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Chapter X.12. Lymphangiomas John J. Chung, MS, MPH This newborn male infant was born to a 30 year old G1P1 mother at 40 weeks gestation via cesarean section. Prenatal ultrasonography performed at 32 weeks gestation revealed a 1 cm x 1 cm x 1 cm hypoechoic but nonseptated mass in the posterior neck. An encephalocele or meningocele were deemed unlikely and the infant was suspected of having a cystic hygroma (a type of lymphatic malformation). No evidence of fetal hydrops or other congenital anomalies were noted. The pregnancy is closely monitored with detailed serial ultrasounds for the duration of the pregnancy. At term, the hypoechoic lesion is 2 cm x 1 cm x 2 cm. While there is still no indication of hydrops fetalis by ultrasonography, a cervical cystic mass could obstruct a vaginal delivery and the mother is advised to undergo a cesarean section. Upon delivery, Apgar scores are 8 and 9 at 1 and 5 minutes. VS T 37.5, HR 110, R 60, BP 51/25, weight 3.3 kg (50th %ile), length 51cm (50th %ile). His head is normocephalic with no evidence of additional cystic masses. Eyes, ears, nose and mouth are all normal. A 2 cm wide mass is noted in the posterior neck. Heart, lung, abdomen, extremity, skin and neurologic examinations are normal. He begins to breast feed normally. Imaging studies fail to demonstrate any other cysts. Because nuchal cysts can grow to obstruct the trachea or esophagus, most of the cyst is surgically excised. Histology of the cyst shows only lymphatic tissue, confirming the diagnosis of a cystic hygroma. Because of its proximity to nerves, the cystic hygroma tissue could not be completely removed. By 12 months of age, local recurrence of the cystic hygroma is evident. Options for recurrent and unresectable lymphangiomas, such as drug sclerotherapy, were discussed with his parents. They are also informed of the possibilities of infection, hemorrhage, and continual recurrence despite treatment. Lymphangiomas or lymphatic malformations (LM) are defined as isolated regions of lymphatic tissue which are thought to occur after the 6th week of gestation, when developing lymphatic tissue fails to properly anastomose (1,2,3). Lymphatic tissue can also improperly anastomose with capillaries, veins, and arteries (4). These isolated regions of lymphatic tissue function to absorb interstitial fluid and enlarge as lymph fluid continues to accumulate with time (3). Depending on their location and size, lymphatic malformations can be benign and asymptomatic or they can press against nerves, organs, or obstruct circulation (4). For example, lymphangiomas in the head and neck can cause airway obstruction, and alter speech and/or mastication (3). The true incidence rate for lymphatic malformations is uncertain, since small ones may not be very evident. The most common lymphatic malformation, cystic hygromas, have an estimated incidence of 1:875 among miscarriages (3). By comparison, hemangiomas are much more common and occur in as many as 10% of 1 year olds (5). Lymphatic malformations are found equally in boys and girls (5). Lymphatic malformations are commonly diagnosed in infancy with more than half of the cases identified prenatally or postpartum and more than 90% diagnosed by the 2nd or 3rd year of life (4,6). Lymphatic malformations rarely regress after birth but can remain asymptomatic until later in life when trauma or infections can cause lymphatic malformations to rapidly grow and interfere with other structures (7). Seventy-five percent of lymphatic malformations are found in the head and neck but lymphatic malformations can occur anywhere (1). Generally, the most common sites are in the head and neck, mediastinum, axilla, and abdomen (1). Lymphangiomas that are microcystic superficial lesions of the skin or mucous membranes have many names: lymphangioma simplex, lymphangioma circumscriptum, capillary lymphangioma and angiokeratoma circumscriptum (4,9). Deeper lymphangiomas can be either microcystic (cavernous lymphangiomas), macrocystic (lymphangioma cystoides, cystic hygromas, or cystic lymphangiomas), or mixed microcystic- macrocystic (4,9). The etiology of lymphangiomas is unknown (10). However, cystic hygromas have been found to be associated with chromosomal abnormalities such as Turner syndrome and Down syndrome (2,3). Chromosomal abnormalities are usually associated with other congenital findings such as mental or developmental retardation, heart defects, or alterations in the development of sexual characteristics at puberty. Diagnosis is principally made on the basis of clinical appearance and imaging. For example, capillary lymphangiomas or lymphangioma simplex are superficial white, purple, or red papules that appear wartlike (9). Such superficial lymphangiomas are usually asymptomatic but can become infected. They can occasionally bleed when the superficial lymphangioma is in communication with ruptured blood vessels. Lymphangioma circumscriptum are superficial clusters of papules that are said to look like frog eggs (9). Lymphangioma circumscriptum is also found in skin or mucous membrane but extend deeper into the dermis than lymphangioma simplex (9). Cavernous lymphangiomas usually involve the skin or mucous membranes but they extend deeper into muscle where they form small, thin-walled, lymph fluid filled spaces referred to as microcysts (9). Cystic lymphangiomas or cystic hygromas are large, well-circumscribed, loculated, lymph fluid-filled spaces (macrocysts) (3,9). Large loculated cysts tend to occur in areas where expansion is possible such as the deep lymph vessels in the neck and head or near other organs. These deep lymphangiomas can be asymptomatic or they can present with signs and symptoms associated with serious complications. Cystic hygromas, usually identified prenatally or antenatally, are especially serious. Considerable lymphedema can accompany growing cystic hygromas which can sometimes lead to hydrops fetalis and intrauterine fetal demise (IUFD) or early perinatal neonatal death (early PND) due to circulatory failure (3). Additionally, the size and position of the cyst may complicate vaginal delivery (3). When aspirated, the cystic space fluid includes proteinaceous fluid with few lymphocytes (1). MRI findings are important in distinguishing between lymphangiomas and other vascular malformations (1). Arterial or venous vascular malformations enhance with contrast during MRI contrast studies, while lymphatic malformations do not. CT scans can also help differentiate venous malformations from lymphangiomas as well as help identify hemorrhages. Plain film radiographs can identify associated skeletal deformities. Ultrasound imaging is particularly useful during the perinatal/neonatal period (4). Specimen biopsies of superficial lesions show typical lymphatic vessels lined by well differentiated, flat, endothelial cells (3,8). Deeper lesions show dilated and interconnected lymph vessels that can form loculations (3). The differential diagnosis includes lymphadenitis, other congenital vascular malformations (hemangiomas, branchial cleft cyst, cellulitis, dermoid cyst), and tumors. Bloody lymphangiomas are often easily confused with hemangiomas or Kaposi's sarcoma (4). Because of the variable location of lymphangiomas, the differential diagnosis should also include site-specific pathologies. For example, the differential diagnosis of a nuchal cystic hygroma should include encephalocele or meningocele, and tumors of the head and neck (3). Small superficial lymphangiomas are generally left untreated if asymptomatic (1). Cystic hygromas identified in a fetus are especially concerning. The fetus is assessed for additional abnormalities that would increase the risk of fetal death or poor postpartum prognosis such as chromosomal abnormalities, hydrops fetalis, and large cyst volumes (2). These factors are important in whether or not the fetus is aborted or delivered vaginally or by cesarean section. In the U.S., deep lymphangiomas such as cystic hygromas and larger superficial lymphangiomas are surgically excised (1,3,6). However, surgical excision is difficult because of the delicate nature of thin- walled lymphatic tissue and the close proximity of lymphatic malformations to nerves, organs, and blood vessels (3,6). As a consequence, complete excision is possible in less than a third of the cases (6). Incomplete excision does eliminate the space occupying effects of the lesion but are complicated by a high risk of recurrence and infection (3). In sclerotherapy, drugs including bleomycin, OK-432 (derivative of low virulence Group A streptococcus pyogenes), and fibrin adhesives are used to stimulate sclerosis and regression (6). In the U.S,. sclerotherapy is generally reserved for recurrent or unresectable lymphangiomas but, in some small studies, sclerotherapy agents have been used in place of surgical excision with good results (3,6). Sclerotherapy complications include ulcers, scarring, and recurrence of lymphangiomas (3,7). Other treatment options include interferon- alpha treatment (7), laser ablation or radiation treatment. Radiation treatment carries a number of complications and is usually reserved as a treatment of last resort (7). Chapter XI.1. Anemia Darryl W. Glaser, MD A 22 month old boy presents to your office with a chief complaint of pallor. A visiting relative who has not seen the child for 5 months told his mother that the boy appears pale. The mother brings him in for a checkup even though she notices no change in his coloring (he has always been fair skinned). On review of symptoms you find that he is an active toddler, with no recent fatigue, exercise intolerance, or increase in sleeping. He has had no blood in his diapers and no black or tarry stools. He is a picky eater, taking small amounts of chicken, pork and some vegetables, but loves milk and drinks six to eight bottles of whole milk per day. Family history reveals a distant aunt who had anemia when she was pregnant but which subsequently resolved. There is no history of splenectomy, gall stones at an early age, or other anemia in the family. Page - 407 Exam: VS: T 37.5, BP 90/52, P 145, RR 16, Height 85.5 cm (50th %ile), Weight 13.2 kg (75th %ile). General appearance: He is a pale appearing, active toddler, holding a bottle, tearing and eating paper from Chapter XI.1.Eyes: Anemia your exam table. No scleral icterus. Pale conjunctiva. Mouth: Dental caries. Chest: Clear. Heart: Mild Darryl W. Glaser, MD II/VI systolic ejection murmur heard best over the upper left sternal border. tachycardia as above, grade Abdomen: Nomonth hepatosplenomegaly. Rectal: Dark brown, soft stool, negative forrelative occultwho blood. A 22 old boy presents to your office with a chief complaint of pallor. A visiting has not seen the child for 5 months told his mother that the boy appears pale. The mother brings him in for a checkup even though she notices no change in his coloring (he6,100, has always skinned). On review symptomsMCV you find is an active with no recent fatigue, CBC: WBC Hgbbeen 6.2fair g/dl, Hct 19.8%, Pltof589,000, 54that fL,heRDW 17%.toddler, Reticulocyte count is exercise intolerance, increase microcytosis, in sleeping. He has had no blood inmild his diapers and no black tarry stools. He is There a picky is eater, 1.8%. The laborreports hypochromia, anisocytosis andorpolychromasia. no taking small amounts of chicken, pork and some vegetables, but loves milk and drinks six to eight bottles of whole milk per day. basophilic stippling. Family history reveals a distant aunt who had anemia when she was pregnant but which subsequently resolved. There is no history of splenectomy, gall stones at an early age, or other anemia in the family. Exam: diagnose VS: T 37.5,iron BP 90/52, P 145, RR 16, Height cmiron (50thand %ile), Weight (75th %ile). appearance: He is a You correctly deficiency anemia, start85.5 oral limit his 13.2 milkkgintake. YouGeneral see him in 3 pale active toddler,and holding a bottle,is tearing paper from yourcount exam 17%. table. Eyes: scleral Pale in conjunctiva. days toappearing, assure compliance his RDW 27%and andeating his reticulocyte WhenNoyou seeicterus. him back Mouth: Dental caries. Chest: Clear. Heart: Mild tachycardia as above, grade II/VI systolic ejection murmur heard best over the upper twoleft weeks mother is amazed at his new interest in table Hgb negative is now for 8.5occult g/dl,blood. and his MCV sternalhis border. Abdomen: No hepatosplenomegaly. Rectal: Darkfoods. brown, His soft stool, 64 fL. Two months later his hemoglobin has completely normalized, and you continue iron CBC: WBC 6,100, Hgb 6.2 g/dl, Hct 19.8%, Plt 589,000, MCV 54 fL, RDW 17%. Reticulocyte counttherapy is 1.8%. for The lab reports microcytosis, hypochromia, mild anisocytosis and polychromasia. There is no basophilic stippling. three more months. You correctly diagnose iron deficiency anemia, start oral iron and limit his milk intake. You see him in 3 days to assure compliance and his RDW is 27% and his reticulocyte count 17%. When you see him back in two weeks his mother is amazed at his new interest in Anemia occurs when the red blood cell mass or hemoglobin content is too low to meet a person's table foods. His Hgb is now 8.5 g/dl, and his MCV 64 fL. Two months later his hemoglobin has completely normalized, and you continue physiologic In children, iron therapydemands. for three more months. "normal" levels vary with age, gender, and geographic location (height above sea level). A summary of normal values is listed below (1): Anemia occurs when the red blood cell mass or hemoglobin content is too low to meet a person's physiologic demands. In children, "normal" levels vary with age, gender, and geographic location (height above sea level). A summary of normal values is listed below (1): Table 1. Lower limit (3rd %ile) of normal hemoglobin (Hgb column) and lower (3rd %ile) and upper (97th %ile) limit of normal MCV andhemoglobin sex (1) (M=males, Table 1. Lower limit (3rd %ile)by ofage normal (Hgb column)F=females). and lower (3rd %ile) and upper (97th %ile) limit of normal MCV by age and sex (1) (M=males, F=females). Age 1-4 5-7 8 - 10 12 - 14 15 - 17 Over 18 Hgb (g/dl) 11.2 11.5 11.8 12 12 (F), 13 (M) 12 (F), 14 (M) Lower MCV limit 72 75 76 76 78 80 Upper MCV limit 85 87 89 89 92 95 Signs of anemia include pallor of the skin, conjunctiva, and mucus membranes, tachycardia, orthostatic hypotension, heart murmur and of edema. Symptoms may include headache, dizziness and and dyspnea. Other signs andtachycardia, symptoms depend on the cause for anemia, Signs anemia include pallor offatigue, the skin, conjunctiva, mucus membranes, orthostatic such as jaundice, urine, orand splenomegaly in hemolytic may anemias (2). fatigue, headache, dizziness and dyspnea. hypotension, heartdark murmur edema. Symptoms include When the diagnosis of anemia is suspected based on signs and symptoms, it can quickly be confirmed by laboratory evaluation. Other and symptoms dependthe onetiology, the cause forcan anemia, such asdue jaundice, darkofurine, splenomegaly Thesigns more difficult task is determining which appear daunting to the myriad causesor of anemia in children. Testing in hemolytic anemias (2). for all these causes at once would be inefficient, time consuming, and expensive. It is, in fact, unnecessary because the differential diagnosis can be narrowed significantly by careful history, thorough examination, and use of various classification schemes. When the diagnosis of anemia is suspected based on signs and symptoms, it can quickly be confirmed by History laboratory evaluation. The more difficult task is determining the etiology, which can appear daunting due to 1) Has there been a sudden onset of pallor, fatigue, or exercise intolerance? Rapid onset of symptoms suggests a more acute the anemia, myriadwhile of causes anemia in children. Testing forchronic all these causes at once would inefficient, time anemia of without symptoms may indicate a more process, allowing the body morebe time to compensate for the low hemoglobinand levels. Note that the presence of symptoms does because not necessarily reflect the level of anemia.can A child whose Hgb drops from consuming, expensive. It is, in fact, unnecessary the differential diagnosis be narrowed 14 to 10 overby one week may be quitethorough symptomatic, while the child in our presentation was virtually asymptomatic significantly careful history, examination, and usecase of various classification schemes. dropping to a Hgb of 6.2 over a period of months. Pallor unrecognized by the patient's day to day caretaker also suggests a gradual process. 2) Any history of blood loss? Obtain a menstrual history. Prolonged, heavy periods are a source for acute blood loss. Over time chronic loss can lead to iron deficiency, especially when superimposed on poor dietary iron intake. 3) Did the child have jaundice in the newborn period or episodes of jaundice in the past? Glucose-6-phosphate dehydrogenase deficiency (G6PD) and hereditary spherocytosis will cause recurrent episodes of jaundice and anemia, especially following illness or stress. 4) Describe the child's diet. When did he start whole milk? How much milk does he drink now? Excessive milk intake with inadequate dietary iron is a common cause of iron deficiency anemia in toddlers. Does he eat anything unusual (paper, dirt) or chew on ice? Pica suggests iron deficiency and can predispose to lead poisoning. History 1) Has there been a sudden onset of pallor, fatigue, or exercise intolerance? Rapid onset of symptoms suggests a more acute anemia, while anemia without symptoms may indicate a more chronic process, allowing the body more time to compensate for the low hemoglobin levels. Note that the presence of symptoms does not necessarily reflect the level of anemia. A child whose Hgb drops from 14 to 10 over one week may be quite symptomatic, while the child in our case presentation was virtually asymptomatic dropping to a Hgb of 6.2 over a period of months. Pallor unrecognized by the patient's day to day caretaker also suggests a gradual process. 