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Year : 2013  |  Volume : 56  |  Issue : 4  |  Page : 446-448
T-lineage acute lymphoblastic leukemia and parvovirus infection in a child with neurofibromastosis-1

1 Department of Pathology, PGIMER, Chandigarh, India
2 Department of Hematology, PGIMER, Chandigarh, India
3 Department of Pediatrics, PGIMER, Chandigarh, India

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Date of Web Publication18-Jan-2014


Neurofibromatosis (NF-1) patients have an increased risk of developing malignancies most commonly rhabdomyosarcomas, optic gliomas, brain tumors and non-lymphocytic leukemias. Acute lymphoblastic leukemia (ALL) has been infrequently reported in association with NF-1. We describe a rare association of NF-1, T-lineage ALL and parvovirus infection in a 12-year-old child. In addition, it is also to emphasize that a high index of suspicion should be kept for parvovirus B19 infection as a cause of bicytopenia/pancytopenia in ALL patients following induction chemotherapy.

Keywords: Acute lymphoblastc leukemia, neurofibromatosis, parvovirus infection

How to cite this article:
Agarwal P, Naseem S, Varma N, Marwaha R K. T-lineage acute lymphoblastic leukemia and parvovirus infection in a child with neurofibromastosis-1. Indian J Pathol Microbiol 2013;56:446-8

How to cite this URL:
Agarwal P, Naseem S, Varma N, Marwaha R K. T-lineage acute lymphoblastic leukemia and parvovirus infection in a child with neurofibromastosis-1. Indian J Pathol Microbiol [serial online] 2013 [cited 2022 Jul 4];56:446-8. Available from: https://www.ijpmonline.org/text.asp?2013/56/4/446/125366

   Introduction Top

Neurofibromatosis (NF-1) is an autosomal dominant disorder with a frequency of 1 in 3000 births. NF-1 patients have an increased risk of developing malignancies estimated to be 4.4-5.2%, most commonly rhabdomyosarcomas, optic gliomas, brain tumors, leukemias and they may develop neuroectodermal malignancies later in life. Among leukemias, NF-1 is predominantly associated with non-lymphocytic leukemia. Consequently, childhood acute lymphoblastic leukemia (ALL) has been infrequently reported in association with NF-1. We describe a rare association of NF-1, T-lineage ALL and parvovirus infection in a 12-year-old child.

   Case Report Top

This was a case report of a 12-year-old male child presented at our center with progressive painless neck swelling and change of voice for a month. There was no history of fever or weight loss. On examination, similar swellings were identified in the axillary and inguinal region. Dermatological examination revealed multiple café-au-lait macules (>20) measuring 3-4 cm. Mother also had similar macules (>6) measuring 4-5 cm. Ophthalmologic examination revealed bilateral Lisch nodules on the iris. There was no evidence of the optic nerve glioma. There was no freckling. Ultrasound abdomen revealed multiple enlarged retroperitoneal and mesenteric lymph nodes. A fine needle aspiration performed from the neck swelling was suggestive of leukemia/lymphoma infiltration. Subsequently, the child underwent complete hematological examination - his hemoglobin (Hb) was 13.7 g/dl; total leucocyte count (TLC) was 6 ΄ 109 cells/L, with 76% neutrophils, 20% lymphocytes and 4% monocytes; platelet count was 2.86 ΄ 109 cells/L. Bone marrow revealed 60% blast, 1.5-2.5 times the size of mature lymphocyte with hyperchromatic nuclei, irregular nuclear margin and scanty cytoplasm [Figure 1]. These blasts were negative for myeloperoxidase stain and block positive for periodic acid Schiff's stain. The bone marrow biopsy was hypercellular showing sheets of immature cells. On flow cytometry immunphenotyping, the blasts showed expression of CD2, CD5, CD7, cytoCD3, CD34, human leukocyte antigens-DR, terminal deoxynucleotidyl transferase and were negative for myeloid and B-lymphoid markers [Figure 2]. Based on the bone marrow and flow cytometric immunophenotyping, diagnosis of T-lineage ALL was made. Child was subsequently started on ALL-Berlin-Frankfurt-Mόnste-Regimen B chemotherapy. A day 14 check marrow was performed thereafter which revealed 7% blasts, erythroblastopenia and giant proerythroblast indicating parvovirus infection [Figure 3]. Patient had bicytopenia at this time with Hb =10.8 g/dl, TLC = 1.1 ΄ 109 cells/L and platelet count 2.44 ΄ 109 cells/L. Patient is now on consolidation phase of chemotherapy.
Figure 1: Bone marrow aspirate at diagnosis, showing predominantly blasts (May-Grunwald Giemsa, ×1000)

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Figure 2: Flow cytometry dot plots-show positi vity for CD2, CD5, CD7, cytoCD3, human leukocyte anti gens-DR and terminal deoxynucleotidyl transferase

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Figure 3: Bone marrow aspirate during inducti on therapy-showing giant proerythroblast with the intra-nuclear inclusion (May-Grunwald Giemsa, ×1000)

