Acute leukemia is the abnormal clonal expansion of blood cell precursors. The abnormality may occur at different stages of maturation of the cell, and this explains the different types of leukemia. Acute leukemia is usually a rapidly progressive disease, although there are occasional patients whose disease remains stable for weeks or even months. In general, however, it is not the leukemic cells per se that cause the morbidity and mortality in this disorder, but a lack of normal blood cells, resulting in anemia, thrombocytopenia, and leukopenia. This is brought about by the leukemic cells “crowding out” the normal cells in the bone marrow. Other data suggest that especially myeloid leukemia cells have an inhibitory effect on normal marrow cells. This lack of normal cells may therefore lead to life-threatening hemorrhage and infection.

The primary classifications of acute leukemia are ALL and acute nonlymphocytic leukemia (ANLL, myeloid leukemia). The distinction is important because the therapy differs for each type (see answer to question 6). The overall ratio of ALL to ANLL is 1 : 6. ALL occurs most commonly in children, whereas ANLL more commonly affects adults.

The FAB classification (Table 7-1) is based largely on the morphologic and histochemical characteristics displayed by the leukemic cells, as well as on the nature of the cell surface antigens and cytogenetic features. This information may lead to changes in patient management, either by directing the course of therapy or by defining the prognosis better. Table 7-1 also includes molecular changes that may affect therapy, but more often affect response to therapy.

Certain genetic and environmental factors may predispose a person to acute leukemia. Many chromosomal alterations exist in the setting of the leukemias. The incidence of leukemia is increased in patients with congenital disorders associated with aneuploidy, such as Down syndrome, congenital

agranulocytosis, celiac disease, Fanconi syndrome, and von Recklinghausen’s neurofibromatosis.

Environmental factors implicated in the development of acute leukemia, particularly ANLL, include exposure to ionizing radiation and chemicals. Occupations and therapy that involve radiation exposure are known to increase the risk for acquiring acute leukemia. Chemicals, particularly the industrial use of benzene, and several therapeutic drugs (chloramphenicol, phenylbutazone, melphalan, chlorambucil, and others) are causal factors in acute leukemia. The findings from animal studies link certain viruses with acute leukemia; however, it is uncertain which viruses are actually an etiologic factor in human forms of leukemia, except for lymphomas caused by viruses that develop into a form of ALL.

The pretreatment evaluation should include the patient’s medical and work history, especially the nature of any radiation or chemical exposure. A physical examination should include the patient’s temperature, plus examination of the optic fundi, lymph node areas, oropharynx and gingivae, perianal area, and cranial nerves. Laboratory studies should consist of a complete blood count with differential (the physician should examine the smear), as well as a blood chemistry profile that includes the measurements of uric acid and lactate dehydrogenase (LDH). Bone marrow aspirates and biopsy specimens should be obtained, and investigations should include cytogenetic studies. A transfusion workup should include human lymphocyte antigen (HLA) typing. Lumbar puncture should be performed in all patients suspected of having ALL or ANLL-M4, and the cerebrospinal fluid specimen should be subjected to the usual studies, plus cytologic analysis. A dental examination should be performed.

In addition, the patient’s condition should be stabilized before antileukemic therapy is initiated. Hemorrhage and infection should be brought under control. Greatly elevated myeloblast counts (e.g., >50,000/mm³) that occur in the setting of ANLL can lead to pulmonary complications as well as fatal intracerebral leukostasis and hemorrhage. Cranial irradiation, hydroxyurea, and leukapheresis have all been used to decrease the numbers of circulating leukemic cells rapidly, and hence reduce the risk of complications. (Because of the physical properties of the lymphocytic leukemic cell, this is rarely a problem in patients with ALL.)

Renal damage stemming from urate nephropathy may exist at the time of presentation or may occur with therapy, therefore urine alkalinization may prevent the need for dialysis. Patients should receive allopurinol (300 to 600 mg) for at least 24 hours before therapy to reduce the uric acid load, and this treatment should be continued until leukopenia and bone marrow hypocellularity have been achieved.