2) Any history of blood loss? Obtain a menstrual history. Prolonged, heavy periods are a source for acute blood loss. Over time chronic loss can lead to iron deficiency, especially when superimposed on poor dietary iron intake. 3) Did the child have jaundice in the newborn period or episodes of jaundice in the past? Glucose-6phosphate dehydrogenase deficiency (G6PD) and hereditary spherocytosis will cause recurrent episodes of jaundice and anemia, especially following illness or stress. 4) Describe the child's diet. When did he start whole milk? How much milk does he drink now? Excessive milk intake with inadequate dietary iron is a common cause of iron deficiency anemia in toddlers. Does he eat anything unusual (paper, dirt) or chew on ice? Pica suggests iron deficiency and can predispose to lead poisoning. 5) Has anyone in the family ever had anemia or low blood counts, or ever been on iron? This may suggest a hereditable cause of anemia, but is not diagnostic. A positive response may simply reflect dietary patterns in siblings. It is quite common for families to recall at least one relative who was anemic at some time, especially during pregnancy. Ask if they are still receiving treatment or if the condition resolved. Also remember that a negative family history does not exclude an inherited anemia. 6) Has anyone in the family ever had their spleen taken out or had gallstones at an early age? Surprisingly, not all patients know the reasons for past procedures, or may have been too young when they occurred. A positive response suggests a family history of a hemolytic anemia (such as hereditary spherocytosis). A negative response does not rule out these causes. 7) What is the child's ethnic origin? Hemoglobinopathies (e.g., sickle cell anemia), thalassemias, and G6PD deficiency are more common in certain ethnic groups. Physical Examination Compare the child's color to his siblings or both parents. Is he active and playful or fatigued? Tachycardia and heart murmur are common in children with anemia, but look for signs of heart failure including tachypnea, rales, hepatomegaly or edema. Splenomegaly may indicate immune hemolytic anemia or hereditary spherocytosis. Look for any skeletal abnormalities as can be seen with the congenital bone marrow failure syndromes. Two classification schemes are frequently employed to narrow down the differential diagnosis in anemia. The first uses the MCV to classify the size of the red blood cell as microcytic, normocytic, or macrocytic. Although it can be quite helpful, the system is imperfect. Since MCV values in children vary with age, the age specific MCV values must be used (See Table 1). Even so, certain conditions do not fit neatly into one category. The anemia of inflammation/chronic disease and of lead poisoning can be microcytic or normocytic, and the anemia seen with liver failure can be normocytic or macrocytic. Microcytic anemias include iron deficiency, thalassemia, chronic inflammation, lead poisoning, and sideroblastic anemia. Normocytic anemias include acute blood loss, immune hemolytic anemia, hereditary spherocytosis, G6PD deficiency, sickle cell anemia, renal disease, and transient erythroblastopenia of childhood (TEC). Macrocytic anemias include folate deficiency, B12 deficiency, liver disease, hypothyroidism, neoplasms and bone marrow failure syndromes such as aplastic anemia, Diamond-Blackfan anemia (DBA) and congenital dyserythropoietic anemia (CDEA) The second classification scheme categorizes anemia by its mechanism. If a patient's hemoglobin is low, it is due to one of three basic reasons: he/she is either not making adequate amounts (decreased production), destroying it (increased destruction), or losing it from somewhere (blood loss). This system is more intuitive and more reliable, but is more difficult to categorize in some cases. A high reticulocyte count indicates that the patient is able to adequately make red cells and is trying to compensate for the anemia, suggesting the cause to be blood loss or destruction. A low reticulocyte count suggests decreased production. Signs of destruction include jaundice, elevated bilirubin, dark urine, splenomegaly, schistocytes and microspherocytes on peripheral smear, and low serum haptoglobin. Decreased production results from iron, folate, or B-12 deficiency, lead toxicity, thalassemia, aplastic anemia, chronic inflammation, neoplasms, TEC, DBA, renal disease, hypothyroidism, CDEA (congenital dyserythropoietic anemia), and sideroblastic anemia. Blood loss results from acute hemorrhage, dysfunctional uterine bleeding (heavy and/or prolonged menstrual periods), pulmonary hemosiderosis (pulmonary hemorrhage), Goodpasture's disease, and gastrointestinal blood loss (peptic ulcer disease, other GI conditions). Increased destruction results from immune hemolytic disease, hereditary spherocytosis, G6PD deficiency, sickle cell disease, thalassemia, DIC (disseminated intravascular coagulation), mechanical heart valves, burns, PNH (paroxysmal nocturnal hemoglobinuria), and hypersplenism. Iron deficiency is the most common cause of anemia in childhood (2). Prevalence of iron deficiency ranges from 5% to 29% of the population, with higher numbers seen in inner city and socioeconomically deprived populations (3,4). It is most common in toddlers and in the adolescent age groups (periods of rapid growth and higher potential for inadequate dietary iron) (5). In infants, early introduction (at age 6 or 8 months) of whole cow's milk into the diet is clearly associated with iron deficiency anemia, and patients consuming larger amounts of milk are at higher risk of anemia (3). This is due to three factors: 1) Cow's milk exerts a direct toxic effect on the intestinal mucosa of infants, leading to prolonged microscopic blood loss in the stools. 2) The caloric value of whole cow's milk is high due to fat content, decreasing the appetite and leading to less intake of potential iron-rich foods. 3) The bioavailability of iron in cow's milk is low (6). Accordingly, the American Academy of Pediatrics recommends that cow's milk not be used in the first year of life. Infants should receive breast milk or iron fortified formulas for the first year of life, and iron-fortified cereal should be added at the age of four to six months (6). Infants with appropriate diets and older children and adolescents with iron deficiency anemia must be evaluated for a source of chronic blood loss. Abnormal uterine bleeding and blood loss from the GI tract are common. Blood loss in the urine is rare, and from the lungs (idiopathic pulmonary hemosiderosis) is exceedingly rare. Hemolytic anemias generally do not lead to iron deficiency because the body reuses the freed iron. Iron deficiency has conclusively been linked to behavioral changes (6) and to lower cognitive achievement in school aged children and adolescents (7). Thus it should be recognized early and treated adequately. Presenting signs and symptoms may be mild because of the gradual onset and the body's ability to compensate for low hemoglobin concentration. Pallor, fatigue, exercise intolerance, headache, or dizziness may be present. Physical exam may reveal pale mucus membranes and skin, especially of the palms, tachycardia with or without heart murmur, and orthostatic hypotension. Laboratory evaluation reveals a low MCV, low hemoglobin and hematocrit, low reticulocyte count, and often an elevated platelet count. The red cell distribution width (RDW), a measure of the difference in size between the smallest and largest RBCs in circulation, may be elevated, denoting a dual population of cells: small (microcytic) iron deficient cells and some normocytic cells with adequate iron. Evaluation of the blood smear reveals microcytosis and hypochromia. Serum iron is low, and total iron binding capacity (TIBC) is elevated with low % saturation. Erythrocyte protoporphyrin is increased. Low serum ferritin is diagnostic of iron deficiency, but normal levels can be misleading because ferritin is an acute phase reactant and can be falsely elevated in inflammation (5). Low-normal ferritin values must be interpreted in light of clues from the history, physical, and other laboratory studies. A bone marrow sample stained for iron shows no iron stores. This test is most definitive, but generally unnecessary and invasive. Treatment with multivitamins containing iron is inadequate once the child is anemic. Oral ferrous sulfate, available in liquid or pill form, at a dose of 3 mg/kg of elemental iron for mild anemia or 6 mg/kg for severe anemia should be instituted. It should be continued for two to three months after normalization of blood counts to replete the total body iron stores. The liquid can stain the teeth so it should be given in juice rather than dropped directly into the mouth. Avoid giving it with milk as milk interferes with its absorption. Lead poisoning is less common today with the federally mandated removal of lead from gasoline, canned food sealants, and paint intended for household use in 1977. Since then, there has been a 90% decrease in the number of children defined as "lead intoxicated" (8). Nationwide, 4.4% of children aged one to five meet this criteria with blood levels above 10 mcg/dL (9). The primary source of lead in children's blood today is from lead based paint in older households. Most is ingested as household dust, with only a minor contribution from paint chips (8). Children under 2 years of age are at highest risk due to exploring behavior and the practice of bringing paint dust- coated fingers and toys to the mouth. Not surprisingly, the age and state of disrepair of the home is an important risk factor. Children in an older but well-maintained home have less exposure than those in an old home with cracked and peeling paint (10). Most lead poisoning is now found through lead screening. The American Academy of Pediatrics recommends that a risk assessment survey be given at health maintenance visits, and if any questions are answered "yes" or "not sure", blood lead levels should be drawn. The survey should be adapted for known lead risks in each community, but should include at least the following three questions (10): 1) Does your child live in or regularly visit a house or childcare facility built before 1950? 2) Does your child live in or regularly visit a house or childcare facility built before 1978 that is being or recently has been renovated or remodeled? 3) Does your child have a sibling or playmate who has or did have lead poisoning? In communities where more than 27% of housing was built before 1950 or where more than 12% of 1 and 2 year olds have elevated blood lead levels, all children should have lead levels drawn at age 9-12 months and age 2 years (10). Acute signs and symptoms of lead intoxication are now rarely seen. Vomiting, abdominal pain, and constipation are nonspecific and common in this age group. Because of prevention, screening, and the use of chelating agents as treatment, encephalopathy, seizure, and coma associated with extremely high lead levels are almost unheard of today. Chronic effects of lead poisoning are more ominous, and include possibly permanent behavioral and cognitive deficits, including decrease in IQ points (11,12). Complete blood counts are often normal in children with low to moderately elevated lead levels. Basophilic stippling, seen as fine blue specks in the RBC membrane under light microscopy, can be prominent. Erythrocyte protoporphyrin is elevated (13). Anemia results from lead's inhibition of enzymes required for hemoglobin synthesis (4), but the microcytic anemia of lead poisoning reported in the past is most likely due to concomitant iron deficiency. Iron deficiency leads to pica which increases risk of lead ingestion, and iron deficiency leads to increased absorption and retention of lead from the GI tract. Treatment depends on the blood lead level (BLL) in mcg/dL (10): I. BLL <10 requires no action. II. Levels of 10-20 require education and action to decrease lead exposure, including frequent hand washing, frequent dusting and mopping, and ideally repair or repainting, followed by repeat BLL in 2-3 months. III. Levels of 20-44 require a detailed history to identify sources of lead exposure, including hobbies (ceramics), vocations (repair of bridges or boats, plumbing, home building/renovating), and contact (car batteries, contaminated soil). Corrective action must be taken to decrease exposure. Consider a home visit or a referral to the local health department for a detailed environmental investigation and referrals for support services. IV. Levels of 45-69 require all of the above plus initiation of chelation therapy. V. Levels of 70 or higher require hospital admission for close observation of mental status and immediate IV chelation. The anemia of inflammation, also called anemia of chronic disease, is the second most common cause of anemia in children after iron deficiency (14). Initially recognized in patients with chronic inflammatory conditions, it has now been shown to occur in the acute setting, accompanying mild self-limiting illnesses such as otitis media or upper respiratory infections (15). The mechanism of anemia is multifactorial, primarily from decreased RBC production (impaired iron utilization and decreased erythropoietin production and response) but also from decreased RBC survival (16). The degree of anemia is usually mild, with hemoglobin concentrations of 10 to 11 g/dl, but can be moderate with hemoglobins of 8 to 9 g/dl. The red blood cells are usually normocytic but can be microcytic (15). Reticulocyte counts are low. Iron studies, if done, show low serum iron, high serum ferritin, and low TIBC. Bone marrow evaluation would show abundant iron stores. Anemia associated with acute inflammation is usually benign and self-limited, resolving 1-2 months after the infection resolves (15). Children with chronic diseases such as rheumatoid arthritis have a more protracted course; even so, the anemia is rarely significant enough to require treatment. High doses of erythropoietin can correct the anemia in those rare cases (14). Folate and vitamin B12 deficiency are rarely seen in children. They cause a macrocytic anemia which may be accompanied by granulocytopenia and thrombocytopenia. Hypersegmented neutrophils may be seen on peripheral smear of patients with B12 deficiency. The diagnosis is confirmed by low serum concentration of the vitamins (4). B12 deficiency requires a Schilling test to determine the cause of the B12 deficiency (intrinsic factor deficiency, malabsorption due to inflammatory bowel disease, etc.). B12 deficiency is also associated with neuropathic symptoms. The thalassemias are a group of inherited disorders of hemoglobin synthesis that cause a microcytic anemia. Aberrant hemoglobins have shortened lifespans, so the anemia may be caused by both decreased RBC production and increased destruction. Thalassemia is fully discussed in a separate chapter. Anemia from bone marrow failure is usually macrocytic. Causes can be congenital (Diamond-Blackfan anemia, congenital dyserythropoietic anemia) or acquired (aplastic anemia, transient erythroblastopenia of childhood). These are discussed in detail in a separate chapter. Replacement of normal bone marrow by malignancy (leukemia or metastatic tumor) can lead to failure of normal red blood cell production, as can restriction of the marrow space by bone in osteopetrosis. Destruction of red blood cells, or hemolysis, causes release of intracellular contents into the plasma. Consequently, indirect (unconjugated) bilirubin, LDH, and AST (SGOT) may be elevated. The urine may be dark due to excreted hemoglobin or bilirubin. The reticulocyte count is elevated (18). Haptoglobin, a protein that binds free hemoglobin, decreases. A low serum haptoglobin is diagnostic of hemolysis. If the red cells are destroyed in the spleen (extravascular hemolysis) red cell fragments are not seen, and the peripheral smear shows polychromasia and microspherocytes. Hereditary Spherocytosis (HS) is the most common cause of hemolytic anemia in children. It is inherited in an autosomal dominant patternin75%ofcases,butfamilyhistoryisnotalwayspositivebecauseofvariationsinseverityevenamongfamilym embers. Abnormal membrane proteins cause a loss of portions of the cell membrane, resulting in a rigid red blood cell with a spherical shape. These cells are trapped in the spleen and destroyed, resulting in hemolytic anemia (17). Patients present with jaundice, anemia, and splenomegaly. The reticulocyte count is elevated, and the MCV is normal. An elevated MCHC strongly suggests HS, as it is rarely elevated in any other condition but is high in 50% of those with HS (18). The peripheral smear usually shows spherocytes, but the degree is variable and depends on smear quality. One cannot rule out HS by a lack of spherocytes reported on a peripheral blood smear. The definitive diagnostic test is the incubated osmotic fragility assay, which shows increased hemolysis to osmotic stress. Patients with HS can have a "hyperhemolytic crisis", which is an acceleration of the rate of hemolysis brought on by infections. They typically present with increased jaundice, pallor, and hemoglobins in the 58 g/dl range during or just after a nonspecific viral illness. Blood transfusions may be required. An "aplastic crisis" can occur following infection with human parvovirus B19, the cause of Fifth disease (erythema infectiosum) (18). This virus stops all red cell production in the marrow. The reticulocyte count falls to 0, and in the face of continued RBC destruction without RBC production, the hemoglobin falls precipitously to levels of 3-6 g/dl. Timely blood transfusions can get these patients through this one time complication. HS patients whose siblings contract Fifth disease must be followed closely. Treatment consists of educating the family about the disease and instructing them to come in for examination and blood work at the first signs of pallor, increased jaundice, or fatigue. Splenectomy is curative but because of the risk of postsplenectomy sepsis, especially in those under age five, the surgery is reserved for those with more severe disease. Indications include frequent hyperhemolytic