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Idiopathic myelofibrosis in an infant
580
T h e Journal o/ P E D I A T R I C S
Idiopathic myelofibrosis in an infant A case involving an infant with idiopathic myelofibrosis is presented, together with a brie[ review o[ the reported cases of this entity in the pediatric age group. This case presented the classical findings o[ fibrosis of the bone marrow, myeloid metaplasia of the liver and spleen, and presence of primitive myeloid cells in the peripheral blood.
Burhan Say, M.D.,* and Izzet Berkel, M.D. ANKARA,
TURKEY
MYELOFIBROSlS was described for the first time by H e u c k in 1879. Since then over 400 cases have been published, a, 9, 12, 18, 17 T h e patients are usually adults over 30 years of age, m a n y being in their sixties or seventies. O n l y 7 pediatric cases of the idiopathic form have been published in the literature, to the best of our knowledge?, 6, 14, 15 This n u m b e r does not include 2 cases with myeloid m e t a p l a s i a w i t h o u t myelofibrosis, 2 cases of myelosclerosis, a n d 2 cases of acute leukemia with myelofibrosis seen in children?, 8, 13, 14, 17, 18
As will be discussed later, most authorities t o d a y think t h a t myelofibrosis is merely a stage, p r o b a b l y a t e r m i n a l one, of the progressive changes t h a t take place in the bone m a r r o w as a result of stimuli by m a n y different agents. I t is possible, therefore, t h a t 4 of the aforementioned cases m i g h t also have resulted in myelofibrosis in the end. E v e n if we include all 6 of these cases, however, it is still obvious t h a t examples o f myeloprolifera-
From Ankara University Hacettepe Medical Center, Hacettepe Children's Hospital, Ankara, Turkey. *Address, Hacettepe, ~ocuk Hastanes{, Ankara, Turkey.
tive syndromes, with or without myelofibrosis of the bone m a r r o w , are not frequently f o u n d in the p e d i a t r i c age group.
CASE REPORT A 7y2-month-old female infant was hospitalized because of fever and a cold of 1 week duration. The fever was reported to be constant. Past history revealed that she was the second child of the family. Pregnancy and delivery were uneventful. Her birth ~weight was 2,500 grams and, until a week prior to admission, she was, apparently, in good condition. Her diet was poor and consisted mainly of milk and small amounts of cereal. The parents were not related and were apparently in good health. Physical examination revealed a somewhat malnourished infant. The temperature was 38.2 ~ C., the weight 5,250 grams. There was marked respiratory distress. Other findings included marked signs of rickets: a large fontanel, rachitic rosary, and metaphyseal enlargement on both wrists: There were moist rales over both lung fields. The liver was palpable 2 cm. and the spleen 8 cm. below the costal margin. Laboratory examination revealed a hemoglobin of 10 Gm. per 100 ml. and the white blood cell count was 18,400 per cubic millimeter. On the peripheral smear there was obvious polychromatophilia. In addition to this,
Volume 64 Number 4
repeated blood smears revealed the presence of occasional normoblasts and early myeloid elements such as myelocytes and metamyelocytes. In the erythrocyte fragility tests hemolysis started at 0.40 per cent and ended at 0.20 per cent. Fetal hemoglobin was 4.5 per cent, The sickling test and the direct and indirect Coombs' tests were negative. Blood chemical determinations revealed: calcium 8.5 mg. per 100 ml., phosphorus 2.8 rag. per I00 ml., alkaline pbosphatase 42.1 Bodansky units, total cholesterol 90 rag. per 100 mI., and the thymoI turbidity test, 3 units. Urinalysis and VDRL were negative. Roentgen examination of the bones revealed the presence of marked rickets and chest roentgenograms showed bilateral bronchopneumonia. Repeated attempts to obtain bone marrow resulted in poor samples. Skin tests for tuberculosis, histopIasmosis, and coccidioidomycosis were negative. There was no growth on repeated blood a n d bone marrow cultures for ordinary bacteria or for fungi. The patient was given parenteral antibiotics on admission and intravenous fluids were administered. Following these a whole blood transfusion was given. Pyrexia persisted in spite of broad spectrum antibiotics. The spleen was thought to be larger than on admission and the lung findings became worse, On the fourth day after admission the hemoglobin level fell to 6 Gm. per 100 ml. and another whole blood transfusion was given. This was repeated on the seventh, ninth, and eleventh days. On the last day of her illness a mild epistaxis was observed. The liver was much enlarged and the pulmonary findings became progressively worse. Retractions and dyspnea were marked and there was obvious cyanosis. Her general condition deteriorated on the eleventh day after admission. She was digitatized at this point but she died on the same day.