These are the phases of therapy used for acute leukemia. Induction therapy is usually the initial therapy and is intended to accomplish complete remission (that is, no signs or symptoms of disease, normal blood counts, and no evidence of leukemia, i.e., <5% blasts in the bone marrow). This therapy is usually administered on an inpatient basis, and is very toxic. Consolidation therapy is given after complete remission is achieved. It is similarly toxic, and consists of either the same drugs as those used in induction therapy or different ones. Its object is to reduce the now clinically undetectable leukemic cell mass as much as possible. Maintenance therapy is usually given on an outpatient basis and is less toxic, although complications of therapy can and do arise. This phase usually lasts for 2 to 3 years. Meningeal prophylactic therapy is given by means of lumbar puncture or through a reservoir placed under the scalp that cannulates the third ventricle. Its goal is to reduce the recurrence rate of leukemia in the central nervous system (CNS), which is considered a sanctuary site.

All four therapy phases are used in ALL. In the treatment of ANLL, there is controversy over the use of maintenance therapy, although a second consolidation phase may be used. Meningeal prophylaxis is not used in the treatment of adult ANLL. However, CNS leukemia is more common in childhood ANLL, and prophylaxis is sometimes used in this setting. In general, the response to treatment and the prognosis are better in patients with ALL than in those with ANLL.

As already noted, acute leukemia is usually a rapidly progressive disease that is fatal without therapy. Because the therapy itself is toxic, the mortality rate during induction therapy for ANLL may reach as high as 20%. Some toxicities are specific to the drug used, and these are not discussed here. Nearly all therapies provoke nausea and vomiting, which can be controlled with medications. More significantly, antileukemic therapy is intended to deplete the bone marrow, with subsequent repopulation by normal cells. During this period of depletion, the patient becomes severely thrombocytopenic and must be supported by platelet transfusions (given prophylactically at various intervals to keep the platelet count above 10,000) and, usually, also by red blood cell transfusions.

Patients also become severely leukopenic, and this makes them very susceptible to infection. The typical signs and symptoms of infection (pus and purulent sputum) are often due to the actions of granulocytes, so infection is often subtle. The oral mucosa and perirectal areas are commonly overlooked sites of infection. Fever in a neutropenic patient must be considered infectious by origin, until proved otherwise. When this happens, examination and cultures should be carried out and broad-spectrum antibiotic therapy started quickly. Antifungal agents are usually added if no improvement is seen after 4 to 7 days of fever. The patient must be monitored carefully and treated for herpes virus infection because disseminated infection can be rapidly fatal.

If the leukemic cell burden is great, antileukemic therapy may precipitate the tumor lysis syndrome, caused by the rapid release of cell degradation products. It is characterized by hyperuricemia (causing urate nephropathy), hyperkalemia, hyperphosphatemia, and hypocalcemia. Advance recognition of patients at risk and subsequent treatment with vigorous hydration, allopurinol, and urine alkalinization 24 to 48 hours before the start of chemotherapy can usually prevent the syndrome. These patients must have their electrolyte, uric acid, phosphorus, calcium, and creatinine status repeatedly checked. Any metabolic abnormalities should be corrected and, if necessary, renal dialysis instituted early. Once the leukemic cell burden is decreased and degradation products cleared, the syndrome resolves.

Most children with ALL respond to therapy and achieve long-term survival. Although 90% of adults with ALL experience complete remission with initial therapy, the median remission duration ranges from 48 to 60 months, depending on the study. Median survival is 3 to 5 years. However, approximately one third of all patients achieve long-term disease-free survival. Late recurrences are rare.

Patients with ANLL face a worse prognosis. Approximately 75% experience complete remission, but most cases recur within 36 months. Of those who achieve complete remission, 20% to 25% show long-term disease-free survival. Bone marrow or stem cell transplantation with high-dose chemotherapy is often used, but is still under investigation as a therapy after the initial chemotherapy in ALL. The timing of transplantation (first remission, first relapse, or second remission), especially in ALL, is controversial. In ANLL, bone marrow transplantation (bone marrow rescue) with high-dose chemotherapy after a first remission has been associated with higher long-term survival rates. Older age (>40 years), use of unrelated donors, and evidence for residual disease at the time of transplantation reduce the efficacy of this treatment approach.

Anemia is usually defined as an abnormally low hematocrit or hemoglobin concentration, and occurs when the rate of erythrocyte loss exceeds the rate of erythrocyte production. The differential diagnosis of anemia depends on whether the MCV is low, high, or normal. Table 7-2 lists the various possible diagnoses for each of these categories. Sometimes with mild anemia, a diagnosis may be entertained if the MCV is in the high or low range of normal.

