Pediatric Hematology and Oncology, 31:489–497, 2014 C Informa Healthcare USA, Inc. Copyright ISSN: 0888-0018 print / 1521-0669 online DOI: 10.3109/08880018.2013.852644
ORIGINAL ARTICLE Cancer in Infants
A Single Center Experience in 266 Patients of Infantile Malignancies Umesh Das,1 L. Appaji,2 B. S. Aruna Kumari,2 Lakshmaiah KC,1 M. Padma,2 Kavitha S,2 and Vishwanath Sathyanarayanan1 1 Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Banglore, Karnataka, India; 2 Department of pediatric Oncology, Kidwai Memorial Institute of Oncology, Banglore, Karnataka, India
Introduction: The diagnosis and management of cancer in infantile age group is a significant challenge to pediatric oncologists. Malignancies occurring in infants often have different clinical and biological behavior in comparison to older children. This study was performed with an aim to find out the profile of infantile cancers at a tertiary care cancer center in South India. Methods: The present study was a retrospective analysis of infants presenting with malignancy between 2003 and 2012 to our center in South India. Result: A total of 4588 pediatric patients were registered in the Department of Pediatric Oncology at our institute between 2003 and 2012. Among those, 266 (5.79%) of the patients were infants (0–1 years). There were 65.75% males and 34.25% females. Solid tumors were the most common malignancy in this age group (72.56%). Leukemias were observed in 67 (25.19%) infants. ALL was the most common hematological malignancy (17.29%) followed by AML (5.64%). Common solid tumors in descending orders were neuroblastoma, soft tissue sarcoma, renal tumors, germ cell tumors, retinoblastoma and hepatoblastoma. Thirteen (4.89%) neonates were seen in our study. The most common malignancy in neonates was neuroblastoma. Conclusion: The distribution of malignancy in infants is quite different from that which is found in older children. Although neuroblastoma is the most common infantile tumor in western countries, in our study leukemia is the most common infantile malignancy. Embryonal tumors such as neuroblastoma, Wilms tumor, retinoblastoma, and hepatoblastoma were more prevalent in infants. Solid tumors were the most common malignancy in infants which is followed by leukemia. Keywords acute lymphoblastic leukemia, infantile malignancy, neuroblastoma, soft tissue sarcoma
INTRODUCTION The diagnosis and management of cancer in infantile age group is a significant challenge to pediatric oncologists. The care of infants with cancer is particularly challenging because of increased vulnerability to the acute complications associated with aggressive, multimodal therapy and the potential long-term sequelae of antineoplastic therapy on growth and development. Malignancies occurring in infants often have a different clinical and biological behavior in contrast to older children even if the histological type of malignancy is the Received 5 August 2013; accepted 3 October 2013; published online 2013. Address correspondence to Dr. Umesh Das, No. 5, OPD block, Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Banglore-560029, Karnataka, India. E-mail: [email protected]
U. Das et al.
same. The response to therapy also differs, indicating unique biologic characteristics of cancer in infants that explain the different clinical outcomes [1–3]. The histological types of cancers in infants and that in older children are also different. Malignancies in infants represents 10% of all cancers diagnosed among children younger than 15 years of age [4]. The most common cancer in infants is neuroblastoma, followed by leukemia, central nervous system (CNS) tumors, retinoblastoma, renal tumors, germ cell tumors (including malignant teratomas), sarcomas, and hepatic tumors [4]. Unlike older children, female infants have a higher incidence of cancer than male infants, although rates for male infants are increasing [2]. Adult cancers usually arise from epithelial tissues and are believed often to be the result of a long standing biological process related to the interaction of exogenous exposures with genetic and other endogenous characteristics among susceptible individuals. However, in young children, particularly infants, the aberrant genetic processes is the main cause of malignancy which fail to protect against the clonal proliferation of cells with unregulated growth potential occurring very early in life and progress very quickly. Although all infantile malignancies are known to be high grade with an aggressive course, but sometimes prognosis is better than adults and young adults. For example, neuroblastoma in less than 1 year of age has good prognosis than the older age group. Due to the unique clinical, genetic, and epidemiologic characteristics of cancers in infants [5, 6], it is becoming increasingly apparent that the study of infant cancer may lead to further understanding of the mechanisms of carcinogenesis. The purpose of the present study was to give an insight into the pattern of distribution of infantile cancer. METHODS In order to