Idiopathic rayelofibrosis
58 1
A
B
Fig. 1. Bone marrow from the vertebra. Increased fibrous tissue with decrease in myeloid elements. (Original magnification: A, x430; B, x970.)
A
AUTOPSY FINDINGS T h e r e was blood-tinged fluid in the pleural cavities. Both lungs showed patchy areas of consolidation, the m y o c a r d i u m was ~ hyperemic a n d there was a huge spleen which w e i g h e d 160 grams (normal 21 to 24 grams) a n d which was hard and markedIy congested. T h e liver weighed 335 grams (normal 250 to 260 grams) a n d revealed mild fatty infiltration. T h e r e were petechial hemorrhages
Fig. 2. Spleen. (Original magnification: A, • B, x970.)
582
Say and Berkel
April 1964
Table I. Myeloproliferative disorders in c h i l d r e n - - a summary of the medical literature
No. I
Author
Age Year ]Month - Sex
Spleen
Bone marrow Biopsy I Autopsy -
Comments
I
Rosenthal and Erf 15
4
F
Enlarged
Fibrosis
Idiopathic myelofibrosis
2
Rosenthal and Err 15
4
F
Enlarged
Fibrosis
Idiopathic myelofibrosis
3
Rosenthal and Err 15
10
F
Enlarged
Fibrosis
Idiopathic myelofibrosis
4
Rosenthal and Err 15
1
F
Enlarged
Fibrosls
Fibrosis
Idiopathic myelofibrosis
5
Erf and Herbut 6
2
F
Enlarged
Fibrosis
Fibrosis
Idiopathic myelofibrosis
6
Churg and Wachstein 2
2
8
F
7
Rosenberg and Taylor 1~
1
11
F
Enlarged
Fibrosis
8
Rosenberg and
1
I
F
Enlarged
Hypocellu- Myeioid.metaplasia
4
Fibrosis
Idiopathic myelofibrosis
Taylor14
Idiopathic myelofibrosis
lare
9
Block and Jacobson1
2
6
M Enlarged
10
Wood and Andrewsis
2
6
M Enlarged
Normal
Myelosclerosis
11
Stodmeister and Sandkuhler a~
~
?
Enlarged
Fibrosis
Myelofibrosis and myelosclerosis
12
Farber a
7
F
Enlarged
Fibrosis
Leukemia and myelofibrosis
13
Rosenbergla
?
?
Enlarged
Fibrosis
Leukemia and myelofibrosis
8
in the rectal mucosa. No lymph node enlargement was seen. T h e m a r r o w of various "bones was examined. I t was yellow in color and could not be expressed from the bones by ordinary pressure. T h e kidneys, adrenal glands, and the pancreas revealed mild hyperemia. Microscopic examination. Bone m a r r o w sections from the sternum and the ribs were examined. T h e y showed only connective tissue framework with an almost complete absence of cellularity. O n l y occasional tiny areas of hematopoiesis could be identified despite extensive search of the slides (Fig. 1). Liver sections showed a moderate degree of fatty metamorphosis. T h e portal spaces were widened through the proliferation of the cellular elements, m a i n l y of the reticu-
Erythroid hyperplasia
Myeloid metaplasia Leukemia, xanthomatosis
lum cell type. Sections stained with Giemza showed immature myelocytes and normoblasts in the portal spaces. In the sinusoids there were also some cells which could not be identified and which were described as cells containing large nuclei with fine reticular chromatin network and a large amount of basophilic cytoplasm. Sections of the spleen showed distorted architecture. Malpighian follicles were enlarged and the sinusoids were prominent, containing immature cells resembling reticulum cells. There were also myelocytes and normoblasts in small aggregates (Fig.. 2). Imprints of the spleen were made and similar cells to those described above were seen. Sections of the kidneys showed perivascular round cell infiltration, some of which were identified as mye-
Volume 64 Number 4
loid cells. Sections of the adrenal glands at the corticomedullary junction showed foci of hematopoiesis. The lungs revealed patchy areas of atelectasis and red blood cells in the alveoli. The other organs revealed nothing of significance microscopically. DISCUSSION
Fibrosis of the bone nlarrow has been reported as secondary to metastatic carcinoma, leukemia, Gaucher's disease, tuberculosis, generalized osteoporosis, and chemical poisonings. Osteomalacia has also been recorded as one of the causes of myelofibrosis. Since rickets is still a common condition in this country, we have studied the bone marrow taken from different sites from over 30 autopsied cases with rickets. No evidence of fibrotic change was observed. When no cause can be found for the fibrotic changes, the lesion is considered to be primary and is identified as idiopathic myelofibrosis. The characteristics of both primary and secondary forms of the disease, in addition to fibrosis of the bone marrow, are myeloid metaplasia and the appearance of immature erythroid and myeloid elements in the peripheral blood. As a result of these changes, most cases of idiopathic myelofibrosis are diagnosed as chronic myelocytic leukemia. The diagnosis of myelofibrosis actually is not very difficult