLA) DR2, are associated with an underlying predisposition to aplastic anemia (). Although aplastic anemia has been causally associated with many agents, including drugs, benzene exposure, insecticides, and viruses, no etiologic agent can be identified in most cases (). A population-based case-control study of aplastic anemia in Thailand found that drugs were the most commonly implicated cause, but they explained only 5% of newly diagnosed cases.
Viruses, similar to drugs, are often implicated, but seldom proven to cause aplastic anemia. Viral infections, especially in chronically ill patients, often lead to transient cytopenias, but frank aplastic anemia is uncommon. These transient cytopenias can be due directly to infection and cytolysis of hematopoietic cells or indirectly through the elaboration of inhibitory cytokines. True aplastic anemia following viruses also appears to usually result from an idiosyncratic immune response directed against hematopoietic stem cells. Acute infection with Epstein-Barr virus (EBV) is often associated with peripheral blood cytopenias. Rarely, acute EBV infection can be complicated by the development of aplastic anemia . There are no convincing data that B19 parvovirus causes aplastic anemia, but this virus is often linked with aplastic anemia due to the unfortunate term aplastic crisis, used to describe the transient red cell aplasia and severe anemia that occurs in sickle cell anemia patients who are acutely infected with B19 parvovirus. The only knowatural host cell of parvovirus B19 is the human erythroid progenitor (36). The receptor for the virus is a neutral glycolipid, globoside, also known as the erythrocyte P antigen. Globoside is expressed on erythroid progenitors, erythrocytes, fetal myocardium, placenta, some megakaryocytes, and endothelial cells; it is not present on hematopoietic stem cells. Other viruses, including a variety of herpesviruses and the human immunodeficiency virus, have been implicated in triggering aplastic anemia, but convincing causal data are lacking. Spontaneous recovery, response to immunosuppression, and response to antiviral therapy have all been described; however, for those with severe disease, conventional therapy (immunosuppression or bone marrow transplantation) should be initiated early.
Seronegative (non-A through non-G) hepatitis precedes the diagnosis of aplastic anemia in 3 to 5% of cases and is recognized as hepatitis-associated aplastic anemia (38). After orthotopic liver transplantation for fulminant seronegative hepatitis, up to 30% of patients will develop aplastic anemia (). In most cases, the hepatitis resolves spontaneously; however, when severe aplastic anemia (SAA) follows, it is often fatal and presents within a few months after the onset of hepatitis (). The pathophysiology of hepatitis-associated aplastic anemia (HAA) is unknown, but is thought to be immune mediated since it responds to immunosuppressive therapy (). Furthermore, patients with HAA hPregnancy-associated aplastic anemia is a rare entity, and despite numerous case reports, the association is not well understood). The onset of aplastic anemia can occur during pregnancy or shortly after delivery. Moreover, in women with a history of aplastic anemia who had been treated into remission with immunosuppressive therapy, there is an increased risk for relapse of aplastic anemia during pregnancy. The European Group for Blood and Marrow Transplantation performed a retrospective study on the outcome of pregnancy in 36 women who had received immunosuppressive therapy to treat aplastic anemia (45). Seven of the pregnancies (19%) were complicated by relapse of aplastic anemia. In contrast to idiopathic aplastic anemia, pregnancy-associated aplastic anemia is often associated with spontaneous remissions. However, in patients with severe disease, therapy should be initiated promptly, since maternal and fetal mortality are not uncommon.ave a skewed T-cell repertoire, and liver biopsies from these patients show lymphocytic infiltration
Clonality and Aplastic Anemia
A controversial, yet biologically important issue pertaining to aplastic anemia is the high incidence of concomitant clonal hematopoiesis, particularly paroxysmal nocturnal hemoglobinuria (PNH) and MDS. Even before the widespread use of immunosuppressive therapy, 5% of patients with aplastic anemia progressed to clonal hematopoiesis. This suggests that the increase in MDS and PNH following immunosuppressive therapy is not a direct consequence of treatment. Rather, the increased survival following immunosuppressive therapy allows time for these underlying clones to develop and expand.
MDS is a clonal hematopoietic stem cell disorder that produces multilineage hematologic cytopenias. It is associated with heterogeneous karyotypic abnormalities, often involving chromosomes 5, 7, or 8. Up to 15% of children and adults with aplastic anemia will develop MDS following immunosuppressive therapy, with monosomy 7 being the most common chromosomal abnormality to emerge (). PNH results from the expansion of an abnormal hematopoietic stem cell that harbors a somatic mutation of the X-linked gene PIGA (). The PIGA gene product is required for glycosylphosphatidyinositol (GPI) anchor biosynthesis; consequently, PNH cells are deficient in all GPI-anchored proteins (GPI-AP). The GPI-APs (CD59 and CD55) protect cells from complement-mediated destruction; their absence explains the complement-mediated intravascular hemolysis associated with PNH.
Small to moderate PNH clones are found in up to 70% of patients with aplastic anemia (). Typically, <20% GPI-AP–deficient granulocytes are detected in aplastic anemia patients at diagnosis, but occasional patients may have larger clones. DNA sequencing of the GPI-AP–deficient cells from aplastic anemia patients reveals clonal PIGA gene mutations (85). Moreover, many of these patients exhibit expansion of the PIGA mutant clone and progress to clinical PNH. While it was once thought that PNH evolving from aplastic anemia is more benign than classic PNH, this observation may be a consequence of lead-time bias, since many of these patients eventually develop classic PNH symptoms after the PIGA mutant clone expands.