explore the pattern of neoplasms seen in infants we have retrospectively analysed infants (age 0–1 yr) registered between 2003 and 2012 at a renowned tertiary care cancer centre under the Department of Pediatric Oncology located in South India. It is the major cancer center covering the entire south India. As our center is a tertiary center most of the suspected or diagnosed cases of malignancies are referred here. We have accepted all suspected/diagnosed malignancy cases that were referred from other health care centers. All undiagnosed cases were evaluated thoroughly and outside diagnosed cases were reconfirmed again either by histopathological slide/block review or repeat testing. Nonmalignant cases were referred back to pediatrician. The hospital database, which was made as per ICDO 10, was utilized for information regarding final diagnosis of all infantile malignancies registered for treatment at our institute and the prevalence of infantile malignancy amongst all pediatric malignancies was established accordingly. Case files of individual patients were analyzed for information regarding age, gender of the patients, and types of malignancy. RESULT A total of 4588 pediatric patients were registered in Department of Pediatric Oncology at our institute between 2003 and 2012. Among those 365 (7.95%) patients were infants (0–1 year) (Table 1). There were 240 (65.75%) males and 125 (34.25%)females. There was male preponderance with male to female ratio was 1.92. After thorough investigations 99 patients were diagnosed to have nonmalignant conditions and patients were referred back to pediatrician for management. Solid tumors were the most common malignancy in infantile age group in our study, which was 72.56%. The ratio of solid tumors to leukemias was 2.88. (Table 2) Leukemias were observed in 67 (25.19%) infants. The five most common malignancies in descending orders in our present study were leukemia, neuroblastoma, soft tissue sarcoma, renal tumors, and germ cell tumors. Pediatric Hematology and Oncology
A profile of Infantile Malignancies
TABLE 1 Total Number of Annually Registered Cases of Infantile Malignancy Year
Male
Female
Total
Total registration (total pediatrics)
2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 Total
12 32 28 23 22 26 27 28 22 20 240 (65.75%)
11 10 13 9 19 14 9 10 17 13 125 (34.25%)
23 42 41 32 41 40 36 38 39 33 365 (7.95%)
432 426 408 439 473 511 439 474 485 501 4588
In the present study, neonates having malignancies were 13 (4.89%) which comprised nine males and four females. Solid tumors were the most common tumor in neonates than hematological malignancies with ratio of 3.3. Neuroblastoma was the most common tumor in neonates. Hematological malignancies and soft tissue sarcoma both occupied the second position. Acute lymphoblastic leukemia, acute myeloid leukemia and myeloproliferative disorder (MPD) were seen in one patient each. Wilms tumor and GCT were found in one neonate each. In the present study acute lymphoblastic leukemia was the most common hematological malignancy followed by acute myeloid leukemia. Acute lymphoblastic leukemia was seen in 46 (17.29%) patients and acute myeloblastic leukemia was seen in 15 (5.64%) patients. Juvenile myelomonocytic leukemia (JMML), which is a unique hematological malignancy in the pediatric group, was found in four patients. JMML was diagnosed as per diagnostic guideline for JMML adopted from the EWOG-MDS 2006 protocol. The median age of presentation in JMML was 6.5 months with male to female ratio was 1:1. None of the patients with JMML had Noonan syndrome. Five patients had Langerhans cell histiocytosis. All patients were males. Other hematological malignancies like chronic MPD and biphenotpic leukemia was one patient each. As a whole in hematological malignancies there was male preponderance. Male to female ratio was 2.94. In our present study, neuroblastoma was the most common infantile solid tumor followed by soft tissue sarcoma and renal tumors (Table 3). Germ cell tumor occupied
TABLE 2 Total Hematological Malignancies and Solid Tumors Year
ALL
AML
CML
2003 2 2 2004 2 3 2005 7 3 2006 5 1 2007 5 1 2008 8 1 2009 5 1 2010 4 2 2011 5 – 2012 3 1 Total 46 (17.29%) 15 (5.64%)
– – – – – – –
Others
leukemia
LCH
Solid tumor
– 4 10 1 (MPD) 5 2 18 – 10 19 – 6 2 15 1 JMML 7 21 – 9 24 2 (BPL = 1, JMML = 1) 8 17 1 (JMML) 7 1 21 1 (JMML) 6 28 – 4 20 6 (2.256%) 67 (25.19) 5 (1.8%) 193 (72.56%)
Note: ALL: acute lymphoblastic leukemia; AML: acute myeloid leukemia; BAL: biphenotypic acute leukemia; CML: chronic myeloid leukemia; JMML: Juvenile myelomonocytic leukemia; LCH: Langerhan’s cell histiocytosis; MPD: myeloproliferative disorder. C Informa Healthcare USA, Inc. Copyright
3
Others
39
Adrenal
9
Extra adrenal 6
Unilateral 18
Bilateral
RB (24)
7
gonadal 20
Extra gonadal
GCT (27)
19
RMS
14
Non-RMS
STS (33)
3
PNET
2
Ewings
15
Hepato
3
CNS
6
Others
Note: CNS: central nervous system; GCT: germ cell tumor; Hepato: hepatoblastoma; PNET: primitive neuroectodermal tumor; RMS: rhabdomyosarcoma; STS: soft tissue sarcoma.
