- Email: [email protected]
The Diagnosis of Leukemia in Childhood
Medicat Ctinics 01 North Amenca January, 1937. Chicago Number
CLINIC OF DR. ARTHUR F. ABT MICHAEL REESE HOSPITAL THE DIAGNOSIS OF LEUKEMIA IN CHILDHOOD THE diagnosis of leukemia in infancy or childhood should offer no particular difficulty when one is confronted with a case presenting the classical symptoms and signs of this condition. However, a group of atypical cases, some nonleukemic in nature which have clinically resembled leukemia, and others of a true leukemic nature which have been mistaken for other diseases, often fail to make diagnosis simple and infallible. I wish to present, therefore, a group of cases which have been of interest and offered differential problems in personal experience. The majority of leukemias in the young are of the acute type. 1 Chronic myeloid leukemia, while of infrequent occurrence, is an accepted and undisputed disease in childhood and the clinical condition is the same as in adult descriptions of the disease. Chronic lymphatic leukemia is said by many never to occur in childhood. There are some well authenticated reports which have recently been collected which make it seem probable that chronic lymphatic leukemia does occur in childhood, though it is certainly the least common type found in young life. 2 In this presentation, therefore, I shall limit myself to a discussion of the acute types of myeloid or lymphatic leukemia. Symptoms.-The symptomatology of leukemia in young life may be very briefly reviewed. The onset is usually acute with fever, headache, loss of appetite, vomiting and asthenia. The initial symptoms are followed by increasing weakness, apathy, pallor, and abdominal or bone or joint pain. Of frequent occurrence are hemorrhages from the mucous membranes 89
ARTHUR F. ABT
or into the skin, cervical adenopathy, stomatitis, and occasionally nervous symptoms. Dyspnea and cough are noted in cases of mediastinal leukemic tumor. Submaxillary and lacrimal gland swellings are sometimes noted, as well as leukemic skin infiltrations. With the rapid development of anemia the skin becomes white or lemon colored. Leukemic infiltrations occasionally occur in the retina and also in the stomach. Infiltrations are more frequent in the intestinal tract, and, when ulcerative, may cause diarrhea. Metastatic infiltrations may cause tumor formation, as in chloroma. From these symptoms it may be seen that leukemia may be mistaken for other conditions if a thorough blood examination is not made. 3 Such diseases as diphtheria, ulcerative stomatitis, angina, purpura, scurvy, and endocarditis may be suspected from the initial symptoms manifested in the mouth and throat and from the hemorrhagic tendency and the febrile course. Cytologic Differentiation.-Leukemia may be suspected when leukocytosis or hyperleukocytosis present, though it may be characterized by leukopenia throughout its course. Morphologic examination of the blood is necessary for a definite diagnosis. Predominance of immature forms of myelocytic or lymphatic type will differentiate myelogenous from lymphatic leukemia. Prevalence of immature cells and smudges aid in the diagnosis. In mature types of cells the oxydase reaction is positive for the myelocytic type and negative for the lymphocytic type. However, younger myelocytic cells, as myeloblasts, are also oxydase-negative. Cases are reported in which monocytes were the predominant type of cell and these are considered by many to be a third type of leukemia known as monocytic leukemia. 4 These are believed by others to belong to the myeloid or the lymphatic types. Stem-cellleukemia is a term applied when very immature cells predominate. Leukemia is most often associated with a leukocytosis, though it is becoming more generally recognized that many cases are characterized by a leukopenia throughout their course.
is
THE DIAGNOSIS OF LEUKEMIA IN CHILDHOOD
91
I have, therefore, divided the material to be presented into, first, a group where leukocytosis occurs and, second, into a group where leukopenia occurs. GROUP I.
DIFFERENTIATION WHEN LEUKOCYTOSIS IS PRESENT
(A) N onleukemic conditions simulating leukemia: 1. Pertussis.
2. 3. 4. 5. 6. 7. 8.
Pneumonia. Sepsis. Von Jaksch's pseudoleukemic anemia. Cooley's Mediterranean erythroblastic anemia. Infectious mononucleosis. Mediastinal tumor. Niemann-Pick essential lipoid histiocytosis.
(B) Leukemia simulating other conditions: 1. Simulating mediastinal tumor. 2. SimUlating rheumatism. 3. Simulating diarrhea. 4. Simulating parotitis.
The following cases illustrate (A) of group I in the classification presented: Pertussis is usually accompanied by leukocytosis and lymphocytosis. Not infrequently hyperleukocytosis of such a degree may be present that a diagnosis of leukemia may be suspected." The following case is illustrative:
Case I.-A female infant seven months of age was brought to the hospital because she had had 4 convulsions during the previous night. A history of a cough of two weeks' duration which had gradually increased in severity was obtained. The infant had vomited several times for two days prior to admission; this was attributed by the mother to the coughing. The convulsive seizures had been of a definite clonic nature and were generalized. The infant had been a normal, full term delivery, breast fed, with no history of previous convulsions. The remainder of the history was irrelevant and there was no history of exposure to pertussis. Physical examination revealed a fat, well-nourished seven-
ARTHUR F. ABT
month-old infant weighing 18 pounds, 14 ounces. The temperature on admission was 100.6° F. There was no craniotabes; the anterior fontanel' admitted 2 fingertips; there were no enlarged bases and no enlargement of the costochondral junctions and no widening of the epiphyses. Otoscopic examination of the ears revealed pale, normal drums. .There was harsh breathing, and a few moist sibilant dIes were heard at the left base posteriorIy. The breath sounds were vesicular throughout and there was no dulness or impairment of resonance. The heart was not enlarged to percussion, the tones were clear, and there were no murmurs. The abdomen and extremities were normal. The routine complete blood examination showed an amazingly high white blood count. The hemoglobin was 80 per cent (Sahli); red blood cell count 5,025,000; white blood cell count 213,000. The differential count showed polymorphonuclears 27 per cent, small lymphocytes TABLE 1 BLOOD FINDINGS IN A CASE OF PERTUSSIS
Day.
White L100d count.
Polymorphonuclears.
----
Lymphocytes. Small.
Large.
Transi-
tional.
Eosinophiles.
philes.
Raso~
Fir.,t (admission)
213,330
27
5
65
0
3
0
Second
115,600
35
8
56
0
1
0
Third
108,000
38
10
50
1
1
0
37
42
18
1
2
24
54
18
1
.1
0 ---
19
66
13
1
1
0
Fourth
95,000
Fifth
88,000
Sixth
86,500
---Eighth
66,000
Tenth
58,000
Twelfth
24,600
Fifteenth
21,000
--0
5 per cent, large lymphocytes 65 per cent, and eosinophils 3 per cent. The detailed blood examination is given in Table I. Pneumonia is sometimes accompanied by high initial white blood counts.
THE DIAGNOSIS OF LEUKEMIA IN CHILDHOOD
93
Case II.-A four-year-old male child was taken sick with fever and slight cough. On initial examination some rales were heard over the right lower chest, and the spleen was palpable. Blood examination showed a white count of over 40,000 with 60 per cent large lymphocytes and mononuclear cells. Two days later the signs of a frank right lower lobular pneumonia were present. Recovery from the pneumonia was uneventful by lysis. There was a gradual drop in the white blood count and the differential count returned to normal on the tenth day. We may consider the blood reaction in this child as of a lymphatic type. While lymphocytosis is physiologically present in the blood of younger children, still there is a type of child, known as the exudative lymphatic type, who will respond under slight or severe infections with a leukocytosis of lymphatic nature besides showing glandular enlargement and enlargement of the spleen. Sepsis in infants and young children may show protean manifestations. A leukemia is often simulated when the focus of the infection is obscure, the onset sudden or insidious with fever, the spleen and lymph nodes enlarged, and when a progressively developing anemia with hemorrhagic manifestations and atypical blood findings occur. The correct clinical diagnosis of the following case was not made clear until the microscopic sections made during a careful pathologicstudy revealed the true nature of the disease. Case III.-A five-year-old male was taken acutely ill with fever and abdominal pain. There was some abdominal muscle spasm. The white blood count showed 22,000 cells, 89 per cent of which were lymphocytes. Appendectomy was followed by pneumonia, following which the white count dropped. Recovery was never complete; the patient developed a stomatitis and febrile periods ensued. The stomatitis cleared and then recurred, accompanied by gingivitis, and an ulcerative lesion of the soft palate developed. Hemorrhages from the mucous membranes of the mouth and purpuric spots of the skin occurred and a dry gangrene of one finger tip was noted. The
94
ARTHUR F. ABT
Fig. I.-Bone marrow from Case Ill; sepsis simulating leukemia. clumps of cocci. (X 390.)
Fig. 2.-Liver from Case Ill; sepsis simulating leukemia. "'of cocci. (X 400.)
Showing
Showing clumps
95
THE DIAGNOSIS OF LEUKEMIA IN CHILDHOOD
spleen was considerably enlarged and the liver palpable. The white blood count rose to 57,000 and finally dropped to 900. A lymphocytic preponderance was noted practically throughout the course of the disease. Autopsy showed an organizing bronchopneumonia with clumps of cocci disseminated in the bone marrow and liver (Figs. 1, 2). Careful examination of the spleen and lymph nodes revealed no trace of leukemic infiltration (Fig. 3). With the clinical course, signs and symp-
.J
Fig. 3.-Section of lymph node from Case Ill; sepsis simulating leukemia. Showing no leukemic infiltration. Marked increase in plasma cells, characteristic of sepsis. (X 400.)
toms, and the blood examinations, this case would have fitted perfectly into a diagnosis of acute lymphatic leukemia. The complete blood findings are given in Table 2. Von Jaksch's anemia infantum, pseudoleukemia, occuts in infants from six months to two years of age. 6 It is characterized by a severe anemia, leukocytosis, and with many nucleated red blood cells and other immature cells in the circulating blood. An enlargement of the liver and spleen is
ARTHUR F. ABT TABLE 2 BLOOD FINDINGS IN A CASE OF SEPSIS
Neutrophiles.
Lymphocytes.
Monocytcs.
22,300
13
87
0
0
14,300
28
70
2
0
3,600,000
6,500
27
73
0
75
3,700,000
9,250
19
81
0
11/25/31
75
3,800,000
18,500
15
81
4
1/11/32
65
3,200,000
37,050
8
92
0
0
3/21/32
30
2,000,000
14,300
9
91
0
0
4/ 4/32
30
1,500,000
57,600
3
93
0
4/14/32
45
2,600,000
33,600
28
70
2
4/18/32
45
2,200,000
13,000
1
99
0
4/25/32
41
1,900,000
3,300
9
91
0
5/ 4/32
30
1,500,000
900
12
88
0
Date.
globin.
Hemo-
Red cells.
White cells.
11/14/31
85
4,100,000
11/15/31
80
3,700,000
11/17/31
80
11/21/31
Lymphoblasts.
I
0 0
I !
I I
I I
I
i
0
4 0 0 0 0
also present. The condition has been associated with rickets and infection, and is probably a severe form of secondary anemia due to the association of these two conditions. Case IV.-The following case illustrates this condition. A thirty-month-old female infant was seen with the complaints TABLE 3 BLOOD FINDINGS IN A CASE OF JAKSCH'S ANEl\lIA
Date.
Hemoglobin.
Red cells.
White cells.
--2/1
35
2,070,000
38,800
2/12
25
2,050,000
40,200
2/17
30
2,080,000
34,600
-----
Neutrophiles.
Lymphocytes.
Monocytes.
Myelocytes.
Normoblasts per 100 white blood cells.
--35 40 2 10 --- --------53 33 3 11 30 --- -----55 30 4 11 SS 53
of vomiting, constipation, loss of weight, and pallor of one month duration. Examination revealed a pale, poorly nourished" infant with a rachitic rosary and widening of the epiph-
97
THE DIAGNOSIS OF LEUKEMIA IN CHILDHOOD
yses. .The liver and spleen were large. The temperature was of a subfebrile character and the Wassermann reaction was negative. The blood findings showed a leukocytosis with an increase in nucleated red blood cells, and a detailed examination of the blood is given in Table 3. Erythroblastic anemia is a rare form of anemia first described and named by Cooley,7 who differentiated it from Von Jaksch's anemia. It occurs in infants of families originating in Mediterranean countries and is of congenital, familial and racial incidence. It is a slowly progressing anemia characterized by large numbers of nucleated red cells in the peripheral blood. There is enlargement of the liver and spleen, a mongoloid facies, and a characteristic change in the bones on x-ray which show a thinning of the cortices and a widening of the medullary portion with prominent trabeculation and radiating spicules from the inner table of the skull.