Peripheral blood smear examination can reveal erythrocyte abnormalities that point to the correct diagnosis of the anemia. Echinocytes, or burr cells, for example are seen in uremia and pyruvate kinase deficiency. Elliptocytes are the abnormal erythrocytes seen in patients with hereditary elliptocytosis.
Nucleated red cells are found in the setting of stress or hematologic disease with bone marrow involvement. Schistocytes or fragments occur in patients with microangiopathic hemolytic anemia. Sickle cells are found in the setting of sickle cell anemia. Spherocytes occur in immune-mediated hemolytic anemia and hereditary spherocytosis. Target cells form in the presence of liver disease and iron deficiency; they also occur after splenectomy.

A reticulocyte is a young circulating red blood cell that exhibits basophilia under vital staining. The reticulocyte count is used to characterize the bone marrow’s attempt to compensate, if at all, for the anemia present. The reticulocyte index (Table 7-3) is a more useful means of characterizing anemia because it is determined by correcting the reticulocyte count for the hematocrit, assuming a normal hematocrit is 45%. This correction is necessary because reticulocytes are counted per 1,000 red blood cells.

An index of less than 2 is found in the setting of the hypoproliferative anemias. These consist of disorders of heme or globin synthesis, such as iron deficiency, anemia stemming from chronic disease, lead poisoning, sideroblastic anemias, and α, β, and other thalassemias; megaloblastic anemias resulting from cobalamin or folate deficiency; myelodysplastic syndromes; aplastic anemias; and other metabolic causes, such as renal insufficiency and hypothyroidism.

Hyperproliferative anemias are associated with a reticulocyte index greater than 2. These anemias arise as the result of acute blood loss; nutrient replacement, such as cobalamin, folate, or iron replacement, but before the resolution of anemia; both hereditary and acquired hemolysis; and primary or secondary polycythemia.

Automated reticulocyte counts introduced for general clinical practice are more accurate than “hand counts” and automatically calculate the reticulocyte index. These automated values also include the total number of reticulocytes, a measurement that might be helpful when obtaining serial values.

The α-thalassemias constitute abnormalities of the gene, or genes, responsible for the synthesis of the α chain of hemoglobin. Humans contain four genes for this purpose and each is responsible for approximately a fourth of the α chains synthesized. Any combination of from one to four of these α genes may be missing. Thalassemia is unapparent clinically when only one gene is missing, and this is called α₁-thalassemia. This defect exists in up to 30% of the American black population. If two of the α genes are missing, the entity is referred to as α₂-thalassemia. These patients are usually asymptomatic, although their hematocrit and MCV may be slightly low. This defect affects approximately 2% of African Americans. When three of the α genes are lacking, the patient exhibits the phenotype of α-thalassemia (Hemoglobin H disease) with a low hematocrit and MCV, and β-chain tetramers or hemoglobin H is found in the red blood cells. When all four α genes are missing, the result is usually a stillborn infant with hydrops fetalis.

α-Thalassemia is the most common form of thalassemia in the Southeast Asian population.

The β-thalassemias consist of abnormalities of the gene, or genes, responsible for the β chain of hemoglobin, and they cause insufficient β-chain synthesis. This leads to the formation of α-chain tetramers and inclusions of this hemoglobin attached to the plasma membranes of erythrocytes, resulting in hemolysis. Patients with heterozygous β-thalassemia exhibit a modest decrease in their hematocrit values and a marked decrease in their MCVs. Patients with homozygous β-thalassemia have severe anemia and low MCVs. They require transfusion, and complications may arise stemming from the excess accumulation of iron.

Electrophoresis may be used to suggest the diagnosis of α-thalassemia in patients missing three genes, and thereby having sufficient fast-migrating hemoglobin H (α_l– and α₂-thalassemia traits may not be detected). The precise number of missing α genes can be determined in hybridization studies through the use of a complementary DNA probe.