One hypothesis to explain the close relationship between PNH and aplastic anemia, and the mechanism whereby the PNH clone achieves dominance, involves a “two-step” model. This model proposes that hematopoietic stem cells randomly and spontaneously acquire PIGA mutations at a very low frequency (step one). Step
two in this model proposes that the immunologic attack that targets hematopoietic stem cells in aplastic anemia spares PNH cells, ostensibly because they lack GPI-anchored proteins. Indeed, PIGA mutant cells can be found at low frequency in most healthy controls). However, recent data suggest that PIGA mutations in healthy controls arise from colony-forming cells rather than hematopoietic stem cells); thus, the relevance of these mutations is unclear. Furthermore, there is no direct evidence to support a GPI-anchored protein being the target of the immune attack in aplastic anemia. Importantly, the two-step model does not explain the similarly high incidence of MDS in aplastic anemia patients.
An alternative hypothesis that could explain the predisposition of patients with aplastic anemia to develop both PNH and MDS has been proposed. MDS and PNH evolving in the setting of aplastic anemia could be analogous to the “field cancerization effect” described in aerodigestive and other solid tumors to explain second primary tumors in the affected tissue. That is, a single insult to the marrow, such as generalized toxic damage or a genetic predisposition, may be responsible for bringing about different forms of marrow disorders; these disorders may occur alone, simultaneously, or sequentially. In aplastic anemia, the bone marrow injury may primarily trigger an autoimmune attack on the hematopoietic stem/progenitor compartment, perhaps by exposing cryptic epitopes through molecular mimicry or by sending a “danger” signal. In de novo PNH or MDS, the injury may primarily produce a genetic mutation that leads to clonal dominance of the affected clone . In other patients, bone marrow injury may induce both an autoimmune hematopoietic attack and a clonal genetic mutation that present either simultaneously or sequentially. Examples of simultaneous presentation can be the aplastic anemia/PNH overlap and hypoplastic MDS (hMDS). Lastly, a third hypothesis proposes that additional mutations occurring in PIGA mutant stem cells are required for clonal expansion PNH
Leukemia
Leukemia is a malignant neoplasm of hemopoietic tissues (blood-forming tissues) which are characterized by the progressive overgrowth of tumour cells-leukemia cells. First tumour cells increase in hematopoietic organs (bone marrow, lymph nodes, spleen) and then hematogenously spread in the whole organism with the infiltration of some organs; and also appear in circulating blood. Progressive overgrowth of leukemia cells leads to anaemia, hemorrhagic syndrome, dystrophic changes in parenchymal (parenchymatous) organs, immunity oppression, ulcero-necrotic and septic complications. Leukemia etiology caot be always identified because it is a polyethiologic disease. The cause can be genetic and inherited factors, chromosomal anomaly, and all factors which can cause cellular mutation in the hematopoietic system. These factors are: viruses (retrovirus HTLV-I, II, Epstein-Barr DNA-virus), ionizing radiation, chemical compounds (benzpyrene, pesticides, herbicides, benzene ring compounds, etc). Classification of leukemia is based on the morphologic and cytochemical peculiarities of bone marrow tumour cells. The acute and chronic leukemia are divided according to the level of differentiation of the tumour blood cells and their development (non-malignant or malignant). Acute leukemia is characterized by the proliferation of non-differentiated or differentiated, blastic cells with malignant development. Chronic leukemia is characterized by the proliferation of differentiated leukemic cells with relative non-malignant development. As to the quantity of leucocytes and leukemic cells there are the following variants of leukemia: leukemic (dozens and hundreds of thousands of cells per 1µ l (microliter) of blood), subleukemic (not more than 15-25 thousands cells), leukopenic (lowering of leucocytes quantity but with their presence), aleukemic (no leukemiс cells in circulating blood).
6. Leukemias typically fill up the marrow with abnormal cells, displacing normal hematopoiesis. The marrow here is essentially 100% cellular, but composed almost exclusively of leukemic cells. Normal hematopoiesis is reduced via replacement (a “myelophthisic” process) or by suppressed stem cell division. Thus, leukemic patients are prone to anemia, thrombocytopenia, and granulocytopenia and all of the complications that ensue, particularly complications of bleeding and infection.
7. At high power, the bone marrow of a patient with acute myelogenous leukemia is seen here. There is one lone megakaryocyte at the right center.
8. There are numerous granulocytic forms seen here, including immature myeloid cells and bands. This condition is one of the myeloproliferative states and is known as chronic myelogenous leukemia (CML) that is most prevalent in middle-aged adults. A useful test to help distinguish this disease is the leukocyte alkaline phosphatase (LAP) score, which should be low with CML and high with a leukemoid reaction.
9. Here is another view of a peripheral blood smear in a patient with CML. Often, the numbers of basophils and eosinophils, as well as bands and more immature myeloid cells (metamyelocytes and myelocytes) are increased. Unlike AML, there are not many blasts with CML.
Acute leukemia with respect to morphologic and cytochemical peculiarities of leucocytes is divided into lymphoblastic and myeloblastic leukemia or lymphoblastic and non-lymphoblastic. As to contemporary knowledge of erythropoiesis among the acute leukemia there are non-differentiated, myeloblastic with blasts maturation, promyelocytic, myelomonocytic, monocytic, monoblastic, erythroleukemia, megakaryoblastic variants which develop from spinal cell or cell precursories of class II-IV. Among the lymphoblastic leukemia according to immunal and cytogenetic characteristics 3 morphologic forms: are distinguishedL1, L2, L3.