Case V.-A Greek male infant, two and one-half years old, had been normal at birth. At eight months of age it was TABLE
4
BLOOD FINDINGS IN A CASE OF COOLEY S ERYTHROBLASTIC ANEMIA
Date.
--10/25
--10/28 --11/1 --11/5 --11/9 --11/14 --11/18 ---
Red cells.
White cells.
Neutrophiles.
35
2,020,000
18,200
49
35
1,960,000
26,000
30
2,700,000
15,200
35
2,600,000
21,600
25
1,400,000
16,800
30
1,800,000
31,900
Hemo. globin.
25
1,140,000
21,500
11/25 --11/30
35
2,120,000
26,400
30
1,760,000
20,000
12/8
25
1,100,000
10,200
---
Lymphocytes.
Monocytes.
- - -- - 41 1
-----39 1 ---- - - 32 1 64 - - -- - 62 26 3 -----47 40 3 - - -- - -- - 58 37 2 -----52 38 9 -----64 27 6 -----49 48 0 -----54
55
43
0
Myelocytes.
9
Normoblasts per 100 white blood cells.
5
6
7
3
3
9
4
10
2
3
3
1
1
4
0
3
1
2
0
noted that his abdomen became prominent. On examination he showed a marked pallor, his temperature was sub febrile VOL. 21-7
ARTHUR F. ABT
with an occasional sudden rise; his expression was dull with a wide flat nose and with his prominent abdomen he gave a somewhat mongoloid appearance. His liver was enlarged and his spleen extended nearly to the umbilicus. A detailed blood picture is given in Table 4. Acute infectious mononucleosis, sometimes termed Pfeiffer's disease or glandular fever, is an acute illness with general glandular swelling, enlargement of the spleen and fever of long or short duration. s There is usually a reddening of the throat and at times follicular spots or a pseudomembranous type of angina are present. A leukocytosis is present and is manifested by an increased number of small and large lymphocytes and monocytes. The course of the disease is usually mild. Thoracic and abdominal symptoms may occur from enlargement of the lymph glands in these regions. The resemblance at the onset to acute leukemia may be striking with the throat lesions, fever, glandular and splenic enlargement. However, the throat lesions are less extensive than in leukemia and clear up rapidly, the disease is generally less severe, and the anemia and hemorrhagic symptoms characteristic of leukemia are absent. Diagnosis from the blood picture alone is not always possible, though some authors maintain that the large lymphocytes and monocytes found in infectious mononucleosis are pathognomonic for this condition. A diagnostic test for infections mononucleosis has recently been reported. It has been found that heterophile antibodies demonstrable in the form of sheep-cell agglutinins have been recorded in high concentration in infectious mononucleosis. The existence of heterophile antibodies was first recognized by Forssman9 and they have been investigated by numerous observers, particularly by Davidsohn1o in recent times. It has been found that certain substances, such as emulsions of cells from the organs of various mammals, birds and fish, when injected into animals such as the rabbit, give rise not only to specific antibodies but also to nonspecific antibodies which may be demonstrated in the form of hemolysis and agglutinins for· slr'eep cells. Davidsohn observed the presence of hetero-
99
THE DIAGNOSIS OF LEUKEMIA IN CHILDHOOD
phile antibodies in serum disease. Paul and Bunnelll l were the first to show that heterophile antibodies in the form of sheep cell agglutinins were present in the serum of a patient suffering with infectious mononucleosis. They found that the antibodies were present in a much higher concentration in this condition than in the blood from serum disease or other conditions. Other investigators have since shown that this test for heterophile agglutinins for sheep cells is a valuable diagnostic procedure in differentiating infectious mononucleosis from other clinical conditions of a similar nature. Agglutination has occurred when the titer of the serum has ranged from 1 :64 to 1 :4096 in cases of infectious mononucleosis. 12 In serum disease the agglutination has been positive in dilutions as high as 1: 64. In other conditions the highest titer for agglutination has been 1: 8. It can,. therefore, be said that cases presenting the clinical signs and symptoms of this disease with the accompimying blood picture whose blood serum shows an agglutination for sheep cells in a dilution of at least 1: 64 can' be diagnosed as infectious mononucleosis. Case VI.-A four-and-one-half-year-old female child was taken acutely ill with fever, .sore throat, vomiting and enlarged TABLE 5 BLOOD FINDINGS IN A CASE OF INFECTIOUS MONONUCLEOSIS
Neutrophiles.
Date.
Heroo .. globin.
Red cells.
White ceUs.
9/25
75
4,500,00C
28,000
50
48 50
14
Lymphocytes.
10/4
75
4,400,000
14,600
42
10/10
79
4,500,000
22,500
26
60
Monocytes.
I
Remarks.
2
I
Spleen 2+
8
I
Spleen 1+
10/20
..
........
22,100
38
60
2
10/28
75
4,400,000
23,300
32
60
8
11/20
78
4,800,000
30,100
24
66
10
12/15
78
4,800,000
17,500
36
54
10
; Spleen 1+ !
Spleen 1+
I Spleen tip I Spleen 0 I
cervical glands. The spleen was palpable 2 fingerbreadths below the costal margin. The acute illness was of four days' duration and the spleen was somewhat smaller after one week
ARTHUR F. ABT
100
and remained palpable for six weeks after the onset. The blood was marked by a leukocytosis with increase in the lymphocytes and mononuclear cells which were persistent for some time. There were no hemorrhages or petechial spots on the skin. The detailed blood examination is given in Table 5.
Essential lipoid histiocytosis (Niemann-Pick disease) is a disease which occurs in infants under two years of
age and is marked by mental and physical retardation, an early enlargement of the abdomen and enormous enlargement of liver and spleenP Irregular fever occurs during the course of the disease. The blood findings are marked by slight to moderate anemia, leukocytosis with some increase in the mononuclear cells. Vacuolization of the lymphocytes and monocytes has been noted.
Case VII.-A female infant aged eight months complained of anorexia, irritability and protuberant abdomen for two months. The infant was pale and irritable, with a suggestive mongoloid appearance and gave signs of mental retardation. TABLE 6 BLOOD FINDINGS IN A CASE OF NIEMANN-PICK DISEASE
Age, months.
Hemoglobin.
Red ceJls.
White cells.
8
SS
3,400,000
14,200
9
63
3,450,000
15,000
10
60
3,840,000
13,250
12
60
3,830,000
15,700
13
62
3,600,000
7,000
IS
80
4,310,000
14,500
Postoperative
65
3,800,000
14,800
Neutro- Lymphophiles. cytes. -----45 55 --35 31
:
--31 60 -----45 SO
Monocytes.
Others. I
..
VacuoIa tion of lymphocytes and monocytes.
I--~'9 5
,
I
- - - - - - - - -! 44 2 54 -----49
48
3
!
The liver and spleen were greatly enlarged. The eyegrounds were normal and the serologic examination was negative. A splenectomy was performed and the typical foam cells were found in the spleen . . The detailed blood examination is given in Table 6.
THE DIAGNOSIS OF LEUKEMIA IN CHILDHOOD
101
The following cases illustrate (B) of Group I: Mediastinal enlargements of the thymic area occur in leukemia.14 This condition may be present before actual blood changes have occurred, and the symptoms from pressure on the trachea may cause dyspnea. Irradiation of the thorax will give relief in those cases where leukemic blood changes have not already occurred and the mass may completely recede, as shown by x-ray examinations. However, the condition is only temporary, as a leukemic blood picture and signs of a true leukemia develop after an interval.
Case VIII.-The case of a ten-year-old boy with a non-
leukemic round-cell tumor of the mediastinum with a leukocytosis of 40,000 simulated this condition. The complaints were cough and a 7-pound loss of weight, shortness of breath, dyspnea and pain in the side present for one month. There was an inconstant fever, and the boy was thin and pale, showed immobility of the left chest, flatness over the left lung anteriorly and dulness posteriorly. Thoracentesis resulted in a dry tap. A laryngeal cough developed and death occurred suddenly. TABLE 7 BLOOD FINDINGS IN A CASE OF MEDIASTINAL TUMOR
Date.
--
Red cells.
5/13
75
4.160,000
15,000
6/7
65
3,800,000
40,000
I
Lymphocytcs.
~Ionocytes.
46
44
10
52
40
White cells. Neutrophiles.
Hemoglouin.
-~-~
..
I
8
---~---------.--
Autopsy showed an infiltrative round-cell tumor of the anterior mediastinum invading the lung and pericardium. The blood fmdings are given in Table 7. Arthritis may be associated with leukemia, with pains and swellings of the jointsY; When the blood count is low, an acute rheumatic fever may be erroneously thought of.
Case IX.-A male, nine years of age, complained of swelling of the right elbow associated with fever. The child was
ARTIIUR F. ABT
102
pale, thin and in considerable pain upon flexing his right arm. There was a considerable swelling of the right elbow, a general glandular enlargement, most marked in the cervical region; a palpable liver and an enlarged spleen. The temperature was 104° F. The white blood count was 10,450. The course of the disease was febrile; an increasing leukocytosis developed; swelling and redness of the left elbow occurred as well as of the metacarpals of the left hand. Finally the white blood count exceeded 40,000 and petechiae and hemorrhages occurred. Autopsy revealed the typical picture of an acute lymphatic leukemia. The detailed blood findings are given in Table 8. TABLE 8 BLOOD FINDiNGS IN A CASE OF LEUKEMIA SIMULATING RHEUMATISM
Neutro· philes.
Myelo. cytes.
Hemoglobin.
Red cells.
White cells.
4/15
60
3,200,000
10,450
4
.93
1
2
4/19
55
3,600,000
8,100
1
95
0
4
4/30
55
3,900,000
15,300
4
86
0
10
5/8
60
3,500,000
23,300
10
80
10
5/10
60
3,200,000
44,800
17
60
8
5/20
60
3,100,000
148,000
8
79
3
5/26
55
3,000,000
340,000
2
98
0
5/30
..
. .......
104,000
6
94
0
6/2
45
2,000,000
96,500
10
80
0
I
10
6/5
40
2,400,000
94,000
0
91
0
I
9
Date.
LymPho-l cytes.
Lbi~~~-
0
I
15
I
10
! I
0 0
Salivary gland enlargement may be associated with
lymphatic leukemia. Mikulicz described a condition of chronic enlargement of the salivary and lacrimal glands, which was bilateral and painless, and which he believed due to a low grade infection. Cases of this type are known as Mikulicz's disease while those associated with other conditions have been termed Mikulicz's syndrome. 16 The relationship of mumps, syphilis and tuberculosis to this disease has been suggested . • A
..t.
THE DIAGNOSIS OF LEUKEMIA IN CIDLDHOOD
I03
Case X.-A nineteen-month-old infant was admitted with
the complaint of bilateral swelling of the face for one month. He was well-nourished, slightly pale, with bilateral swelling of the submaxillary, parotid and lacrimal glands (Fig. 4). There was a general glandular enlargement. The white count on admission was 11,200, and this showed a decrease with a later
Fig. 4.-Nineteen-month-old infant with acute lymphatic leukemia, Case X. Showing swelling of submaxillary, parotid, and lacrimal glands, as well as enlargement of liver and spleen: Mikulicz's syndrome.
rise and terminal fall. The spleen was at first slightly palpable and later became greatly enlarged. During the last week of the disease the spleen rapidly shrank until it was barely palpable and the facial swellings receded. At autopsy the typical findings of acute lymphatic leukemia were demonstrated. The detailed blood findings are given in Table 9.
104
ARTHUR F. ABT
TABLE 9 BLOOD FINDINGS IN A CASE OF LEUKEMIA SIMULATING MIKULIC7.'S DISEASE
Lymphocytes.
Myelocytes.
Date.
Hemo· globin.
Red cells.
White cells.
Neutrophiles.
5/15
60
3,300,000
11,200
16
72
8
5/21
50
3,100,000
14,200
6
90
4
5/29
60
3,000,000
2,400
20
80
0
6/6
55
2,750,000
5,300
50
42
3
6/9
50
3,300,000
3,720
64
31
5
7/10
65
3,700,000
2,500
51
38
3
7/16
65
4,600,000
7,850
24
72
2
7/19
..
........
12,600
13
73
5
7/29
45
2,600,000
24,550
1
92
5
7/31
40
2,200,000
6,350
1
96
3
I I
0
8/4
35
1,500,000
2,000
0
98
2
0
8/7
..