The findings yielded by hemoglobin electrophoresis are usually diagnostic in the setting of β-thalassemia. Because α-chain synthesis is normal in these patients, the other hemoglobins seen in adults, including hemoglobin A₂ and F, are increased in a compensatory manner. Therefore, patients with heterozygous β-thalassemia would have elevated hemoglobin A₂ and F levels with hemoglobin A present. Patients with homozygous β-thalassemia would have no hemoglobin A and markedly elevated hemoglobin F and A₂ levels.

Sickle cell disease is the most commonly recognized clinically significant hemoglobinopathy. It stems from a substitution of valine for glutamic acid in the β chain of hemoglobin and can be diagnosed by electrophoresis. Sickle cell anemia results when both β chains are abnormal. Sickled cells should be evident on
a peripheral blood smear. Hemoglobin S is less soluble than normal hemoglobin at a low oxygen tension, causing the hemoglobin molecules to crystallize, which deforms the red blood cells. These misshapen cells greatly increase the blood viscosity, which leads to small-vessel occlusion and hence pain and organ infarctions, specifically stroke as well as pulmonary, renal, and bone infarction.

Sickle cell disease may be manifested by a variety of crises: Pain is the most common symptom, and is thought to be secondary to red blood cell sludging and infarction. Splenic sequestration and dactylitis are common in children, but rare in adults. Aplastic anemia is uncommon, but is typically associated with infections, and is anticipated when reticulocyte counts decrease in the face of worsening of anemia. Megaloblastic anemia is usually secondary to folate deficiency, and arises because abnormal cells have a shortened life span. This increases the turnover of red blood cells and places an increased demand on folate stores. Sickle cell patients who enter with pain crisis or “chest syndrome” are at risk for multiorgan failure. When it becomes apparent that liver, kidney, and/or pulmonary function are declining, these patients should be considered for exchange transfusion.

The sickle cell trait is almost always asymptomatic because only one of the two β chains is abnormal. It can also be diagnosed by electrophoresis, and this is most important for the purposes of genetic counseling.

The coagulation system is quite complex, but can be viewed as consisting of at least three major components: the vascular endothelium, the blood
coagulation proteins (both those that promote clotting and those that lyse clots by means of the fibrinolytic system), and the platelets. The coagulation cascade represents a series of proteins that, when initiated, forms a fibrin clot. A simple outline of the cascade is shown in Table 7-4. Complex issues such as the exact mechanisms by which anticoagulants, such as protein C and protein S, function and how factor VII may activate factor IX are not completely understood.

Vascular endothelial integrity can be assessed using the bleeding time. In this test, a nick is made in the skin under standardized conditions, and the time to cessation of bleeding is measured.

The blood coagulation proteins are usually evaluated by in vitro studies using the patient’s citrate-anticoagulated plasma. This is done by adding back various components of the coagulation cascade to the patient’s plasma to induce clot, and the procedure is standardized against plasma from an individual with normal plasma coagulation components. The two most common tests for doing
this are the prothrombin time (PT) and the partial tissue thromboplastin time (PTT). The PT measures the extrinsic pathway of the coagulation cascade, and this is done by adding tissue thromboplastin to the patient’s plasma. If there is a deficit in any of the common pathway components or factor VII, the clotting time is prolonged abnormally. The PTT measures the intrinsic and common pathways; a deficit in the common or intrinsic pathway proteins results in a prolonged PTT. A third, less commonly used, screening test is the thrombin time, which measures only the last step in the cascade— the conversion of fibrinogen to fibrin— and is done by adding thrombin to the patient’s plasma. Therefore, if the patient has too little fibrinogen or a dysfunctional fibrinogen protein, the time is prolonged. Finally, each of the components of the cascade, including factors I to XIII, can be assayed directly to evaluate for deficits.

Platelets can be evaluated both quantitatively (by the platelet count) and functionally. Platelet function can be assessed by the bleeding time; qualitatively defective platelets do not form an adequate platelet plug and the bleeding time is prolonged. In addition, platelets can be analyzed in vitro for their aggregability using platelet stimulants (e.g., ristocetin).

The vascular endothelium may be fragile in the setting of several acquired conditions, including vasculitis and long-term steroid use. This is important to realize because it may cause the bleeding time to be prolonged despite normal platelet number and function.