27
Wilm’s
Neurblastoma (48)
Distribution of Solid Tumors
Renal tumor (30)
TABLE 3
A profile of Infantile Malignancies
the fourth position in most common solid malignancy in infants. Out of 193 infants of solid tumor malignancy, 50 patients had neuroblastoma; it was 18.79% of all infantile malignancies and 25.90% of total solid tumors malignancy. Adrenal tumors were the most common (in 40 patients) compared to extra adrenal. Soft tissue sarcomas were the second most common (n = 31) solid tumor in infants. Male preponderance was seen in this tumor also. The incidence of rhabdomyosarcoma was more than the nonrhabdoid one. Fourteen male patients had rabdomyosarcoma, but in case of nonrhabdoid soft tissue sarcoma, females were outnumbering the males. The third most common solid tumor in our study was renal tumor, which was 15.54% of solid tumors and 11.28% of infantile malignancies. Out of 30 patients with renal tumor, 27 were the Wilms tumor and three were non Wilms renal tumor. Germ cell tumors were the fourth most common solid tumor in infantile malignancies in our study. Germ cell tumors comprised 10.15% of total infantile malignancies and 13.99% of solid tumors. Extra gonadal GCT was more common than gonadal GCT (ratio 2.86) in infantile age group. Gonadal GCT had male preponderance whereas extragonadal GCT had a female preponderance. Retinoblastoma was the fifth most common solid tumor in our study, which was 12.45% of solid tumors in infancy. Retinoblastoma was more common in females with male female ratio of 0.84. Both unilateral and bilateral retinoblastoma had female preponderance. In infantile age group bilateral retinoblastoma was the common than the unilateral retinoblastoma (ratio 3:1). Another common tumor in infantile age was hepatoblastoma, which was more common in males with male female ratio of 4:1. PNET, CNS tumors were seen three patients each, and Ewings sarcoma was seen in two of the patients.
DISCUSSION From these analyses, it is clear that tumor is predominant in infants and it is likely that a two hit theory demonstrated in retinoblastoma and Wilms tumor, is also applicable to other infantile tumors [7]. Infantile cancer is a special condition. In infants, there is a temporal relationship between oncogenesis and embryogenesis. The etiological factors for infantile cancer include inherited, acquired or constitutional; parental, intrauterine, and immediate postnatal environmental exposures; and transplacental metastasis There are many evidences that support genetic susceptibility as one of the major cause of infantile cancer. The obvious examples are the familial Wilms tumor and retinoblastoma which usually occur at an early age than the sporadic one. Leukemia in Down’s syndrome, familial adenometous polyposis with hepatoblastoma occurs at an early age. Rearrangements of chromosome 11q23 are common in infantile leukemias, comprising more than 70% of the observed chromosome abnormalities in children less than 1 year of age [8]. The N-myc, WT 1 gene and RB 1 genes are associated with hereditary cancers like neuroblastoma, Wilms tumor, and retinoblastoma respectively. Some acquired or constitutional abnormality may lead to cancer predisposition during the fetal development. The activation or suppression of these genes cause dysregulation of the normal developmental process and sometimes leads to cancer transformation. Some fetal and neonatal malignant tumors that clinically manifest in the first few months of life can spontaneously regress (MPD in Down’s syndrome, neuroblastoma) supports speculations about the physiologic expression of oncogenes by embryonic cells, and their role in modulation of oncogenesis [5]. C Informa Healthcare USA, Inc. Copyright