. .......
1,550
0
100
0
II
I I
I
Mono· cytes.
I I I
I
I I
i I
4 0 0 5 0 8
I I
I I
2 9 2
0
I
The conditions above described were associated with leukocytosis. The following conditions are associated with leukopenia. GROUP II.
DIFFERENTIATION WHEN LEUKOPENIA IS PRESENT
(A) N onleukemic conditions simulating leukemia: 1. Sepsis.
2. Agranulocytosis. 3. Gaucher's disease. 4. NonIipoid splenohepatomegaly; Letterer-Siwe's disease. 5.. Aplastic anemia. 6. Malaria.
CB) Aleukemic leukemia simulating other conditions: 1. Simulating sepsis. 2. Simulating appendicitis. 3. Simulating aplastic anemia.
The following cases illustrate CA) of Group II in the classification. Sepsis in infants and children may be marked by leukopenia, often of a severe degree. The disease may be manifested by hemorrhages, petechiae and enlargements of liver and sple~n, and closely simulating leukemiaP 'J •
.....
THE DIAGNOSIS OF LEUKEMIA IN CHILDHOOD
105
Case XI.-A female infant, nine months of age, presented the complaints of anemia and purpuric spots on the skin for six weeks. The infant was acutely ill, with marked pallor and a distended abdomen. The liver and spleen were both considerably enlarged. The blood findings showed a progressive anemia with leukopenia and a relative lymphocytosis. They are given in detail in Table 10. TABLE 10 BLOOD FINDINGS IN A CASE OF SEPSIS WITH LEUKOPENIA
Hemoglobin.
Red cells.
2/16
52
2/20
53 40
1,900,000
Date.
3/10 3/15
30
Undiffer- i entiated I
White cells.
Neutrophiles.
Lympbocytes.
2,800,000
20,600
43
57
0
0
2,600,000
8,600
56
31
1
12 myelocytcs.
0
70
30
65
35
9CO,OOO
4,000
I
3,600
0
mono-
cytes.
Others.
I I
I I I I I
0 0 --
Agranulocytic angina, or malignant neutropenia, is not so common in children as in adults 1S The disease is characterized by an ulcerative nasopharyngitis, leukopenia and reduction or absence of granulocytes_ Lymphocytes and monocytes are unchanged. The fundamental pathology occurs in the bone marrow. Causes of neutropenia are (1) shifting of neutrophiles from the peripheral blood; (2) normal bone marrow, excessive destruction of neutrophiles; (3) exhaustion or inability of bone marrow to produce neutrophiles. The bone marrow is hyperplastic and microscopically shows decrease in activity of myelocytic cells. Many authors question the entity of this disease as described by Schultze, and prefer to consider the symptoms a syndrome which is capable of being produced by various etiologic agents. Gaucher's disease is characterized by an insidious onset with the gradual enlargement of the spleen and later of the liver_ Leukopenia is the characteristic blood finding with little change in the differential count. Hemorrhagic diathesis is
106
ARTHUR F. ABT
absent, and the course is protracted. Splenic puncture reveals typical Gaucher cells, pathognomonic for the disease.
Letterer-Siwe's Disease. Nonlipoid Splenohepatomegaly,so-caUed "Reticulo-endotheliosis."-I recently
have encountered a very interesting case belonging to this group, which was mistaken clinically for aleukemic lymphatic leukemia. 19a This condition is characterized by a marked splenomegaly with moderate to considerable enlargement of the liver, a hemorrhagic tendency chiefly manifested as purpura, an involvement of the osseous system which may be manifested by tumor formation, or only may be recognized with the aid of the x-ray or, pathologically, a general enlargement of the lymph glands, and a blood picture which is characterized by a severe secondary anemia and slight leukocytosis to leukopenia. The pathologic changes are characterized by a generalized hyperplasia and proliferation of the cells of the reticulo-endothelial system in various organs. The characteristic cells are large mononuclear cells, round or polygonal in shape, containing a nucleus poor in chromatin and a pale staining cytoplasm. Splenic puncture may reveal an increased number of these typical pale staining cells of a nonlipoid nature so that a correct clinical diagnosis may be made. The course of the disease is gradually downhill, accompanied by fever of a continuous nature. The duration of the disease has varied from a few weeks to several years. Aplastic anemia is a progressive anemia associated with splenomegaly, leukopenia and granulopenia and marked by a diminution of the granulocytic elements in the differential picture and a lack of regeneration of t,he red blood cells. The characteristic pathologic finding is a fatty or fibrous replacement of the bone marrow. The disease is probably a symptomcomplex and may be caused by numerous etiologic factors. The condition can only be positively diagnosed by a pathologic examination of the bone marrow. Malaria, while not often seen in temperate zones, may be confus~ with leukemia in regions where it is prevalent. 19b
THE DIAGNOSIS OF LEUKEMIA IN CIDLDHOOD
107
The splenomegaly with leukopenia may be mistaken for an aleukemic leukemia. There are cases reported in which malaria has complicated a leukemia. In chronic malaria the monocytes are often increased and occasionally a myelocytic increase may be noted. Where it is possible to demonstrate the malarial parasites in the blood the differential diagnosis should not be difficult. The following cases illustrate CB) of Group II: Aleukemic leukemia and sepsis with leukopenia are at times extremely difficult to differentiate. The following case is illustrative and proved at autopsy to be one of aleukemic lymphatic leukemia.
Case XII.-A seven-year-old female child complained of fever, vomiting,nose bleed and pallor of two weeks' duration.
Fig. S.-Microscopic section of liver from · case of aleukemic lymphatic leu!{emia simulating sepsis. Case XII. Showing periportal leukemic infiltration of liver. (X 650.)
On admission the temper~ture was 103° F., there was some bleeding from the nose, and the spleen was slightly enlarged.
r08
ARTHUR F. ABT
There was a marked anemia with leukopenia. Hemolytic streptococci were cultured from the blood. A diagnosis of sepsis was made and 5 transfusions were given at intervals. After six weeks the hemoglobin and red count were within normal values and the white count 7400. The child was afebrile and was discharged in excellent condition. Two weeks later she returned with a marked anemia and petechiae on the extremities. There was 32,800 white cells, of which 96 per
Fig. 6.-Microscopic section of kidney from case of aleukemic lymphatic leukemia simulating sepsis. Case XII. Showing leukemic infiltration. (X 600.)
cent were lymphocytes. A septic course marked by angina and hemorrhages ended in death. ,The autopsy revealed the characteristic findings of lymphatic leukemia (Figs. 5, 6). The detailed blood examinations are given in Table 11. Aleukemic leukemia may simulate appendicitis. It will be noted that in a previous case here reported a child was operated for appendicitis and developed a sepsis simulating leu~emia until autopsy proved the true condition.
THE DIAGNOSIS OF LEUKEMIA IN CmLDHOOD TABLE
I09
11
BLOOD FINDINGS IN A CASE OF ALEUKEMIC LEUKEMIA SIMULATING SEPSIS
Date.
Hemoglobin.
Red cells.
White cells.
10/23
30
1,060,000
2,125
Neutrophiles.
Lymphocytes.
Monocytes.
24
75
0
I
Myelocytes. 1
Five blood transfusion s 12/7
65
4,100,000
7,400
38
57
5
12/24
40
1,900,000
32,800
2
96
2
12/27
35
1,500,000
5,600
9
89
2
12/31
40
2,000,000
14,000
20
75
5
1/3
..
I ........
9,500
15
80
5
1/7
30
1,500,000
2,700
5
93
2
I
0
I i
I i
0 0 0 0
I I
0
Case XIII.-A male child, six years of age, developed a sudden night attack of pain in the lower abdomen, tenderness and rigidity in the lower right quadrant with a white blood count of 6000. The appendix was removed and revealed little evidence of inflammation. A similar attack occurred three weeks after operation and attacks of pain with fever occurred at intervals. Numerous transfusions were given, the leuTABLE
12
BLOOD FINDINGS IN A CASE OF ALEUKEMIC LEUKEMIA SIMULATING APPENDICITIS
Date.
Hemoglobin.
Red cells.
8/11
White cells.
Neutrophiles.
Lymphocytes.
Monocytes.
Immature Iymphocytes.
40
3,800,000
3500
40
60
0
0
8/18
50
2,600,000
2100
20
66
2
12
9/1
58
3,600,000
5400
10
87
1
2
9/25
40
2,250,000
6200
8
80
3
9 7
10/1
42
2,900,000
5300
9
80
4
10/17
46
2,800,000
5000
4
88
2
I
!
6
kocytes dropped and pentnucleotide was administered. There was a septic course with gradual decline. Liver and spleen were never palpable. At autopsy the diagnosis of lymphatic leukemia was established. The detailed blood examination is given in Table 12.
110
ARTHUR F. ABT
Aleukemic leukemia may simulate aplastic anemia and, as has been said, the diagnosis can only be definitely established by a pathologic examination of the bone marrow. 20 The following unusual case which was under close observation for over two years showed an almost constant leukopenia accompanied by splenomegaly, anemia and lymphocytosis. The prolonged course and associated blood findings with neutropenia and the findings of myelocytes on only 2 occasions made a clinical diagnosis of aplastic anemia seem probable. Case XIV.-A female child was first admitted at the age of four years with the complaints of weakness, loss of weight and night-sweats. The child was thin and pale with enlarged abdomen; anemia was marked. The liver and spleen were palpable. There were a few purpuric spots on the skin. Over a two-year period there were repeated exacerbations of fever, hemorrhages and enlargements of liver and spleen. During periods the symptoms subsided and the anemic condition improved. There were occasional complaints of pain over the long bones. Numerous transfusions were given during the course of the disease. Two months before the fatal termination blindness developed in the left eye. At times during the course of the disease the liver and spleen were barely palpable, while at other periods the enlargement reached to the umbilicus. Autopsy showed typical leukemic infiltrations of myeloid cells and the final diagnosis was chronic aleukemic myeloid leukemia. The detailed blood findings are given in Table 13. Leukemia in the Newborn Period.-Leukemia may occur at a very early age. V. Kornmann 21 describes its occurrence in the newborn period in a six weeks' old female infant. Autopsy demonstrated that the case was one of acute myeloid leukemia of the myeloblastic type. In 1922 Koch 22 described this disease in 2 newborn infants. In 1924 StranSky 23 described myeloid leukemia in a three weeks' old female infant. In the same year Opitz24 described the disease in a twelve weeks' old infant. Biingeler25 in 1931 described congenital myeloid leukemia in a stillborn child. These 6 reports
THE DIAGNOSIS OF LEUKEMIA IN CHILDHOOD
III
TABLE 13 BLOOD FINDINGS IN A CASE OF ALEUKEMIC LEUKEMIA SIMULATING APLASTIC
Date.
Hemoglobin.
I Red cells.
l White cells.
6/11/31
50
2,100,00e
2200
6/25
65
2,.100,000
3750
7/8
55
3,200,000
4300
7/22
65
3,400,000
3600
8/4
55
3,100,000
3250
9/18
4200
60
3,800,000
10/4
60
3,900,000
10/25
55
2,60C,000
11/13
55
2,900,000
11/30
75
4,500,000
12/31
75
5,100,000
70
3,000,000
Neutrophiles.
I Lymphocytes.
Monocytes.
Myclocytes.
Immature leukocytes.
---------------
13 86 0 1 0 - - -- - -- - -- - - ---84 0 16 0 0 --------------11 86 3 0 0 --------------84 16 0 0 0 - - - ---- - - -- - - - - 61 3 0 0 36 --------------19 0 0 5 76
--------------0 2 5900 26 62 10 -----------------4 6 0 4900 26 64 ---- - - -----1 62 5 0 32 5000 - - - - - - - - - -.-- - - 0 53 7 0 5500 40 - - -- - - - - - - - - ---22 70 8 0 0 5900 - - - - - - ---- - - -- - 1 0 1 2800 10 88 --------------7 1 84 8 0 1700 --------------18 14 65 3 0 4800 - - -- - -- - - - - - - - - ---2 6 0 0 1400 92 -----------0 6 1600 16 84 0 --------------~--
2/ 4/32 4/6
45
2,500,000
5/26
70
4,100,000 1,200,000
7/ 1
30
8/ 9
40
1,300,000
10/31
70
4,400,000
11/27
..