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   Discussion Top

Leukemia in a child with NF-1 was first reported more than 30 years ago. It develops as a result of mutations in the NF1 gene which is located on 17q11.2. The product of this gene interacts with the ras p21 protein and may regulate ras activity. Mutations of the ras gene have been reported in some myelogenous leukemias (juvenile myelogenous leukemia and myelodysplastic syndrome (MDS) but they are relatively less common in ALL. Although children with NF-1 are at increased risk of leukemia, ALL develops only rarely compared with malignant myeloid diseases, such as MDS and myeloproliferative neoplasms. A population based study revealed a 5-10 fold risk of ALL in association with NF-1 and a much higher risk of chronic myelomonocytic leukemia (200 fold ).[1] In another study by Bader and Miller [2] who reviewed 29 patients with childhood leukemia associated with NF-1 found a ratio of ALL:AML of 1:2.2, which is markedly different from the ratio of 4:1 found in normal children. There are limited published reports of ALL in NF-1, [3],[4],[5] including two interesting reports by Horigome et al. [3] and Cajaiba et al. [4] Horigome et al. [3] described ALL with eosinophilia in a 5-year-old boy with NF-1. Cajaiba et al. [4] reported an unusual case of NF-1 in a 6-year-old female having two more distinct, apparently unrelated clinical entities including T-cell lymphoblastic lymphoma and Gaucher disease.

The increased risk of leukemia in NF-1 is considered as enigmatic because it is one of the few malignancies associated with NF-1 that does not primarily involve cells derived from the neural crest. In a recent study by Balgobind et al .[5] the deletion of NF-1 has been described in three pediatric T-lineage ALL patients lacking clinical evidence of NF-1, suggesting that NF-1 inactivation may provide an additional proliferative hit in pediatric T-lineage ALL.

Shannon et al. [6] demonstrated loss of heterozygosity of the NF-1 allele in the bone marrow of five out of nine children with NF-1 and MDS and acute non-lymphocytic leukemia, indicating that NF-1 acts as a tumor suppressor in myeloid cells. The only specific clonal abnormality reported in a child with ALL in their study involved deletion of 17p, on which the p53 tumor-suppressor gene is located. They concluded that future cases of leukemia or NHL in children with NF-1 should be analyzed for cytogenetic abnormalities.

The diagnosis of NF-1 requires two or more of the following signs: Café-au-lait spots 5-15 mm in greatest diameter, two or more pigmented iris hamartomas (Lisch nodules), freckling in the axillary or inguinal region, optic glioma, a distinctive osseus lesion, multiple neurofibromas and a first-degree relative with NF-1. The gene product of the NF-1 gene is neurofibromin. Neurofibromin helps regulate cellular growth and differentiation by regulating the ras pathway. The absence of neurofibromin results in increased levels of activated ras-guanosine triphosphate, causing uncontrolled mitogenic signals to be sent to the nucleus resulting in increased proliferation. Literature also suggests that activating ras mutations may result in increased T- or B-cell malignancies in animals.

In addition, the present case demonstrated parvovirus infection in the induction phase of chemotherapy. Pediatric patients with ALL receiving chemotherapy have been reported to be at high risk for acquiring parvovirus infections. Since the receptor for parvovirus is blood group "P" antigen, it has great tropism for erythroid cell precursors in the bone marrow. The pathophysiological role of parvovirus infection in interference with erythropoesis is due to direct cytopathic effect mediated by VP2 protein of parvovirus, which inhibits colony formation of blast forming units in the bone marrow and immunological mediation by cytokines Tumor necrosis factor-a and interferon-g, which may even result in pancytopenia.

Clinical complications following parvovirus B19 infection in children with ALL were first described about 20 years ago. Following which case reports of parvovirus infection in ALL patients during either induction therapy or maintenance therapy have been reported. [7] Furthermore, few authors have studied the frequency of parvovirus infection in ALL patients. Kishore et al. [8] did a pilot study to analyze the frequency of parvovirus infection and its implications in new onset acute leukemia (mostly ALL) and lymphoma in children. They analyzed 70 serum samples from 35 newly diagnosed children with hematological malignancies (on induction therapy) together with 34 controls (solid tumors). Children were examined clinically and for anti-B19 IgM antibodies by quantitative ELISA and B19 deoxyribonucleic acid (DNA) by polymerase chain reaction (PCR) (VP1-VP2) and nested-PCR (VP1 unique). Parvovirus infection was seen in 17.1% children. B19 infected children had unexplained anemia (80%) and required more blood transfusions (6.6 ± 4.8 units vs. 3.0 ± 2.6 units) besides induction chemotherapy was delayed (60%) and required longer duration of therapy (29.2 ± 20 vs. 6.3 ± 7.8 days) (P < 0.02) They concluded that B19 infection should be considered in children with ALL as it frequently caused unexplained anemia and delay in induction chemotherapy.