if one keeps this possibility in mind: In a case in which one fails to obtain a specimen of cellular bone marrow after repeated attempts and where there are normoblasts, polychromatophilia and immature myeloid elements in the smear of the peripheral blood, this diagnosis should be considered. Also, if the spleen or liver punctures reveal the presence of myeloid metaplasia, this diagnosis becomes more likely. However, an exact diagnosis of primary or secondary myelofibrosis can be made. only by direct examination of a portion of the bone marrow obtained by a surgical biopsy. In our case, the diagnosis was established before death and was confirmed later by postmortem examination. Clinical aspects of myelofibrosis. T h e sex
Idiopathic myelofibrosis
583
incidence in adults shows almost equal distribution between men and women with a slight predominance in men. On the other hand, all the pediatric cases of idiopathic myelofibrosis reported so far, including ours, have been in females. This point should not be overemphasized since the total number of published cases is extremely small. Table I summarizes the pediatric cases. The ages of these pediatric ones were 4 months in 2 eases, 15 7 months in our case, 16 months, ~'~ 23 months, 1. 2 years, 6 32 months, 2 and 10 years? 5 In all of these cases the signs and symptoms at the onset were fatigue, weakness, loss of weight, shortness of breath, and, in some cases, a palpable abdominal mass which was an enormous spleen. Splenomegaly was present in every case but 2, although in one other case the spleen was only slightly palpable at the costal margin. The size of the spleen seems to have some relation to the duration of the disease since the patient without a palpable spleen as well as the one with slight splenomegaly were both only 4 months old. Our patient appears to be an exception to this because she had an extremely large spleen at the age of 7 months. The liver enlargement seems to follow a similar pattern to that of the spleen and in every instance except one a moderate lymphadenopathy was observed. In all the pediatric cases except one s the roentgenograms of the bones have been reported as normal. However, in our case there was evidence of rickets. In some of the adult cases of long duration, as well as in a pediatric case with acute leukemia, the presence of osteosclerosis has been reported? The most significant diagnostic factor besides the bone marrow and visceral biopsies is the picture of the peripheral blood smear. Here one finds marked polychromatophilia, basophilic stippling, normoblastosis, and reticulocytosis along with immature myeloid elements, namely, myelocytes and metamyelocytes. Anemia is usually seen at some time during the course of the disease but, especially in adult cases, it is not unusual to find a relatively normal hemoglobin level. In our case
584
Say and Berkel
the hemoglobin on admission was 10 Gm. but later fell to 6 Gm. without any obvious evidence of blood loss or hemolysis. The patient required 2 blood transfusions at this point. The pediatric cases mentioned all displayed very low hemoglobin levels, approximately 4 to 5 Gin. In our case the leukocyte count was normal. However, in 2 cases in infants the count was under 2,000. In adults the white count is usually within normal limits. Another significant finding is the appearance of megakaryocytes or the nuclei of megakaryocytes in the peripheral blood smear of these patients. This has not been reported in children nor was it observed in our case. Thrombocytopenia, which is occasionally observed in adults, has not been documented in the pediatric age group. Etiology. The etiology of primary myelofibrosis is not known. Err and Herbut G in their review discuss m a n y possibilities and include the results o f their experimental studies. They have postulated that chronic occlusion of the marrow vessels might play an etiologic role. EngelP considers the etiologic possibility of allergy and Nettleship 1~ thinks that antibody reactions may be responsible for the fibrotic changes. At present, the most wideIy accepted idea on etiopathogenesis is the one proposed by Dameshek * and his co-workers, which we also favor. According to Dameshek * the bone marrow is capable of proliferating "en masse" as well as along particular cell lines. He thinks fibrosis may be just a type of proliferation. It is possible that a myelostimulatory factor is activated by different agents. In one review the pediatric subjects with myelosclerosis and the ones with myeloid metaplasia alone are included? 4 It is thought by those authors that in cases of myelofibrosis the bone marrow reveals progressive changes from hyperplasia to hypoplasia and from this to a widespread fibrosis. If the patient survives, this m a y or m a y not be followed by the laying down of bone in the fibrous retieulum and by the development of osteosclerosis. On the other hand some investigators think of idiopathic myelofibrosis as a form of chronic granuloeytic leukemia in which