3,600,000
3200
0 74 4 0 16 - - 9 - - - 6 1 - - - 1 0 - - - 0 - 1 - 20 --
12/ 9
20
900,000
3800
--I-~--15 78 3 4 0
7900
substantiate the occurrence of leukemia in the newborn period of life. Biingeler's case is of special interest as it occurred in a stillborn infant of seven months' gestation measuring 38 cm. in length and weighing 1620 Gm. Smears from blood of the vena cava and heart revealed 80 per cent myeloblasts and myelocytes. Many of these cells gave a positive oxydase reaction. There were many myeloid cells noted in the liver, spleen, myocardium, lungs, kidneys, and other organs. We may, therefore, be permitted to speak of a congenital type of leukemia. Baar and Stransky 26 quote several cases of congenital or newborn leukemia from the older literature and state that the existence of this condition has been proved beyond doubt. They further cite cases in which leukemic mothers have given birth to normal children. From the cases which
II2
ARTHUR F. ABT
they cite they conclude that acute or chronic leukemia is not transmitted from mother to child. There are several conditions occurring in the newborn which may be mistaken for leukemia. Under the term erythroblastosis of the newborn is now included the condition formerly known as icterus gravis neonatorum. 27 Newborn infants suffering from this condition either at birth or a few hours thereafter develop a rapidly deepening jaundice which is asso-
meqak or'jOC'lte
platelet 3
Q-
t@-~/~ monocyte ,1'
tree mocropho.qes
fibroblast Fig. 7.-5chematic repres~ntation showing the potentialities for the development of granulocytes, normoblasts, macrophages and fibroblasts from hematocytoblasts and lymphocytes. (Maximow and Bloom's Textbook of Histology.)
ciated with anemia and a great number of immature erythrocytes in the circulating blood. Associated with the jaundice, anemia and erythroblastic blood picture are familial history, slight edema, extensive extramedullary hematopoietic foci in the liver and various organs with increased iron deposition and occasionally a nuclear icterus in the brain. The blood picture is characterized by a severe hyperchromic anemia with great numbers . .... of immature red blood cells and occasional young wnite cell . forms. Poikilocytosis, polychromatophilia with . '~
THE DIAGNOSIS OF LEUKEMIA IN CHILDHOOD
I I3
stippling and increase in reticulated blood cells are noted. The icterus index is markedly increased and a biphasic van den Bergh reaction is present. It might 'be easy in examination of the blood smear from such a case to mistake the nucleated red blood cells, some of which are present in a very early form, for leukocytes. Several investigators, in fact, have termed this condition fetal erythroleukoblastosis
Fig. 8.-Tissue culture from normal blood, showing development of macrophages and fibroblasts. (After Maximow, 1928.)
study of the pathologic histology has corivincingly showed that erythroblastosis of the newborn is not related to leukemia. From present knowledge the cause of erythroblastosis of the newborn can best be ascribed to an embryonal persistence of hem~topoiesis of erythrocytes in various organs. Congenital syphilis may manifest itself by fever, purpura, enlargement of the liver and spleen, with anemia and occasionally with the presence of a great number of normoblasts VOL. 21-8
II4
ARTIfUR F. ABT
,I Fig. 9.-A stained smear from peripheral blood of a case of stem-cellleukemia. (After Timofejewsky and Benewolenskaja.)'
" " f,.-.~~;I 5:-:· . ."_:'
«
[~
--
Fig. lO.-Tissue culture from blood of patient shown in Fig. 9, showing growth of granulocytes and normoblasts. The stem cells from the original blood may now be identified as myeloblasts. (After Timofejewsky and Benewolenskaja.)
and a few immature myeloid cells in the blood stream. 29 If the typical luetic manifestations which accompany these phys-
THE DIAGNOSIS OF LEUXEMIA IN CHILDHOOD
II5
ical and hematologic findings are recognized, the differentiation from leukemia should not be difficult. Tissue Oulture of Blood.-Since 1914 when it was first attempted, tissue cultures of leukemic blood have been made in attempts to differentiate and establish the origin of the cell types involved in the leukemias. so In cultures of normal blood it has been found that macrophages and fibroblasts develop from lymphocytes and monocytes (Figs. 7, 8). In cultures of lymphatic leukemia the lymphocytes again develop into macrophages and fibroblasts. On the other hand, in cultures of blood from myeloid leukemia the myeloblasts develop not only into macrophages and fibroblasts but also into myelocytes, granulocytes and normoblasts. sI It is thus possible that by tissue culture we may be able to separate lymphoblasts from myeloblasts in cases of stem-cellleukemia where differentiation is otherwise impossible (Figs. 9, 10). The following report may illustrate the value of tissue culture of the blood in determining the type of leukemia.
Oase XV.-E. S.,· a thirteen-year-old girl, was taken ill
with fever, epistaxis, bleeding from the gums, and purpura. Her spleen and liver were, enlarged and there was general glandular enlargement. The child was acutely ill. Peripheral blood examination is given in Table 14. TABLE 14 \
Date.
11/19 11/27
Hemoglobin.
Lymphocytes.
Red cells.
White cells.
Oxydase reaction. Small.
55
2.464,000
55,400
..
........
155,OOe
Large.
I
86
Entirely negative.
Alllymphocytes.
Entirely negative.
14
.-
'Morphologically, we believed that we were dealing with an acute lymphatic leukemia. However, tissue cultures of the blood from this patient, at eighteen hours, contained at least 65 per cent myelocytes. We, therefore, had determined that
rr6
ARTHUR F. ABT
the cells in the peripheral blood which we took to be all lymphocytes and which were oxydase-negative, were in reality cells of the myeloid series, probably oxydase-negative myeloblasts. Instead of an acute lymphatic leukemia the case was really one of acute myeloblastic leukemia. CONCLUSIONS
A group of nonleukemic and leukemic cases are here discussed and illustrative examples presented to show how atypical cases of leukemia may be confused with nonleukemic conditions including those with leukocytosis and those with leukopenia. Cytologic as well as blood tissue culture methods of differentiation are briefly discussed. In some of these atypical cases clinical differentiation may be impossible. Sometimes even after the most careful pathologic review, the exact nature of the case may remain in doubt. BmLIOGRAPHY 1. Naegeli,
2. 3. 4. 5.
0.: Diagnostiche und Allgemeine Probleme bei Leukamien, Miinchen. med. Wchnschr., 80: 635, April 28, 1933; Cooke, J. V.: Acute Leukemia in Children, J.A.M.A., 101": 432, Aug. 5, 1933. Rupilius, K.: Ein Beitrag zu den Blutkrankheiten im Kindesalter, Jahrb. f. Kinderh., 143: 65, August, 1934; DeBruin, M.: Chronic Lymphatic Leukemia in Childhood, Folia Haemat., 48: 433, 1932. Abt, Isaac A.: Significance of Lymphocytosis in Infants and Children, MED. CLIN. N. A., 12: 24, July, 1928. Clough, Paul W.: Monocytic Leukemia, Bull. Johns Hopkins Hosp., 51: 148, Sept., 1932. Abt, Arthur F.: Extreme Leukocytosis in Pertussis, MED. CLIN. N. A., 14: 1229, 1931.
6. Pfaundler and Schlossman: Diseases of Children (English Translation edited by Peterman), Chapter on Diseases of Blood, translated by Arthur F. Abt, 2: 191, J. B. Lippincott Co., Philadelphia, 1935. 7. Cooley, T. B., Witwer, E. R., and Lee, Pearl: Anemia in Children with Splenomegaly and Peculiar Bone Changes, Am. J. Dis. Child., 34: 347, Sept., 1927. 8. Glanzmann, E.: Das Lymphaemoide Driisenfieber, Beihefte, Jahrb. f. Kinderh., S. Karger, Berlin, 1930. 9. Forssmann, J.: Die Herstellung hochwertiger spezifischer Schafhamolysine ohne Verwendung von Schafblut, Biochem. Ztschr., 37: 78, 1911. 10, Da1,lidsohn, L.: Heterophile Antigens and Antibodies, Arch. Path., 4: "
776, 1927.
THE DIAGNOSIS OF LEUKEMIA IN CHILDHOOD
II
7
11. Paul and Bunnell: The Presence of Heterophile Antihodies in Infectious Mononucleosis, Am. J. M. Sc., 183: 90, Jan., 1932. 12. Bunnell, W. W.: A Diagnostic Test for Infectious Mononucleosis, Am. J. M. Se., 186: 346, Sept., 1933. 13. Abt, Arthur F., and Bloom, William: Essential Lipoid Histiocytosis (Type Niemann-Pick), JAM.A., 90: 2076, June 30, 1928. 14. Cooke, J. V.: Mediastinal Tumor in Acute Leukemia, Am. J. Dis. Child., 44: 1153, December, 1932. 15. Smith, Carl H.: Leukopenic Myeloid Leukemia Associated with Arthritis, Am. J. Dis. Child., 45: 123, January, 1933; Poynton, F. J., and Lightwood, R.: Lymphatic Leukemia with Infiltration of Periosteum Simulating Acute Rheumatism, Lancet, 222, 1: 1192, June 4, 1932. 16. Schaffer, A. J., and Jacobsen, A. W.: Mikulicz's Syndrome, Am. J. Dis. Child., 34: 327, Sept., 1927; Reuben, Mark S., and Douglas, H.: Mikuliez's Syndrome in Leukemia, Arch. Pediat., 47: 442, July, 1930. 17. Brennemann, J., and Bigler, J. A.: Sepsis with Leukopenia (Agranulocytosis) in Children, Am. J. Dis. Child., 40: 515, Sept., 1930. 18. Givan, T. B., and Shapiro, B.: Agranulocytosis in Childhood, Am. J. Dis. Child., 46: 550, Sept., 1933; Willi, H.: Agranulocytosis in Childhood, J ahrb. f. Kinderh., 142: 102, March, 1934; Piersol, George M., and Steinfeld, E.: Granulopenia, Arch. Int. Med., 49: 578, April, 1932; Jaffe, R. H.: Bone Marrow in Agranulocytosis, Arch. Path., 16: 611, Nov., 1933. 19a. Abt, Arthur F., and Denenholz, Edward J.: Letterer-Siwe's Disease, Am. J. Dis. Child., 51: 499, March, 1936. 19b. Morrison, Samuel: Certain Phases of the Leukemia Problem, Internat. Med. Digest, 22: 373, June, 1933. 20. Abt, Isaac A.: A Case of Aleukemic Leukemia with Clinical Symptoms of Aplastic Anemia, MED. CLIN. N. A., 8: 427, Sept., 1924. 21. Kornmann, V.: Beitrag zur friihkindlichen und angeborenen Myeloischen Leukamie, Zeitschr. f. Kinderh., 56: 440, July, 1934; Simonett, R.: Myeloid Leukemia in an Infant of Seven Months, Rev. di Clin. Pediat., Feb., 1932. 22. Koch: Ref. Zbl. Path., 33: No. 1, 1922. 23. Stransky: Congenital Myeloid Leukemia in an Infant, Monatschr. f. Kinderh., 29: 654, 1925; Clinical Hematology of Infants; Arregenerative Anemia in Young Children, Ztschr. f. Kinderh., 39: 553, 1925. 24. Opitz: Acute Myelosis in Infants, Med. Klin., 20: 891, June, 1924. 25. Biingeler, W.: Angeborene Leukamie, Frankfurt. Ztschr. f. Path., 41: 257, 1931. 26. Baar, H., and Stransky, E.: Klinische Haematologie des Kindesalters, 1720, Deuticke, Leipzig, 1928. 27. Abt, Arthur F.: Erythroblastosis in Icterus Gravis Neonatorum, J. Pediat., 3: 7, July, 1933; Anemia of the Newborn, Am. J. Dis. Child., 43: 337, Feb., 1932. 28. Salomonsen, L.: Uber fetale Erythro-Ieukoblastose, Ztschr. f. Kinderh., 51: 181, June 27, 1931.
II8
ARTHUR F. ART
29. Pfaundler and Schlossman: Diseases of Children (English Translation edited by Peterman), Chapter on Diseases of Blood, translated by Arthur F. Abt, Vol. 11, 225, J. B. Lippincott Co., Philadelphia, 1935. 30. Maximow, A. A., and Bloom, WiIIiam: A Textbook of Histology, p. 102, W. B. Saunders Co., Philadelphia, 1934, 2nd edition. 31. Timofejewsky, A. D., and Benewolenskaja, S. W.: Neue Beobachtungcn an lymphoiden ZeIIen der myeloiden und lymphatischen Leukiimie in Explantation-Versuchen, Arch. f. expo ZeIIforsch., (8), 1, 1929.