10. Here is the normal appearance of a benign reactive lymph node. At the top is the capsule and just under that a subcapsular sinus where lymphatics enter that drain tissues peripheral to the node. Beneath the capsule is the paracortical zone with lymphoid follicles having a pale germinal center in which the immune responses are often generated. Beneath this are sinusoids extending to the center of the node.
Clinicopathologic characteristic. The first manifestation of the acute leukemia is the presence of blastic cells in the bone marrow of breast bone as a result of which it changes its colour and consistence (red, succulent, sometimes with grey shade under non-differentiated form; pyoid in myeloblastic form; raspberry-red in lymphoblastic leukemia). In the circulating blood the leukemic (leucemicus) hiatus develops. It is a great number of blastic cells, too little of mature, and the total absence transferring cell forms. There is a substitution of bone marrow with the new blastic leukemic cells. Gradually leukemic infiltration appears in the spleen, liver, lymph nodes, kidneys, meninges (brain tunic) (neuroleukemia in lymphoblastic leukemia), mucous tunics of gastrointestinal tract, lungs (leukemic pneumonitis in myeloblastic leukemia) and other organs. There develops anaemia, thrombocytopenia, and hemorrhagic syndrome on skin, mucous tunics, serous tunic, internal organs, cerebrum, necrotic tonsillitis (angina), septic complications, and dystrophic changes in parenchymatous organs.
Children have acute leukemia more often; it can be an inherited form of the disease. There are nodular infiltrations in different organs. The most common is T-dependent lymphoblastic leukemia, the less common is myeloblastic leukemia.
Causes of death: septic complications (especially at un-differentiated forms), ulcero-necrotic complications, hemorrhages (especially dangerous to the cerebrum which are in promyelocytic leukemia, progressive disease).
Medical pathomorphism: under the influence of therapy in leukemia the hemorrhagic diathesises, necrotic changes in mucous membrane of the mouth (oral) cavity; more often the ulcero-necrotic changes are met in tunics of gastroiintestinal tract; leukemic pneumonics, leukemic meningitis.
Chronic leukemia is divided into leukemia of myelocytic origin, leukemia of lymphocytic origin, and leukemia of monocytic origin (myelomonocytic leukemia and histiocytosis).
At high magnification is seen a lymph node follicle with a germinal center containing larger lymphocytes undergoing activation. At the lower right is the subcapsular sinus.
This is a more pronounced reactive change in a lymph node, with a larger follicle and germinal center containing macrophages. In general, lymph nodes in a benign reactive process are more likely to enlarge quickly and be tender.
At high magnification, the germinal center in this reactive lymph node follicle has prominent macrophages with irregular cellular debris (so-called “tingible body macrophages”). Blood vessels are also more prominent.
Here is a lymph node involved by lymphoma, a malignant process characterized by the proliferation of neoplastic lymphoid cells. The capsule of the node has been invaded and the lymphomatous cells extend into the surrounding adipose tissue. Note that the follicles are numerous and irregularly sized. This is a malignant lymphoma, small cleaved cell type, follicular (also known as: malignant lymphoma, poorly differentiated lymphocytic type, nodular).
This pattern of malignant lymphoma is diffuse and no lymphoid follicles are identified. Under low power, note that the normal architecture of the lymph node is obliterated. The lymph node is replaced by an infiltrate of small (mature-appearing) neoplastic lymphocytes, and the infiltrate extends through the capsule of the lymph node and into the surrounding fat. The diagnosis is: malignant lymphoma, small lymphocytic type, diffuse (also known as: “well-differentiated” lymphocytic lymphoma).
Chronic leukemia of myelocytic origin or myeloproliferative syndrome are represented generally by chronic myelosis or chronic myeloid leukemia, chronic erythromyelosis, polycythemia, erythromia, myelofibrosis. Chronic myeloid leukemia has two stages: monoclonal non-malignant and polyclonal malignant. The first stage lasts for several years and is characterized by the progressive increase of neutrophils with change to myelocytes. At the later stage in 3-6 months there develops polyclonism, blastic cell form appear (myeloblasts, erythroblasts, monoblasts and other), blast crisis appears, the quantity of erythrocytes in blood increases to several millions per 1µ l, all manifestations of acute leukemia develop.
Morphology: The bone marrow is reddish grey, succulent and pyoid; the blood is greyish red; internal organs are anaemic; the spleen weight is abruptly increased to 6-
Myelofibrosis is characterized by the presence of myeloid leukemia manifestations and the change of bone marrow to connective or bone (osseous) tissue. Thus the disease has a prolonged non-malignant course.
Erythromia is encountered in elderly people and is characterized by an increase in the mass of erythrocytes, thrombocytes, granulocytes in circulating blood, increased blood (arterial) pressure, inclination to thrombosis, splenomegaly.
Chronic leukemia of lymphocytic origin are represented by chronic lympholeukemia, skin lymphomatosis (Caesary’s disease), and paraproteinemic leukemia. Chronic lympholeukemia develops in elderly people, appears from B-lymphocytes, but with abrupt lowering of immunoglobulin formation, the development of autoimmune reactions, the increased quantity of leucocytes in circulating blood to 100 thousands per 1 µ l, leukemic infiltrates are present in all organs.