April 1964
fibrosis may develop 'to some degree as a secondary process. M a n y examples of this sequence in adults have been published. 7 Apparently myelofibrosis occurs also in children with acute leukemia?, 13 Some investigators have described cases of idiopathic myelofibrosis resulting from chronic bone marrow failure or from myel0phytisic anemia with compensatory myeloid meta.plasia?l, 1~ The occurrence of fibrosis of the bone marrow has also been reported after benzene intoxication, chronic inflammation, or the administration of estrogenic substances. According to Sandkuhler, myelofibrosis in children is usually due to toxic damage to the bone marrow or results from scarification of the bone marrow caused by inflammatory reactions? 6 Such a pediatric case, from the Children's Hospital of Michigan, is recorded by Stodmeister and Sandkuhler? 7 Treatment. The treatment of this condition has been essentially symptomatic. Splenectomy or roentgen radiation of the spleen seem to be of no value Mthough this has not been tried on any pediatric cases. Testosterone has been tried since it is antagonistic to estrogen, a substance with myelofibrotic activity. As far as we could find in the literature, onIy Erf and Herbut ~ and recently Kennedy ~ have reported remissions with this treatment in a few cases. The 6 patients described by Kennedy, however, revealed marked improvement after being treated with huge doses of testosterone for prolonged periods2 Two women, aged 55 and 75, and one m a n of 64 reportedly responded with increased hemoglobin, reticulocytosis, cessation of transfusion requirements, and hypercellular marrow. Three other patients also showed improvement by a prolongation of the intervals between transfusions. None of the pediatric cases were treated with androgens. It has been suggested that therapy with cortisone is helpful in some cases. However, more studies must be completed before any definitive conclusion can be drawn. PROGNOSIS
On the whole the prognosis for these patients is poor, although some adult patients
Volume 64 Number 4
h a v e lived for m a n y years. I n the p e d i a t r i c age g r o u p the o u t c o m e seems to be m o r e serious; at the time of this r e p o r t all the p a t i e n t s e x c e p t one have died.
Idiopathic mydofibrosis
9. 10. 11.
REFERENCES
1. Block, M., and Jacobson, L. O.: /vIyeloid metaplasia, J. A. M. A. 143: t390, 1950. 2. Churg, J., and Wachstein, M.: Osteoselerosis, myelofibrosis and leukemia, Am. J. M. Sc. 207: 141, 1944. 3. Clinical pathological conference, J. P~DIAT. 61: 145, 1962. 4. Dameshek, W.: Some speculations on the myeloproliferative syndromes, Blood 6: 372, 1951. 5. Engell, H. C.: Myeloscleros's, Acta reed. scandinav. 129: 371, 1947. 6. Err, L. A., and Herbut, P. A.: Primary and secondary myetofibrosis, Ann. Int. Med. 21: 863, 1944. 7. Heller, E. L., Lewisohn, M. G., and Palin, W. E.: Aleukemic myelosis, Am. J. Path. 23: 327, 1947. 8. Heuck, G.: Zwei F~ille von Leuk/imie Mit eigenthiimlichen Blut Resp. Knochenmarks-
12.
13. 14. 15. 16. 17. 18. 19.
585
befund, Virchow's Arch. f. Path. Anat. 78: 475; 1879. Kennedy, B. J.: Effect of androgenic hormone in myelofibrosis, J. A. M. A. 182: 116, 1962. Nettleship, A.: Bone marrow changes produced by specific antibodies, Am. J. Path. 18: 689, 1942. Peace, R. J.: Myelonecrosis, extramedullary, myelopoiesis and leukoerythroblastosis, Am. J. Path. 29: 1029, 1953. Pitcock, J. A., Reinhard, E. H., Justus, B. W., and Mendelsohn, R. S.: A clinical and pathological study of seventy cases of myelofibrosis, Ann. Int. Med. 57: 73, 1962. Rosenberg, H.: Personal communication. Rosenberg, H. S., and Taylor, F. M.: The myeloproliferative syndrome in children, J. Pediat. 52: 407, 1958. Rosenthal, N., and Err, L. A.: Clinical observations on osteopetrosis and myelofibrosis, Arch. Int. Med. 71: 793, 1943. Sandkuhler, S. T.: Personal communication. Stodmelster, R., and Sandkuhler, S. T.: Osteomyelosklerose und Knochenmarkfibrose, Georg Thieme-Verlag, Stuttgart, 1953. Wood, E. E., and Andrews, C. T.: Subacute myelosclerosis, Lancet 2: 739, 1949. Wyatt, J. P., and Sommers, S. C.: Chronic marrow failure, myelosclerosis and extramedullary hematopoiesis, Blood 5: 328, 1950.