CLINIC OF DR. ARTHUR F. ABT MICHAEL REESE HOSPITAL THE DIAGNOSIS OF LEUKEMIA IN CHILDHOOD THE diagnosis of leukemia in infancy or childhood should offer no particular difficulty when one is confronted with a case presenting the classical symptoms and signs of this condition. However, a group of atypical cases, some nonleukemic in nature which have clinically resembled leukemia, and others of a true leukemic nature which have been mistaken for other diseases, often fail to make diagnosis simple and infallible. I wish to present, therefore, a group of cases which have been of interest and offered differential problems in personal experience. The majority of leukemias in the young are of the acute type. 1 Chronic myeloid leukemia, while of infrequent occurrence, is an accepted and undisputed disease in childhood and the clinical condition is the same as in adult descriptions of the disease. Chronic lymphatic leukemia is said by many never to occur in childhood. There are some well authenticated reports which have recently been collected which make it seem probable that chronic lymphatic leukemia does occur in childhood, though it is certainly the least common type found in young life. 2 In this presentation, therefore, I shall limit myself to a discussion of the acute types of myeloid or lymphatic leukemia. Symptoms.-The symptomatology of leukemia in young life may be very briefly reviewed. The onset is usually acute with fever, headache, loss of appetite, vomiting and asthenia. The initial symptoms are followed by increasing weakness, apathy, pallor, and abdominal or bone or joint pain. Of frequent occurrence are hemorrhages from the mucous membranes 89
ARTHUR F. ABT
or into the skin, cervical adenopathy, stomatitis, and occasionally nervous symptoms. Dyspnea and cough are noted in cases of mediastinal leukemic tumor. Submaxillary and lacrimal gland swellings are sometimes noted, as well as leukemic skin infiltrations. With the rapid development of anemia the skin becomes white or lemon colored. Leukemic infiltrations occasionally occur in the retina and also in the stomach. Infiltrations are more frequent in the intestinal tract, and, when ulcerative, may cause diarrhea. Metastatic infiltrations may cause tumor formation, as in chloroma. From these symptoms it may be seen that leukemia may be mistaken for other conditions if a thorough blood examination is not made. 3 Such diseases as diphtheria, ulcerative stomatitis, angina, purpura, scurvy, and endocarditis may be suspected from the initial symptoms manifested in the mouth and throat and from the hemorrhagic tendency and the febrile course. Cytologic Differentiation.-Leukemia may be suspected when leukocytosis or hyperleukocytosis present, though it may be characterized by leukopenia throughout its course. Morphologic examination of the blood is necessary for a definite diagnosis. Predominance of immature forms of myelocytic or lymphatic type will differentiate myelogenous from lymphatic leukemia. Prevalence of immature cells and smudges aid in the diagnosis. In mature types of cells the oxydase reaction is positive for the myelocytic type and negative for the lymphocytic type. However, younger myelocytic cells, as myeloblasts, are also oxydase-negative. Cases are reported in which monocytes were the predominant type of cell and these are considered by many to be a third type of leukemia known as monocytic leukemia. 4 These are believed by others to belong to the myeloid or the lymphatic types. Stem-cellleukemia is a term applied when very immature cells predominate. Leukemia is most often associated with a leukocytosis, though it is becoming more generally recognized that many cases are characterized by a leukopenia throughout their course.
is
THE DIAGNOSIS OF LEUKEMIA IN CHILDHOOD
91
I have, therefore, divided the material to be presented into, first, a group where leukocytosis occurs and, second, into a group where leukopenia occurs. GROUP I.
DIFFERENTIATION WHEN LEUKOCYTOSIS IS PRESENT
(A) N onleukemic conditions simulating leukemia: 1. Pertussis.
2. 3. 4. 5. 6. 7. 8.
Pneumonia. Sepsis. Von Jaksch's pseudoleukemic anemia. Cooley's Mediterranean erythroblastic anemia. Infectious mononucleosis. Mediastinal tumor. Niemann-Pick essential lipoid histiocytosis.
(B) Leukemia simulating other conditions: 1. Simulating mediastinal tumor. 2. SimUlating rheumatism. 3. Simulating diarrhea. 4. Simulating parotitis.
The following cases illustrate (A) of group I in the classification presented: Pertussis is usually accompanied by leukocytosis and lymphocytosis. Not infrequently hyperleukocytosis of such a degree may be present that a diagnosis of leukemia may be suspected." The following case is illustrative:
Case I.-A female infant seven months of age was brought to the hospital because she had had 4 convulsions during the previous night. A history of a cough of two weeks' duration which had gradually increased in severity was obtained. The infant had vomited several times for two days prior to admission; this was attributed by the mother to the coughing. The convulsive seizures had been of a definite clonic nature and were generalized. The infant had been a normal, full term delivery, breast fed, with no history of previous convulsions. The remainder of the history was irrelevant and there was no history of exposure to pertussis. Physical examination revealed a fat, well-nourished seven-
ARTHUR F. ABT
month-old infant weighing 18 pounds, 14 ounces. The temperature on admission was 100.6° F. There was no craniotabes; the anterior fontanel' admitted 2 fingertips; there were no enlarged bases and no enlargement of the costochondral junctions and no widening of the epiphyses. Otoscopic examination of the ears revealed pale, normal drums. .There was harsh breathing, and a few moist sibilant dIes were heard at the left base posteriorIy. The breath sounds were vesicular throughout and there was no dulness or impairment of resonance. The heart was not enlarged to percussion, the tones were clear, and there were no murmurs. The abdomen and extremities were normal. The routine complete blood examination showed an amazingly high white blood count. The hemoglobin was 80 per cent (Sahli); red blood cell count 5,025,000; white blood cell count 213,000. The differential count showed polymorphonuclears 27 per cent, small lymphocytes TABLE 1 BLOOD FINDINGS IN A CASE OF PERTUSSIS
Day.
White L100d count.
Polymorphonuclears.
----
Lymphocytes. Small.
Large.
Transi-
tional.
Eosinophiles.
philes.
Raso~
Fir.,t (admission)
213,330
27
5
65
0
3
0
Second
115,600
35
8
56
0
1
0
Third
108,000
38
10
50
1
1
0
37
42
18
1
2
24
54
18
1
.1
0 ---
19
66
13
1
1
0
Fourth
95,000
Fifth
88,000
Sixth
86,500
---Eighth
66,000
Tenth
58,000
Twelfth
24,600
Fifteenth
21,000
--0
5 per cent, large lymphocytes 65 per cent, and eosinophils 3 per cent. The detailed blood examination is given in Table I. Pneumonia is sometimes accompanied by high initial white blood counts.
THE DIAGNOSIS OF LEUKEMIA IN CHILDHOOD
93
Case II.-A four-year-old male child was taken sick with fever and slight cough. On initial examination some rales were heard over the right lower chest, and the spleen was palpable. Blood examination showed a white count of over 40,000 with 60 per cent large lymphocytes and mononuclear cells. Two days later the signs of a frank right lower lobular pneumonia were present. Recovery from the pneumonia was uneventful by lysis. There was a gradual drop in the white blood count and the differential count returned to normal on the tenth day. We may consider the blood reaction in this child as of a lymphatic type. While lymphocytosis is physiologically present in the blood of younger children, still there is a type of child, known as the exudative lymphatic type, who will respond under slight or severe infections with a leukocytosis of lymphatic nature besides showing glandular enlargement and enlargement of the spleen. Sepsis in infants and young children may show protean manifestations. A leukemia is often simulated when the focus of the infection is obscure, the onset sudden or insidious with fever, the spleen and lymph nodes enlarged, and when a progressively developing anemia with hemorrhagic manifestations and atypical blood findings occur. The correct clinical diagnosis of the following case was not made clear until the microscopic sections made during a careful pathologicstudy revealed the true nature of the disease. Case III.-A five-year-old male was taken acutely ill with fever and abdominal pain. There was some abdominal muscle spasm. The white blood count showed 22,000 cells, 89 per cent of which were lymphocytes. Appendectomy was followed by pneumonia, following which the white count dropped. Recovery was never complete; the patient developed a stomatitis and febrile periods ensued. The stomatitis cleared and then recurred, accompanied by gingivitis, and an ulcerative lesion of the soft palate developed. Hemorrhages from the mucous membranes of the mouth and purpuric spots of the skin occurred and a dry gangrene of one finger tip was noted. The
94
ARTHUR F. ABT
Fig. I.-Bone marrow from Case Ill; sepsis simulating leukemia. clumps of cocci. (X 390.)
Fig. 2.-Liver from Case Ill; sepsis simulating leukemia. "'of cocci. (X 400.)
Showing
Showing clumps
95
THE DIAGNOSIS OF LEUKEMIA IN CHILDHOOD
spleen was considerably enlarged and the liver palpable. The white blood count rose to 57,000 and finally dropped to 900. A lymphocytic preponderance was noted practically throughout the course of the disease. Autopsy showed an organizing bronchopneumonia with clumps of cocci disseminated in the bone marrow and liver (Figs. 1, 2). Careful examination of the spleen and lymph nodes revealed no trace of leukemic infiltration (Fig. 3). With the clinical course, signs and symp-
.J
Fig. 3.-Section of lymph node from Case Ill; sepsis simulating leukemia. Showing no leukemic infiltration. Marked increase in plasma cells, characteristic of sepsis. (X 400.)
toms, and the blood examinations, this case would have fitted perfectly into a diagnosis of acute lymphatic leukemia. The complete blood findings are given in Table 2. Von Jaksch's anemia infantum, pseudoleukemia, occuts in infants from six months to two years of age. 6 It is characterized by a severe anemia, leukocytosis, and with many nucleated red blood cells and other immature cells in the circulating blood. An enlargement of the liver and spleen is
ARTHUR F. ABT TABLE 2 BLOOD FINDINGS IN A CASE OF SEPSIS
Neutrophiles.
Lymphocytes.
Monocytcs.
22,300
13
87
0
0
14,300
28
70
2
0
3,600,000
6,500
27
73
0
75
3,700,000
9,250
19
81
0
11/25/31
75
3,800,000
18,500
15
81
4
1/11/32
65
3,200,000
37,050
8
92
0
0
3/21/32
30
2,000,000
14,300
9
91
0
0
4/ 4/32
30
1,500,000
57,600
3
93
0
4/14/32
45
2,600,000
33,600
28
70
2
4/18/32
45
2,200,000
13,000
1
99
0
4/25/32
41
1,900,000
3,300
9
91
0
5/ 4/32
30
1,500,000
900
12
88
0
Date.
globin.
Hemo-
Red cells.
White cells.
11/14/31
85
4,100,000
11/15/31
80
3,700,000
11/17/31
80
11/21/31
Lymphoblasts.
I
0 0
I !
I I
I I
I
i
0
4 0 0 0 0
also present. The condition has been associated with rickets and infection, and is probably a severe form of secondary anemia due to the association of these two conditions. Case IV.-The following case illustrates this condition. A thirty-month-old female infant was seen with the complaints TABLE 3 BLOOD FINDINGS IN A CASE OF JAKSCH'S ANEl\lIA
Date.
Hemoglobin.
Red cells.
White cells.
--2/1
35
2,070,000
38,800
2/12
25
2,050,000
40,200
2/17
30
2,080,000
34,600
-----
Neutrophiles.
Lymphocytes.
Monocytes.
Myelocytes.
Normoblasts per 100 white blood cells.
--35 40 2 10 --- --------53 33 3 11 30 --- -----55 30 4 11 SS 53
of vomiting, constipation, loss of weight, and pallor of one month duration. Examination revealed a pale, poorly nourished" infant with a rachitic rosary and widening of the epiph-
97
THE DIAGNOSIS OF LEUKEMIA IN CHILDHOOD
yses. .The liver and spleen were large. The temperature was of a subfebrile character and the Wassermann reaction was negative. The blood findings showed a leukocytosis with an increase in nucleated red blood cells, and a detailed examination of the blood is given in Table 3. Erythroblastic anemia is a rare form of anemia first described and named by Cooley,7 who differentiated it from Von Jaksch's anemia. It occurs in infants of families originating in Mediterranean countries and is of congenital, familial and racial incidence. It is a slowly progressing anemia characterized by large numbers of nucleated red cells in the peripheral blood. There is enlargement of the liver and spleen, a mongoloid facies, and a characteristic change in the bones on x-ray which show a thinning of the cortices and a widening of the medullary portion with prominent trabeculation and radiating spicules from the inner table of the skull.