Heegaard et al. [9] performed a serologic study on the clinical and hematologic implications of parvovirus infection in 75 children with ALL from the time of initial admission until discontinuation of chemotherapy. They observed that 8% (4/48) of seronegative patients seroconverted and infection triggered profound anemia and thrombocytopenia. B19-specific IgG disappeared in 26% (8/31) of B19-seropositive patients and these patients were significantly younger and the B19 IgG titers were lower on admission compared with patients who continuously displayed B19 IgG. B19 DNA was detected in the seroconverting patients and this helped in determining the time of infection, which coincided with a B19 epidemic in 75% (3/4) of patients. Generally, patients presented with fever and myalgia; a rash, indicative of B19 infection, was observed in only one patient. They concluded that B19 infection was able to mimic a leukemic relapse or therapy-induced cytopenia and led to hospital admission, frequent blood sampling, renewed bone marrow aspirates, multiple transfusions of red blood cells or platelets and cessation of maintenance chemotherapy for up to 3 weeks. They recommended that B19 should be assayed at diagnosis of leukemia to avoid subsequent diagnostic uncertainty and during treatment in seronegative patients exhibiting unexplained cytopenia.

In another study by Lindblom et al. [10] on 117 children with ALL, 18 children (15%) were found to be parvovirus DNA positive. Children with ALL who were infected with parvovirus became cytopenic, leading to reduced treatment intensity and to complications during treatment. They suggested screening for parvovirus DNA in pediatric patients with ALL having unexplained cytopenia, as parvovirus infection can cause severe cytopenia and can mimic a leukemic relapse or therapy induced cytopenia.

It is important to keep this in mind, as such children usually present with pancytopenia so it should not be always considered as a therapeutic failure. In the post-chemotherapy marrow, the erythroid cell series is the first lineage to regenerate, but the maturation arrest in erythropoiesis with giant pronormoblasts would suggest parvovirus B19 infection.

   Conclusion Top

We have reported this case due to rare association of NF-1, T-lineage ALL and parvovirus infection in a young child. In addition, it is to emphasize that a high index of suspicion should be kept for parvovirus B19 infection as a cause of bicytopenia/pancytopenia in ALL patients following induction chemotherapy.

   References Top

1.Stiller CA, Chessells JM, Fitchett M. Neurofibromatosis and childhood leukaemia/lymphoma: A population-based UKCCSG study. Br J Cancer 1994;70:969-72.  Back to cited text no. 1
2.Bader JL, Miller RW. Neurofibromatosis and childhood leukemia. J Pediatr 1978;92:925-9.  Back to cited text no. 2
3.Horigome H, Sumazaki R, Iwasaki N, Imoto N, Kinugasa H, Saito M, et al. Fatal eosinophilic heart disease in a child with neurofibromatosis-1 complicated by acute lymphoblastic leukemia. Heart Vessels 2005;20:120-2.  Back to cited text no. 3
4.Cajaiba MM, Reyes-Múgica M. Gaucher or pseudo-Gaucher? The challenge of several diseases colliding in a pediatric patient. Hum Pathol 2009;40:594-8.  Back to cited text no. 4
5.Balgobind BV, Van Vlierberghe P, van den Ouweland AM, Beverloo HB, Terlouw-Kromosoeto JN, van Wering ER, et al. Leukemia-associated NF1 inactivation in patients with pediatric T-ALL and AML lacking evidence for neurofibromatosis. Blood 2008;111:4322-8.  Back to cited text no. 5
6.Shannon KM, O'Connell P, Martin GA, Paderanga D, Olson K, Dinndorf P, et al. Loss of the normal NF1 allele from the bone marrow of children with type 1 neurofibromatosis and malignant myeloid disorders. N Engl J Med 1994;330:597-601.  Back to cited text no. 6
7.Gadage VS, Viswanathan S, Kunal S, Subramanian PG, Gujral S. Parvovirus B19 presenting with persistent pancytopenia in a patient of T-ALL post induction chemotherapy diagnosed on bone marrow examination. Indian J Pathol Microbiol 2011;54:603-5.  Back to cited text no. 7
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8.Kishore J, Sen M, Kumar A, Kumar A. A pilot study on parvovirus B19 infection in paediatric haematological malignancies. Indian J Med Res 2011;133:407-13.  Back to cited text no. 8
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9.Heegaard ED, Schmiegelow K. Serologic study on parvovirus b19 infection in childhood acute lymphoblastic leukemia during chemotherapy: Clinical and hematologic implications. J Pediatr Hematol Oncol 2002;24:368-73.  Back to cited text no. 9
10.Lindblom A, Heyman M, Gustafsson I, Norbeck O, Kaldensjö T, Vernby A, et al. Parvovirus B19 infection in children with acute lymphoblastic leukemia is associated with cytopenia resulting in prolonged interruptions of chemotherapy. Clin Infect Dis 2008;46:528-36.  Back to cited text no. 10

Correspondence Address:
Shano Naseem
Department of Hematology, PGIMER, Chandigarh - 160 012
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0377-4929.125366

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