T h e Journal o/ P E D I A T R I C S
Idiopathic myelofibrosis in an infant A case involving an infant with idiopathic myelofibrosis is presented, together with a brie[ review o[ the reported cases of this entity in the pediatric age group. This case presented the classical findings o[ fibrosis of the bone marrow, myeloid metaplasia of the liver and spleen, and presence of primitive myeloid cells in the peripheral blood.
Burhan Say, M.D.,* and Izzet Berkel, M.D. ANKARA,
TURKEY
MYELOFIBROSlS was described for the first time by H e u c k in 1879. Since then over 400 cases have been published, a, 9, 12, 18, 17 T h e patients are usually adults over 30 years of age, m a n y being in their sixties or seventies. O n l y 7 pediatric cases of the idiopathic form have been published in the literature, to the best of our knowledge?, 6, 14, 15 This n u m b e r does not include 2 cases with myeloid m e t a p l a s i a w i t h o u t myelofibrosis, 2 cases of myelosclerosis, a n d 2 cases of acute leukemia with myelofibrosis seen in children?, 8, 13, 14, 17, 18
As will be discussed later, most authorities t o d a y think t h a t myelofibrosis is merely a stage, p r o b a b l y a t e r m i n a l one, of the progressive changes t h a t take place in the bone m a r r o w as a result of stimuli by m a n y different agents. I t is possible, therefore, t h a t 4 of the aforementioned cases m i g h t also have resulted in myelofibrosis in the end. E v e n if we include all 6 of these cases, however, it is still obvious t h a t examples o f myeloprolifera-
From Ankara University Hacettepe Medical Center, Hacettepe Children's Hospital, Ankara, Turkey. *Address, Hacettepe, ~ocuk Hastanes{, Ankara, Turkey.
tive syndromes, with or without myelofibrosis of the bone m a r r o w , are not frequently f o u n d in the p e d i a t r i c age group.
CASE REPORT A 7y2-month-old female infant was hospitalized because of fever and a cold of 1 week duration. The fever was reported to be constant. Past history revealed that she was the second child of the family. Pregnancy and delivery were uneventful. Her birth ~weight was 2,500 grams and, until a week prior to admission, she was, apparently, in good condition. Her diet was poor and consisted mainly of milk and small amounts of cereal. The parents were not related and were apparently in good health. Physical examination revealed a somewhat malnourished infant. The temperature was 38.2 ~ C., the weight 5,250 grams. There was marked respiratory distress. Other findings included marked signs of rickets: a large fontanel, rachitic rosary, and metaphyseal enlargement on both wrists: There were moist rales over both lung fields. The liver was palpable 2 cm. and the spleen 8 cm. below the costal margin. Laboratory examination revealed a hemoglobin of 10 Gm. per 100 ml. and the white blood cell count was 18,400 per cubic millimeter. On the peripheral smear there was obvious polychromatophilia. In addition to this,
Volume 64 Number 4
repeated blood smears revealed the presence of occasional normoblasts and early myeloid elements such as myelocytes and metamyelocytes. In the erythrocyte fragility tests hemolysis started at 0.40 per cent and ended at 0.20 per cent. Fetal hemoglobin was 4.5 per cent, The sickling test and the direct and indirect Coombs' tests were negative. Blood chemical determinations revealed: calcium 8.5 mg. per 100 ml., phosphorus 2.8 rag. per I00 ml., alkaline pbosphatase 42.1 Bodansky units, total cholesterol 90 rag. per 100 mI., and the thymoI turbidity test, 3 units. Urinalysis and VDRL were negative. Roentgen examination of the bones revealed the presence of marked rickets and chest roentgenograms showed bilateral bronchopneumonia. Repeated attempts to obtain bone marrow resulted in poor samples. Skin tests for tuberculosis, histopIasmosis, and coccidioidomycosis were negative. There was no growth on repeated blood a n d bone marrow cultures for ordinary bacteria or for fungi. The patient was given parenteral antibiotics on admission and intravenous fluids were administered. Following these a whole blood transfusion was given. Pyrexia persisted in spite of broad spectrum antibiotics. The spleen was thought to be larger than on admission and the lung findings became worse, On the fourth day after admission the hemoglobin level fell to 6 Gm. per 100 ml. and another whole blood transfusion was given. This was repeated on the seventh, ninth, and eleventh days. On the last day of her illness a mild epistaxis was observed. The liver was much enlarged and the pulmonary findings became progressively worse. Retractions and dyspnea were marked and there was obvious cyanosis. Her general condition deteriorated on the eleventh day after admission. She was digitatized at this point but she died on the same day.