Deficits in the blood coagulation proteins may be congenital or acquired. The most common congenital disorders consist of deficiencies in factor VIII (hemophilia A) or factor IX (hemophilia B, or Christmas disease), which are inherited in an X-linked manner. Another common congenital disorder is von Willebrand’s disease, in which there is a deficit in von Willebrand’s factor. This factor is bound to factor VIII and is necessary for both platelet function and for clotting to take place by the intrinsic pathway.

Deficiencies in various factors can be acquired when their production is antagonized, as occurs with sodium warfarin (Coumadin; DuPont Pharma, Wilmington, DE) therapy, a substance that inhibits the production of activated vitamin K–dependent factors (factors II, VII, IX, X, and protein C and S). Another common situation that causes deficiencies in various factors is liver disease; because the liver is the site for the synthesis of nearly all the coagulation factors, severe liver disease results in deficient production of factors. Malnutrition, malabsorption, and liver disease can all lead to a deficit in vitamin K, with a subsequent deficit in the vitamin K–dependent factors. Finally, the overwhelming consumption of all factors can result in a coagulopathy, as occurs in disseminated intravascular coagulation (DIC).

The platelet population can be depressed because of either underproduction or excessive destruction. Underproduction occurs as a consequence of bone marrow suppression (brought about by chemotherapy, infections, drugs, or infiltration with other cells, such as occurs in the setting of leukemia or
cancer). Excessive destruction can occur in the setting of an enlarged spleen (sequestration), bleeding (consumption) or consumptive disorders (DIC or thrombotic thrombocytopenic purpura/hemolytic uremic syndrome), and on an autoimmune basis [idiopathic thrombocytopenic purpura (ITP)].

Qualitative defects can be congenital, but are more often acquired and due to drug exposure (aspirin, nonsteroidal antiinflammatory drugs, and some antibiotics) or uremia.

Although any of the bleeding disorders may result in excessive hemorrhage associated with such events as surgical procedures, trauma, or gastrointestinal bleeding, each displays some characteristic features. Vascular fragility is typically associated with subcutaneous ecchymoses. Plasma coagulation protein deficiencies in patients with hemophilia are associated with spontaneous soft tissue and joint bleeds. Other plasma factor deficiencies, as well as platelet deficits, are associated with diffuse ecchymoses (cutaneous and soft tissue). Platelet deficits are also manifested by petechiae (small capillary hemorrhages in mucosal surfaces and areas of increased hydrostatic pressure, such as the ankles and feet) and purpura (larger areas of hemorrhage). Von Willebrand’s disease is unique in that it may present with both soft tissue bleeding (factor VII deficiency) and mucosal bleeding (platelet dysfunction).

Evaluation of the bleeding patient begins with a good history taking. It needs to be determined if the condition is of long standing or is new. Questions about previous bleeding episodes (nosebleeds, bruising, menstrual flow, bleeding with trauma, surgery, and delivery) as well as family history are vital for determining the nature of the disorder. A careful drug history, including over-the-counter drug use, must be taken. The patient’s medical history and a review of symptoms may reveal evidence of autoimmune disorders or intercurrent illness.

Physical examination is important in evaluating the sites of bleeding (cutaneous, mucosal, soft tissue, or joint bleeding sites, as well as petechiae). An enlarged spleen and evidence of liver disease (e.g., spiders or hemangiomata) or malnutrition should be sought, and the patient’s overall medical condition should be assessed.

A screening for bleeding disorders should include a platelet count, PT, and PTT; if any of these results are abnormal or if there is evidence of mucosal bleeding, determination of a bleeding time may also be indicated.

If the PT or PTT is prolonged, the next step in the evaluation should be a 1:1 mix in which the patient’s plasma is mixed with normal plasma and the PT and PTT are determined again. If the patient is deficient in some factor, the normal plasma partially corrects this deficiency and the PT or PTT are corrected to a normal value. If an inhibitor to a particular factor is present, this inhibitor also blocks the action of the normal plasma, and the PT or PTT are not corrected. The most common inhibitor is the lupus anticoagulant, which is seen in the presence and absence of autoimmune disease; it is usually
associated with an elevated PTT that is not corrected with a 1:1 mix. It is associated with an increased risk of clotting, not bleeding.