Case V.-A Greek male infant, two and one-half years old, had been normal at birth. At eight months of age it was TABLE
4
BLOOD FINDINGS IN A CASE OF COOLEY S ERYTHROBLASTIC ANEMIA
Date.
--10/25
--10/28 --11/1 --11/5 --11/9 --11/14 --11/18 ---
Red cells.
White cells.
Neutrophiles.
35
2,020,000
18,200
49
35
1,960,000
26,000
30
2,700,000
15,200
35
2,600,000
21,600
25
1,400,000
16,800
30
1,800,000
31,900
Hemo. globin.
25
1,140,000
21,500
11/25 --11/30
35
2,120,000
26,400
30
1,760,000
20,000
12/8
25
1,100,000
10,200
---
Lymphocytes.
Monocytes.
- - -- - 41 1
-----39 1 ---- - - 32 1 64 - - -- - 62 26 3 -----47 40 3 - - -- - -- - 58 37 2 -----52 38 9 -----64 27 6 -----49 48 0 -----54
55
43
0
Myelocytes.
9
Normoblasts per 100 white blood cells.
5
6
7
3
3
9
4
10
2
3
3
1
1
4
0
3
1
2
0
noted that his abdomen became prominent. On examination he showed a marked pallor, his temperature was sub febrile VOL. 21-7
ARTHUR F. ABT
with an occasional sudden rise; his expression was dull with a wide flat nose and with his prominent abdomen he gave a somewhat mongoloid appearance. His liver was enlarged and his spleen extended nearly to the umbilicus. A detailed blood picture is given in Table 4. Acute infectious mononucleosis, sometimes termed Pfeiffer's disease or glandular fever, is an acute illness with general glandular swelling, enlargement of the spleen and fever of long or short duration. s There is usually a reddening of the throat and at times follicular spots or a pseudomembranous type of angina are present. A leukocytosis is present and is manifested by an increased number of small and large lymphocytes and monocytes. The course of the disease is usually mild. Thoracic and abdominal symptoms may occur from enlargement of the lymph glands in these regions. The resemblance at the onset to acute leukemia may be striking with the throat lesions, fever, glandular and splenic enlargement. However, the throat lesions are less extensive than in leukemia and clear up rapidly, the disease is generally less severe, and the anemia and hemorrhagic symptoms characteristic of leukemia are absent. Diagnosis from the blood picture alone is not always possible, though some authors maintain that the large lymphocytes and monocytes found in infectious mononucleosis are pathognomonic for this condition. A diagnostic test for infections mononucleosis has recently been reported. It has been found that heterophile antibodies demonstrable in the form of sheep-cell agglutinins have been recorded in high concentration in infectious mononucleosis. The existence of heterophile antibodies was first recognized by Forssman9 and they have been investigated by numerous observers, particularly by Davidsohn1o in recent times. It has been found that certain substances, such as emulsions of cells from the organs of various mammals, birds and fish, when injected into animals such as the rabbit, give rise not only to specific antibodies but also to nonspecific antibodies which may be demonstrated in the form of hemolysis and agglutinins for· slr'eep cells. Davidsohn observed the presence of hetero-
99
THE DIAGNOSIS OF LEUKEMIA IN CHILDHOOD
phile antibodies in serum disease. Paul and Bunnelll l were the first to show that heterophile antibodies in the form of sheep cell agglutinins were present in the serum of a patient suffering with infectious mononucleosis. They found that the antibodies were present in a much higher concentration in this condition than in the blood from serum disease or other conditions. Other investigators have since shown that this test for heterophile agglutinins for sheep cells is a valuable diagnostic procedure in differentiating infectious mononucleosis from other clinical conditions of a similar nature. Agglutination has occurred when the titer of the serum has ranged from 1 :64 to 1 :4096 in cases of infectious mononucleosis. 12 In serum disease the agglutination has been positive in dilutions as high as 1: 64. In other conditions the highest titer for agglutination has been 1: 8. It can,. therefore, be said that cases presenting the clinical signs and symptoms of this disease with the accompimying blood picture whose blood serum shows an agglutination for sheep cells in a dilution of at least 1: 64 can' be diagnosed as infectious mononucleosis. Case VI.-A four-and-one-half-year-old female child was taken acutely ill with fever, .sore throat, vomiting and enlarged TABLE 5 BLOOD FINDINGS IN A CASE OF INFECTIOUS MONONUCLEOSIS
Neutrophiles.
Date.
Heroo .. globin.
Red cells.
White ceUs.
9/25
75
4,500,00C
28,000
50
48 50
14
Lymphocytes.
10/4
75
4,400,000
14,600
42
10/10
79
4,500,000
22,500
26
60
Monocytes.
I
Remarks.
2
I
Spleen 2+
8
I
Spleen 1+
10/20
..
........
22,100
38
60
2
10/28
75
4,400,000
23,300
32
60
8
11/20
78
4,800,000
30,100
24
66
10
12/15
78
4,800,000
17,500
36
54
10
; Spleen 1+ !
Spleen 1+
I Spleen tip I Spleen 0 I
cervical glands. The spleen was palpable 2 fingerbreadths below the costal margin. The acute illness was of four days' duration and the spleen was somewhat smaller after one week
ARTHUR F. ABT
100
and remained palpable for six weeks after the onset. The blood was marked by a leukocytosis with increase in the lymphocytes and mononuclear cells which were persistent for some time. There were no hemorrhages or petechial spots on the skin. The detailed blood examination is given in Table 5.
Essential lipoid histiocytosis (Niemann-Pick disease) is a disease which occurs in infants under two years of
age and is marked by mental and physical retardation, an early enlargement of the abdomen and enormous enlargement of liver and spleenP Irregular fever occurs during the course of the disease. The blood findings are marked by slight to moderate anemia, leukocytosis with some increase in the mononuclear cells. Vacuolization of the lymphocytes and monocytes has been noted.
Case VII.-A female infant aged eight months complained of anorexia, irritability and protuberant abdomen for two months. The infant was pale and irritable, with a suggestive mongoloid appearance and gave signs of mental retardation. TABLE 6 BLOOD FINDINGS IN A CASE OF NIEMANN-PICK DISEASE
Age, months.
Hemoglobin.
Red ceJls.
White cells.
8
SS
3,400,000
14,200
9
63
3,450,000
15,000
10
60
3,840,000
13,250
12
60
3,830,000
15,700
13
62
3,600,000
7,000
IS
80
4,310,000
14,500
Postoperative
65
3,800,000
14,800
Neutro- Lymphophiles. cytes. -----45 55 --35 31
:
--31 60 -----45 SO
Monocytes.
Others. I
..
VacuoIa tion of lymphocytes and monocytes.
I--~'9 5
,
I
- - - - - - - - -! 44 2 54 -----49
48
3
!
The liver and spleen were greatly enlarged. The eyegrounds were normal and the serologic examination was negative. A splenectomy was performed and the typical foam cells were found in the spleen . . The detailed blood examination is given in Table 6.
THE DIAGNOSIS OF LEUKEMIA IN CHILDHOOD
101
The following cases illustrate (B) of Group I: Mediastinal enlargements of the thymic area occur in leukemia.14 This condition may be present before actual blood changes have occurred, and the symptoms from pressure on the trachea may cause dyspnea. Irradiation of the thorax will give relief in those cases where leukemic blood changes have not already occurred and the mass may completely recede, as shown by x-ray examinations. However, the condition is only temporary, as a leukemic blood picture and signs of a true leukemia develop after an interval.
Case VIII.-The case of a ten-year-old boy with a non-
leukemic round-cell tumor of the mediastinum with a leukocytosis of 40,000 simulated this condition. The complaints were cough and a 7-pound loss of weight, shortness of breath, dyspnea and pain in the side present for one month. There was an inconstant fever, and the boy was thin and pale, showed immobility of the left chest, flatness over the left lung anteriorly and dulness posteriorly. Thoracentesis resulted in a dry tap. A laryngeal cough developed and death occurred suddenly. TABLE 7 BLOOD FINDINGS IN A CASE OF MEDIASTINAL TUMOR
Date.
--
Red cells.
5/13
75
4.160,000
15,000
6/7
65
3,800,000
40,000
I
Lymphocytcs.
~Ionocytes.
46
44
10
52
40
White cells. Neutrophiles.
Hemoglouin.
-~-~
..
I
8
---~---------.--
Autopsy showed an infiltrative round-cell tumor of the anterior mediastinum invading the lung and pericardium. The blood fmdings are given in Table 7. Arthritis may be associated with leukemia, with pains and swellings of the jointsY; When the blood count is low, an acute rheumatic fever may be erroneously thought of.
Case IX.-A male, nine years of age, complained of swelling of the right elbow associated with fever. The child was
ARTIIUR F. ABT
102
pale, thin and in considerable pain upon flexing his right arm. There was a considerable swelling of the right elbow, a general glandular enlargement, most marked in the cervical region; a palpable liver and an enlarged spleen. The temperature was 104° F. The white blood count was 10,450. The course of the disease was febrile; an increasing leukocytosis developed; swelling and redness of the left elbow occurred as well as of the metacarpals of the left hand. Finally the white blood count exceeded 40,000 and petechiae and hemorrhages occurred. Autopsy revealed the typical picture of an acute lymphatic leukemia. The detailed blood findings are given in Table 8. TABLE 8 BLOOD FINDiNGS IN A CASE OF LEUKEMIA SIMULATING RHEUMATISM
Neutro· philes.
Myelo. cytes.
Hemoglobin.
Red cells.
White cells.
4/15
60
3,200,000
10,450
4
.93
1
2
4/19
55
3,600,000
8,100
1
95
0
4
4/30
55
3,900,000
15,300
4
86
0
10
5/8
60
3,500,000
23,300
10
80
10
5/10
60
3,200,000
44,800
17
60
8
5/20
60
3,100,000
148,000
8
79
3
5/26
55
3,000,000
340,000
2
98
0
5/30
..
. .......
104,000
6
94
0
6/2
45
2,000,000
96,500
10
80
0
I
10
6/5
40
2,400,000
94,000
0
91
0
I
9
Date.
LymPho-l cytes.
Lbi~~~-
0
I
15
I
10
! I
0 0
Salivary gland enlargement may be associated with
lymphatic leukemia. Mikulicz described a condition of chronic enlargement of the salivary and lacrimal glands, which was bilateral and painless, and which he believed due to a low grade infection. Cases of this type are known as Mikulicz's disease while those associated with other conditions have been termed Mikulicz's syndrome. 16 The relationship of mumps, syphilis and tuberculosis to this disease has been suggested . • A
..t.
THE DIAGNOSIS OF LEUKEMIA IN CIDLDHOOD
I03
Case X.-A nineteen-month-old infant was admitted with
the complaint of bilateral swelling of the face for one month. He was well-nourished, slightly pale, with bilateral swelling of the submaxillary, parotid and lacrimal glands (Fig. 4). There was a general glandular enlargement. The white count on admission was 11,200, and this showed a decrease with a later
Fig. 4.-Nineteen-month-old infant with acute lymphatic leukemia, Case X. Showing swelling of submaxillary, parotid, and lacrimal glands, as well as enlargement of liver and spleen: Mikulicz's syndrome.
rise and terminal fall. The spleen was at first slightly palpable and later became greatly enlarged. During the last week of the disease the spleen rapidly shrank until it was barely palpable and the facial swellings receded. At autopsy the typical findings of acute lymphatic leukemia were demonstrated. The detailed blood findings are given in Table 9.
104
ARTHUR F. ABT
TABLE 9 BLOOD FINDINGS IN A CASE OF LEUKEMIA SIMULATING MIKULIC7.'S DISEASE
Lymphocytes.
Myelocytes.
Date.
Hemo· globin.
Red cells.
White cells.
Neutrophiles.
5/15
60
3,300,000
11,200
16
72
8
5/21
50
3,100,000
14,200
6
90
4
5/29
60
3,000,000
2,400
20
80
0
6/6
55
2,750,000
5,300
50
42
3
6/9
50
3,300,000
3,720
64
31
5
7/10
65
3,700,000
2,500
51
38
3
7/16
65
4,600,000
7,850
24
72
2
7/19
..
........
12,600
13
73
5
7/29
45
2,600,000
24,550
1
92
5
7/31
40
2,200,000
6,350
1
96
3
I I
0
8/4
35
1,500,000
2,000
0
98
2
0
8/7
..