U. Das et al.
Parental exposure to environmental agents are related to infantile cancer. Maternal history of prior fetal loss, paternal exposure to X-rays and maternal exposure to naturally-occurring topoisomerase II inhibitors increase risk of infantile acute lymphoblastic leukemia [9–11] Maternal use of marijuana, maternal exposure to topoisomerase II inhibitors increase risk of AML [12, 13]. Maternal diet deficient in fruits, vegetables, vitamin C, folate, and nitrate associated with increased risk of CNS tumor in infants [13]. Maternal occupational exposure to metals, hydrocarbons, paints, and pigments and paternal occupational exposure to metals are associated with increased risk of hepatic tumor [11]. Although these studies are not conclusive, but they indicate that some malignancies occurring in infants may be due to preconceptional or in utero exposure of the developing fetus to environmental agents. Campbell et al. reported 102 cases of neonatal cancers, representing 2% of all pediatric malignancies [2]. In that study, authors reported that neuroblastoma (47%) was the most common neonatal tumor, which was followed by retinoblastoma (17%), soft tissue sarcoma (12%), CNS tumors (9%), leukemia (8%), and a few cases of Wilms tumors, liver tumors, and miscellaneous tumors. In our study, neonatal cancers were 4.89% of infantile malignancies and neuroblastoma (38.46% of neonatal tumor) was the most common tumor, which was followed by hematological malignancies and soft tissue sarcoma (23% each). In the three neonates, acute lymphoblastic leukemia, acute myeloid leukemia and MPD were present in one each. Among neonatal malignancies in our study there was male predominance which was also reported by Campbell et al. [2]. In comparison to infantile malignancies where solid tumors were more common, leukemias were the most common malignancies (38%) in childhood in our center. Out of these, 70% was acute lymphoblastic leukemia and rest were AML and other hematological malignancies. Lymphomas were the second most common tumor in childhood which was less in infants, and we have not seen any infant having lymphoma. Although CNS tumors were the second most common childhood malignancy in the western countries, it occupied the third position in our childhood cancer study. Other tumors in descending orders were retinoblastoma, renal tumor and bone tumor, soft tissue sarcoma, adrenal tumor, and hepatic tumors. In contrast to the US [14] study where females were outnumber than males, present study showed male predominance in infantile malignancies with male female ratio of 1.92. Two other studies from Thailand [15] and Taiwan [16] were also reported male preponderance of infantile malignancies. Interestingly, retinoblastoma, germ cell tumors, and central nervous tumor were more common in female than male (Table 4). Although neuroblastoma was the most common infantile tumor in western world, leukemia was the most common malignancy in Asian subcontinent (Table 5). Wiangnon et al. [15] and Yang CP et al. [16] reported that leukemia was the most common malignancy in infantile age group, which supported the results of the current study. Neuroblastoma was reported by Kenny et al. [14] 27% but in Asian subcontinent TABLE 4 Male Female Ratio in Some Common Malignancies Malignancies Neuroblastoma Leukemia Renal CNS Retinoblastoma Sarcoma GCT Hepatic
Male:Female 2.84 2.94 1.5 0.5 0.85 1.81 0.92 4 Pediatric Hematology and Oncology
A profile of Infantile Malignancies
TABLE 5 Distributions of Infantile Malignancies (%) in Various Studies Malignancies Neuroblastoma Leukemia Renal CNS Retinoblastoma Sarcoma GCT Hepatic Lymphoma Others
US [14]
Thailand [15]
Taiwan [16]
Present study (%)
27 13 11 15 13 5 9 4 1 2
12.9 33 7.7 5.6 7.7 8 11.3 10.5 2 0.8
14.6 25.6 9.8 11 17.1 6.1 9.8 6.1 – –
18 25 11 1 9 12 10 5 0 2
range was varies from 12.6–14.6% of infantile malignancy. In our study, it was 18% which was more or less similar to the other two Asian studies. Leukemia was 25% in the present study which was similar to the Taiwan study [16], but very high incidence was noted by Wiangnon et al. [15], study from Thailand (33%). The incidence of renal tumors, hepatoblastoma, and germ cell tumor in our study was on par with the international data. The incidence of hepatic tumor was reported as 10.5% in Thailand study. As compared to western data the incidence of sarcoma was high in our present study. In fact, it was very high when compared to other reported data. The infantile leukemia has unique epidemiology and distinctive clinical and biological features. Infantile ALL most commonly associated with poor outcome due to presence of poor prognostic factors including hyperleukocytosis, CNS disease at diagnosis, massive hepato splenomegaly, CD10 negativity, and a poor early response to therapy [17–20]. Generally, all cases of ALL in infantile age group have an early pre-B phenotype. Specific adverse prognostic factors in this population include age younger than 3 months, WBC count greater than 200,000 per cumm, and MLL gene rearrangement, especially t(4;11). This group of the EFS is less than 20% with early relapse,