episodes, symptomatic anemia leading to limitation of lifestyle, gallstones, or growth retardation. G6PD deficiency is the most common of the RBC enzyme defects. The enzyme deficiency causes the red blood cells to be more sensitive to oxidative stress (17). Hemolysis ensues, resulting in jaundice and anemia. It is an X-linked disorder and so it mostly affects males, but females can be variably affected due to random inactivation of one X chromosome or they can be homozygous (mother is a carrier and father has G6PD deficiency). The clinical course is marked by episodic jaundice. Prolonged neonatal jaundice is sometimes seen. Older patients may have a history of jaundice, pallor and anemia that accompanies infections or certain drugs or foods. Different individuals and different ethnic groups (Asian, African, Mediterranean) may have different mutations which result in differing G6PD deficiency severities, so the patients may have different susceptibilities to severe neonatal jaundice, kernicterus and acute hemolytic reactions. Laboratory evaluation reveals a normocytic anemia with variable evidence of hemolysis such as increased bilirubin, decreased haptoglobin, and hemoglobinuria. The blood smear shows fragmented cells, schistocytes, and may show characteristic "bite" cells or "ghost" cells. Special stains for Heinz bodies, denatured hemoglobin, may be positive. A specific G6PD assay is available, and if low, is diagnostic. The test may be falsely elevated to normal levels during or just after acute hemolysis due to a high reticulocyte count, so it should be repeated several weeks after the hemolytic event if the diagnosis appears likely (18). Patients can make auto-antibodies against red blood cell antigens due to autoimmune syndromes, medications, infections (EBV, mycoplasma, or nonspecific viruses), or unknown reasons. The presentation is variable, but characteristic findings of hemolytic anemia are the norm. Blood smears show microspherocytes but schistocytes are not seen. The direct Coombs test is positive. Treatment with corticosteroids usually results in resolution of the hemolytic anemia (4,17). Intravenous immune globulin (IVIg) and splenectomy have been used with success in cases refractory to corticosteroids. Maternal antibodies against infant red blood cell groups can cross the placenta and cause varying degrees of hemolysis (alloimmune hemolytic disease of the newborn). The clinical picture ranges from mild hyperbilirubinemia to hydrops and death, but is most often benign and self-limited. Observation alone or treatment with phototherapy is usually adequate. With intravascular hemolysis, as seen in disseminated intravascular coagulation (DIC), hemolytic-uremic syndrome and burns, mechanical injury to red blood cells causes hemolysis within the blood vessel rather than in the spleen. Red blood cell fragments (schistocytes) are therefore commonly seen on peripheral blood smears (4). Treatment involves correction of the underlying condition. Because the defect is extrinsic to the red cell, transfused blood is hemolyzed as quickly as is the patient's, and so transfusion is only a temporizing measure. Sickle cell anemia is a hemoglobinopathy common in African, Caribbean, Middle Eastern, and Mediterranean peoples. A mutation in the hemoglobin molecule causes red cells to take on a rigid sickled shape, causing obstruction of flow through the microvasculature. Complications due to tissue hypoxia and hemolytic anemia can be profound. Sickle cell anemia is discussed fully in a separate chapter. Chapter XI.2. Thalassemia Kelley A. Woodruff, MD A 12 month old female of Hawaiian, Chinese, Portuguese and Japanese ethnicity is noted to have a hemoglobin of 9.1 g/dl with an MCV of 58 on a routine CBC screen at her one year well child check up. She is otherwise healthy and has no complaints. PE is normal. On a review of this child's medical record, you note the presence of Hemoglobin Barts on her newborn screen. Thalassemia is one of the most confusing of the hemoglobinopathies, mostly due to confusing nomenclature, lack of easy diagnostic tests, and its similarity to iron deficiency anemia. Whereas both thalassemia and iron deficiency anemia are characterized by microcytic hypochromic anemias, iron deficiency anemia is easily corrected with iron supplementation, but iron supplementation does not correct the anemia due to thalassemia. In any anemic state, there is increased gut absorption of iron. Even in nontransfused patients, iron overload is often noted in the more severe forms of thalassemia. Since thalassemia is not an iron deficiency problem, it is not be corrected by additional iron. In fact, in thalassemia over time, the body becomes iron overloaded, and iron is "stored" in the organs (liver, endocrine organs and heart), which can cause significant morbidity and mortality. There are two basic types of thalassemia: alpha thalassemia and beta thalassemia. They have nothing to do with one another. Alpha thalassemia usually results from the deletion of any number of the 4 genes necessary to make alpha globin chains. Occasionally, an alpha globin gene is abnormal instead of being completely deleted. Beta thalassemia usually results from an abnormal gene in one or both of the genes necessary for beta globin chain production. Occasionally, the entire gene (on one allele) is actually deleted. The alpha and beta genes are located on different chromosomes and therefore, abnormalities of each are inherited separately. Beta thalassemia usually occurs from abnormal beta genes, or less commonly, a deletion of a beta gene. In beta thalassemia, there is a large lack of normal beta chain production, thus causing a relative excess amount of alpha chains, which clump together. This abnormal hemoglobin is very unstable, and leads to erythrocyte death in the bone marrow. Beta thalassemia minor occurs when only one gene is affected, causing a moderate, lifelong anemia. This typically requires no treatment other than recognition for the purposes of patient education, to avoid supplemental iron, and for genetic counseling. Beta thalassemia major, historically called Cooley's Anemia, occurs when both genes necessary for beta globin production are affected. Since beta chains are not present in fetal hemoglobin, beta thalassemia does not manifest itself in newborns. Beta thalassemia presents at 6 months of age when adult hemoglobin has replaces fetal hemoglobin. Peripheral anemia, caused by the disease, sends signals to the bone marrow to increase production of erythrocytes (e.g., via erythropoietin), however, erythrocyte production is abnormal (ineffective). This process is called "ineffective erythropoiesis". With time, the marrow cavities (skull bones, facial bones, and ribs) expand, leading to the classical facial features and skull X-ray findings ("hair on end" in untreated patients due to excessive extramedullary hematopoiesis). Erythrocytes that do enter the circulation are noted to be abnormal by the reticuloendothelial system (spleen and liver), and are taken up by these organs with ensuing enormous hepatosplenomegaly. In untreated patients, death usually occurs by the end of the second decade of life from anemia and congestive heart failure. Currently, part of the standard treatment for beta thalassemia major is lifelong transfusions given every 2-4 weeks. The intent of these transfusions is to keep their hemoglobin trough above 9 or 10 gm/dl. This will, in effect, shut off the patient's own erythropoiesis and stop the vicious cycle of anemia stimulating "ineffective erythropoiesis". With each milliliter of transfused packed red blood cells, the patient receives one milligram of elemental iron. Iron, in addition to being relatively difficult to absorb, is also not easily excreted. Thus, such transfused patients quickly become iron overloaded. Untreated, iron overload will be fatal. Regularly transfused patients need to be on lifelong chelation therapy to help their bodies excrete the excess iron. There are no effective oral iron chelation agents. Currently, most regularly transfused thalassemia patients receive their chelation as a subcutaneous infusion of deferoxamine over 10 hours each night (lifelong). With the combination of transfusion and chelation therapy, life expectancy can to be normal. A form of alpha thalassemia occurs when any number of the four genes that control alpha globin production are missing, thereby causing an excess of non-alpha globin chains. The various forms of alpha thalassemia with their genetic correlate are listed below: A. 4 normal alleles (normal) B. 3 normal / 1 missing gene (silent carrier) C. 2 normal / 2 missing genes (thal trait) D. 1 normal / 3 missing genes ("Hemoglobin H disease") E. 4 missing genes (results in hydrops fetalis) Silent carriers are 1 missing alpha gene. They have no clinical abnormalities. Their hemoglobin, and hemoglobin electrophoresis are normal and their MCV is borderline normal. Those with alpha thalassemia trait are clinically normal, but their hemoglobin is slightly low and their hemogram demonstrates microcytic indices. Their hemoglobin electrophoresis is normal unless it is done in the newborn period at which time Hemoglobin Barts is present (recall this finding in the case example at the beginning of the chapter). Traditionally, people with alpha thalassemia trait are taught that they have a benign condition and no further education is provided. However, it should be emphasized that although the anemia is benign, supplemental iron must be AVOIDED to prevent harmful iron buildup. There is suspected sustained morbidity in persons with thalassemia trait, who are on repeated, or continued iron supplementation. Additionally, such iron supplementation is generally useless, even in menstruating females, as their stores are readily replenished by a greater degree of absorption of dietary iron from the gut. The extra iron is stored in the organs, leading to end organ dysfunction. Additionally, parents with this, so called, "benign" alpha thalassemia trait, can produce offspring with fatal hydrops fetalis if both parents pass on alleles with two defective alpha genes. The name Hemoglobin H disease is a misnomer. In developed countries with otherwise good medical care, it is not a disease, but rather a condition. People with Hemoglobin H condition can live healthy, long lives. They are not transfusion dependent, as are those with beta thalassemia major. There are some rare variants, such as Hemoglobin H Constant Springs, (the Constant Springs is an abnormal gene, rather than a deletion, named after a U.S. city where it was first identified), that can be dependent on lifelong monthly transfusions. These people are missing 2 genes from one allele, and have the severely dysfunctional Constant Springs gene on the other allele. People with Hemoglobin H need to avoid all forms of supplemental iron, and pregnant women need very close prenatal care for their own health matters. Since the bone marrow of thalassemia patients requires excess folic acid (due to erythroid hyperplasia), most clinicians advise lifelong supplementation of 1 milligram daily of folic acid to avoid relative folate deficiency. During times of severe illness, or in pregnancy, the hemoglobin may drop significantly below baseline in Hemoglobin H disease, and a transfusion may be recommended. Again, iron is generally not deficient and, thus iron supplementation is not helpful, nor is it appropriate. When four beta chains clump together, Hemoglobin H is formed. In infants, gamma chains predominate over beta chains, and Hemoglobin Barts (four gamma chains) is formed. Hemoglobin H and Hemoglobin Barts are both useless, with no effective oxygen carrying capacity. There has been a lot of confusion between this abnormal Hemoglobin H (4 beta chains clumped together) and the clinical condition in which 3 alpha genes are missing, called "Hemoglobin H disease or condition". The abnormal Hemoglobin H exists (in varying amounts) in all 4 clinical alpha thalassemia categories. Similarly in newborns, Hemoglobin Barts exists in varying amounts in all alpha thalassemia categories. Hemoglobin H and Hemoglobin Barts do not cause the degree of ineffective erythropoiesis seen in beta thalassemia. Therefore, the classical "thal facies", "hair on end" skull X-rays, and enormous hepatosplenomegaly, all typical of beta thalassemia, are not seen to such degree in severe alpha thalassemia. Hemoglobin E results from a single amino acid substitution on the beta globin chains. It is very common in the golden triangle of Laos, Cambodia, and Thailand. In the heterozygous form, it affects one out of three persons in this region. Heterozygous Hemoglobin E by itself is not harmful and causes no anemia. However, when combined with beta thalassemia minor, significant anemia develops over time. Such people usually become transfusion dependent later in the first decade of life, and if treatment is not sought or maintained, early death is most likely. The effects of Hemoglobin E on Hemoglobin H are not clear. Homozygous Hemoglobin E usually causes mild microcytic hypochromic anemia, which resembles alpha thalassemia trait. Chapter XI.5. Newborn Hematology Robert W. Wilkinson, MD This is a newborn female born to a 17 year old gravida 1, para 0, B+, mother at 39 weeks gestation. Maternal risk factors include a kidney infection in the second trimester. All other risk factors are negative. After an uneventful vaginal delivery, the infant is discharged at two days of life breast feeding at home. On the third day of life, moderate jaundice is noted and a bilirubin in the primary care doctor's office is 18. Home phototherapy is started, but on day six, the bilirubin is 22.9 with the direct component of 0.4. She is hospitalized for inpatient phototherapy. Her hemoglobin was 15.7 earlier, and it has now dropped to 13.4. The bilirubin continues to rise to 25.6 in spite of phototherapy. A G6PD is normal and the reticulocyte count is 3.1. Stools are negative for occult blood. The blood smear shows moderate aniso and poikilocytosis. She is transferred to a tertiary pediatric center where she is noted to be normal except for marked jaundice. Her mother is of German decent and her father is Caucasian and Puerto Rican. Her mother was treated for newborn jaundice due to presumed ABO incompatibility. Others in her family also had neonatal jaundice. The father's history is unremarkable. No other family member had neonatal jaundice or anemia or gallstones. Upon admission, vital signs are normal. She is visibly jaundiced and a spleen tip is palpable. Labs show a bilirubin of 25, white count of 17.5, platelets of 230,000 and an unremarkable differential. The hemoglobin is now down to 10.7 in spite of a reticulocyte count of 4%. In addition, the smear now shows moderate schistocytes with burr cells and moderate spherocytes. Blood type is B+ and the Coombs is negative. She is transfused and phototherapy continues until the bilirubin falls to 12. The infant has an otherwise uneventful course in the hospital and the final diagnosis is hyperbilirubinemia and anemia due to hereditary spherocytosis. In addition, alpha thalassemia trait is found on her newborn screen. Incubated red cell osmotic fragility studies on the mother and other maternal family member are consistent with hereditary spherocytosis. At the moment of birth, the physician can be confronted with complex hematologic problems seen at no other time in life. Newborn red cells are much different than in older children and white cell and platelet disorders can be quite unique. Coagulation factors are abnormal and hemostasis can be markedly altered. Normal values for most newborn blood tests are different compared to children and adults. Interpretation of results in term and premature newborns can be critical. Significant red cell disorders in the newborn period may be associated with a family history of anemia, jaundice, falling hemoglobin and reticulocytosis in addition to abnormal RBC morphology. The presence of surface antibodies (e.g., anti-A and/or anti-B) may be helpful or the deficiency of intraerythrocytic enzymes (e.g., G6PD deficiency). Finally hemoglobinopathies and thalassemia may offer an almost infinite combination of symptoms and signs in the newborn. Virtually all red cell problems are isolated and the rest of the hemogram is normal. Marrow failure resulting in pancytopenia with associated infections and altered hemostasis is vary rare. Definitive studies on red cells can be delayed for three months when the infant is well and their blood volume is larger. As in the above case, studies of maternal family members subsequently confirmed the diagnosis of hereditary spherocytosis. It is important to remember that in the perinatal period (28 weeks gestation to 28 days after birth) there are normal physiologic changes occurring in red cells. Some of these changes include switching from fetal to adult hemoglobin production, a 30% drop in hemoglobin, a fall in mean red cell volume (MCV) as well as changes in membrane pliability and intracellular enzyme levels. RBC survival is further impacted by acquired infections, medications, and other high-risk conditions. Repeated monitoring of hemoglobin and reticulocyte counts is warranted in the sick and unstable newborn. Hydrops fetalis results from severe intrauterine hemolysis and anemia necessitating emergency exchange transfusion. The cause is usually due to severe alpha thalassemia, red cell surface antibodies or congenital infections. Rh incompatibility usually presents with rapid hemolysis and varying degrees of anemia and jaundice (depending on the extent of maternal sensitization and antibody production). White blood cell abnormalities may be asymptomatic and incidental or associated with fever, infection, and altered host resistance. Wide fluctuation in the WBC count can be noted depending on marrow production of granulocytes. Infection, antibodies, and medications call all affect the circulating neutrophil pool. This is the pool of granulocytes sampled with a venipuncture. Interpretation of a peripheral WBC count can be difficult when trying to determine the risk of infection or