Idiopathic rayelofibrosis
58 1
A
B
Fig. 1. Bone marrow from the vertebra. Increased fibrous tissue with decrease in myeloid elements. (Original magnification: A, x430; B, x970.)
A
AUTOPSY FINDINGS T h e r e was blood-tinged fluid in the pleural cavities. Both lungs showed patchy areas of consolidation, the m y o c a r d i u m was ~ hyperemic a n d there was a huge spleen which w e i g h e d 160 grams (normal 21 to 24 grams) a n d which was hard and markedIy congested. T h e liver weighed 335 grams (normal 250 to 260 grams) a n d revealed mild fatty infiltration. T h e r e were petechial hemorrhages
Fig. 2. Spleen. (Original magnification: A, • B, x970.)
582
Say and Berkel
April 1964
Table I. Myeloproliferative disorders in c h i l d r e n - - a summary of the medical literature
No. I
Author
Age Year ]Month - Sex
Spleen
Bone marrow Biopsy I Autopsy -
Comments
I
Rosenthal and Erf 15
4
F
Enlarged
Fibrosis
Idiopathic myelofibrosis
2
Rosenthal and Err 15
4
F
Enlarged
Fibrosis
Idiopathic myelofibrosis
3
Rosenthal and Err 15
10
F
Enlarged
Fibrosis
Idiopathic myelofibrosis
4
Rosenthal and Err 15
1
F
Enlarged
Fibrosls
Fibrosis
Idiopathic myelofibrosis
5
Erf and Herbut 6
2
F
Enlarged
Fibrosis
Fibrosis
Idiopathic myelofibrosis
6
Churg and Wachstein 2
2
8
F
7
Rosenberg and Taylor 1~
1
11
F
Enlarged
Fibrosis
8
Rosenberg and
1
I
F
Enlarged
Hypocellu- Myeioid.metaplasia
4
Fibrosis
Idiopathic myelofibrosis
Taylor14
Idiopathic myelofibrosis
lare
9
Block and Jacobson1
2
6
M Enlarged
10
Wood and Andrewsis
2
6
M Enlarged
Normal
Myelosclerosis
11
Stodmeister and Sandkuhler a~
~
?
Enlarged
Fibrosis
Myelofibrosis and myelosclerosis
12
Farber a
7
F
Enlarged
Fibrosis
Leukemia and myelofibrosis
13
Rosenbergla
?
?
Enlarged
Fibrosis
Leukemia and myelofibrosis
8
in the rectal mucosa. No lymph node enlargement was seen. T h e m a r r o w of various "bones was examined. I t was yellow in color and could not be expressed from the bones by ordinary pressure. T h e kidneys, adrenal glands, and the pancreas revealed mild hyperemia. Microscopic examination. Bone m a r r o w sections from the sternum and the ribs were examined. T h e y showed only connective tissue framework with an almost complete absence of cellularity. O n l y occasional tiny areas of hematopoiesis could be identified despite extensive search of the slides (Fig. 1). Liver sections showed a moderate degree of fatty metamorphosis. T h e portal spaces were widened through the proliferation of the cellular elements, m a i n l y of the reticu-
Erythroid hyperplasia
Myeloid metaplasia Leukemia, xanthomatosis
lum cell type. Sections stained with Giemza showed immature myelocytes and normoblasts in the portal spaces. In the sinusoids there were also some cells which could not be identified and which were described as cells containing large nuclei with fine reticular chromatin network and a large amount of basophilic cytoplasm. Sections of the spleen showed distorted architecture. Malpighian follicles were enlarged and the sinusoids were prominent, containing immature cells resembling reticulum cells. There were also myelocytes and normoblasts in small aggregates (Fig.. 2). Imprints of the spleen were made and similar cells to those described above were seen. Sections of the kidneys showed perivascular round cell infiltration, some of which were identified as mye-
Volume 64 Number 4
loid cells. Sections of the adrenal glands at the corticomedullary junction showed foci of hematopoiesis. The lungs revealed patchy areas of atelectasis and red blood cells in the alveoli. The other organs revealed nothing of significance microscopically. DISCUSSION
Fibrosis of the bone nlarrow has been reported as secondary to metastatic carcinoma, leukemia, Gaucher's disease, tuberculosis, generalized osteoporosis, and chemical poisonings. Osteomalacia has also been recorded as one of the causes of myelofibrosis. Since rickets is still a common condition in this country, we have studied the bone marrow taken from different sites from over 30 autopsied cases with rickets. No evidence of fibrotic change was observed. When no cause can be found for the fibrotic changes, the lesion is considered to be primary and is identified as idiopathic myelofibrosis. The characteristics of both primary and secondary forms of the disease, in addition to fibrosis of the bone marrow, are myeloid metaplasia and the appearance of immature erythroid and myeloid elements in the peripheral blood. As a result of these changes, most cases of idiopathic myelofibrosis are diagnosed as chronic myelocytic leukemia. The diagnosis of myelofibrosis actually is not very difficult if one keeps this