ORIGINAL ARTICLE Cancer in Infants
A Single Center Experience in 266 Patients of Infantile Malignancies Umesh Das,1 L. Appaji,2 B. S. Aruna Kumari,2 Lakshmaiah KC,1 M. Padma,2 Kavitha S,2 and Vishwanath Sathyanarayanan1 1 Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Banglore, Karnataka, India; 2 Department of pediatric Oncology, Kidwai Memorial Institute of Oncology, Banglore, Karnataka, India
Introduction: The diagnosis and management of cancer in infantile age group is a significant challenge to pediatric oncologists. Malignancies occurring in infants often have different clinical and biological behavior in comparison to older children. This study was performed with an aim to find out the profile of infantile cancers at a tertiary care cancer center in South India. Methods: The present study was a retrospective analysis of infants presenting with malignancy between 2003 and 2012 to our center in South India. Result: A total of 4588 pediatric patients were registered in the Department of Pediatric Oncology at our institute between 2003 and 2012. Among those, 266 (5.79%) of the patients were infants (0–1 years). There were 65.75% males and 34.25% females. Solid tumors were the most common malignancy in this age group (72.56%). Leukemias were observed in 67 (25.19%) infants. ALL was the most common hematological malignancy (17.29%) followed by AML (5.64%). Common solid tumors in descending orders were neuroblastoma, soft tissue sarcoma, renal tumors, germ cell tumors, retinoblastoma and hepatoblastoma. Thirteen (4.89%) neonates were seen in our study. The most common malignancy in neonates was neuroblastoma. Conclusion: The distribution of malignancy in infants is quite different from that which is found in older children. Although neuroblastoma is the most common infantile tumor in western countries, in our study leukemia is the most common infantile malignancy. Embryonal tumors such as neuroblastoma, Wilms tumor, retinoblastoma, and hepatoblastoma were more prevalent in infants. Solid tumors were the most common malignancy in infants which is followed by leukemia. Keywords acute lymphoblastic leukemia, infantile malignancy, neuroblastoma, soft tissue sarcoma
INTRODUCTION The diagnosis and management of cancer in infantile age group is a significant challenge to pediatric oncologists. The care of infants with cancer is particularly challenging because of increased vulnerability to the acute complications associated with aggressive, multimodal therapy and the potential long-term sequelae of antineoplastic therapy on growth and development. Malignancies occurring in infants often have a different clinical and biological behavior in contrast to older children even if the histological type of malignancy is the Received 5 August 2013; accepted 3 October 2013; published online 2013. Address correspondence to Dr. Umesh Das, No. 5, OPD block, Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Banglore-560029, Karnataka, India. E-mail: [email protected]
U. Das et al.
same. The response to therapy also differs, indicating unique biologic characteristics of cancer in infants that explain the different clinical outcomes [1–3]. The histological types of cancers in infants and that in older children are also different. Malignancies in infants represents 10% of all cancers diagnosed among children younger than 15 years of age [4]. The most common cancer in infants is neuroblastoma, followed by leukemia, central nervous system (CNS) tumors, retinoblastoma, renal tumors, germ cell tumors (including malignant teratomas), sarcomas, and hepatic tumors [4]. Unlike older children, female infants have a higher incidence of cancer than male infants, although rates for male infants are increasing [2]. Adult cancers usually arise from epithelial tissues and are believed often to be the result of a long standing biological process related to the interaction of exogenous exposures with genetic and other endogenous characteristics among susceptible individuals. However, in young children, particularly infants, the aberrant genetic processes is the main cause of malignancy which fail to protect against the clonal proliferation of cells with unregulated growth potential occurring very early in life and progress very quickly. Although all infantile malignancies are known to be high grade with an aggressive course, but sometimes prognosis is better than adults and young adults. For example, neuroblastoma in less than 1 year of age has good prognosis than the older age group. Due to the unique clinical, genetic, and epidemiologic characteristics of cancers in infants [5, 6], it is becoming increasingly apparent that the study of infant cancer may lead to further understanding of the mechanisms of carcinogenesis. The purpose of the present study was to give an insight into the pattern of distribution of infantile cancer. METHODS In order to explore the pattern of