Congenital leukemia--organ involvement in six autopsy cases.PB Badhe, SY Sane
Dept of Pathology, Seth GS Medical College, Parel, Bombay, Maharashtra.
Six cases of congenital leukemia were encountered in pediatric autopsies carried out over a period of 7 years. The postmortem findings of these cases were analysed and presented along with antemortem peripheral and bone marrow smear. All the cases were diagnosed as acute myeloid leukemia. Gross changes were observed in lungs, liver, spleen and kidneys. Histological abnormalities were detected in these organs as well as the heart, pancreas and intestine. Lymph node follicles were well preserved in all. The thymus showed a normal lobular pattern with interstitial infiltrate. Bone marrow showed myeloid blast cells with depletion of the erythroid and megakaryocytic cells.
Keywords: Autopsy, Female, Human, Infant, Newborn, Kidney, pathology,Leukemia, Myelocytic, Acute, congenital,pathology,Liver, pathology,Male, Spleen, pathology,
Congenital leukemia (i.e diagnosed from birth to 4 weeks of age) is rare. To date, just over 100 cases are reported,,. The clinical picture simulates septicaemia and congenital infection. Diagnosis depends on detailed hernatiological investigations or on autopsy confirmation. We describe here organ involvement in six cases of congenital leukemia confirmed at autopsy.
Six cases of congenital leukemia were encountered in pediatric autopsies during a seven-year period (about 2000 autopsies). A complete post-mortem was performed with imprint smears of various organs like liver, spleen, kidney, and bone marrow and correlated with antemortem peripheral and bone marrow smears.
The clinical data was taken from medical records and is shown in [Table - 1]. Serological investigations like VDRL were negative. History of leukemia was not obtained in the mothers of the children and there was no history of exposure to radiation.
Imprints and smears stained with Wright's and Haematoxylin and Eosin (H & E) stain showed large blast cells with round to oval nuclei, having three to four nucleoli and a moderate amount of cytoplasm. These cells resembled the myeloid series. In one case, cytochemical study was done which was positive for peroxidase, chloracetate esterase (CAE) and nonspecific esterase (NSE), but negative for periodic Acid Schiff (PAS) stain. Hence, it could be subtyped into M-4 i.e. myelomonoblastic leukemia according to FAB (French, American & British) classification.
Gross features of organs in all the 6 cases were as follows:
The lungs were firm and friable with focal areas of haemorrhages. Hepatosplenomegaly was present in all. The kidneys which were enlarged in four cases, showed on cut section, an enlarged cortex, white, firm and with focal areas of haemorrhages. Other organs appeared unremarkable.
On histological examination, lungs showed a dense immature cell infiltrate in the interstitium in all cases; additionally bronchopneumonia was seen in two cases and hemorrhage with meconium aspiration in a single case. The liver showed widely dilated sinusoids with a diffuse infiltrate by immature cells of the myeloid series. The hepatocytes were compressed, portal areas wide and infiltrated by immature cells in all six cases and in one case patches of hemorrhage and necrosis were seen. Red pulp of the spleen was diffusely infiltrated by immature cells with sparsely distributed lymphoid follicles. Hemorrhage was seen in two cases. Kidneys showed a heavy, diffuse, interstitial infiltrate by similar leukemic cells. Glomeruk and tubules were normal and were widely separated by these infiltrates (See [Figure - 1]). Meningeal infiltration by immature cells, were seen in two cases, but parenchymal infiltrate was not observed in any of these cases. Heart showed focal myocardial infiltrate in two cases. Mesenteric and hilar lymph nodes showed interfollicular infiltrate by leukemic cells in two cases, but the follicles were well preserved in all six cases. Thymus similarly showed normal lobular pattern with dense interstitial infiltrate in four cases associated with loss of normal zoning. Depletion of lymphocytes resulting in atrophy was seen in a single case.
Pancreatic sections studied in one case, showed leukemic cell infiltrates in the interstitium. Intestine showed large patches of infiltrate in the submucous layer and mucosa in three cases with involvement of all the layers in a single case. Bone marrow could be studied in five cases and showed increase in myeloid blast cells with depletion of the erythroid and the megakaryocytic cells, which was confirmed on imprint smears.