possibility in mind: In a case in which one fails to obtain a specimen of cellular bone marrow after repeated attempts and where there are normoblasts, polychromatophilia and immature myeloid elements in the smear of the peripheral blood, this diagnosis should be considered. Also, if the spleen or liver punctures reveal the presence of myeloid metaplasia, this diagnosis becomes more likely. However, an exact diagnosis of primary or secondary myelofibrosis can be made. only by direct examination of a portion of the bone marrow obtained by a surgical biopsy. In our case, the diagnosis was established before death and was confirmed later by postmortem examination. Clinical aspects of myelofibrosis. T h e sex
Idiopathic myelofibrosis
583
incidence in adults shows almost equal distribution between men and women with a slight predominance in men. On the other hand, all the pediatric cases of idiopathic myelofibrosis reported so far, including ours, have been in females. This point should not be overemphasized since the total number of published cases is extremely small. Table I summarizes the pediatric cases. The ages of these pediatric ones were 4 months in 2 eases, 15 7 months in our case, 16 months, ~'~ 23 months, 1. 2 years, 6 32 months, 2 and 10 years? 5 In all of these cases the signs and symptoms at the onset were fatigue, weakness, loss of weight, shortness of breath, and, in some cases, a palpable abdominal mass which was an enormous spleen. Splenomegaly was present in every case but 2, although in one other case the spleen was only slightly palpable at the costal margin. The size of the spleen seems to have some relation to the duration of the disease since the patient without a palpable spleen as well as the one with slight splenomegaly were both only 4 months old. Our patient appears to be an exception to this because she had an extremely large spleen at the age of 7 months. The liver enlargement seems to follow a similar pattern to that of the spleen and in every instance except one a moderate lymphadenopathy was observed. In all the pediatric cases except one s the roentgenograms of the bones have been reported as normal. However, in our case there was evidence of rickets. In some of the adult cases of long duration, as well as in a pediatric case with acute leukemia, the presence of osteosclerosis has been reported? The most significant diagnostic factor besides the bone marrow and visceral biopsies is the picture of the peripheral blood smear. Here one finds marked polychromatophilia, basophilic stippling, normoblastosis, and reticulocytosis along with immature myeloid elements, namely, myelocytes and metamyelocytes. Anemia is usually seen at some time during the course of the disease but, especially in adult cases, it is not unusual to find a relatively normal hemoglobin level. In our case
584
Say and Berkel
the hemoglobin on admission was 10 Gm. but later fell to 6 Gm. without any obvious evidence of blood loss or hemolysis. The patient required 2 blood transfusions at this point. The pediatric cases mentioned all displayed very low hemoglobin levels, approximately 4 to 5 Gin. In our case the leukocyte count was normal. However, in 2 cases in infants the count was under 2,000. In adults the white count is usually within normal limits. Another significant finding is the appearance of megakaryocytes or the nuclei of megakaryocytes in the peripheral blood smear of these patients. This has not been reported in children nor was it observed in our case. Thrombocytopenia, which is occasionally observed in adults, has not been documented in the pediatric age group. Etiology. The etiology of primary myelofibrosis is not known. Err and Herbut G in their review discuss m a n y possibilities and include the results o f their experimental studies. They have postulated that chronic occlusion of the marrow vessels might play an etiologic role. EngelP considers the etiologic possibility of allergy and Nettleship 1~ thinks that antibody reactions may be responsible for the fibrotic changes. At present, the most wideIy accepted idea on etiopathogenesis is the one proposed by Dameshek * and his co-workers, which we also favor. According to Dameshek * the bone marrow is capable of proliferating "en masse" as well as along particular cell lines. He thinks fibrosis may be just a type of proliferation. It is possible that a myelostimulatory factor is activated by different agents. In one review the pediatric subjects with myelosclerosis and the ones with myeloid metaplasia alone are included? 4 It is thought by those authors that in cases of myelofibrosis the bone marrow reveals progressive changes from hyperplasia to hypoplasia and from this to a widespread fibrosis. If the patient survives, this m a y or m a y not be followed by the laying down of bone in the fibrous retieulum and by the development of osteosclerosis. On the other hand some investigators think of idiopathic myelofibrosis as a form of chronic granuloeytic leukemia in which