neoplasms seen in infants we have retrospectively analysed infants (age 0–1 yr) registered between 2003 and 2012 at a renowned tertiary care cancer centre under the Department of Pediatric Oncology located in South India. It is the major cancer center covering the entire south India. As our center is a tertiary center most of the suspected or diagnosed cases of malignancies are referred here. We have accepted all suspected/diagnosed malignancy cases that were referred from other health care centers. All undiagnosed cases were evaluated thoroughly and outside diagnosed cases were reconfirmed again either by histopathological slide/block review or repeat testing. Nonmalignant cases were referred back to pediatrician. The hospital database, which was made as per ICDO 10, was utilized for information regarding final diagnosis of all infantile malignancies registered for treatment at our institute and the prevalence of infantile malignancy amongst all pediatric malignancies was established accordingly. Case files of individual patients were analyzed for information regarding age, gender of the patients, and types of malignancy. RESULT A total of 4588 pediatric patients were registered in Department of Pediatric Oncology at our institute between 2003 and 2012. Among those 365 (7.95%) patients were infants (0–1 year) (Table 1). There were 240 (65.75%) males and 125 (34.25%)females. There was male preponderance with male to female ratio was 1.92. After thorough investigations 99 patients were diagnosed to have nonmalignant conditions and patients were referred back to pediatrician for management. Solid tumors were the most common malignancy in infantile age group in our study, which was 72.56%. The ratio of solid tumors to leukemias was 2.88. (Table 2) Leukemias were observed in 67 (25.19%) infants. The five most common malignancies in descending orders in our present study were leukemia, neuroblastoma, soft tissue sarcoma, renal tumors, and germ cell tumors. Pediatric Hematology and Oncology
A profile of Infantile Malignancies
TABLE 1 Total Number of Annually Registered Cases of Infantile Malignancy Year
Male
Female
Total
Total registration (total pediatrics)
2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 Total
12 32 28 23 22 26 27 28 22 20 240 (65.75%)
11 10 13 9 19 14 9 10 17 13 125 (34.25%)
23 42 41 32 41 40 36 38 39 33 365 (7.95%)
432 426 408 439 473 511 439 474 485 501 4588
In the present study, neonates having malignancies were 13 (4.89%) which comprised nine males and four females. Solid tumors were the most common tumor in neonates than hematological malignancies with ratio of 3.3. Neuroblastoma was the most common tumor in neonates. Hematological malignancies and soft tissue sarcoma both occupied the second position. Acute lymphoblastic leukemia, acute myeloid leukemia and myeloproliferative disorder (MPD) were seen in one patient each. Wilms tumor and GCT were found in one neonate each. In the present study acute lymphoblastic leukemia was the most common hematological malignancy followed by acute myeloid leukemia. Acute lymphoblastic leukemia was seen in 46 (17.29%) patients and acute myeloblastic leukemia was seen in 15 (5.64%) patients. Juvenile myelomonocytic leukemia (JMML), which is a unique hematological malignancy in the pediatric group, was found in four patients. JMML was diagnosed as per diagnostic guideline for JMML adopted from the EWOG-MDS 2006 protocol. The median age of presentation in JMML was 6.5 months with male to female ratio was 1:1. None of the patients with JMML had Noonan syndrome. Five patients had Langerhans cell histiocytosis. All patients were males. Other hematological malignancies like chronic MPD and biphenotpic leukemia was one patient each. As a whole in hematological malignancies there was male preponderance. Male to female ratio was 2.94. In our present study, neuroblastoma was the most common infantile solid tumor followed by soft tissue sarcoma and renal tumors (Table 3). Germ cell tumor occupied
TABLE 2 Total Hematological Malignancies and Solid Tumors Year
ALL
AML
CML
2003 2 2 2004 2 3 2005 7 3 2006 5 1 2007 5 1 2008 8 1 2009 5 1 2010 4 2 2011 5 – 2012 3 1 Total 46 (17.29%) 15 (5.64%)
– – – – – – –
Others
leukemia
LCH
Solid tumor
– 4 10 1 (MPD) 5 2 18 – 10 19 – 6 2 15 1 JMML 7 21 – 9 24 2 (BPL = 1, JMML = 1) 8 17 1 (JMML) 7 1 21 1 (JMML) 6 28 – 4 20 6 (2.256%) 67 (25.19) 5 (1.8%) 193 (72.56%)
Note: ALL: acute lymphoblastic leukemia; AML: acute myeloid leukemia; BAL: biphenotypic acute leukemia; CML: chronic myeloid leukemia; JMML: Juvenile myelomonocytic leukemia; LCH: Langerhan’s cell histiocytosis; MPD: myeloproliferative disorder. C Informa Healthcare USA, Inc. Copyright
3
Others
39
Adrenal
9
Extra adrenal 6
Unilateral 18
Bilateral
RB (24)
7
gonadal 20
Extra gonadal
GCT (27)
19
RMS
14
Non-RMS
STS (33)
3
PNET
2
Ewings
15
Hepato
3
CNS
6
Others
Note: CNS: central nervous system; GCT: germ cell tumor; Hepato: hepatoblastoma; PNET: primitive neuroectodermal tumor; RMS: rhabdomyosarcoma; STS: soft tissue sarcoma.