Terminal cause of death was due to respiratory distress following leukemia in four cases and secondary bronchopneumonia in two cases.
Congenital leukemia is defined as leukemia that develops in utero. Because of the doubling time of leukernic cells, the disease should be clinically evident within the first month of life. Thereafter, the terms perinatal or infantile leukemia may be used. In contrast to childhood leukemia in which acute lymphoblastic leukemia predominates, in congenital leukemia, acute myelocytic leukemia outnumbers acute lymphoblastic leukemia (9:1). Though more than 100 well-documented cases have been described,,, the exact incidence of congenital leukemia is unknown.
Of the cases reported as congenital leukemias, a majority had acute myeloid leukemia (AML). Two neonates with acute lymphoblastic leukemia (ALL) were reported in whom the blasts had immunological markers consistent with the pre-B phenotype,. ALL, chronic myeloid leukemia (CML) and erythroleukemia have also been observed in this period,.
All our cases were diagnosed as AML. Subtyping was possible only in one case (diagnosis of M-4) with the help of antemortem peripheral and bone marrow smears, imprints of non-hemopoietic organs and bone marrow and a cytochemical study which was positive for peroxidose, CAE and NSE and negative for PAS. This case had a bluish skin plaque 3 cm x 1 cm in diameter (leukemia cutis). Such skin involvement is seen only in 50% of cases of AML, being more common in the M-5 subtype.
The aetiology of congenital leukemia like that of other leukemias is unknown. Congenital leukemia has occurred in infants whose mother had leukemia, before or during pregnancy. Fetal x-ray exposure has not consistently been associated with an increased incidence of leukemia. Association with chromosomal anomalies like Down's syndrome,,,, Turner's syndrome, mosaic monosomy, and trisomy has been well documented. Signs and symptoms in the newborn are petechiae, purpura, hepatosplenomegaly, lethargy, pallor and poor feeding. Many infants die of respiratory distress secondary to pulmonary leukostasis and bronchopneumonia. Two of our cases had terminal bronchopneumonia, one had hemorrhage and meconium aspiration and the rest showed pulmonary leukostasis.
Clinically, it is important to differentiate congenital leukemia from other leukoerythroblastic conditions, which are seen in response to bacterial infection, hypoxemia and severe hemolysis in the neonate. Other differential diagnosis includes congenital syphilis, intrauterine viral disease, neuroblastoma and the transient myeloprofiferation syndrome associated with Down's syndrome,,,. At autopsy, there was no morphological evidence of intrauterine infection; serologicai test for VDRL could be done in two cases and were negative.
Cerebral parenchymal involvement though reported in cases of ALL, only one case showed meningeal infiltration. Hepatosplenornegaly was seen in all our cases; liver infiltration was diffuse involving the portal triad and sinusoids hence pattern typing to differentiate AML from CML as is seen in older children, was not possible. Kidney lumps were seen in three cases, and renal function tests like BUN and serum creatinine were preserved despite the extensive interstitial infiltrate, probably because the infiltrate was pushing the tubules and glomeruli but was not infiltrating them. Antemortern urine examination for the presence of leukemic cells was not done and possibly these cells being present in the interstitium and not the tubules do not leak in to the urine.
Lymphoid organs like thymus, spleen and lymph nodes showed preservation of lymphoid follicles with infiltration of the interstitium, which was in favour of a myeloid origin.
Survival time in congenital leukemia is almost, without exception, extremely brief, ranging from a few days to less than six months and hence it should be differentiated from myeloproliferative disorders associated with Down's syndrome which show a characteristic complete clinical and hematological recovery within weeks or months of diagnosis without specific antileukemic treatment,.
Treatment of congenital leukemia would be identical with leukemia occurring in the older child, with the exception of cranial irradiation. The latter is contraindicated in the newborn because it would limit subsequent brain and skull growth. Thus, the pro nosis for a newborn with leukemia remains unknown,.
[Figure - 1][Table - 1]