underlying pathophysiology. A bone marrow examination can be very helpful in assessing granulocyte production and the risk of infection. Most WBC aberrations are secondary or reactive to a disease process, but occasionally rare hereditary disorders can present in the neonate. These are usually associated with an increased risk of infection (e.g., chronic granulomatous disease) or as part of a recognizable syndrome (e.g., Jobs syndrome). Congenital leukemia is extremely rare but striking leukemoid reactions can occur. Of note is the transient myeloproliferative condition or pseudoleukemia that may be observed in neonates with Down syndrome. Of prime importance when evaluating infants with any white cell aberration is the real risk of infection and the need for antimicrobials. Platelet problems in the newborn present almost exclusively with thrombocytopenia and bleeding. Thrombocytopenia can be isolated or associated with other cytopenias. A low platelet count results from either decreased production or peripheral consumption of platelets. By examining the bone marrow and/or the mean platelet volume (MPV usually higher in younger platelets seen in consumptive disorders), the underlying pathophysiology can usually be identified. Most thrombocytopenias are consumptive and due to maternal antiplatelet antibodies, congenital infections, or part of complex DIC seen in sick newborns. It is paramount to compare the amount of clinical bleeding to the degree of thrombocytopenia in order to quickly make the right diagnosis and determine the need for transfusion or other therapy. Hemorrhagic disease of the newborn is usually seen from day 2 to 4 of life resulting from vitamin K deficiency and the subsequent failure to produce clotting factors II, VII, IX and X. The prothrombin time is markedly prolonged and serious life threatening hemorrhaging can occur in many organ systems. This transient deficiency of vitamin K is thought to result from poor placental transfer, marginal content in breast milk, inadequate intake of breast milk and a sterile gut (lack of vitamin K producing GI flora). Hemorrhaging can be prevented by the intramuscular administration of prophylactic vitamin K shortly after birth. Chapter XI.6. Bleeding Disorders Desiree Medeiros, MD This 4 year old female is referred to the hematology department with a chief complaint of acute onset of easy bruising and "rash" for 3 days. She has not had epistaxis, oral bleeding, gross blood in urine or stools. She has never had palpable bruises, hemarthroses or deep muscle bleeds in the past. She has no history of fever or appetite changes. She had upper respiratory infection symptoms approximately 2 weeks ago. There is no travel history. She has 2 older brothers, neither of whom have had bleeding symptoms. Family history is negative for frequent nosebleeds, oral bleeding, menorrhagia or excessive bleeding with surgery or trauma. There is no history of malignancies, or autoimmune disorders. Exam: VS are normal. Height and weight are at the 50th percentile. She is a healthy appearing, cooperative girl in no acute distress. HEENT exam demonstrates no signs of bleeding or bruising. Heart and lung exams are normal. Her abdomen demonstrates no hepatosplenomegaly. A diffuse petechial rash is noted on her neck, trunk, extremities and groin. Nonpalpable ecchymoses of varying ages are present on shins and arms. Her neurologic examination demonstrates no deficits. CBC shows Hgb 12.8, Hct 38.5, WBC 6,000 with a normal differential. Platelet count is low at 5,000. PT and PTT 12.0 and 32 seconds, respectively. Review of the peripheral smear shows normal morphology of red and white blood cell lines. The platelets are reducedinnumberandthemajorityofthemareincreasedinsize. Abonemarrowaspirateisnotperformed. She is diagnosed with immune thrombocytopenic purpura. She is followed closely with weekly CBCs. Her bruises and petechiae fade by her next visit and her platelet count returns to 240,000 one month later. Bleeding disorders can either be inherited or acquired and are due to defects in either primary or secondary hemostasis. While evaluating a child with a bleeding tendency, the history and physical examination should be directed at differentiating between these. An appropriate history can be more helpful in evaluating these children than any laboratory test. Bruising with or without preceding trauma can be due to a defect in either primary or secondary hemostasis although deep palpable bruises are usually due to a clotting factor defect. Petechiae are usually due to a platelet or blood vessel defect. One should ask about a history of mucosal bleeding (including epistaxis, oral bleeding, gastrointestinal, genitourinary and menstrual bleeding), bleeding from injury or following procedures such as circumcision and tonsillectomy, and deep tissue or musculoskeletal bleeding. Age of onset, frequency and severity of each bleeding complaint should be determined and an extensive family history and medication history should be obtained. The child should be examined for signs of bleeding, such as petechiae, bruising, mucosal bleeding, and oozing from venipuncture sites. Differentiate between superficial bruises and deep palpable ecchymoses, making note of their location. Special attention should be made to the joints and large muscle areas, looking for deep tissue bleeding. Laboratory studies assist in confirming suspicions raised from the history and physical. Routine screening laboratory studies should include complete blood count (CBC) with a platelet count, prothrombin time (PT) and activated partial thromboplastin time (PTT). Further specific testing should be performed based on the working diagnosis. These include a PTT mixing study (which helps differentiate a factor deficiency from an acquired inhibitor), bleeding time, factor assays, von Willebrand studies, and platelet aggregation tests. The bleeding time is an uncommonly ordered test during which a standardized small laceration is created on the patient's forearm and the time for the bleeding to stop is measured and compared to standard times. This test is prolonged in conditions of thrombocytopenia and platelet dysfunction. Platelet aggregation studies are special studies that can be done to test the aggregation of platelets in response to several known agents which induce platelet aggregation in vitro such as adenosine diphosphate (ADP), epinephrine and collagen. Page - 421 The more commonly encountered bleeding disorders are discussed in further depth in this chapter. I. Primary Hemostasis (platelets) A. Quantitative (thrombocytopenia) 1. ITP 2. Hemolytic uremic syndrome (HUS) 3. Thrombotic thrombocytopenic purpura (TTP) 4. Medications 5. Marrow failure (leukemia, aplastic anemia) 6. Platelet sequestration, consumption and dilution B. Qualitative (poor platelet function) 1. Inherited platelet aggregation defect 2. Drug effect II. Secondary Hemostasis (coagulation) A. Congenital factor deficiency 1. Hemophilia A and B 2. von Willebrand disease 3. Other factor deficiencies (rare) B. Acquired factor deficiency 1. Vitamin K deficiency 2. Liver failure C. Antiphospholipid antibody Defects in Primary Hemostasis Quantitative disorders result in thrombocytopenia, either due to decreased bone marrow production or increased platelet Defects in Primary platelet Hemostasis destruction. Quantitative platelet disorders result in thrombocytopenia, either due to decreased bone marrow production Immune Thrombocytopenic Purpura or increased platelet destruction. Immune or idiopathic thrombocytopenic purpura (ITP) is one of the most common acquired bleeding disorders of childhood. Usually, it is a benign, self-limited disease that occurs in previously healthy children. The typical course in an untreated child is resolution of bleeding symptoms 3 to 10 days after diagnosis, regardless of the platelet count and an increase in the platelet count within 1 to 3 weeks. Immune Thrombocytopenic Purpura The platelet count returns to normal in 4 to 8 weeks in approximately half of patients and two thirds of children have resolution by 3 months after diagnosis. By 6 months, platelet counts have returned to normal (>150,000 per cubic mm) in 80% of patients. The remainder are defined having chronic ITP (1,2). Most children follow a course consistent acute ITP, in which the platelet counts are very Immune orasidiopathic thrombocytopenic purpura (ITP) is one of thewith most common acquired bleeding low, butof they recover as noted above.it Adults more commonly followdisease a course consistent within chronic ITP, in which the platelet counts are disorders childhood. Usually, is a benign, self-limited that occurs previously healthy usually moderately low, but the thrombocytopenia persists for long periods of time and often for life. If patients with chronic ITP sustain children. The typical course in an untreated child is resolution of bleeding symptoms 3 to 10 days after significant consequences from recurrent bleeding, a splenectomy is sometimes necessary to raise their platelet count. diagnosis, of the platelet count and circulating an increase in the platelet within 1ontothe3platelet weeks.membrane The (1). The ITPregardless is an immune-mediated disorder in which antiplatelet antibodiescount target epitopes platelet count returns to are normal in 4 todestroyed 8 weeksbyinmacrophages approximately half of patientssystem. and two thirdswith of children antibody-coated platelets subsequently in the reticuloendothelial Children ITP present with sudden onset of by bruising, petechiae anddiagnosis. occasionallyBy epistaxis. Thereplatelet may be acounts history of a preceding viraltoinfection have resolution 3 months after 6 months, have returned normalor a recent live-virus immunization (1). There should be no evidence of other disorders causing thrombocytopenia, such as systemic lupus erythematosus or (>150,000 per cubic mm) in 80% of patients. The remainder are defined as having chronic ITP (1,2). Most HIV infection. These children appear well except for bruises and petechiae. A minority of patients have mucous membrane hemorrhage, children a course consistent with acute whichThey thedo platelet arepallor, veryorlow, but they such asfollow menorrhagia, gastrointestinal bleeding or oral ITP, blood in blisters. not havecounts jaundice, hepatosplenomegaly. recover as above. Adults more commonly follow a of course chronic which thecount is Thenoted most important laboratory assessment in the evaluation ITP is consistent the CBC and with peripheral bloodITP, smear.inThe platelet typically very low cubic mm) and therethrombocytopenia is appreciable bleeding, the hemoglobin concentration normal as is the platelet counts are (<20,000 usually per moderately low,unless but the persists for long periods ofistime and leukocyte count. The peripheral smear shows morphology of allconsequences cell lines except from the platelets are reduced in number often for life. If patients with chronic ITPnormal sustain significant recurrent bleeding, a and tend to be large. PT and PTT are normal and do not need to be performed. The bleeding time is predictably prolonged and unnecessary in the splenectomy to raise their platelet count. evaluation ofisa sometimes child with ITP.necessary When indicated by the medical history and physical examination, evaluation for HIV, systemic lupus erythematosus, or Evan's syndrome should be considered. Bone marrow aspiration should be considered in patients with hepatosplenomegaly, abnormalities on the CBC. ITPlymphadenopathy, is an immune-mediated disorderorinother which circulating antiplatelet antibodies target epitopes on the Management of ITP in a child includes education and reassurance of the child's parents. The child's activities should be limited, and platelet membrane (1). The antibody-coated platelets are subsequently destroyed by macrophages in the aspirin and NSAID containing medications should not be used. Children without significant clinical bleeding may be closely observed reticuloendothelial system. Children with ITPcount present with suddenit onset bruising, petechiae anduntil it returns to with CBCs once or twice weekly. Once the platelet begins to increase, may beof measured every 2 to 3 weeks occasionally epistaxis. There may count be a has history of a preceding infection orplatelet a recent live-virus normal (>150,000). Once the platelet normalized, recurrence isviral rare and follow-up counts are unnecessary (1,2). A few children with ITP bleeding significant enough to warrant medical management. Standard therapy options include oral or IV immunization (1).have There should be no evidence of other disorders causing thrombocytopenia, such as corticosteroids (which block the reticuloendothelial system's destruction of antibody-coated platelets and reduce synthesis of antiplatelet systemic lupus erythematosus or HIV infection. These children appear well except for bruises and antibodies), IVIG (IV gamma globulin which inhibits Fc receptors on phagocytes, allowing antibody-coated platelets to circulate and alters petechiae. A minority of B-cell patients haveand mucous as(which menorrhagia, T-lymphocyte subsets and function reduces membrane autoantibody hemorrhage, production), andsuch Anti-D is the anti-serum against the Rh(D) gastrointestinal bleeding blood blisters. do notit have jaundice, pallor, or hepatosplenomegaly. antigen on erythrocytes andor byoral coating Rh(D) positive They erythrocytes, decreases platelet destruction). uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) TheHemolytic mostHUS important laboratory assessment in the evaluation of ITP is the CBC and peripheral blood smear. and TTP are closely related disorders caused by microvascular occlusion of arterioles and capillaries producing ischemia of Themultiple platelet countHUS is typically very low (<20,000 per cubic mm) andhemolytic unless there is and appreciable organs. is a combination of thrombocytopenia, microangiopathic anemia, acute renal bleeding, failure (4). It occurs the mostly hemoglobin concentration normal as is TTP the is leukocyte count. The peripheral smearinclude: showsthrombocytopenia, normal in children and has a fairlyisgood prognosis. characterized by a pentad of features which microangiopathic neurologic disturbances, renal dysfunction and and fevertend (4). Ittooccurs in young and teenagers morphology of allhemolytic cell linesanemia, except the platelets are reduced in number be large. PTadults and PTT are and carriesand a high and notThe treated. Table 1 time compares both disorders. normal do mortality not needif unrecognized to be performed. bleeding is predictably prolonged and unnecessary in the evaluation of a child with ITP. When indicated by the medical history and physical examination, evaluation for HIV, systemic lupus erythematosus, or Evan's syndrome should be considered. Bone marrow aspiration should be considered in patients with lymphadenopathy, hepatosplenomegaly, or other abnormalities on the CBC. Management of ITP in a child includes education and reassurance of the child's parents. The child's activities should be limited, and aspirin and NSAID containing medications should not be used. Children without significant clinical bleeding may be closely observed with CBCs once or twice weekly. Once the platelet count begins to increase, it may be measured every 2 to 3 weeks until it returns to normal (>150,000). Once the platelet count has normalized, recurrence is rare and follow-up platelet counts are unnecessary (1,2). A few children with ITP have bleeding significant enough to warrant medical management. Standard therapy options include oral or IV corticosteroids (which block the reticuloendothelial system's destruction of antibody-coated platelets and reduce synthesis of antiplatelet antibodies), IVIG (IV gamma globulin which inhibits Fc receptors on phagocytes, allowing antibodycoated platelets to circulate and alters T-lymphocyte subsets and B-cell function and reduces autoantibody production), and Anti-D (which is the anti-serum against the Rh(D) antigen on erythrocytes and by coating Rh(D) positive erythrocytes, it decreases platelet destruction). Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) HUS and TTP are closely related disorders caused by microvascular occlusion of arterioles and capillaries producing ischemia of multiple organs. HUS is a combination of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure (4). It occurs mostly in children and has a fairly good prognosis. TTP is characterized by a pentad of features which include: thrombocytopenia, microangiopathic hemolytic anemia, neurologic disturbances, renal dysfunction and fever (4). It occurs in young adults and teenagers and carries a high Page - 422 mortality if unrecognized and not treated. Table 1 compares both disorders. Table 1: Comparison of HUS and TTP Feature HUS TTP Course Age usually <3 yr M=F Prodrome: infection, diarrhea Recurrence rare Age usually 3rd decade F>M Prodrome less common Recurrence common Diagnosis Triad Acute renal failure Thrombocytopenia Microangiopathic anemia Pentad CNS disturbance Thrombocytopenia Microangiopathic anemia Renal dysfunction Fever Etiologic factors E. coli, Shigella gastroenteritis, Pregnancy, autoimmune disease, pneumococcus malignancy, drugs Treatment Renal dialysis Corticosteroids - no help Transfuse only if necessary Plasma exchange Corticosteroids AVOID transfusions Prognosis Good Poor A variety of drugs have been reported to cause thrombocytopenia either by drug-induced platelet destruction or bone marrow suppression. Heparin emphasis because it is so commonly used. Heparin does not inhibit platelet function but it may A variety of drugs havemerits beenspecial reported to cause thrombocytopenia either by drug-induced platelet sometimes cause thrombocytopenia. There are two types of heparin-induced thrombocytopenia (HIT). The first occurs 2 to 5 days after destruction or bone marrow suppression. Heparin merits special emphasis because it is so commonly used. initiation of heparin. Platelet counts rarely fall below 100,000 per cubic mm and normalize within 1 to 5 days. This type is thought to Heparin inhibit platelet function it heparin may sometimes cause thrombocytopenia. areafter twothe initiation of resultdoes from not platelet aggregation secondary to abut direct effect (4). The second type of HIT occurs 3 There to 15 days typesheparin of heparin-induced thrombocytopenia (HIT). The first occurs to mechanism 5 days after initiation of heparin. (4). Platelet counts fall below 40,000. Arterial thrombosis may occur. 