. .......
1,550
0
100
0
II
I I
I
Mono· cytes.
I I I
I
I I
i I
4 0 0 5 0 8
I I
I I
2 9 2
0
I
The conditions above described were associated with leukocytosis. The following conditions are associated with leukopenia. GROUP II.
DIFFERENTIATION WHEN LEUKOPENIA IS PRESENT
(A) N onleukemic conditions simulating leukemia: 1. Sepsis.
2. Agranulocytosis. 3. Gaucher's disease. 4. NonIipoid splenohepatomegaly; Letterer-Siwe's disease. 5.. Aplastic anemia. 6. Malaria.
CB) Aleukemic leukemia simulating other conditions: 1. Simulating sepsis. 2. Simulating appendicitis. 3. Simulating aplastic anemia.
The following cases illustrate CA) of Group II in the classification. Sepsis in infants and children may be marked by leukopenia, often of a severe degree. The disease may be manifested by hemorrhages, petechiae and enlargements of liver and sple~n, and closely simulating leukemiaP 'J •
.....
THE DIAGNOSIS OF LEUKEMIA IN CHILDHOOD
105
Case XI.-A female infant, nine months of age, presented the complaints of anemia and purpuric spots on the skin for six weeks. The infant was acutely ill, with marked pallor and a distended abdomen. The liver and spleen were both considerably enlarged. The blood findings showed a progressive anemia with leukopenia and a relative lymphocytosis. They are given in detail in Table 10. TABLE 10 BLOOD FINDINGS IN A CASE OF SEPSIS WITH LEUKOPENIA
Hemoglobin.
Red cells.
2/16
52
2/20
53 40
1,900,000
Date.
3/10 3/15
30
Undiffer- i entiated I
White cells.
Neutrophiles.
Lympbocytes.
2,800,000
20,600
43
57
0
0
2,600,000
8,600
56
31
1
12 myelocytcs.
0
70
30
65
35
9CO,OOO
4,000
I
3,600
0
mono-
cytes.
Others.
I I
I I I I I
0 0 --
Agranulocytic angina, or malignant neutropenia, is not so common in children as in adults 1S The disease is characterized by an ulcerative nasopharyngitis, leukopenia and reduction or absence of granulocytes_ Lymphocytes and monocytes are unchanged. The fundamental pathology occurs in the bone marrow. Causes of neutropenia are (1) shifting of neutrophiles from the peripheral blood; (2) normal bone marrow, excessive destruction of neutrophiles; (3) exhaustion or inability of bone marrow to produce neutrophiles. The bone marrow is hyperplastic and microscopically shows decrease in activity of myelocytic cells. Many authors question the entity of this disease as described by Schultze, and prefer to consider the symptoms a syndrome which is capable of being produced by various etiologic agents. Gaucher's disease is characterized by an insidious onset with the gradual enlargement of the spleen and later of the liver_ Leukopenia is the characteristic blood finding with little change in the differential count. Hemorrhagic diathesis is
106
ARTHUR F. ABT
absent, and the course is protracted. Splenic puncture reveals typical Gaucher cells, pathognomonic for the disease.
Letterer-Siwe's Disease. Nonlipoid Splenohepatomegaly,so-caUed "Reticulo-endotheliosis."-I recently
have encountered a very interesting case belonging to this group, which was mistaken clinically for aleukemic lymphatic leukemia. 19a This condition is characterized by a marked splenomegaly with moderate to considerable enlargement of the liver, a hemorrhagic tendency chiefly manifested as purpura, an involvement of the osseous system which may be manifested by tumor formation, or only may be recognized with the aid of the x-ray or, pathologically, a general enlargement of the lymph glands, and a blood picture which is characterized by a severe secondary anemia and slight leukocytosis to leukopenia. The pathologic changes are characterized by a generalized hyperplasia and proliferation of the cells of the reticulo-endothelial system in various organs. The characteristic cells are large mononuclear cells, round or polygonal in shape, containing a nucleus poor in chromatin and a pale staining cytoplasm. Splenic puncture may reveal an increased number of these typical pale staining cells of a nonlipoid nature so that a correct clinical diagnosis may be made. The course of the disease is gradually downhill, accompanied by fever of a continuous nature. The duration of the disease has varied from a few weeks to several years. Aplastic anemia is a progressive anemia associated with splenomegaly, leukopenia and granulopenia and marked by a diminution of the granulocytic elements in the differential picture and a lack of regeneration of t,he red blood cells. The characteristic pathologic finding is a fatty or fibrous replacement of the bone marrow. The disease is probably a symptomcomplex and may be caused by numerous etiologic factors. The condition can only be positively diagnosed by a pathologic examination of the bone marrow. Malaria, while not often seen in temperate zones, may be confus~ with leukemia in regions where it is prevalent. 19b
THE DIAGNOSIS OF LEUKEMIA IN CIDLDHOOD
107
The splenomegaly with leukopenia may be mistaken for an aleukemic leukemia. There are cases reported in which malaria has complicated a leukemia. In chronic malaria the monocytes are often increased and occasionally a myelocytic increase may be noted. Where it is possible to demonstrate the malarial parasites in the blood the differential diagnosis should not be difficult. The following cases illustrate CB) of Group II: Aleukemic leukemia and sepsis with leukopenia are at times extremely difficult to differentiate. The following case is illustrative and proved at autopsy to be one of aleukemic lymphatic leukemia.
Case XII.-A seven-year-old female child complained of fever, vomiting,nose bleed and pallor of two weeks' duration.
Fig. S.-Microscopic section of liver from · case of aleukemic lymphatic leu!{emia simulating sepsis. Case XII. Showing periportal leukemic infiltration of liver. (X 650.)
On admission the temper~ture was 103° F., there was some bleeding from the nose, and the spleen was slightly enlarged.
r08
ARTHUR F. ABT
There was a marked anemia with leukopenia. Hemolytic streptococci were cultured from the blood. A diagnosis of sepsis was made and 5 transfusions were given at intervals. After six weeks the hemoglobin and red count were within normal values and the white count 7400. The child was afebrile and was discharged in excellent condition. Two weeks later she returned with a marked anemia and petechiae on the extremities. There was 32,800 white cells, of which 96 per
Fig. 6.-Microscopic section of kidney from case of aleukemic lymphatic leukemia simulating sepsis. Case XII. Showing leukemic infiltration. (X 600.)
cent were lymphocytes. A septic course marked by angina and hemorrhages ended in death. ,The autopsy revealed the characteristic findings of lymphatic leukemia (Figs. 5, 6). The detailed blood examinations are given in Table 11. Aleukemic leukemia may simulate appendicitis. It will be noted that in a previous case here reported a child was operated for appendicitis and developed a sepsis simulating leu~emia until autopsy proved the true condition.
THE DIAGNOSIS OF LEUKEMIA IN CmLDHOOD TABLE
I09
11
BLOOD FINDINGS IN A CASE OF ALEUKEMIC LEUKEMIA SIMULATING SEPSIS
Date.
Hemoglobin.
Red cells.
White cells.
10/23
30
1,060,000
2,125
Neutrophiles.
Lymphocytes.
Monocytes.
24
75
0
I
Myelocytes. 1
Five blood transfusion s 12/7
65
4,100,000
7,400
38
57
5
12/24
40
1,900,000
32,800
2
96
2
12/27
35
1,500,000
5,600
9
89
2
12/31
40
2,000,000
14,000
20
75
5
1/3
..
I ........
9,500
15
80
5
1/7
30
1,500,000
2,700
5
93
2
I
0
I i
I i
0 0 0 0
I I
0
Case XIII.-A male child, six years of age, developed a sudden night attack of pain in the lower abdomen, tenderness and rigidity in the lower right quadrant with a white blood count of 6000. The appendix was removed and revealed little evidence of inflammation. A similar attack occurred three weeks after operation and attacks of pain with fever occurred at intervals. Numerous transfusions were given, the leuTABLE
12
BLOOD FINDINGS IN A CASE OF ALEUKEMIC LEUKEMIA SIMULATING APPENDICITIS
Date.
Hemoglobin.
Red cells.
8/11
White cells.
Neutrophiles.
Lymphocytes.
Monocytes.
Immature Iymphocytes.
40
3,800,000
3500
40
60
0
0
8/18
50
2,600,000
2100
20
66
2
12
9/1
58
3,600,000
5400
10
87
1
2
9/25
40
2,250,000
6200
8
80
3
9 7
10/1
42
2,900,000
5300
9
80
4
10/17
46
2,800,000
5000
4
88
2
I
!
6
kocytes dropped and pentnucleotide was administered. There was a septic course with gradual decline. Liver and spleen were never palpable. At autopsy the diagnosis of lymphatic leukemia was established. The detailed blood examination is given in Table 12.
110
ARTHUR F. ABT
Aleukemic leukemia may simulate aplastic anemia and, as has been said, the diagnosis can only be definitely established by a pathologic examination of the bone marrow. 20 The following unusual case which was under close observation for over two years showed an almost constant leukopenia accompanied by splenomegaly, anemia and lymphocytosis. The prolonged course and associated blood findings with neutropenia and the findings of myelocytes on only 2 occasions made a clinical diagnosis of aplastic anemia seem probable. Case XIV.-A female child was first admitted at the age of four years with the complaints of weakness, loss of weight and night-sweats. The child was thin and pale with enlarged abdomen; anemia was marked. The liver and spleen were palpable. There were a few purpuric spots on the skin. Over a two-year period there were repeated exacerbations of fever, hemorrhages and enlargements of liver and spleen. During periods the symptoms subsided and the anemic condition improved. There were occasional complaints of pain over the long bones. Numerous transfusions were given during the course of the disease. Two months before the fatal termination blindness developed in the left eye. At times during the course of the disease the liver and spleen were barely palpable, while at other periods the enlargement reached to the umbilicus. Autopsy showed typical leukemic infiltrations of myeloid cells and the final diagnosis was chronic aleukemic myeloid leukemia. The detailed blood findings are given in Table 13. Leukemia in the Newborn Period.-Leukemia may occur at a very early age. V. Kornmann 21 describes its occurrence in the newborn period in a six weeks' old female infant. Autopsy demonstrated that the case was one of acute myeloid leukemia of the myeloblastic type. In 1922 Koch 22 described this disease in 2 newborn infants. In 1924 StranSky 23 described myeloid leukemia in a three weeks' old female infant. In the same year Opitz24 described the disease in a twelve weeks' old infant. Biingeler25 in 1931 described congenital myeloid leukemia in a stillborn child. These 6 reports
THE DIAGNOSIS OF LEUKEMIA IN CHILDHOOD
III
TABLE 13 BLOOD FINDINGS IN A CASE OF ALEUKEMIC LEUKEMIA SIMULATING APLASTIC
Date.
Hemoglobin.
I Red cells.
l White cells.
6/11/31
50
2,100,00e
2200
6/25
65
2,.100,000
3750
7/8
55
3,200,000
4300
7/22
65
3,400,000
3600
8/4
55
3,100,000
3250
9/18
4200
60
3,800,000
10/4
60
3,900,000
10/25
55
2,60C,000
11/13
55
2,900,000
11/30
75
4,500,000
12/31
75
5,100,000
70
3,000,000
Neutrophiles.
I Lymphocytes.
Monocytes.
Myclocytes.
Immature leukocytes.
---------------
13 86 0 1 0 - - -- - -- - -- - - ---84 0 16 0 0 --------------11 86 3 0 0 --------------84 16 0 0 0 - - - ---- - - -- - - - - 61 3 0 0 36 --------------19 0 0 5 76
--------------0 2 5900 26 62 10 -----------------4 6 0 4900 26 64 ---- - - -----1 62 5 0 32 5000 - - - - - - - - - -.-- - - 0 53 7 0 5500 40 - - -- - - - - - - - - ---22 70 8 0 0 5900 - - - - - - ---- - - -- - 1 0 1 2800 10 88 --------------7 1 84 8 0 1700 --------------18 14 65 3 0 4800 - - -- - -- - - - - - - - - ---2 6 0 0 1400 92 -----------0 6 1600 16 84 0 --------------~--
2/ 4/32 4/6
45
2,500,000
5/26
70
4,100,000 1,200,000
7/ 1
30
8/ 9
40
1,300,000
10/31
70
4,400,000
11/27
..