Morphology: the bone marrow is red; the spleen is increased to
Tumours of plasmatic cells or paraproteinemic leukemia develop from B-lymphocytic system, the precursors of plasmatic cells. These cells synthesize the pathologic proteins, paraproteins. This type of leukemia includes: myeloma (myelomatosis, plasmocytoma, Kahler’s disease), Waldenström’s macroglobulinemia, Franklin’s disease of heavy chains. Myeloma is characterized by the spread of tumour cells of lymphoplasmocytic line – myelomic cells in bone marrow with bones destruction. The abnormal proteins (paraproteins) accumulate in circulating blood, which segregates into urine through the kidneys (Bence-Jones protein).Depending on the character of myelomic infiltrates in the bone marrow, diffusive, diffusive-nodal and multiple forms of disease are distinguished. The most affected are the flat bones (skull and ribs), vertebras, more seldom tubular with the development of bone tissue destruction. In the bones osteolysis and osteoporosis develop. Myelomic infiltration is also observed in the internal organs: spleen, liver, kidneys, lungs, lymph nodes. Complications: paraproteinemic nephrosis, *myelomicly wrinkled kidneys*, renal amyloidosis (amyloid nephrosis), inflammatory changes as pneumonia, pyelonephritis. The other forms of paraproteinemic leukemia are seldom accompanied with bones destructions.
Tumour diseases of lymph nodes or lymphomas. To this group belong: lymphosarcoma, mycosis fungoides, Caesary’s disease, reticulosarcoma, Hodgkin’s disease (lymphogranulomatosis). There are Hodgkin’s and non-Hodgkin’s lymphomas. They can be B- and T-cellular. Lymphomas or lymphocytomas are ectomarrow tumours which consist of different lymphocytes or of lymphocytes and prolymphocytes. They appear in lymph nodes or lymphoid tissue of the other internal organs. They are characterized by the local growth and non-malignant course. The first manifestation of lymphomas are increased peripheral lymph nodes, they become thicker, mobile, non-painful. Later there appear the manifestations of intoxication, general weakness, weight loss, night sweat, which is the manifestation of the tumour process. Transformation into lymphosarcoma is rarely met and after the long time.
Many non-Hodgkin’s lymphomas seen in adults are large cell lymphomas such as the one here at medium power, but they can be associated with immunosuppressed states (such as AIDS), and are typically of B cell origin. The cells are large, with prominent nucleoli and abundant cytoplasm. This disease tends to be localized (low stage), but with more rapid enlargement, and a greater propensity to be extranodal than the low grade lymphomas.
Lymphosarcoma is a malignant lymphoma of mediastinal, extraperitoneal, inguinal lymph nodes, and lymph tissue of gastroiintestinal tract. The nodes increase with the necrotic and hemorrhagic areas. Process generalization courses lymphaticly and hematogenously. To this group belong: Burkitt’s lymphoma (Burkitt’s tumor) – endemic disease of African children when facial skeleton bones are damaged. The cause is the herpetiformis virus.
The malignant lymphocytes here are very large with a moderately abundant cytoplasm, and the nuclei are round to ovoid with prominent nucleoli and occasional mitoses. The diagnosis is diffuse large B cell lymphoma (also known as immunoblastic lymphoma). The major differential diagnosis in this case would be a metastatic carcinoma. The presence of monoclonal immunoglobulin as demonstrated by immunoperoxidase technique would help to confirm this lesion as a malignant lymphoma. Demonstration of CD19 and 20 antigens would classify it as B cell in origin.
A bone marrow biopsy can reveal malignant lymphoma. Here, there is a peritrabecular infiltrate of small blue cells which is the lymphomatous infiltrate.
Mycosis fungoides is a non-malignant T-cellular skin lymphoma.
Hodgkin’s disease (lymphogranulomatosis) is a chronic recurrent lymphoma with the affection of cervical, mediastinal, extraperitoneal, inguinal lymph nodes. There are isolated (local) and spread (generalized) forms. The spleen is often affected (necrosis nidi of white with yellow colour, sclerosis, lymphocytic infiltration), that’s why it turns to variegated and porphyric look. In lymph nodes there appear prolypheration of leucocytes, histiocytes, reticular cells, eosinophils, plasmatic cells, neutrophilic leucocytes, necrosis and sclerosis nidi, atypical mononuclear small and big Hodgkin’s cells, polynuclear giant Rid-Berezovsky-Stemberg’s cells. There are four clinicopathologic forms of disease: predominance of lymph tissue (lymphohistiocytic) variant – I-II stages of disease, its localized form, nodular sclerosis is met ion-malignant course of disease, mixed-cellular variant appears in disease spread and corresponds to the II-III stages, the oppression of lymph tissue variant is typical for the generalized form and has a malignant course, sometimes called Hodgkin’s sarcoma.
Chronical myeloleucosis
Following organ transplantation, particularly for heart, but also to a lesser extent with kidney and bone marrow, immunosuppressive therapy may promote an expansion of Epstein-Barr virus (EBV) infected T-cells, seen here with immunoperoxidase staining for EBV. This is a post-transplantation lymphoproliferative disorder (PTLD), which acts like a lymphoma, but will recede when immunosuppression is diminished, if possible.
The skull demonstrates the characteristic rounded “punched out” lesions of multiple myeloma.