27
Wilm’s
Neurblastoma (48)
Distribution of Solid Tumors
Renal tumor (30)
TABLE 3
A profile of Infantile Malignancies
the fourth position in most common solid malignancy in infants. Out of 193 infants of solid tumor malignancy, 50 patients had neuroblastoma; it was 18.79% of all infantile malignancies and 25.90% of total solid tumors malignancy. Adrenal tumors were the most common (in 40 patients) compared to extra adrenal. Soft tissue sarcomas were the second most common (n = 31) solid tumor in infants. Male preponderance was seen in this tumor also. The incidence of rhabdomyosarcoma was more than the nonrhabdoid one. Fourteen male patients had rabdomyosarcoma, but in case of nonrhabdoid soft tissue sarcoma, females were outnumbering the males. The third most common solid tumor in our study was renal tumor, which was 15.54% of solid tumors and 11.28% of infantile malignancies. Out of 30 patients with renal tumor, 27 were the Wilms tumor and three were non Wilms renal tumor. Germ cell tumors were the fourth most common solid tumor in infantile malignancies in our study. Germ cell tumors comprised 10.15% of total infantile malignancies and 13.99% of solid tumors. Extra gonadal GCT was more common than gonadal GCT (ratio 2.86) in infantile age group. Gonadal GCT had male preponderance whereas extragonadal GCT had a female preponderance. Retinoblastoma was the fifth most common solid tumor in our study, which was 12.45% of solid tumors in infancy. Retinoblastoma was more common in females with male female ratio of 0.84. Both unilateral and bilateral retinoblastoma had female preponderance. In infantile age group bilateral retinoblastoma was the common than the unilateral retinoblastoma (ratio 3:1). Another common tumor in infantile age was hepatoblastoma, which was more common in males with male female ratio of 4:1. PNET, CNS tumors were seen three patients each, and Ewings sarcoma was seen in two of the patients.
DISCUSSION From these analyses, it is clear that tumor is predominant in infants and it is likely that a two hit theory demonstrated in retinoblastoma and Wilms tumor, is also applicable to other infantile tumors [7]. Infantile cancer is a special condition. In infants, there is a temporal relationship between oncogenesis and embryogenesis. The etiological factors for infantile cancer include inherited, acquired or constitutional; parental, intrauterine, and immediate postnatal environmental exposures; and transplacental metastasis There are many evidences that support genetic susceptibility as one of the major cause of infantile cancer. The obvious examples are the familial Wilms tumor and retinoblastoma which usually occur at an early age than the sporadic one. Leukemia in Down’s syndrome, familial adenometous polyposis with hepatoblastoma occurs at an early age. Rearrangements of chromosome 11q23 are common in infantile leukemias, comprising more than 70% of the observed chromosome abnormalities in children less than 1 year of age [8]. The N-myc, WT 1 gene and RB 1 genes are associated with hereditary cancers like neuroblastoma, Wilms tumor, and retinoblastoma respectively. Some acquired or constitutional abnormality may lead to cancer predisposition during the fetal development. The activation or suppression of these genes cause dysregulation of the normal developmental process and sometimes leads to cancer transformation. Some fetal and neonatal malignant tumors that clinically manifest in the first few months of life can spontaneously regress (MPD in Down’s syndrome, neuroblastoma) supports speculations about the physiologic expression of oncogenes by embryonic cells, and their role in modulation of oncogenesis [5]. C Informa Healthcare USA, Inc. Copyright