3,600,000
3200
0 74 4 0 16 - - 9 - - - 6 1 - - - 1 0 - - - 0 - 1 - 20 --
12/ 9
20
900,000
3800
--I-~--15 78 3 4 0
7900
substantiate the occurrence of leukemia in the newborn period of life. Biingeler's case is of special interest as it occurred in a stillborn infant of seven months' gestation measuring 38 cm. in length and weighing 1620 Gm. Smears from blood of the vena cava and heart revealed 80 per cent myeloblasts and myelocytes. Many of these cells gave a positive oxydase reaction. There were many myeloid cells noted in the liver, spleen, myocardium, lungs, kidneys, and other organs. We may, therefore, be permitted to speak of a congenital type of leukemia. Baar and Stransky 26 quote several cases of congenital or newborn leukemia from the older literature and state that the existence of this condition has been proved beyond doubt. They further cite cases in which leukemic mothers have given birth to normal children. From the cases which
II2
ARTHUR F. ABT
they cite they conclude that acute or chronic leukemia is not transmitted from mother to child. There are several conditions occurring in the newborn which may be mistaken for leukemia. Under the term erythroblastosis of the newborn is now included the condition formerly known as icterus gravis neonatorum. 27 Newborn infants suffering from this condition either at birth or a few hours thereafter develop a rapidly deepening jaundice which is asso-
meqak or'jOC'lte
platelet 3
Q-
t@-~/~ monocyte ,1'
tree mocropho.qes
fibroblast Fig. 7.-5chematic repres~ntation showing the potentialities for the development of granulocytes, normoblasts, macrophages and fibroblasts from hematocytoblasts and lymphocytes. (Maximow and Bloom's Textbook of Histology.)
ciated with anemia and a great number of immature erythrocytes in the circulating blood. Associated with the jaundice, anemia and erythroblastic blood picture are familial history, slight edema, extensive extramedullary hematopoietic foci in the liver and various organs with increased iron deposition and occasionally a nuclear icterus in the brain. The blood picture is characterized by a severe hyperchromic anemia with great numbers . .... of immature red blood cells and occasional young wnite cell . forms. Poikilocytosis, polychromatophilia with . '~
THE DIAGNOSIS OF LEUKEMIA IN CHILDHOOD
I I3
stippling and increase in reticulated blood cells are noted. The icterus index is markedly increased and a biphasic van den Bergh reaction is present. It might 'be easy in examination of the blood smear from such a case to mistake the nucleated red blood cells, some of which are present in a very early form, for leukocytes. Several investigators, in fact, have termed this condition fetal erythroleukoblastosis
Fig. 8.-Tissue culture from normal blood, showing development of macrophages and fibroblasts. (After Maximow, 1928.)
study of the pathologic histology has corivincingly showed that erythroblastosis of the newborn is not related to leukemia. From present knowledge the cause of erythroblastosis of the newborn can best be ascribed to an embryonal persistence of hem~topoiesis of erythrocytes in various organs. Congenital syphilis may manifest itself by fever, purpura, enlargement of the liver and spleen, with anemia and occasionally with the presence of a great number of normoblasts VOL. 21-8
II4
ARTIfUR F. ABT
,I Fig. 9.-A stained smear from peripheral blood of a case of stem-cellleukemia. (After Timofejewsky and Benewolenskaja.)'
" " f,.-.~~;I 5:-:· . ."_:'
«
[~
--
Fig. lO.-Tissue culture from blood of patient shown in Fig. 9, showing growth of granulocytes and normoblasts. The stem cells from the original blood may now be identified as myeloblasts. (After Timofejewsky and Benewolenskaja.)
and a few immature myeloid cells in the blood stream. 29 If the typical luetic manifestations which accompany these phys-
THE DIAGNOSIS OF LEUXEMIA IN CHILDHOOD
II5
ical and hematologic findings are recognized, the differentiation from leukemia should not be difficult. Tissue Oulture of Blood.-Since 1914 when it was first attempted, tissue cultures of leukemic blood have been made in attempts to differentiate and establish the origin of the cell types involved in the leukemias. so In cultures of normal blood it has been found that macrophages and fibroblasts develop from lymphocytes and monocytes (Figs. 7, 8). In cultures of lymphatic leukemia the lymphocytes again develop into macrophages and fibroblasts. On the other hand, in cultures of blood from myeloid leukemia the myeloblasts develop not only into macrophages and fibroblasts but also into myelocytes, granulocytes and normoblasts. sI It is thus possible that by tissue culture we may be able to separate lymphoblasts from myeloblasts in cases of stem-cellleukemia where differentiation is otherwise impossible (Figs. 9, 10). The following report may illustrate the value of tissue culture of the blood in determining the type of leukemia.
Oase XV.-E. S.,· a thirteen-year-old girl, was taken ill
with fever, epistaxis, bleeding from the gums, and purpura. Her spleen and liver were, enlarged and there was general glandular enlargement. The child was acutely ill. Peripheral blood examination is given in Table 14. TABLE 14 \
Date.
11/19 11/27
Hemoglobin.
Lymphocytes.
Red cells.
White cells.
Oxydase reaction. Small.
55
2.464,000
55,400
..
........
155,OOe
Large.
I
86
Entirely negative.
Alllymphocytes.
Entirely negative.
14
.-
'Morphologically, we believed that we were dealing with an acute lymphatic leukemia. However, tissue cultures of the blood from this patient, at eighteen hours, contained at least 65 per cent myelocytes. We, therefore, had determined that
rr6
ARTHUR F. ABT
the cells in the peripheral blood which we took to be all lymphocytes and which were oxydase-negative, were in reality cells of the myeloid series, probably oxydase-negative myeloblasts. Instead of an acute lymphatic leukemia the case was really one of acute myeloblastic leukemia. CONCLUSIONS
A group of nonleukemic and leukemic cases are here discussed and illustrative examples presented to show how atypical cases of leukemia may be confused with nonleukemic conditions including those with leukocytosis and those with leukopenia. Cytologic as well as blood tissue culture methods of differentiation are briefly discussed. In some of these atypical cases clinical differentiation may be impossible. Sometimes even after the most careful pathologic review, the exact nature of the case may remain in doubt. BmLIOGRAPHY 1. Naegeli,
2. 3. 4. 5.
0.: Diagnostiche und Allgemeine Probleme bei Leukamien, Miinchen. med. Wchnschr., 80: 635, April 28, 1933; Cooke, J. V.: Acute Leukemia in Children, J.A.M.A., 101": 432, Aug. 5, 1933. Rupilius, K.: Ein Beitrag zu den Blutkrankheiten im Kindesalter, Jahrb. f. Kinderh., 143: 65, August, 1934; DeBruin, M.: Chronic Lymphatic Leukemia in Childhood, Folia Haemat., 48: 433, 1932. Abt, Isaac A.: Significance of Lymphocytosis in Infants and Children, MED. CLIN. N. A., 12: 24, July, 1928. Clough, Paul W.: Monocytic Leukemia, Bull. Johns Hopkins Hosp., 51: 148, Sept., 1932. Abt, Arthur F.: Extreme Leukocytosis in Pertussis, MED. CLIN. N. A., 14: 1229, 1931.
6. Pfaundler and Schlossman: Diseases of Children (English Translation edited by Peterman), Chapter on Diseases of Blood, translated by Arthur F. Abt, 2: 191, J. B. Lippincott Co., Philadelphia, 1935. 7. Cooley, T. B., Witwer, E. R., and Lee, Pearl: Anemia in Children with Splenomegaly and Peculiar Bone Changes, Am. J. Dis. Child., 34: 347, Sept., 1927. 8. Glanzmann, E.: Das Lymphaemoide Driisenfieber, Beihefte, Jahrb. f. Kinderh., S. Karger, Berlin, 1930. 9. Forssmann, J.: Die Herstellung hochwertiger spezifischer Schafhamolysine ohne Verwendung von Schafblut, Biochem. Ztschr., 37: 78, 1911. 10, Da1,lidsohn, L.: Heterophile Antigens and Antibodies, Arch. Path., 4: "
776, 1927.
THE DIAGNOSIS OF LEUKEMIA IN CHILDHOOD
II
7
11. Paul and Bunnell: The Presence of Heterophile Antihodies in Infectious Mononucleosis, Am. J. M. Sc., 183: 90, Jan., 1932. 12. Bunnell, W. W.: A Diagnostic Test for Infectious Mononucleosis, Am. J. M. Se., 186: 346, Sept., 1933. 13. Abt, Arthur F., and Bloom, William: Essential Lipoid Histiocytosis (Type Niemann-Pick), JAM.A., 90: 2076, June 30, 1928. 14. Cooke, J. V.: Mediastinal Tumor in Acute Leukemia, Am. J. Dis. Child., 44: 1153, December, 1932. 15. Smith, Carl H.: Leukopenic Myeloid Leukemia Associated with Arthritis, Am. J. Dis. Child., 45: 123, January, 1933; Poynton, F. J., and Lightwood, R.: Lymphatic Leukemia with Infiltration of Periosteum Simulating Acute Rheumatism, Lancet, 222, 1: 1192, June 4, 1932. 16. Schaffer, A. J., and Jacobsen, A. W.: Mikulicz's Syndrome, Am. J. Dis. Child., 34: 327, Sept., 1927; Reuben, Mark S., and Douglas, H.: Mikuliez's Syndrome in Leukemia, Arch. Pediat., 47: 442, July, 1930. 17. Brennemann, J., and Bigler, J. A.: Sepsis with Leukopenia (Agranulocytosis) in Children, Am. J. Dis. Child., 40: 515, Sept., 1930. 18. Givan, T. B., and Shapiro, B.: Agranulocytosis in Childhood, Am. J. Dis. Child., 46: 550, Sept., 1933; Willi, H.: Agranulocytosis in Childhood, J ahrb. f. Kinderh., 142: 102, March, 1934; Piersol, George M., and Steinfeld, E.: Granulopenia, Arch. Int. Med., 49: 578, April, 1932; Jaffe, R. H.: Bone Marrow in Agranulocytosis, Arch. Path., 16: 611, Nov., 1933. 19a. Abt, Arthur F., and Denenholz, Edward J.: Letterer-Siwe's Disease, Am. J. Dis. Child., 51: 499, March, 1936. 19b. Morrison, Samuel: Certain Phases of the Leukemia Problem, Internat. Med. Digest, 22: 373, June, 1933. 20. Abt, Isaac A.: A Case of Aleukemic Leukemia with Clinical Symptoms of Aplastic Anemia, MED. CLIN. N. A., 8: 427, Sept., 1924. 21. Kornmann, V.: Beitrag zur friihkindlichen und angeborenen Myeloischen Leukamie, Zeitschr. f. Kinderh., 56: 440, July, 1934; Simonett, R.: Myeloid Leukemia in an Infant of Seven Months, Rev. di Clin. Pediat., Feb., 1932. 22. Koch: Ref. Zbl. Path., 33: No. 1, 1922. 23. Stransky: Congenital Myeloid Leukemia in an Infant, Monatschr. f. Kinderh., 29: 654, 1925; Clinical Hematology of Infants; Arregenerative Anemia in Young Children, Ztschr. f. Kinderh., 39: 553, 1925. 24. Opitz: Acute Myelosis in Infants, Med. Klin., 20: 891, June, 1924. 25. Biingeler, W.: Angeborene Leukamie, Frankfurt. Ztschr. f. Path., 41: 257, 1931. 26. Baar, H., and Stransky, E.: Klinische Haematologie des Kindesalters, 1720, Deuticke, Leipzig, 1928. 27. Abt, Arthur F.: Erythroblastosis in Icterus Gravis Neonatorum, J. Pediat., 3: 7, July, 1933; Anemia of the Newborn, Am. J. Dis. Child., 43: 337, Feb., 1932. 28. Salomonsen, L.: Uber fetale Erythro-Ieukoblastose, Ztschr. f. Kinderh., 51: 181, June 27, 1931.
II8
ARTHUR F. ART
29. Pfaundler and Schlossman: Diseases of Children (English Translation edited by Peterman), Chapter on Diseases of Blood, translated by Arthur F. Abt, Vol. 11, 225, J. B. Lippincott Co., Philadelphia, 1935. 30. Maximow, A. A., and Bloom, WiIIiam: A Textbook of Histology, p. 102, W. B. Saunders Co., Philadelphia, 1934, 2nd edition. 31. Timofejewsky, A. D., and Benewolenskaja, S. W.: Neue Beobachtungcn an lymphoiden ZeIIen der myeloiden und lymphatischen Leukiimie in Explantation-Versuchen, Arch. f. expo ZeIIforsch., (8), 1, 1929.