The rounded “punched out” lesions of multiple myeloma appear as lucent areas with this skull radiograph.
Round lesions filled with a soft reddish material are indicative of foci of myeloma in this section of vertebral bone.
At low power, the abnormal plasma cells of multiple myeloma fill the marrow.
At medium power, the plasma cells of multiple myeloma here are very similar to normal plasma cells, but they may also be poorly differentiated. Usually, the plasma cells are differentiated enough to retain the function of immunoglobulin production. Thus, myelomas can be detected by an immunoglobulin “spike” on protein electrophoresis, or the presence of Bence-Jones proteins (light chains) in the urine. Immunoelectrophroesis characterizes the type of monoclonal immunoglobulin being produced.
Here is a smear of bone marrow aspirate from a patient with multiple myeloma. Note that there are numerous plasma cells with eccentric nuclei and a perinuclear halo of clearer cytoplasm.
Here is a 5 cm lymph node (obviously from a patient with lymphadenopathy). The node should normally be soft and pink and less than 1 cm in size. This lymph node is involved with Hodgkin lymphoma. This gross appearance could pass for a non-Hodgkin lymphoma as well.
This is a liver that is involved with Hodgkin lymphoma. The staging of Hodgkin’s disease is very important in determining therapy. Thus, it is important to determine whether the patient has only a single lymph node region involved, multiple node regions, or extranodal involvement. This picture could probably suffice for non-Hodgkin lymphomatous hepatic disease as well.
This is Hodgkin lymphoma of the nodular sclerosis type. This is the most frequent type that often has a low stage and therefore a good prognosis. Note the bands of pink collagenous tissue (the sclerosis) dividing the field in this lymph node.
At medium power, nodular sclerosing Hodgkin lymphoma has prominent bands of fibrosis. Staging of Hodgkin lymphoma is important to try and determine therapy and the prognosis. Staging is often done by radiographic means, with CT scans used to determine where lymphadenopathy is located, ultrasonography to determine size and lesions of liver and spleen, and chest radiograph. Histologic diagnosis is typically made from biopsy of an involved lymph node. A bone marrow biopsy may be performed as well. Staging laparotomy is less commonly used nowadays because the radiographic procedures are excellent.
At high power, there are scattered large cells with a surrounding prominent clear space, an artefact of formalin fixation. These are the lacunar cells characteristic for the nodular sclerosis type of Hodgkin lymphoma.
Note the large cells with large, pale nuclei containing large purple nucleoli at the arrowheads. These are Reed-Sternberg cells that are indicative of Hodgkin’s disease. Most of the cellular content of foci of Hodgkin lymphoma consists of reactive lymphoid cells. There are four main subtypes of classic Hodgkin lymphoma with CD15+ Reed-Sternberg cells and variants: lymphocyte rich, nodular sclerosis, mixed cellularity, and lymphocyte depletion. The lymphocyte predominance subtype with CD15- Reed-Sternberg variant cells acts more like a low-grade B-cell lymphoma.
Hodgkin lymphoma (HL) is a lymphoproliferative malignancy that accounts for only 1% of newly diagnosed malignancies in the United States; however, the disease’s importance to the field of medical oncology is out of proportion to its clinical incidence. From a historical point of view, HL was the first cancer in which the curative potential of combination chemotherapy was demonstrated. Second, because affected patients are often young, there is a great potential for adding years of productive life by giving curative therapy. Third, because patients with HL are often cured, HL serves as a clinical laboratory for investigating the late effects of cancer therapy.
HL usually presents as solitary or generalized lymphadenopathy and most commonly occurs in young adults, although any age group may be affected. The disease appears to spread in a contiguous fashion, and most patients present with disease limited to the lymph nodes or to the lymph nodes and spleen. Even when the disease is advanced, cure is possible. Overall, cure can be achieved in approximately 80% of patients with HL. Treatment of limited disease often incorporates radiation therapy and combination chemotherapy, whereas treatment of advanced disease is generally limited to combination chemotherapy alone.
Although HL has been a success story of modern cancer medicine, this success has in some ways been paradoxical. First, the successful therapy of HL has been empirical and derived through understanding prognostic features and patterns of spread. Clinical success has been independent of understanding the pathogenesis of HL or its cell of origin. One can only speculate as to whether understanding the molecular pathogenesis of HL will lead to targeted therapy and improved clinical results. Second, although major clinical advances in HL depended heavily on pathologic staging, including staging laparotomy, staging laparotomy is no longer used in clinical practice. However, because both radiation therapy and chemotherapy are curative modalities, and because many relapsing patients can be cured, clinical staging rather than surgical staging is generally used as the basis for therapeutic planning. The abandonment of staging laparotomy has occurred without negative clinical consequences and staging laparotomy has become a procedure of historical interest only. Third, the high rate of success associated with salvage therapy means that it is difficult to make specific optimal treatment recommendations for the primary treatment of many patients with HL. In contrast to many areas of oncology, salvage therapy in HL can produce cures. As a result, in HL, event-free survival is not a meaningful surrogate marker for cure. Since late complications, including malignancy, can compromise the long-term efficacy of treatments that appear superior in the short run, therapies that produce superior disease-free survival at 5 years may not be associated with superior survival at 15 years. When considering therapy for patients with HL, one must realize that valid alternatives exist in addition to what may be considered the “best therapy” based on short-term observations.