2The is immune mediated. Treatment involves discontinuation of heparin. Platelet counts rarely fall below 100,000 per cubic mm and normalize within 1 to 5 days. This type is thought to result from platelet aggregation secondary to a direct heparin effect (4). The second type of HIT Decreased numbers of platelets result from impaired platelet production due to leukemia, aplastic anemia or bone marrow occurs 3 to 15 due days the initiation heparin (4). Platelet counts fall below 40,000. Arterial thrombosis suppression to after viral infection or drugs.ofThese are discussed in separate chapters. May-Hegglin anomaly is characterized by mild to may moderate occur. The mechanismand is immune mediated. Treatment involves discontinuation of heparin. thrombocytopenia the presence of Dohle bodies in the leukocytes. Kasabach-Merritt (giant hemangioma) syndrome is due to localized intravascular coagulation from low blood flow through the abnormal vascular tissue and is associated with thrombocytopenia (4). Foreign bodies in the circulation (central venous catheters and prosthetic valves) are sites for platelet consumption. Platelet loss also results from extracorporeal circulation and exchange transfusions. Massive plasma and blood transfusions lead to a dilutional thrombocytopenia. Finally, platelet counts may be low as a result of sequestration when the spleen is enlarged. Qualitative platelet disorders (defects in platelet aggregation) are very rare. Most are inherited as autosomal recessive traits. Patients present with bleeding similar to that seen with thrombocytopenia. They complain of skin and mucous membrane bleeding, recurrent epistaxis, gastrointestinal bleeding, menorrhagia, and prolonged bleeding with injury or surgery (5). Aspirin (ASA) and non- Etiologic factors E. coli, Shigella gastroenteritis, Pregnancy, autoimmune disease, pneumococcus malignancy, drugs Treatment Renal dialysis Corticosteroids - no help Transfuse only if necessary Plasma exchange Corticosteroids AVOID transfusions Prognosis Good Poor Decreased numbers of platelets result from impaired platelet production due to leukemia, aplastic anemia or A variety of drugs have been to cause thrombocytopenia either drug-induced destruction or bone marrow bone marrow suppression due toreported viral infection or drugs. These arebydiscussed in platelet separate chapters. Maysuppression. Heparin merits special emphasis because it is so commonly used. Heparin does not inhibit platelet function but it may Hegglin anomaly is characterizedThere by mild to types moderate thrombocytopenia and the(HIT). presence of Dohle sometimes cause thrombocytopenia. are two of heparin-induced thrombocytopenia The first occurs 2bodies to 5 days after in the leukocytes. Kasabach-Merritt hemangioma) syndrome due to localized initiation of heparin. Platelet counts rarely(giant fall below 100,000 per cubic mm andisnormalize within 1 to 5intravascular days. This type is thought to result from from plateletlow aggregation secondary to a direct heparin effect (4). The tissue second type occurs 3 to 15 days after the initiation of coagulation blood flow through the abnormal vascular and of is HIT associated with heparin (4). Platelet(4). counts fall below 40,000. thrombosis(central may occur. The mechanism immune mediated.valves) Treatment thrombocytopenia Foreign bodies in Arterial the circulation venous cathetersis and prosthetic areinvolves discontinuation of heparin. sites for platelet consumption. Platelet loss also results from extracorporeal circulation and exchange transfusions. Massive plasma and result bloodfrom transfusions lead production to a dilutional thrombocytopenia. platelet Decreased numbers of platelets impaired platelet due to leukemia, aplastic anemiaFinally, or bone marrow suppression duelow to viral or drugs. These are when discussed separateischapters. May-Hegglin anomaly is characterized by mild to counts may be as ainfection result of sequestration theinspleen enlarged. moderate thrombocytopenia and the presence of Dohle bodies in the leukocytes. Kasabach-Merritt (giant hemangioma) syndrome is due to localized intravascular coagulation from low blood flow through the abnormal vascular tissue and is associated with thrombocytopenia (4). Qualitative platelet in platelet very Most areconsumption. inherited asPlatelet autosomal Foreign bodies in thedisorders circulation (defects (central venous cathetersaggregation) and prosthetic are valves) arerare. sites for platelet loss also recessive traits. Patients present with similar to that seen withand thrombocytopenia. They complain results from extracorporeal circulation and bleeding exchange transfusions. Massive plasma blood transfusions lead to a dilutional thrombocytopenia. plateletbleeding, counts mayrecurrent be low as aepistaxis, result of sequestration when thebleeding, spleen is enlarged. of skin and mucousFinally, membrane gastrointestinal menorrhagia, and prolonged bleeding with injury or surgery (5). Aspirin (ASA) and non- steroidal anti-inflammatory drugs Qualitative platelet disorders (defects in platelet aggregation) are very rare. Most are inherited as autosomal recessive traits. (NSAIDs) are common causes of to temporary platelet dysfunction. Laboratory usually Patients present with bleeding similar that seen with thrombocytopenia. They complain ofevaluation skin and mucous membrane bleeding, demonstrates a normal platelet count, bleeding time bleeding and abnormal platelet aggregation recurrent epistaxis, gastrointestinal bleeding,prolonged menorrhagia, and prolonged with injury or surgery (5). Aspirinstudies. (ASA) and nonsteroidal anti-inflammatory drugs (NSAIDs) are common temporary platelet dysfunction. Laboratory evaluation Coagulation studies (PT, PTT) are usually normal.causes The of most common platelet aggregation defects are usually demonstrates a normal platelet count, prolonged bleeding time and abnormal platelet aggregation studies. Coagulation studies (PT, PTT) described in table 2 below. are usually normal. The most common platelet aggregation defects are described in table 2 below. Table 2: Platelet aggregation defects Platelet aggregation studies Platelet count Glanzmann thrombasthenia Abnormal to all agonists Normal Bernard-Soulier syndrome Abnormal to ristocetin Decreased Giant platelets Storage pool defect (Dense body deficiency, Gray platelet syndrome) Abnormal 2nd phase of aggregation Normal Abnormal platelet granules on electron microscopy ASA/NSAID Abnormal to arachidonic acid and abnormal secondary aggregation to ADP and epinephrine. Normal Drug induced enzyme effect inhibiting platelet granule release This is the most common cause of platelet dysfunction Condition Other Defects in Secondary Hemostasis Hemophilia Hemophilia is an X-linked inherited bleeding disorder transmitted from female carriers to their male children. It is due to a deficiency of factor VIII (Hemophilia A or "Classic hemophilia") or factor IX (Hemophilia B or "Christmas disease"). Hemophilia A is more common, occurring in 1/5000 male births while hemophilia B occurs in 1/15,000 (6). Signs and symptoms vary depending on the severity of the hemophilia. Severity is defined by baseline factor levels: severe <1%, moderate 1-5%, mild >5% (6,7). Children with severe hemophilia usually present in the first year of life with a history of extensive deep palpable ecchymoses. There may be a history of bleeding from the circumcision. After the age of 2 years, they begin to develop spontaneous hemarthroses or deep muscle bleeds. They can have mucosal bleeds, such as oral bleeding with procedures and hematuria. The bleeding is usually not catastrophic. Instead, it is prolonged and continuous without therapy. A head injury is considered an emergency since it is potentially life threatening if not treated appropriately. Children with milder forms of hemophilia may present later in life with a history of easy bruising or prolonged bleeding following injury. They usually do not have spontaneous bleeding. Laboratory findings include a markedly prolonged PTT (>100 seconds) and a decreased factor VIII or IX activity. Other screening tests (PT, platelet count and bleeding time) should be normal. The mainstay of therapy is replacing the deficient clotting factor with factor VIII or IX concentrate (6,7). Page - 423 Defects in Secondary Hemostasis Hemophilia Hemophilia is an X-linked inherited bleeding disorder transmitted from female carriers to their male children. It is due to a deficiency of factor VIII (Hemophilia A or "Classic hemophilia") or factor IX (Hemophilia B or "Christmas disease"). Hemophilia A is Bothmore human derived and recombinant factor concentrates are available. In the past, factor replacement common, occurring in 1/5000 male births while hemophilia B occurs in 1/15,000 (6). Signs and symptoms vary depending on the carried a risk of hemophilia. transmission of viral infections, especially hepatitis andmoderate C, and 1-5%, HIV.mild This>5% risk(6,7). has Children been with severity of the Severity is defined by baseline factor levels: severe B <1%, reduced current viralpresent inactivation techniques andawith the recombinant factor. unit severewith hemophilia usually in the first year of life with history of availability extensive deepof palpable ecchymoses. ThereEach may be a history of bleeding from the increase circumcision. theVIII age oflevel 2 years, to develop spontaneous or deep muscle bleeds. They of factor VIII will the After factor bythey 2%begin and has an 8 to 12 hour hemarthroses half-life. Each unit of factor can have mucosal such oral bleeding The bleeding is usually not depends catastrophic. IX will increase thebleeds, factor IXaslevel by 1% with and procedures has an 18and to hematuria. 24 hour half-life (6,7). Dosing on Instead, the it is prolonged and continuous without therapy. A head injury is considered an emergency since it is potentially life threatening if not treated location and severity of with the milder bleed.forms In addition to factor replacement, hemophilia benefit from bleeding appropriately. Children of hemophilia may present later in lifemales with awith history of easy bruising or prolonged supportive often require intervention. acidPTT is an followingmeasures, injury. Theyphysical usually dotherapy not haveand spontaneous bleeding.orthopedic Laboratory findings include Aminocaproic a markedly prolonged (>100 seconds) a decreased factor VIII or be IX activity. Other screening plateletmembrane count and bleeding time) Mild shouldfactor be normal. oraland antifibrinolytic and can used adjunctively to tests treat(PT, mucous bleeding. VIII mainstay of be therapy is replacing the deficient clotting factorconcentrated with factor VIIIintranasal or IX concentrate (6,7). Both human derived and deficient The patients may treated with intravenous or highly desmopressin recombinant factor concentrates are available. In the past, factor replacement carried a risk of transmission of viral infections, especially (DDAVP) a release VIIIviral stores. Thesetechniques boys need be the cautioned toof recombinant hepatitis which B and C,causes and HIV. This riskin hasendogenous been reduced factor with current inactivation andtowith availability avoid contact such VIII as tackle football, boxing wrestling. is an nationally recognized thatunit hemophilia factor. Eachsports unit of factor will increase the factor VIIIor level by 2% andIthas 8 to 12 hour half-life. Each of factor IX will increasecenters the factorhave IX level by 1% and an 18 to 24of hour half-lifewith (6,7).hemophilia. Dosing depends on the location and severity of have the bleed. In treatment improved thehasprognosis patients Patients and their families addition to factor replacement, males with hemophiliapromptly benefit fromatsupportive measures, physical therapy and often require orthopedic a home supply of factor and infuse themselves the earliest sign of a bleed. Prophylaxis has been intervention. Aminocaproic acid is an oral antifibrinolytic and can be used adjunctively to treat mucous membrane bleeding. Mild factor instituted in most severely affected individuals they infuse themselves regularly (DDAVP) two to three VIII deficient patients may be treated with intravenouswhere or highly concentrated intranasal desmopressin whichtimes causesaa release in week and/or prior a sports order tocautioned prevent tospontaneous bleeds. This has reduced muchorofwrestling. the endogenous factorto VIII stores. activity These boysinneed to be avoid contact sports such as tackle football, boxing It is nationally recognizedinthat treatment centers have improved the prognosis of patients with hemophilia. Patients chronic arthropathy thishemophilia population. Today, young people with hemophilia can lead independent and and their families havelives. a home supply of factor and infuse themselves promptly at the earliest sign of a bleed. Prophylaxis has been instituted in nearly normal most severely affected individuals where they infuse themselves regularly two to three times a week and/or prior to a sports activity in order to prevent spontaneous bleeds. This has reduced much of the chronic arthropathy in this population. Today, young people with von hemophilia Willebrand (vWD)and is the most common candisease lead independent nearly normal lives. inherited bleeding disorder. It affects 1% to 2% of the population. Von Willebrand factor is a cofactor for platelet adhesion and a carrier protein for factor VIII vonThe Willebrand Disease form is transmitted as an autosomal dominant trait. Severity of bleeding (8,9). most common von Willebrand disease (vWD) is the most common inherited bleeding disorder. It affects 1% to 2% of the population. von symptoms depends on the type and subtype. Types 1 and 3 result in quantitative defects of the von Willebrand factor is a cofactor for platelet adhesion and a carrier protein for factor VIII (8,9). The most common form is transmitted as an Willebrand protein (i.e., while symptoms Type 2 isdepends due toona the qualitative defect Types in the1 von autosomal dominant trait. deficiency) Severity of bleeding type and subtype. and 3Willebrand result in quantitative defects of the von Willebrand proteinare (i.e., deficiency) while protein. The vWD types listed in table 3. Type 2 is due to a qualitative defect in the von Willebrand protein. The vWD types are listed in table 3. Table 3 - von Willebrand disease subtypes Type Defect Bleeding symptoms Type 1 (common) Quantitative: Decreased vWF Mild Type 2 (uncommon) 2A 2B 2N 2M Qualitative: Normal vWF levels vWF not "sticky" enough vWF too "sticky" Lacking receptor for factor VIII binding Lacking receptor for platelet binding Variable Potentially severe Similar to hemophilia Fairly mild Type 3 (rare) Quantitative absent vWF Severe Patients with vWD often have a positive family history of bleeding and easy bruisability in addition to the personal bleeding history. The bleeding symptoms be similar to that family seen withhistory thrombocytopenia or platelet dysfunction and usually involve the Patients with vWD oftencanhave a positive of bleeding and easy bruisability in addition tomucous the membranes and patients present complaints of recurrent oral bleeding and menorrhagia. In personal bleeding history. Thewith bleeding symptoms canepistaxis, be similar to that with seendental withcare, thrombocytopenia oraddition, they often have a history of easy or spontaneous bruising and post-operative bleeding. More rarely, one may elicit a history of gastrointestinal platelet dysfunction and usually involve the mucous membranes and patients present with complaints of or genitourinary bleeding. Types 2N and 3 may also have deep tissue bleeding, similar to the bleeding seen in moderate or severe recurrent epistaxis, oral bleeding with dental care, and menorrhagia. In addition, they often have a history hemophiliacs. of easy orThe spontaneous bruisingtests andinpost-operative bleeding. More rarely, one elicit a history of activity most useful screening patients with suspected vWD are bleeding time, PTTmay and von Willebrand factor (ristocetin cofactor). Ristocetin cofactor is a functional of the protein. least bleeding, one of thesesimilar screeningtotests will be gastrointestinal or genitourinary bleeding. Types assay 2N and 3 von mayWillebrand also have deep At tissue abnormal in 97% of patients with vWD (10). Other useful studies include platelet count, von Willebrand factor (vWF) antigen and factor the bleeding seen in moderate or severe hemophiliacs. VIII activity. Once the diagnosis of vWD is made, the vWF multimeric assay and platelet aggregation studies will determine the type of vWD. With deficient or defective von Willebrand factor, there will be abnormal platelet aggregation to ristocetin. Other platelet Theaggregation most useful screening in patients with suspected vWD are bleeding time, PTT and von Willebrand studies should betests normal. It is important to keep in mind that vWF is an cofactor acute phaseisreactant and therefore, vWD can be affected by cigarette factor activity (ristocetin cofactor). Ristocetin a functional assaystudies of theforvon Willebrand protein. smoking, stress, exercise, pregnancy, corticosteroids, birth control pills, etc. In addition, people who are blood group O have a lower At least one of these screening tests will be abnormal in 97% of patients with vWD (10). Other useful normal range for vWF antigen and ristocetin cofactor activity. When there is a strong suspicion that a patient has vWD, the laboratory studies include count, von evaluation mayplatelet need to be repeated upWillebrand to 3 times. factor (vWF) antigen and factor VIII activity. Once the diagnosisInofmost vWD is ofmade, thebleeding vWF multimeric and platelet aggregation studies