April 1964
fibrosis may develop 'to some degree as a secondary process. M a n y examples of this sequence in adults have been published. 7 Apparently myelofibrosis occurs also in children with acute leukemia?, 13 Some investigators have described cases of idiopathic myelofibrosis resulting from chronic bone marrow failure or from myel0phytisic anemia with compensatory myeloid meta.plasia?l, 1~ The occurrence of fibrosis of the bone marrow has also been reported after benzene intoxication, chronic inflammation, or the administration of estrogenic substances. According to Sandkuhler, myelofibrosis in children is usually due to toxic damage to the bone marrow or results from scarification of the bone marrow caused by inflammatory reactions? 6 Such a pediatric case, from the Children's Hospital of Michigan, is recorded by Stodmeister and Sandkuhler? 7 Treatment. The treatment of this condition has been essentially symptomatic. Splenectomy or roentgen radiation of the spleen seem to be of no value Mthough this has not been tried on any pediatric cases. Testosterone has been tried since it is antagonistic to estrogen, a substance with myelofibrotic activity. As far as we could find in the literature, onIy Erf and Herbut ~ and recently Kennedy ~ have reported remissions with this treatment in a few cases. The 6 patients described by Kennedy, however, revealed marked improvement after being treated with huge doses of testosterone for prolonged periods2 Two women, aged 55 and 75, and one m a n of 64 reportedly responded with increased hemoglobin, reticulocytosis, cessation of transfusion requirements, and hypercellular marrow. Three other patients also showed improvement by a prolongation of the intervals between transfusions. None of the pediatric cases were treated with androgens. It has been suggested that therapy with cortisone is helpful in some cases. However, more studies must be completed before any definitive conclusion can be drawn. PROGNOSIS
On the whole the prognosis for these patients is poor, although some adult patients
Volume 64 Number 4
h a v e lived for m a n y years. I n the p e d i a t r i c age g r o u p the o u t c o m e seems to be m o r e serious; at the time of this r e p o r t all the p a t i e n t s e x c e p t one have died.
Idiopathic mydofibrosis
9. 10. 11.
REFERENCES
1. Block, M., and Jacobson, L. O.: /vIyeloid metaplasia, J. A. M. A. 143: t390, 1950. 2. Churg, J., and Wachstein, M.: Osteoselerosis, myelofibrosis and leukemia, Am. J. M. Sc. 207: 141, 1944. 3. Clinical pathological conference, J. P~DIAT. 61: 145, 1962. 4. Dameshek, W.: Some speculations on the myeloproliferative syndromes, Blood 6: 372, 1951. 5. Engell, H. C.: Myeloscleros's, Acta reed. scandinav. 129: 371, 1947. 6. Err, L. A., and Herbut, P. A.: Primary and secondary myetofibrosis, Ann. Int. Med. 21: 863, 1944. 7. Heller, E. L., Lewisohn, M. G., and Palin, W. E.: Aleukemic myelosis, Am. J. Path. 23: 327, 1947. 8. Heuck, G.: Zwei F~ille von Leuk/imie Mit eigenthiimlichen Blut Resp. Knochenmarks-
12.
13. 14. 15. 16. 17. 18. 19.
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befund, Virchow's Arch. f. Path. Anat. 78: 475; 1879. Kennedy, B. J.: Effect of androgenic hormone in myelofibrosis, J. A. M. A. 182: 116, 1962. Nettleship, A.: Bone marrow changes produced by specific antibodies, Am. J. Path. 18: 689, 1942. Peace, R. J.: Myelonecrosis, extramedullary, myelopoiesis and leukoerythroblastosis, Am. J. Path. 29: 1029, 1953. Pitcock, J. A., Reinhard, E. H., Justus, B. W., and Mendelsohn, R. S.: A clinical and pathological study of seventy cases of myelofibrosis, Ann. Int. Med. 57: 73, 1962. Rosenberg, H.: Personal communication. Rosenberg, H. S., and Taylor, F. M.: The myeloproliferative syndrome in children, J. Pediat. 52: 407, 1958. Rosenthal, N., and Err, L. A.: Clinical observations on osteopetrosis and myelofibrosis, Arch. Int. Med. 71: 793, 1943. Sandkuhler, S. T.: Personal communication. Stodmelster, R., and Sandkuhler, S. T.: Osteomyelosklerose und Knochenmarkfibrose, Georg Thieme-Verlag, Stuttgart, 1953. Wood, E. E., and Andrews, C. T.: Subacute myelosclerosis, Lancet 2: 739, 1949. Wyatt, J. P., and Sommers, S. C.: Chronic marrow failure, myelosclerosis and extramedullary hematopoiesis, Blood 5: 328, 1950.