Early History
In 1832, Thomas Hodgkin presented a paper entitled On Some Morbid Appearances of the Absorbent Glands and Spleen (1). His report was an autopsy description of seven patients, and the major original thesis presented in the paper was that the entity he was describing was a primary process involving the lymph glands and spleen rather than a reactive inflammatory condition. In 1856, Samuel Wilks published a series of cases involving enlargement of the lymph glands (2) and noted Hodgkin’s original description. In 1865, Wilks wrote Cases of Enlargement of the Lymphatic Glands and Spleen (or Hodgkin’s Disease) with Remarks, updating and extending his findings. Thus, Thomas Hodgkin’s name became linked to the disorder. Of note, some of the cases included in Hodgkin’s initial report were likely cases of tuberculous lymphadenopathy or eveon-Hodgkin lymphoma.
After these gross pathologic descriptions, the first microscopic description of HL was reported by Langhans (4) in 1872. This report was followed by independent reports by Sternberg in 1898 (5) and by Reed in 1902 (6) describing the characteristic giant cells that came to be known as Reed-Sternberg cells. At the time of these early reports, all comments regarding the cause of HL were purely speculative. Not surprising, these early authors were divided over whether HL represented an infectious disease, an inflammatory disorder, or a malignancy involving the lymph glands. Considering that HL is a malignant disease for which there is epidemiologic evidence of a possible viral etiology and that the microscopic appearance is that of a small number of malignant cells surrounded by an exuberant host reaction, all of these opinions (malignant, inflammatory, infectious) may be partially correct.
Epidemiology and Etiology
Approximately 7,500 new cases of HL are diagnosed in the United States each year. In most economically developed countries, there is a bimodal age distribution, with one peak occurring in the third decade of life and the second peak occurring after age 50 years. The occurrence of HL in patients between the ages of 15 and 39 has been positively associated with increased maternal education, decreased numbers of siblings and playmates, and single-family dwellings in childhood . In less economically developed countries, HL is less common but affects children, most of whom are boys; mixed cellularity HL and lymphocyte-depleted HL are more commonly seen . These data have been interpreted as supporting the hypothesis that HL is caused by an infectious agent, and it has been postulated that malignancy is more likely to occur when exposure to the agent in question is delayed until late adolescence or early adulthood. This concept of differential sequelae dependent on age at exposure to an infectious agent is similar to that used to explain the association of paralysis with poliovirus in susceptible populations.
The arguments for an infectious etiology of HL date back to the earliest descriptions of the disorder. Mycobacterium tuberculosis was the first organism to be suspected of causing HL (13,14). However, once it was known that HL is associated with immune defects, M. tuberculosis came to be seen as a consequence rather than a cause of HL. In the 1970s, the hypothesis of an infectious etiology for HL was supported by reports of clustering among
exposed high school students in New York state (). However, additional population-based studies have led to the conclusion that the apparent clustering was due to chance alone Epstein-Barr virus (EBV) has been another proposed cause of HL, and the circumstantial evidence is considerable. The incidence of HL is elevated among patients with a history of EBV infection . EBV has been associated with other related malignancies, including Burkitt lymphoma and the lymphomas that occur after organ transplantation. Using modern molecular biology techniques, EBV genome fragments have been found in Reed-Sternberg cells from approximately one half of patients with HL ), more commonly in cases of mixed cellularity HL. Additionally, the EBV DNA associated with Reed-Sternberg cells in HL has been shown to be monoclonal, establishing that EBV preceded the development of HL. Interestingly, prognosis appears to be better in HL that is EBV positive, as compared to cases that are EBV negative.
HL occurring in early childhood or in older adults is more likely to be EBV associated than are cases of HL occurring in young adults. However, in a recent study, patients with documented EBV-positive infectious mononucleosis were followed for an extensive period). In this selected population, 29 cases of HL developed and 16 (55%) were positive for EBV. The risk of EBV-positive HL was increased by a factor of 4 as compared to patients who never had documented EBV-positive infectious mononucleosis; the median latency for HL after EBV infection was 4.1 years. There was no increase of EBV-negative HL in this population. However, this association of EBV with HL does not prove a causal relationship. The data are equally compatible with the theory that EBV may predispose patients to the development of HL. In this regard it has beeoted that Reed-Sternberg cells express only a subset of the latent viral genes required for the transformation of B cells in vitro (28). Additionally, with HL developing in fewer than 1 in 1,000 cases ) of infectious mononucleosis, additional factors must be required for the development of HL. Although studies of the relationship between EBV and HL continue , the role of EBV in the etiology of HL is unlikely to be resolved in the near future.
The idea that HL may represent an uncommon host response to a common agent has received additional support in a study of monozygotic and dizygotic twins. Monozygotic twins, who would be expected to have similar immune responses, had a 99-fold increased risk of being concordant for having HL, supporting a role for genetic susceptibility or abnormal immune response, or both, in the etiology of HL. If an abnormal immune response is related to the development of HL, one might expect an increased incidence of HL in immunodeficient patients, including those patients infected with the human immunodeficiency virus (HIV). Although the initial data were mixed, it has become clear that the incidence of HL is elevated in patients with HIV and acquired immunodeficiency syndrome (AIDS). An increased incidence of HL has beeoted in recipients of allogeneic bone marrow transplants Additionally, a patient has been reported with reversible methotrexate-associated lymphoproliferative disorder that eventually evolved into HL.