determine cases vWD the symptoms areassay quite mild, and therapy includes education andwill measures for localthe control of Aminocaproic acid isor useful in treating mucous membrane bleeding. Desmopressin (DDAVP)platelet causes a release of factor VIII typebleeding. of vWD. With deficient defective von Willebrand factor, there will be abnormal and vWF from storage sitesOther and is useful in treating bleedingstudies symptoms in patients with mild (type 1) vWD. Patient with severe forms of aggregation to ristocetin. platelet aggregation should be normal. vWD (type 3) or a qualitative defect of the vWF (types 2A, 2B, 2N) may need replacement with Humate-P (a factor VIII product It is important to keep in mind that vWF is an acute phase reactant and therefore, studies for vWD can be affected by cigarette smoking, stress, exercise, pregnancy, corticosteroids, birth control pills, etc. In addition, people who are blood group O have a lower normal range for vWF antigen and ristocetin cofactor activity. When there is a strong suspicion that a patient has vWD, the laboratory evaluation may need to be repeated up to 3 times. In most cases of vWD the bleeding symptoms are quite mild, and therapy includes education and measures for local control of bleeding. Aminocaproic acid is useful in treating mucous membrane bleeding. Desmopressin (DDAVP) causes a release of factor VIII and vWF from storage sites and is useful in treating bleeding symptoms in patients with mild (type 1) vWD. Patient with severe forms of vWD (type 3) or a qualitative defect of the vWF (types 2A, 2B, 2N) may need replacement with Humate-P (a factor VIII product containing vWF) (8,9). Once diagnosed and followed and treated in a comprehensive hemophilia treatment center, people with vWD can lead normal lives. Other Factor Deficiencies Deficiencies in other fluid factors are much more rare than deficiencies in factors VIII, IX or vWF. Factor XI deficiency presents with variable bleeding and a prolonged PTT. Bleeding symptoms do not correlate with the factor level (11). It is more common in the Ashkenazi Jewish population. Deficiencies of the contact factors (factor XII-Hageman factor, high molecular weight kininogen, and prekallikrein) are associated with a significantly prolonged PTT without bleeding symptoms (11). Deficiencies of factors II, V, VII, X and XIII are very rare. For most of these, bleeding symptoms occur in those whose factor levels are <5% to 10% (11). Factor VII deficiency should be considered with isolated prolongation of the PT. Factors II, V, and X are common pathway factors and present with prolongation of both PT and PTT. Factor XIII deficiency is associated with bleeding from the umbilical stump and intracranial hemorrhage with a normal PT and PTT. It is only symptomatic in patients whose level is <1%. Treatment consists of replacement of the deficient factor with fresh frozen plasma or, if available, specific factor concentrate (11). Acquired Defects of Secondary Hemostasis Vitamin K is needed for the synthesis of factors II, VII, IX and X. Vitamin K is vital to the carboxylation of glutamic acid residues which is needed for the calcium and phospholipid-dependent activation of these factors (1). The most common circumstance in which vitamin K deficiency leads to bleeding is hemorrhagic disease of the newborn. Without vitamin K supplementation, significant GI and cutaneous hemorrhage may develop within a few days (1). After the newborn period, vitamin K is absorbed from the GI tract. Deficiency may then result from nutritional deficits, malabsorption, or alteration in intestinal flora. Treatment must be directed at the underlying disorder and vitamin K supplementation. Decreased synthesis of coagulation proteins occurs in severe liver disease. Abnormalities in the liver's capacity to synthesize one or more clotting factors may result in problems with hemostasis. Treatment involves replacement of the decreased factor(s) with fresh frozen plasma. Liver disease may also lead to portal hypertension and platelet sequestration in the spleen. Disseminated intravascular coagulation (DIC) occurs in patients who are critically ill and therefore, rapid diagnosis is essential. Fever, hypotension, acidosis, oliguria, or hypoxia may be present. In addition, petechiae, purpura, and oozing from wounds and venipuncture sites may develop. Although not always clinically evident, microvascular and large vessel thrombosis may occur. The platelet count is typically decreased due to consumption and platelet destruction. The PT and PTT are prolonged from depletion of factors V, VIII, IX, and XI. Fibrinogen is decreased. Fibrin degradation products and the D-dimer assay are increased. The mainstay of therapy is to treat the underlying disease. However, this may not always be enough to correct serious bleeding or thrombosis. Additional therapy consists of replacing clotting factors and platelets and possibly the use of heparin and antifibrinolytic agents (1). Circulating inhibitors such as heparin and the lupus anticoagulant (antiphospholipid antibody) often lead to abnormalities in screening coagulation laboratory values. These cause a prolonged PTT which is not corrected with 1:1 dilution with normal plasma (the PTT mixing study). If the patient has a factor deficiency such as hemophilia, adding normal plasma to the patient's plasma, will partially correct the factor deficiency and the PTT will normalize. If the PTT does not normalize by adding normal plasma, this implies that an anticoagulant is present in the patient's plasma. The term “lupus anticoagulant” is misleading because it can occur in many clinical settings other than in SLE and the anticoagulant effects plasma. Liver disease may also lead to portal hypertension and platelet sequestration in the spleen. Disseminated intravascular coagulation (DIC) occurs in patients who are critically ill and therefore, rapid diagnosis is essential. Fever, hypotension, acidosis, oliguria, or hypoxia may be present. In addition, petechiae, purpura, and oozing from wounds and venipuncture sites may develop. Although not always clinically evident, microvascular and large vessel thrombosis may occur. The platelet count is typically decreased due to consumption and platelet destruction. The PT and PTT are prolonged from depletion of factors V, VIII, IX, and XI. Fibrinogen is decreased. Fibrin degradation products and the D-dimer assay are increased. The mainstay of therapy is to treat the underlying disease. However, this may not always be enough to correct serious bleeding or thrombosis. Additional therapy consists of replacing clotting factors and platelets and possibly the use of heparin and antifibrinolytic agents (1). Circulating inhibitors such as heparin and the lupus anticoagulant (antiphospholipid antibody) often lead to abnormalities in arescreening only observed vitro with of the PTT, but isnot excessive bleeding. Instead, when coagulationin laboratory values.prolongation These cause a prolonged PTT which notwith corrected with 1:1 dilution with normal plasma (the it PTT mixing study). itIf may the patient has a factor deficiency such as hemophilia, adding normal plasma to the patient's plasma, partially occurs in adults, be associated with spontaneous abortion, and thromboembolism. In thewillpediatric correct the factor deficiency and the in PTT will normalize. If the PTT does notoften normalize by adding anormal implies that an population, it usually occurs otherwise healthy children, following viralplasma, illnessthisand is transient anticoagulant is present in the patient's plasma. The term “lupus anticoagulant” is misleading because it can occur in many clinical settings with rare clinical sequelae (1). other than in SLE and the anticoagulant effects are only observed in vitro with prolongation of the PTT, but not with excessive bleeding. Instead, when it occurs in adults, it may be associated with spontaneous abortion, and thromboembolism. In the pediatric population, it usually occurs in otherwise healthy children, often following a viral illness and is transient with rare clinical sequelae (1). A summary of laboratory studies for bleeding disorders is listed below. Routine tests are commonly orderedAby non-hematologists. tests are not ordered are onlyordered ordered (most commonly summary of laboratory studiesSpecial for bleeding disorders is listed below. routinely Routine testsand are commonly by non-hematologists. tests are not ordered routinely and are only ordered (most commonly by hematologists and other subspecialists) when a bleeding bySpecial hematologists and other subspecialists) when a bleeding disorder is highly suspected. disorder is highly suspected. Tests for: Abnormal in: Disorders of platelet quantity ITP, HUS, TTP, thrombocytopenia due to bone marrow suppression, platelet consumption. PT Extrinsic and common coagulation Pathway (factors I, II, V, VII, X) Factor deficiency (I, II, V, VII, X), liver failure, vitamin K deficiency, coumadin, warfarins. PTT Intrinsic and common pathway (factors I, II, V, X, VIII, IX, XI, XII) Factor deficiency (I, II, V, X, VIII, IX, XI, XII), heparinization, circulating anticoagulants, vWD Circulating anticoagulants. PTT corrects with factor deficiency, but it does not normalize with circulating antibodies/anticoagulants. Bleeding time Platelet function ASA, NSAIDs, platelet function disorders (see table 2), vWD Platelet aggregation Platelet function ASA, NSAIDs, platelet function disorders (see table 2), vWD Ristocetin cofactor vWF function vWD vWF antigen vWF quantity vWD Routine tests: Platelet count Special tests: PTT mixing study vWF multimeric assay Defines type of vWD vWD Chapter XI.7. Transfusion Medicine Kelley A. Woodruff, MD A 7 year old boy is being worked up for profound pancytopenia. He was well until one week ago when his grandparents noted pallor. He has had no recent history of fever, and is otherwise well. He was initially seen yesterday in the hematology clinic, where a CBC showed a hemoglobin of 5.3 g/dl, WBC 1.9 K/ml with 96% lymphocytes, and a platelet count of 4,000. He has a bone marrow aspirate scheduled for tomorrow. He is brought back in to the clinic today, because he has epistaxis, which has been ongoing for 1 hour now. He states he feels weak and dizzy. Exam: He is afebrile, BP 110/40, HR is 186 with a mild gallop. Weight is 26 kg (75%ile). He is lying down, with a tissue to his nose, and bright red blood is dripping out. He is alert and oriented, nontoxic, and comfortable. He is pale appearing, conversing appropriately, and no other overt bleeding is noted. His abdomen is benign. CBC today shows hemoglobin 5.1, WBC 1.3, and platelet count 5,000. After IV access is obtained, he is given a fluid bolus and a "type and hold" for blood status is ordered. The start of transfusion medicine occurred during World War II when the major blood types A, B, AB and O, and Rh factor were identified. Type A persons have A antigen on the membrane of their red blood cells. They develop anti-B antibodies shortly after birth without any prior antigenic stimulation, thus these antibodies are called natural antibodies. Type B persons have B antigen on the membranes of their red blood cells, and such persons naturally have anti-A antibodies in their plasma. Type AB persons have both A and B antigens, and no anti-A or anti-B antibodies in their plasma. Type O persons, who lack these major red cell membrane antigens, have both anti-A and anti-B antibodies. When crossmatching a unit of blood for a transfusion, the biggest concern is to avoid giving the patient antigen that would react with their own antibodies. Thus, people with type O blood are considered to be universal donors, with regard to red blood transfusions, since there are no major (A or B) antigens on their red blood cells. Most transfusions of red blood are given as packed red blood cells (PRBCs) that have most of the plasma removed. Each unit of PRBCs is about 250 ml, depending on the type of preservative used, and each ml provides 1 milligram of elemental iron. The fastest rate of transfusing a patient should be 5 ml/kg/hour. Generally, a transfusion is ordered as 10-15 ml/kg given over 2 to 3 hours. The advent of platelet transfusions in the early 1970's changed the survival rate for many diseases. Today, single donor platelets are usually considered the optimal product for most platelet transfusion needs. A single donor unit of platelets is based on the adult dose and contains about 225 ml per unit. It is obtained via pheresis from one donor and takes about 4 hours to donate, compared to 30 minutes to donate one pint of whole blood. Platelets extracted from a unit of whole blood (called random platelets) contain about 50 ml per unit. Usually about 6-8 random units (i.e., 6-8 different donor exposures!) need to be pooled together to equal the volume of one unit of single donor platelets. Single donor platelet transfusions are usually given over 1 hour. A hemolytic transfusion reaction results when an antibody-antigen reaction causes (donor) red cell lysis. It is most severe when a patient has circulating antibody that reacts with donor antigen (RBCs). Some antigens produce stronger hemolytic reactions than others. For example, transfusion reactions involving A and B antigens will cause a brisk, severe hemolysis, leading to fatalities from renal failure. The Duffy and Kell antigens also cause significant hemolysis. The Lewy antigen leads to a mild hemolysis that is not usually fatal (remembered by the mnemonic Duffy dies, Kell kills, and Lewy lives). There are many other less common antigens, natural and acquired, that are screened for in the direct antibody test (DAT) during crossmatching. A patient having a hemolytic transfusion reaction may present with lower back pain, and hemoglobinuria. The treatment consists of supportive care, especially intravenous hydration to help protect the kidneys from damage. Corticosteroids may also be beneficial. Another type of transfusion reaction is associated with urticaria, or less commonly, fevers. These reactions are typically caused by extraneous donor proteins, which are foreign to the recipient. These proteins are usually carried in the plasma of the donor product. Therefore, such reactions are usually seen more often with platelet transfusions than with red cell transfusions, since the platelet products carry more plasma than the packed red cell units. Urticaria reactions are usually mild, and treated with diphenhydramine and sometimes IV corticosteroids. Epinephrine is only rarely required. Fevers are usually mild and self-limited, and can be managed with acetaminophen. Irradiation of blood products will inhibit the replication of nucleated cells (e.g., WBCs) in the donor product, by damaging their DNA. This radiation dose will not kill common organisms known to contaminate blood products. All transfusion products have donor stray white blood cells, which, in theory, could replicate when transfused into an immunocompromised host. This would cause a graft versus host (GVH) situation, which, when arising from a blood transfusion, is often fatal. Therefore, all blood products given to infants, oncology patients, or other immunocompromised hosts should be irradiated. The exception, of course, is a stem cell product for a stem cell (bone marrow) transplant. If these stem cells were irradiated, the new graft would not grow, and there would be no transplant. Infusion filters should be used for all transfusions of packed red blood cells and platelets. The only exception to this is the infusion of a stem cell product for any type of stem cell transplant. There are many types of filters. Their main purpose is to filter out either extraneous white blood cells or large foreign proteins. The use of a filter during a transplant of stem cells would filter out the very stem cells that are intended for the patient! Since filters will not dependably remove all white blood cells, filters cannot replace irradiation to prevent graft versus host disease. Infections acquired from transfusions are rare due to improved screening methods by blood banks. Infectious agents that can be transmitted through transfusions include HIV, Hepatitis B, Hepatitis C, Parvovirus and malaria. Blood is actively screened for all these agents and discarded if contamination is even suspected. Cytomegalovirus (CMV) infection can also be transmitted through blood transfusions. It is harbored in a dormant state in the white blood cells of previously infected persons. Since 80% of most adult populations are positive for past CMV infection, most donated blood is CMV serology positive. CMV infection can be transmitted to severely immunocompromised persons with no prior infection. Such an incident might occur during a bone marrow transplant. Since newborns up to age 4 months are considered immunocompromised and have no previous CMV infection, all newborns receive CMV negative blood. Clinicians should familiarize themselves with the options for ordering, holding, or preparing for a PRBC transfusion. A "draw and tag" should be ordered for a patient who might possibly need a transfusion during the hospital stay (but the probability of this is low). In this case, a blood sample is drawn from the patient and the patient is tagged with a special blood products identification bracelet which is matched to the specimen drawn and a set of labels which will be used on any blood products which might be ordered for the patient in the next few days. If blood products are required for this patient, they can be ordered from the blood bank. The blood bank will crossmatch the blood using the previously drawn and labeled specimen. A "type and hold", also called a "type and screen", should be ordered for a patient who has a moderate likelihood of requiring a transfusion during the hospital stay. The patient is drawn and tagged as in the "draw and tag" procedure. Additionally, the patient's blood type and Rh are determined and a screening test is performed for unexpected antibodies and minor compatibility group profiling. Thus, the patient's blood type and Rh are known which saves some time in case a crossmatch is needed. A "type and