If the platelet count is very low (20,000/mm³) and the PT and PTT are normal, a bone marrow biopsy may be indicated to determine whether there are adequate platelet precursors in the bone marrow. If platelet precursors are absent, an underproduction state exists; if precursors are present, this implies that the low platelet count stems from peripheral destruction. Using the detection of antiplatelet antibodies as evidence for the autoimmune destruction of platelets is not reliable because some normal people have antiplatelet antibodies without peripheral destruction, whereas the titers in people with ITP may be low.

Blood components can be used to correct deficiencies in the divisions of the coagulation system. Fresh frozen plasma contains various percentages of each of the coagulation proteins and can be used when more than one factor is deficient (e.g., vitamin K–dependent factors). Cryoprecipitate contains von Willebrand’s factor, fibrinogen, and factor VIII, but is most commonly used in people with an acquired fibrinogen deficiency (e.g., DIC and liver disease). Because of the risk of viral infection (it is pooled from multiple donors), cryoprecipitate is no longer used as frequently for patients with mild hemophilia and von Willebrand’s disease. Instead, desmopressin (DDAVP) is now used in the treatment of these diseases, as well as in the platelet dysfunction associated with uremia and other qualitative defects. This drug works by stimulating the release of von Willebrand’s factor (factor VIII) from the endothelium. There are also specific heat-treated factor concentrates for factors VIII and IX, which can be used in the management of hemophilia.

Quantitative platelet problems caused by underproduction, as well as some consumptive states such as uncontrolled bleeding, can be treated with platelet transfusions. This is often futile in the setting of autoimmune destruction until the autoimmune process is arrested; in fact, platelet transfusion may accelerate destruction by stimulating the immune system. The usual initial treatment for ITP is with high-dose prednisone, followed by splenectomy if the prednisone fails to block the immune destruction. Transfusing platelets into a patient who has uremia or who is taking a drug that renders his or her own platelets dysfunctional is also futile because the transfused platelets quickly become affected as well.

Breast cancer is the most common neoplasm in women, with an incidence that continues to rise and currently stands at 1 in 10 women. The incidence rises dramatically with age.

Breast cancer is considered to be a systemic disease from the time of diagnosis, regardless of the stage. The average doubling time varies from 23 to 500 days. Therefore, a 1-cm tumor may have existed for 2 to 17 years before diagnosis.

Despite local control, affected patients continue to die at a rate faster than that seen in age-matched control subjects for the first 30 years after treatment. In addition, patients dying from any cause are found to have evidence of tumor at autopsy. The most common sites of distant metastases are the bone, liver, and lung.

Paraneoplastic conditions that may be associated with breast cancer include hypercalcemia, neuromuscular disorders, dermatomyositis, acanthosis nigricans, and hemostatic abnormalities.

Common secondary malignancies in patients with breast cancer consist of cancer in the opposite breast, ovarian cancer, and colorectal carcinoma.

High-risk factors (threefold or greater increase) for the development of breast cancer are:

Intermediate-risk factors (1.2- to 1.5-fold increase) for the development of breast cancer consist of menstruation (either early menarche or late menopause); oral estrogen with progesterone therapy; alcohol consumption; diabetes mellitus; history of cancer of the uterus, ovary, or colon; and obesity.

Women older than 20 years should perform breast self-examination every month. Premenopausal women should examine their breasts 5 to 7 days after the end of their menstrual cycle, and postmenopausal women should do this on the same day of every month.

Women should have their breasts examined by a physician every 2 to 3 years between the ages of 20 and 40 years and annually thereafter. The American Cancer Society and other agencies have recommended that a baseline mammogram should be obtained between the ages of 35 and 39 years, with mammograms obtained every 1 to 2 years in women aged 40 to 49 years and then yearly after the age of 50 years.

The TNM (primary tumor, regional nodes, metastases) classification and the various stages of breast cancer are outlined in Table 7-5.

Table 7-6 summarizes the 5- and 10-year survival statistics associated with the various TNM stages. These statistics do not take into account results of adjuvant chemotherapy, but are useful in designing trials using adjuvant chemotherapy.

The patient’s hormonal status also has a bearing on her prognosis, in that estrogen- and progesterone receptor-positive tumors possess a 70% to 85% chance of responding to hormonal therapy; those women with only one-receptor positivity have exhibited a slightly lower response rate to hormone manipulation. Women with receptor-negative tumors do not respond to hormone manipulation.