Histopathology
Accurate histopathology plays a critical role in the management of the patient with HL because the diagnosis of HL requires biopsy of an involved lymph node or, rarely, of an involved extranodal site. Fortunately for clinicians, concordance between pathologists regarding the diagnosis of HL is high, often exceeding 90% (35). HL can be confused with atypical inflammatory reactions that can occur in some patients with infectious mononucleosis (36) or in patients receiving diphenylhydantoin (37). An additional problem in HL relates to surgical sampling of nodes. Nodes showing only inflammation may be interspersed with nodes showing HL, and if the surgeon chooses which node to biopsy solely on the basis of simplifying the procedure, the diagnosis may be missed (38). In general, it is probably worthwhile to biopsy the largest node in a patient suspected of having HL or non-Hodgkin lymphoma (NHL). However, a notable exception to this occurs in patients with inguinal adenopathy, which may reflect reactive processes and provide misleading information. Whenever the diagnosis of HL or NHL is considered, the handling of the biopsy should be coordinated between the operating room and the hematopathology laboratory so that the tissue is processed in a manner that minimizes artifact and maximizes the opportunity to obtain a diagnosis.
The grouping of lymphomas into the mutually exclusive categories of HL and NHL gives the impression that these disorders are totally separate. However, although the distinction between HL and NHL is clear in the majority of cases, the boundary between the disorders is indistinct in some areas. Patients with chronic lymphocytic leukemia can develop large transformed cell lymphomas (Richter syndrome) that may resemble HL. The nodular subtype of lymphocyte-predominant HL may resemble low-grade non-Hodgkin lymphoma. Approximately one fourth of cases originally classified as lymphocyte-depleted HL were reclassified as NHL when present classification criteria were used. Studies of Ki-1–positive anaplastic large cell lymphoma illustrate that HL and this subtype of NHL have marked morphologic similarities. However, the majority of studies have shown that the gene rearrangement occurs only in anaplastic large cell lymphoma and not in HL.
Pathologically, HL is distinguished from other lymphomas by the presence of large binucleated or multinucleated cells (i.e., Reed-Sternberg cells) generally surrounded by a benign reactive host response consisting of lymphocytes, histiocytes, granulocytes, eosinophils, and plasma cells. Reed-Sternberg cells are large cells with abundant cytoplasm and generally contain two or more nuclei and two or more inclusionlike nucleoli. Variant forms of Reed-Sternberg cells exist, especially in the nodular sclerosis subtype of HL and the nodular form of lymphocyte-predominant HL. Reed-Sternberg cells are not absolutely specific for HL and have beeoted in cases of infectious mononucleosis and other malignancies including lymphoma, carcinomas, and sarcomas . Therefore, Reed-Sternberg cells are not sufficient to establish the diagnosis of HL because that diagnosis depends on the presence of both the characteristic Reed-Sternberg cells and the characteristic cellular environment in which the Reed-Sternberg cells are found. In addition to the use of standard hematopathologic criteria, immunostaining for CD15 (Leu-M1) and CD30 (Ki-1) may be helpful in confirming the diagnosis of HL. The neoplastic cells of HL, both classic Reed-Sternberg cells and Reed-Sternberg variants, tend to stain positively with these antibodies
The subclassification of HL depends in large part on the ratio of neoplastic to reactive cells. The Jackson-Parker classification, which is of historical interest only, was supplanted in 1966, by Lukes and Butler. This classification, modified that same year at the Rye Conference , divided HL into four categories: Lymphocyte predominance, nodular sclerosis, mixed cellularity, and lymphocyte depletion. Nearly all of the major clinical studies that form the basis of our present understanding of HL have used the Rye classification system.
The data are taken from one large tumor registry and three large series of referred patients and are subject to biases in the selection process. However, the general agreement among the series suggests that this is a fairly reliable estimate regarding the relative incidence of the subtypes of HL.
Because the subtypes of HL differ slightly with respect to common clinical features, the histopathologic subclassification of HL provides the clinician with some useful information. Lymphocyte-predominant HL is associated with the least tendency to have advanced disease and with the most favorable prognosis, whereas lymphocyte-depleted HL is associated with the greatest tendency to have advanced disease and the worst prognosis.
Myelodysplastic Syndrome
Myelodysplastic syndrome (MDS) is a form of hematopoietic hyperplasia and dysplasia with peripheral cytopenia. MDS originates from hematopoietic stem cell defects with multiple genetic abnormalities and clonal proliferation of hematopoietic cells, T lymphocytes, and clonal or polyclonal B lymphocytes. Several stages are identified: (1) refractory anemia (RA), with less than 5% blasts in the bone marrow; refractory anemia with ringed sideroblasts (RARS), with less than 5% blasts; refractory anemia with excess blasts (RAEB), with 5% to 20% bone marrow blasts; and refrac tory anemia with excess blasts in transformation (RAEB-T), with 20% to 30% bone marrow blasts and more than 5% blasts in the blood. Anemia and fatigue are early symptoms, followed by neutropenia, infections, thrombocytopenia, and bleeding. Bone marrow aspirates show a megaloblastic erythropoiesis with ring sideroblasts, increased myeloblasts, and hypolobulated megakaryocytes. Transition to acute myelogenous leukemia AMD occurs in 40% to 50% of advanced cases.