crossmatch" should be ordered when the patient will be getting a transfusion. The patient is drawn and tagged. The patient's blood type, Rh, and antibody screens are performed. A unit of blood is then selected for the patient and compatibility testing is performed with the patient's specimen and the donor unit's PRBCs. This unit is then held for the patient. This unit cannot be used for any other patient, so a "type and crossmatch" should only be ordered when a transfusion is highly likely. In a true emergency with a rapidly hemorrhaging and hypovolemic patient, the time required for blood typing and crossmatching (20 to 30 minutes) may not be available. Transfusing with O negative PRBCs (if available) is the best emergency option. In the meantime, a type and crossmatch should be in progress. Type specific blood (the patient's type and Rh are known, but a crossmatch has not yet been performed) is sometimes useful until a crossmatch is completed. There are many ethical issues which need to be considered when transfusing patients. Because of the rare possibility of morbidity and mortality from transfusions, written and informed consent must always be obtained before a transfusion is given. The patient (or patient's guardian) must be fully informed of the rare possibilities of infectious agents and transfusion reactions. Full consideration must be given to the necessity of a transfusion. In short, if spontaneous resolution of the problem (anemia, thrombocytopenia, or other morbidity in which a transfusion is thought to be beneficial) can be expected, or if alternative treatments exist, the transfusion should be avoided. When considering a transfusion, the actual morbidity and mortality from the underlying problem itself, without a transfusion, must be weighed against the rare problems that may result from the transfusion itself. Adult patients may refuse a transfusion for themselves, regardless of their reasons, even in the face of death (e.g., Jehovah's Witness patients). A parent may also refuse a transfusion for their child. However, if a physician strongly believes that a child has a life-threatening condition that can only be effectively treated with a transfusion of a blood product, the physician is obligated to take legal action. Chapter XII.2. Leukemia and Lymphoma Bruce T. Shiramizu, MD This is a 10 year old boy who presents to the emergency department with a chief complaint of fever and increasing tiredness. He was well until 2 weeks ago when he had an upper respiratory illness (URI). He has been tired with decreased activity since the URI, and has missed school and sports practices for 2 days. He has a decreased appetite and has lost 2 pounds over the last 2 weeks. He has some shortness of breath when he climbs stairs, but his parents deny cough, fever, nausea, emesis, bruising, headache, or visual problems. His past medical health, including birth history, immunizations, and other medical problems is unremarkable. He lives with his two parents and 6 year old brother, all of whom are healthy. The sibling and parents had similar URI symptoms 2 weeks ago, but everyone else is back to normal activity levels. There is no family history of relevant medical problems. Exam: VS T 38.5 degrees C, P 120, R 32, BP 110/56. Height & weight at the 80th percentile. He is alert, tired and slightly pale appearing, but in no apparent distress. His head is normocephalic without scalp lesions. His hair texture is normal. His ear canals and TMs are normal. Pupils are equal and reactive to light. Conjunctivae are pale. His fundi are normal. His nasal passages are clear. His mucous membranes are dry and pale. His posterior pharynx is erythematous without lesions and no tonsillar enlargement. His dentition and gums are normal. No nuchal rigidity is present. He has bilateral cervical nodes, posterior cervical nodes, axillary nodes, and inguinal nodes palpable (about 1-2 cm), mobile and nontender. His chest exam (breasts, lungs, heart) is normal except for some tachycardia. His abdomen is flat and non-tender with normal bowel sounds. His liver edge is palpable at the costal margin. His spleen is palpable 4 cm below the left costal margin. His back is normal. His skin shows no lesions, bruises or petechiae. Upper and lower extremities are normal. His neurological exam is normal. Laboratory: CBC Hgb 7, Hct 24, MCV 100, WBC 56,000, Differential 14% lymphoblasts, 80% lymphocytes, 6% atypical lymphocytes. Platelets 23,000. Chest x-ray shows clear lung fields but a wide mediastinum. He is admitted to the hospital and a diagnostic workup including a bone marrow aspirate and biopsy reveals acute lymphoblastic leukemia. There are different types of leukemia but the most common leukemia that occurs in children is acute lymphoblastic leukemia (ALL). ALL is the most common cancer in children representing 23% of cancer diagnoses among children younger than 15 years of age and occurring at an annual rate of approximately 31 per million (1). Approximately 2,400 children and adolescents younger than 20 years of age are diagnosed with ALL each year in the USA. There is a sharp peak in ALL incidence among children ages 2 to 3 years. Lymphomas,ingeneral,aredividedintotwobroadcategories,Hodgkin'sdisease(HD)andnonHodgkin'slymphoma(NHL). Asagroup, it is the third most common childhood malignancy with HD and NHL accounting for approximately 10% of cancers in children less than 20 years of age (2). In the United States, there are about 800 new cases of NHL diagnosed each year. Incidence is approximately 10 per 1,000,000. For both ALL and lymphoma (HD and NHL), the signs and symptoms may be similar but non-specific. The clinical manifestations may present insidiously or acutely, as an incidental finding on a routine complete blood count analysis or as a life-threatening infection or respiratory distress. Some characteristics which may present at the time of diagnosis are lethargy, fever, joint pain, bleeding, abdominal pain, CNS manifestations, and/or difficulty breathing secondary to a mediastinal mass. On physical examination, there may be pallor, hepatosplenomegaly, petechiae, and/or lymphadenopathy. Because some rare cases may be difficult to diagnose even with proper diagnostic biopsies, other diagnoses should be entertained. These include viral infections such as Epstein-Barr virus, cytomegalovirus; other malignancies such as neuroblastoma; hematological disorders such as aplastic anemia, histiocytosis, idiopathic (immune) thrombocytopenic purpura (ITP); and juvenile rheumatoid arthritis. In general, the differential diagnosis between ALL and NHL has been debated for years, and the criteria utilized to distinguish between the two categories of diseases have been arbitrary. While both entities can be of B-cell or T-cell phenotype, the distinction between NHL and ALL is currently based on the degree of bone marrow involvement. Children who have more than 25% infiltration of their marrow with blast cells are considered to have ALL. Treatment and management of ALL and NHL are based on proper diagnosis and staging to determine the extent of disease involvement. Diagnosis is made from either the bone marrow (ALL) or tissue (NHL), and includes immunophenotyping, cytogenetics, flow cytometry, and/or molecular studies such as gene rearrangements. Recommended staging studies include a careful physical examination, complete blood count, bone marrow aspirate or biopsy, lumbar puncture, and radiographic studies including possible nuclear medicine studies to assess the extent of disease. Prior to instituting specific therapy, measures should be instituted to treat emergent problems, particularly in patients with advanced disease and who may have associated airway compression or superior vena cava obstruction. Measures should also be in place to be able to monitor and intervene for treatment related problems such as tumor lysis. Tumor lysis can occur spontaneously or as a result of chemotherapy leading to serious metabolic complications such as hyperuricemia, hyperkalemia, and hyperphosphatemia. This could ultimately lead to renal failure or cardiac arrest if left untreated. Successful treatment of children with ALL and NHL requires the control of systemic disease (marrow, liver and spleen, lymph nodes, etc.) as well as the treatment (or prevention) of extramedullary disease particularly in the central nervous system (CNS) (1,3). The main goal of therapy is to begin induction treatment as soon as the diagnosis is made in order to obtain remission. After inducing remission, the next goal is to maintain remission. In general, therapy is based on cytotoxic drugs affecting the rapidly dividing cells during the cell cycle. Multiple drugs are used because each class of drugs acts on a different part of the cell cycle with the intent of interrupting cell division in the majority of malignant cells. The concept of inducing remission initially is to try and rapidly destroy the majority of malignant cells within the first 30 days of treatment. Ongoing and subsequent treatment strategies are based on the concept that malignant cells that "escaped" the induction phase will enter the cell cycle over a period of time and will then be affected by the drugs. Most of the drugs are administered orally, intravenously, or intramuscularly. CNS treatment and/or prophylaxis is administered via a lumbar puncture (intrathecal). Occasionally, emergency treatment has to be considered for life-threatening situations such as airway compression, spinal cord compression, etc. This can be accomplished with the use of radiation to the involved sites. The immune system is compromised throughout the duration of therapy. Therefore one must be attentive to any signs or symptoms of septicemia. Additionally, exposure to infectious agents including live vaccines should be avoided. In general, there are clinical and laboratory findings present at the time of diagnosis which may correlate with prognosis. A high tumor burden, whether assessed by total white blood cell count for ALL or high stage disease in NHL (or elevated serum LDH) has been consistently found to be an important prognostic factor. Other factors might include specific chromosome abnormalities, age, race, or gender. Recently, the rapidity of response to induction therapy or the presence of residual disease has been examined as a predictor of outcome. Approximate 75-80% of children and adolescents with ALL and NHL will survive at least 5 years with modern chemotherapy although outcome is variable depending on a number of factors. Since nearly all children will achieve remission with proper treatment, one of the main obstacles today is how to effectively treat bone marrow or CNS relapses. Other challenges are the result of successful treatment and related to screening and treating long term complications from therapy. These include CNS sequelae affecting cognition and learning, growth failure, reproductive sequelae, cardiac sequelae, and secondary malignancies. Chapter XII.3. Solid Tumor Childhood Malignancies Christina Keolanani Kleinschmidt An 18 month old female presents to the office for her well-child examination. A third year medical student is allowed to take the history and perform the initial examination. On a routine ophthalmoscopy exam, the student notices that the child does not have a red reflex in the right eye. This is reported to the physician who confirms the exam finding. There is no history of weight loss, anorexia, crossed eyes, fever, or irritability. Exam: VS T 37.0, P 110, R 26, BP 92/42. Height, weight, head circumference are all at the 40th percentile. She is alert and active. Leukocoria is present in the right eye. A normal red reflex observed in the left eye. Pupils are equal and reactive. The eyes are conjugate. Facial function is good. The remainder of the physical examination is negative. Clinical Course: The child is referred to an ophthalmologist. An ophthalmoscopy exam performed under general anesthesia reveals atumorintheposteriorpoleoftherighteye. AnorbitalCTdemonstratesthatthetumorisconfinedtotheglobe(i.e.,nospreadoutside the eye). Since the tumor is small it is treated with laser photoablation. Careful follow ups are scheduled to monitor for recurrences or development of secondary tumors. This chapter will cover the four most common malignant solid tumors of childhood: retinoblastoma, osteosarcoma, neuroblastoma and Wilms' tumor. Retinoblastoma Retinoblastoma is a slow growing malignant tumor of the retina that may be confined to the eye for up to months or even years. In the United States it is the seventh most common pediatric malignancy (1). About 90% of cases occur before the age of 5. Bilateral tumors occur at an earlier age than unilateral tumors. The mean age of diagnosis in bilateral tumors is 12 months whereas unilateral tumors occur at a mean of 24 months of age (2). The exact molecular pathogenesis has been elucidated for retinoblastoma, which results when there is a mutation in the retinoblastoma gene found on the long arm of chromosome 13 at band 14 (13q14). The gene is a tumor suppressor gene that is involved in regulating the cell cycle. In order for retinoblastoma to manifest, both Rb alleles must be mutated (the essence of the two hit hypothesis). In the hereditary form of retinoblastoma, the individual inherits a mutant Rb gene from the germ line. Another mutation must occur in a somatic retinal cell in order for retinoblastoma to manifest itself. In the nonhereditary form, both mutations must occur in the same somatic retinal cell. When both are mutated, defective intracellular transcription and unchecked cell proliferation leads to malignant transformation (3). If it is not detected during the routine ophthalmoscopic exam or suspected due to family history, the first presenting sign may be a white pupillary reflex called leukocoria, which is frequently noted on flash photography as a white reflex instead of the usual flash photography "red eye". Parents will often notice this and bring this to the attention of the child's physician, usually after a significant delay. This sign is present in approximately 60% of the patients and is attributed to the formation of a central posterior pole tumor. Another 20% may present instead with strabismus due to tumor involvement of the macula. Retinal detachment may also be detected. The patient may also present with a red, painful eye, poor vision, unilateral pupil dilation, heterochromia (the iris color of each eye are not the same), or nystagmus. If the tumor is in an advanced stage, the patient may present with constitutional symptoms and signs as well as neurologic defects, orbital mass, proptosis, or blindness (1). Leukocoria is difficult to detect during a routine exam. If it is not detected during the exam, yet the parent reports an abnormal pupil, a referral should still be made to an ophthalmologist. Ophthalmoscopy done by a specialist through dilated pupils is the most important test performed to diagnose retinoblastoma. If the child is young, this must be done under general anesthesia. Parents and siblings should also have a dilated ophthalmoscopic examination to rule out unsuspected or dormant tumors (2). A CT scan can also be used to detect intraocular calcification, optic nerve involvement, and extraocular extension of the tumor (4). Careful examination is required to rule out any other disorders that resemble retinoblastoma. The differential for a mass should include astrocytic hamartomas and granulomas of Toxocara canis, Coat's disease, retinopathy of prematurity, and persistent hyperplastic primary vitreous should be suspected when there is retinal detachment (1). Treatment options for retinoblastoma include enucleation, external beam radiation, plaque radiation, laser photoablation, thermotherapy, cryotherapy, and chemotherapy. The choice of treatment will ultimately depend on the size, location, and extent of the tumor, whether it is bilateral or unilateral, if there is visual potential, or if extraocular disease or metastasis is present. Enucleation is performed on large unilateral tumors that have led to severe visual impairment. Individuals with optic nerve invasion, secondary glaucoma, and seeding into the pars planta have also undergone enucleation (5). In the past, enucleation was performed on the eye with the most advanced disease in bilateral tumors. However, chemotherapy and local therapy have successfully replaced this practice (2). In the past, standard therapy for the least involved eye in bilateral tumors has been external beam radiation. However, long term consequences such as cataract formation, radiation retinopathy, optic neuropathy, and the development of secondary tumors has lead to the search for alternative treatments. Radioactive plaque therapy (or brachytherapy, in which radioactive seeds are implanted close to the tumor) has since been employed to restrict the area of the orbit exposed to radiation. This procedure has reduced the harsh consequences of radiation. Brachytherapy has also been used to treat unilateral tumors. Small tumors have also responded well to other types of local therapy, in particular cryotherapy and laser photoablation (5). Chemotherapy is also a common therapy used in the treatment of retinoblastoma. In the past, it was used basically to treat advanced extraocular disease. Today, it is used when there is extraocular extension, metastasis, and positive cerebrospinal fluid findings. It is also used if accidental dissemination of tumor cells has occurred. For example if a previous intraocular procedure was done before the diagnosis of retinoblastoma was made, the patient may be treated prophylactically with chemotherapy (5). The extent of optic nerve involvement, extension of the tumor, and choroidal involvement directly influences mortality. The outcome has been excellent in individuals suffering from unilateral intraocular tumors. Individuals with optic nerve extension beyond the lamina cribrosa have only a 40% 5 year survival rate (4). A cure rate of greater than 90% has been seen after enucleation of unilateral intraocular tumors. The use of local ablation with or without chemotherapy is also usually successful (3). Patients with a germ line mutation of the Rb gene fare a worse outcome. These are individuals who were born with one mutant Rb gene and sustained a subsequent spontaneous mutation in a somatic Rb gene. They have poor survival rates and have a reduced likelihood of salvage of vision. If they survive retinoblastoma they are at an increased risk for developing a secondary cancer. More than 90% will develop a secondary cancer within 32 years after treatment (1). This is because the retinoblastoma gene is linked to nonocular tumors, most notably osteosarcoma (1). Osteosarcoma Osteosarcoma is a malignant mesenchymal tumor of bone with resultant osteoid formation. It is the third most common cancer in children and adolescents (6). It has a bimodal incidence with the first peak occurring in the second decade of life and the second peak occurring in the elderly. It is more common in boys than in girls. The common sites of involvement are the metaphyseal regions of the distal femur, proximal tibia, and proximal humerus (7). The exact cause of osteosarcoma is unknown, but it has been linked to a variety of syndromes and genetic changes. Most notably, it has been strongly correlated with a germ line mutation of the Rb gene. Patients with retinoblastoma have a significantly increased risk for the development of osteosarcoma. If these individuals were treated with radiation, their susceptibility increases further (7). Alkylating agents and other antineoplastic drugs, have also been reported to increase the risk of developing this neoplasm. Individuals suffering from Li-Fraumeni syndrome, a familial cancer syndrome associated with a germ line mutation, are also predisposed (8). Patients usually present with pain and swelling most commonly at the knee. The pain may be intermittent and most commonly occurs at night causing it to be often dismissed as growing pains. Since individuals afflicted with this disease are commonly going through their "growth spurt", this conclusion seems rational. It may further be mistaken by the patient as a sports injury. However, not all patients present with a history of trauma. Physicians must take care not to make the same assumptions. Additional clinical findings may help them distinguish this disease from benign growing pains. These findings include a palpable mass, limited range of motion, tenderness, and warmth (8). However, since none of these findings may be present initially, an imaging study is often necessary to diagnose osteosarcoma during its earliest stage. The diagnosis of osteosarcoma can be made on: x-ray of the affected bone, MRI, CT scan, radionuclide bone scan, and biopsy. Radiographs may display a mixed lytic and blastic lesion. In more advanced cases, a sunburst pattern of new bone formation and lifting of thebonycortexmaycreatewhatiscalledaCodmantriangle(4). AnMRIofthelesionandtheentireboneisdonetoevaluatethetumor's proximity to nerves and blood vessels as well as its extension into a joint or soft tissue. CT of the chest, and bone scintigraphy detects sites of metastasis (6). After all of these procedures are done, a biopsy can be performed to make the definitive diagnosis. Together, these procedures should help to differentiate osteosarcoma from other bone disorders such as histiocytosis, Ewing's sarcoma, lymphoma, and osteomyelitis (8). In the past, osteosarcoma was treated with surgery alone. However, the survival rate was poor even for nonmetastatic cases, since most patients have non-detectable micrometastases at presentation. Surgical treatment combined with chemotherapy has greatly improved the survival rate. Treatment options available today include chemotherapy, amputation, and limb salvage procedures (7). Previously, surgical treatment meant amputation of the affected bone. The bone would be amputated 7 cm proximal to the proximal border of the tumor to minimize recurrence. The patient would then undergo chemotherapy. However, with the advent of even more effective chemotherapeutic agents, limb salvage treatment is the new therapeutic approach to osteosarcoma. The patient undergoes preoperative chemotherapy to induce primary tumor necrosis and treat micrometastatic disease (6). A block excision of the tumor and prosthetic replacement is then performed (7). Contraindications for limb salvage therapy include involvement of a neurovascular bundle by the tumor, immature skeletal age (especially for the lower limb), infection in the region of the tumor, and extensive muscle involvement that would result in poor functionality (4). This multi-agent approach has greatly improved survival rates. Approximately 75% of patients with nonmetastatic osteosarcoma of the extremity are cured. Even individuals with lung metastases have shown a 20% to 30% cure rate when treated aggressively with chemotherapy and resection of lung nodules (8). This is an improvement because pulmonary metastasis has been the major obstacle in curing patients with osteosarcoma. Neuroblastoma Neuroblastoma is a neoplasm of childhood that arises from neural crest cells involved in the development of sympathetic nervous tissue. It is the most common extracranial solid tumor of childhood, occurring at a rate of 1 case per 10,000 persons. Young children are the primary targets, with the median age of diagnosis occurring at 2 years of age. It rarely occurs in children over 10 years of age and it has a slight predilection for boys (2). The exact cause of neuroblastoma is unknown, but it has been associated with various disorders and mutations. It has been tied to disorders that involve neural crest development such as Hirschsprung's disease and neurofibromatosis type I. It has also been linked with several different types of genetic changes. These changes include n-myc proto-oncogene amplification, chromosome 1p deletion and chromosome 17q gain (9). It is believed that the 1p deletion and 17q gain are the result of an unbalanced translocation between these two sites (10). The exact role of these changes in the pathogenesis of neuroblastoma has not been elucidated. Neuroblastoma develops from sympathetic neuroblasts anywhere along the sympathetic chain ganglia or in the adrenal medulla. Spontaneous malignant transformation is believed to occur when sympathetic neuroblasts fail to differentiate. When there is complete failure of differentiation, a neuroblastoma forms. Primary tumors occur 50% in the adrenal gland, 30% in retroperitoneal sympathetic ganglia, and 20% in cervical and thoracic ganglion (9). The patient's clinical presentation depends on the location of the primary tumor, the size of the tumor, and if it has metastasized. The typical constitutional symptoms of cancer, fever, general malaise, and pain, are present. Complicating the patient's clinical presentation is the fact that approximately 75% of patients will present with metastatic disease at the time of diagnosis. Common sites of metastasis are lymph nodes, bone marrow, liver, skin, orbit, or bone (especially facial bones, skull, and appendicular bone) (2). Adrenal and retroperitoneal tumors present as an abdominal mass extending from the flank to the midline of the abdomen. The mass is usually firm, irregular, and nontender. If the mass begins to enlarge and extend further in the cavity, abdominal distention, anorexia and weight loss occur. The mass may also be a result of hepatomegaly due to tumor metastasis, so physicians must take care not to miss this diagnosis. Retroperitoneal tumors may extend into the paraspinal area and compress on the spinal cord. Thoracic tumors may compress the spinal cord and cause paraplegia. Lower lumbar tumors may cause cauda equina syndrome (10). Thoracic and cervical ganglion may also compress on surrounding structures. Thoracic masses may be an incidental finding on a chest x-ray done to evaluate dyspnea or other upper respiratory problems. A cervical tumor presents as a hard, fixed mass associated with Horner's syndrome or tracheal compression (10). These patients may present with myosis, ptosis, anhydrosis, flushing, and apparent enophthalmos. On the initial visit, the patient may also present with bone or ocular problems that indicate metastasis to these regions. The bone metastasis may manifest as bone pain with refusal to walk and reported tenderness, swelling, or the finding of a localized lump. If the tumor extends into the marrow, bone marrow suppression may occur. This manifests as anemia and weakness. Periorbital metastasis is associated with orbital ecchymosis and proptosis, also described as "raccoon eyes" (10). Clinical manifestations may also be a result of substances released from the tumors. Release of vasoactive intestinal peptide (VIP) may cause intractable secretory diarrhea leading to hypokalemia and dehydration. Release of catecholamines from the tumors is rare and may cause hypertension, tachycardia, palpitations, profuse sweating, and flushing (9). Another mysterious syndrome associated with neuroblastoma is opsomyoclonus (also called opsoclonus). This syndrome consists of myoclonic jerks and random eye movements sometimes associated with cerebellar ataxia. It is sometimes called the dancing eyes and dancing feet syndrome because of its physical presentation. The exact mechanism is unknown but hypotheses implicate either a peptide produced by the tumor or immunologic cross reactivity between the tumor and cerebellar neurons (10). Bone pain may resemble symptoms seen in rheumatoid arthritis, rheumatic fever, osteomyelitis, and acute leukemia. Abdominal masses are also present in Wilms' tumor, lymphoma, mesenteric cysts, hydronephrosis, and splenomegaly. Intractable diarrhea may be due to malabsorptive states (11). If the historical and physical findings lead to the suspicion of neuroblastoma, a complete blood count, urinalysis, and imaging studies should be done. A CBC may show anemia and thrombocytopenia indicating extension into the bone marrow. Special urine chemistry may pick up catecholamine metabolites such as homovanillic acid (HVA) and vanillylmandelic acid (VMA), break down products of the catecholamines secreted by the tumor. The skeletal survey may discover bone metastases. MRI may also detect bone metastases as well as intraspinal tumors (11). At initial presentation, ultrasound is useful for diagnosing intra-abdominal tumors and can display calcifications (11), but ultrasound interpretation requires skilled expertise. Falsely negative studies are misleading for the clinician unless an alternate imaging study such as a CT scan is done to make the diagnosis. The diagnosis must be confirmed by histologic examination. Neuroblastoma is known as one of the small, blue, round cell tumors of childhood. Histologically, it is characterized by undifferentiated neuroblast aggregates that are separated by fibrovascular septae. Neuroblastomas that mature into benign ganglioneuromas due to spontaneous regression or therapy-induced maturation may have a mixture of undifferentiated and differentiated cells (10). Some neuroblastomas (especially in infants) may undergo spontaneous regression, even if widely disseminated at initial presentation. Treatment depends on the stage of the tumor and its histology. Surgical resection is the primary treatment for those who have a localized tumor that is resectable. This includes patients with tumors that are localized to one side of the midline or those which cross the midline without encasement of major blood vessels. Radiation is indicated in those with localized, unresectable tumors that have not responded to initial chemotherapy. Chemotherapy is used in patients with advanced stages of neuroblastoma (2). The main prognostic factors for neuroblastoma are the age of the patient, the stage of the disease, presence of n-myc amplification, and chromosome 1p deletion. Children who are younger than 1 year old and have favorable histology have better survival rates for all stages than those older than 1 year. For example, a child older than 1 year with stage 2 disease has an 85% disease-free survival whereas a child younger than 1 year with stage 2 disease has nearly a 95% disease-free survival (10). Wilms' Tumor Wilms' tumor is a malignant embryonic neoplasm of the kidney most commonly seen in young children. It is the second most common abdominal tumor in children (neuroblastoma is more common). It peaks at ages 1 through 3 years with the median age of diagnosis occurring at 3.5 years in those with unilateral involvement (13). Bilateral involvement presents at an earlier age than unilateral involvement. The exact cause of Wilms' tumor is unknown, but mutations in the short arm of chromosome 11 have been detected in approximately 30% of the patients (15). The Wilms' tumor suppressor gene (WT1) is located on locus 11p13 and acts to regulate transcription of other genes during normal renal development (16). Mutation of WT1 predisposes an individual to nephrogenic rests, benign clusters of blastemal and stromal cells, which may be subjected to further mutation leading to malignant transformation (2). Deletion of this locus has been linked to the WAGR (see below) and Denys-Drash syndromes. These are syndromes that consist of various congenital anomalies in conjunction with Wilms' tumor. Individuals with the WAGR syndrome present with Wilms' tumor, aniridia, genitourinary malformations, and mental retardation (15). Those who suffer from Denys-Drash syndrome have Wilms' tumor, nephropathy, and genital abnormalities (15). A second locus has recently been discovered at the 11p15 locus. It is denoted as the WT2 gene, but its exact functions have not been elucidated. Some hypothesize that the gene is actually IGF2 (insulin growth factor 2), which encodes for a growth factor found in abundance in Wilms' tumor (2). The BeckwithWiedemann syndrome has been linked to this locus. Patients with Beckwith-Wiedemann syndrome display organomegaly (liver, kidney, adrenal, and pancreas), macroglossia, omphalocele, and hemihypertrophy (15). Individuals with this syndrome have a 10-20% incidence of tumor development, including Wilms' tumor (16). This neoplasm most commonly presents as an asymptomatic abdominal mass discovered by parents during bathing or by a doctor during a routine exam. The mass is usually smooth, firm and rarely crosses the midline. Individuals who are symptomatic may present with abdominal pain, fever, anemia, hematuria, and hypertension. The tumor may compress on the renal artery causing renal ischemia leading to renin secretion with resulting hypertension (2). Post-streptococcal glomerulonephritis may be mistakenly diagnosed in cases presenting with hematuria and hypertension. Individuals may also present with abnormalities that may link them with the syndromes associated with Wilms' tumor (WAGR, Denys-Drash, BeckwithWiedemann). Rarely, a paraneoplastic syndrome may arise in which erythropoietin is released causing polycythemia (15). An abdominal mass is linked with a variety of diseases all of which needs to be included in the differential. Those that are of importance include neuroblastoma, rhabdomyosarcoma, leiomyosarcoma, renal cell sarcoma, fibrosarcoma, hydronephrosis, polycystic kidney, adrenal hemorrhage, and renal vein thrombosis (13). Imaging studies (ultrasound or CT) are required to confirm the presence of a renal mass. Once a Wilms' tumor is suspected, a complete blood count, liver and kidney function tests, skeletal survey, and chest x-ray should also be done. Ultrasound or CT helps localize the mass, identifies associated genitourinary abnormalities, confirms function of the contralateral kidney, and indicates if there is extension to the inferior vena cava (16). CT scan is better at detecting subtle intra-abdominal abnormalities such as tumor spread, lymph node enlargement, vascularity, etc. Chest x-rays are done to look for evidence of lung metastasis. A definitive diagnosis is made based on biopsy results (13). The National Wilms' Tumor Study Group Staging System is the most common criteria used to stage a tumor. This system stages tumors according to information gathered by clinicians, surgeons, and pathologists. The first line of treatment is surgical resection whenever possible. During the procedure the surgeon should remove the tumor taking precautions to prevent tumor spillage. While the abdomen is open, the contralateral kidney should be inspected to detect involvement. The liver should also be inspected for evidence of metastasis. The renal vein should be checked to see if the tumor has extended to this area. Lastly, a retroperitoneal lymph node sample should be obtained for histopathology. If the tumor is inoperable either due to large size or the presence of invasion, a biopsy should be taken and other forms of therapy started (15). This tumor is sensitive to chemotherapy and radiation so either of these treatment options are possible therapeutic choices. If there is bilateral Wilms' tumor, complete resection is not an option since dialysis or a renal transplant would be required to prevent uremia. Instead, renal sparing surgery is preferred. First, a biopsy must be done to confirm bilateral involvement and to get histologic data to grade the tumors. Next, preoperative chemotherapy, appropriate for the stage of the tumor, is begun which lasts for up to six weeks. An abdominal CT scan is then done to determine if resection is possible. If it looks good, surgical excision is done. If it does not appear to be resectable, a second-look procedure is done in which another biopsy is taken and a partial resection is attempted. If a partial resection is not possible, then chemotherapy is utilized with or without radiation (16). The prognosis of the patient is based on the histology (grade) and stage of the tumor. A favorable histology is one in which blastemal, stromal, and epithelial elements may be seen. An unfavorable histology is an anaplastic one detectable by the presence of gigantic polypoid nuclei within the tumor sample (14). Four year Wilms' tumor survival (4): Stage I with favorable histology (96%), stage II with favorable histology (92%), stage III with favorable histology (87%), stage IV with favorable histology (83%), unfavorable histology (60%).