U. Das et al.
Parental exposure to environmental agents are related to infantile cancer. Maternal history of prior fetal loss, paternal exposure to X-rays and maternal exposure to naturally-occurring topoisomerase II inhibitors increase risk of infantile acute lymphoblastic leukemia [9–11] Maternal use of marijuana, maternal exposure to topoisomerase II inhibitors increase risk of AML [12, 13]. Maternal diet deficient in fruits, vegetables, vitamin C, folate, and nitrate associated with increased risk of CNS tumor in infants [13]. Maternal occupational exposure to metals, hydrocarbons, paints, and pigments and paternal occupational exposure to metals are associated with increased risk of hepatic tumor [11]. Although these studies are not conclusive, but they indicate that some malignancies occurring in infants may be due to preconceptional or in utero exposure of the developing fetus to environmental agents. Campbell et al. reported 102 cases of neonatal cancers, representing 2% of all pediatric malignancies [2]. In that study, authors reported that neuroblastoma (47%) was the most common neonatal tumor, which was followed by retinoblastoma (17%), soft tissue sarcoma (12%), CNS tumors (9%), leukemia (8%), and a few cases of Wilms tumors, liver tumors, and miscellaneous tumors. In our study, neonatal cancers were 4.89% of infantile malignancies and neuroblastoma (38.46% of neonatal tumor) was the most common tumor, which was followed by hematological malignancies and soft tissue sarcoma (23% each). In the three neonates, acute lymphoblastic leukemia, acute myeloid leukemia and MPD were present in one each. Among neonatal malignancies in our study there was male predominance which was also reported by Campbell et al. [2]. In comparison to infantile malignancies where solid tumors were more common, leukemias were the most common malignancies (38%) in childhood in our center. Out of these, 70% was acute lymphoblastic leukemia and rest were AML and other hematological malignancies. Lymphomas were the second most common tumor in childhood which was less in infants, and we have not seen any infant having lymphoma. Although CNS tumors were the second most common childhood malignancy in the western countries, it occupied the third position in our childhood cancer study. Other tumors in descending orders were retinoblastoma, renal tumor and bone tumor, soft tissue sarcoma, adrenal tumor, and hepatic tumors. In contrast to the US [14] study where females were outnumber than males, present study showed male predominance in infantile malignancies with male female ratio of 1.92. Two other studies from Thailand [15] and Taiwan [16] were also reported male preponderance of infantile malignancies. Interestingly, retinoblastoma, germ cell tumors, and central nervous tumor were more common in female than male (Table 4). Although neuroblastoma was the most common infantile tumor in western world, leukemia was the most common malignancy in Asian subcontinent (Table 5). Wiangnon et al. [15] and Yang CP et al. [16] reported that leukemia was the most common malignancy in infantile age group, which supported the results of the current study. Neuroblastoma was reported by Kenny et al. [14] 27% but in Asian subcontinent TABLE 4 Male Female Ratio in Some Common Malignancies Malignancies Neuroblastoma Leukemia Renal CNS Retinoblastoma Sarcoma GCT Hepatic
Male:Female 2.84 2.94 1.5 0.5 0.85 1.81 0.92 4 Pediatric Hematology and Oncology
A profile of Infantile Malignancies
TABLE 5 Distributions of Infantile Malignancies (%) in Various Studies Malignancies Neuroblastoma Leukemia Renal CNS Retinoblastoma Sarcoma GCT Hepatic Lymphoma Others
US [14]
Thailand [15]
Taiwan [16]
Present study (%)
27 13 11 15 13 5 9 4 1 2
12.9 33 7.7 5.6 7.7 8 11.3 10.5 2 0.8
14.6 25.6 9.8 11 17.1 6.1 9.8 6.1 – –
18 25 11 1 9 12 10 5 0 2
range was varies from 12.6–14.6% of infantile malignancy. In our study, it was 18% which was more or less similar to the other two Asian studies. Leukemia was 25% in the present study which was similar to the Taiwan study [16], but very high incidence was noted by Wiangnon et al. [15], study from Thailand (33%). The incidence of renal tumors, hepatoblastoma, and germ cell tumor in our study was on par with the international data. The incidence of hepatic tumor was reported as 10.5% in Thailand study. As compared to western data the incidence of sarcoma was high in our present study. In fact, it was very high when compared to other reported data. The infantile leukemia has unique epidemiology and distinctive clinical and biological features. Infantile ALL most commonly associated with poor outcome due to presence of poor prognostic factors including hyperleukocytosis, CNS disease at diagnosis, massive hepato splenomegaly, CD10 negativity, and a poor early response to therapy [17–20]. Generally, all cases of ALL in infantile age group have an early pre-B phenotype. Specific adverse prognostic factors in this population include age younger than 3 months, WBC count greater than 200,000 per cumm, and MLL gene rearrangement, especially t(4;11). This group of the EFS is less than 20% with early relapse,