Osteomyelofibrosis
Chronic myeloproliferative diseases, clonal neoplastic disorders with variable myelofibrosis and a terminal blastic phase, include PCV, Osteomyelofibrosis, CML, and PTH (primary thrombcythemia). Osteomyelofibrosis, also referred to as agnogenic myeloid metaplasia, myelosclerosis, and idiopathic myeloid metaplasia, occurs primarily in older populations exposed to viral infections or toxic chemicals. Patients report fatigue, fever and night sweats, weight loss, upper abdominal fullness (splenomegaly, hepatomegaly), and bleeding. Peripheral blood shows “teardrop” poikilocytosis (dacry-ocytes), normoblasts, immature myeloid cells and megathrombo-cytes with the bone marrow in early hematopoietic hyperplasia, and predominance of megakaryocytes and granulocytes. Megakaryocytes include many pleomorphic giant forms with nuclear atypia, naked nuclei, and cytoplasmic fragments. Life expectancy varies according to risk factors (low Hb level and low WBC count) from 93 months to 13 months.
CHRONIC MYELOGENOUS LEUKEMIA
Chronic myelogenous leukemia (CML), another chronic myelopro¬liferative disease, is defined by myeloid hyperplasia, leukocytosis, basophilia, and splenomegaly. CML is associated with a characteris¬tic chromosomal translocation, the Philadelphia chromosome, which provides the mutated cells with a proliferative advantage. Clinical features are fatigue, weight loss, sweats, bone pain, anemia, hepatosplenomegaly, and petechial hemorrhages. An
initial chronic phase of CML (<10% blasts in bone marrow) is followed by an accelerated phase with final inevitable and fatal blast crisis (>30% blasts in the bone marrow with promyelocytes). Variants of CML include chronic myelomonocytic leukemia (CMML), which must be distinguished from MDSs. The life expectancy of p< tients with CML depends on disease progression and type of treatment; 45% to 65% of patients survive 5 years.
Primary Thrombocythemia
Primary thrombocythemia (PTH) is a chronic myeloproliferative disease with progressive megakaryocyte hyperplasia, peripheral thrombocytosis (>600,000/mL), splenomegaly, and hemorrhagic and thrombotic complications. The bone marrow contains partially clustered giant megakaryocytes and promegakaryocytes with mitoses, cytoplasmic fragments, and prominent emperipolesis (engulfment of a cell by a cell other than phagocytes). Clinical features may include hemorrhagic or thrombotic episodes or both headache, dizziness, paresthesias, and other neurologic symptoms. Microvascular occlusions cause microinfarcts in several organs and occasional digital gangrene. Large vessel thrombosis occurs most frequently in femoral, renal, coronary, gastrointestinal (Gl), and other arteries. In approximately 3% to 10% of patients, blastic transformation with features of myelogenous, myelomonocytic, megakaryocyte, or even lymphoblastic leukemia is reported. The 10-year survival rate for patients with PTH is 65% to 80%.
Acute Myelogenous Leukemia
Acute myelogenous leukemia (AML) is an acute myeloproliferative disease representing approximately 90% of all acute leukemias. Approximately 22% of cases develop in patients with MDSs. Patients usually present with malaise and fatigue, frequently after a flulike illness, and may have resistant skin infections, unusual pallor, and bleeding from the gums and the nose. Blood smears show leukopenia of 1000 WBCs/mL or excessive leukocytosis up to 200,000 WBCs/mL with increase in immature cells. The liver and the spleen are enlarged and infiltrated by atypical blasts. Additional symptoms result from metabolic and electrolyte derangements (hypokalemia, hypercalcemia), agranulocytosis (necrotizing enterocolitis), or rapid lysis of leukemic blasts (tumor lysis syndrome: urate nephropathy, hyperphosphatemia, muscle cramps, arrhythmias). Survival rates for all AML subtypes combined are 40% at 15 months and approximately 20% at 50 months
Acute myelogenous leukemia (AML)-MO and AML-M1 constitute the most immature types of AML and can be difficult to distinguish from acute lymphoblastic leukemia or monoblastic or megakary-oblastic leukemia. They present with more than 30% blasts with hardly any positive myeloperoxidase reaction. AML-MO cells are usually positive for terminal deoxynucleotidyl transferase (TdT) and CD34 (hematopoietic stem cell marker). AML-M1 types show approximately 10% promyelocytes, suggesting some myelopoietic differentiation. The prognosis is poor. AML-M2 shows signs ofmaturation beyond promyelocytes. There are more than 30% blasts, and promyelocytes account for 3% to 20% of leukemic cells with occasional maturation of eosinophils and basophils. Maturing cells contain intracytoplasmic red rodlike structures (Auer rods) and stain strongly for chloroacetate esterase and peroxidase enzyme activities. The 50% of patients who have t(8;21) chromosomal translocations have a slightly better prognosis than those without translocations.
Acute promyelocytic leukemia (AML-M3) is characterized by atypical promyelocytes in the bone marrow and hypergranular cells with multiple Auer rods (Auer bundles). Patients with M3 leukemia are generally younger (median age, 31 years) and have lower WBC counts than patients with more common leukemias. They frequently have coagulation disorders with hemorrhage and disseminated intravascular coagulation (DIC). There are diagnostic
chromosomal t(15q+;17q-) translocations, which cause a fusion of the retinoic acid receptor-a region on chromosome 17 to a region in chromosome 15 (PML-RARoc) and seem to account for a differentiation blockage of the myeloid lineage. Differentiation can be induced by administration of all-trans retinoic acid, with complete remission of disease in 70% to 85% of patients.
CD79a
