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Neonatal neuroblastoma in otolaryngology: A case and literature review
not available in VTW/JSS 26 (2019) 100674
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology Case Reports journal homepage: http://www.elsevier.com/locate/PEDEO
Case Report
Neonatal neuroblastoma in otolaryngology: A case and literature review Maxwell J. Bergman a, Navin R. Prasad b, Caitlin M. Brumfiel b, Earl H. Harley Jr. b, * a b
Department of Otolaryngology - Head & Neck Surgery, Ohio State University Wexner Medical Center, Columbus, OH, 43212, USA Department of Otolaryngology - Head & Neck Surgery, Medstar Georgetown University Hospital, Washington, DC, 20007, USA
A R T I C L E I N F O
A B S T R A C T
Keywords: Neuroblastoma Airway Pediatric Treatment Outcomes
A male born at 35 2/7 weeks gestation was found at one week of life to have a left-sided neck mass following a period of prolonged respiratory distress. The mass was associated with elevated urine catecholamine metabolites levels, and upon subsequent biopsy and PET scan was diagnosed as a stage 2A risk group L2 neuroblastoma. The patient was treated with four cycles of chemotherapy, and the residual tumor became stable in size several months after conclusion of chemotherapy. This differs from the classic presentation of neuroblastoma, which is a rapidly enlarging abdominal mass in a less than 2-year-old child. In this article, we detail the management of this patient and review the epidemiology, genetics, typical and otolaryngology-specific presentations, diagnosis, and treatment of neonatal neuroblastomas. Our review models the current understanding of neuroblastoma pa thology in the neonatal population for the perspective of otolaryngology.
1. Case A male born at 35 2/7 weeks gestation was initially transferred to Medstar Georgetown University Hospital (MGUH) at 12 hours of life due to worsening respiratory status requiring intubation, surfactant admin istration, and ventilation. Pregnancy was complicated by preeclampsia and premature rupture of membranes. He was stabilized and transferred to an outside hospital but transferred back to MGUH one week later due to persistent desaturations and increased work of breathing. Significant swelling of the left side of the infant’s neck was noted at that time and there was concern that mass effect was causing the respiratory distress. Family history was negative for neonatal masses or malignancy. Physical exam revealed a firm mass present over the left lateral neck, as well as left-sided miosis concerning for Horner syndrome. The patient was initially treated with methylprednisolone for what was presumed to be a hemangioma. Magnetic resonance angiography (MRA) of the neck showed a 3.1� 3.4 � 3.4 cm, well-defined, solid, heterogeneous mass with internal vascularity and microcalcifications (Fig. 1). The mass was noted to have multiple hyperechoic areas consistent with necrosis and to displace, but not invade, the common carotid, internal jugular vein, and trachea. Ultrasound-guided biopsy results revealed a small round blue cell tumor with diffuse, strong immunoreactivity for chromogranin and synaptophysin, confirming the diagnosis of neuroblastoma, while
negative for MYC-N, GFAP, and S100. Subsequent MRI and PET scans were negative for metastases. Bilateral bone marrow biopsy showed no marrow involvement by the neuroblastoma. Iodine-123 meta iodo benzylguanidine (MIBG) scan showed no radiotracer accumulation, even in the site of the primary mass. The tumor was diagnosed as a stage 2A neuroblastoma per the International Neuroblastoma Staging System (INSS; Fig. 2); the risk group was L2 per the International Neuroblas toma Risk Group (INRG) Pretreatment Classification Schema (Fig. 3). Repeat ultrasound a week later demonstrated an increased size of the mass. The tumor was deemed unresectable due to its location and chemotherapy was initiated with etoposide, carboplatin, and filgrastim. Urine catecholamines were monitored weekly and downtrended with treatment. A subsequent cycle of chemotherapy included cyclophos phamide and doxorubicin in addition to the aforementioned agents. Imaging studies after the second cycle showed a 62% reduction in tumor size, and repeat PET showed no areas of radiotracer accumulation other than in the left neck lesion. During chemotherapy, the patient was unable to tolerate oral feeds due to impaired swallowing and was fed exclusively through nasogastric tube and subsequent gastrostomy tube. He was discharged after his fourth cycle of chemotherapy with significantly decreased size of the left neck neuroblastoma on MRI and normalized urine catecholamines. Repeat PET scans after finishing chemotherapy showed no residual uptake by the primary tumor and no detectable metastatic sites.
* Corresponding author. Medstar Georgetown University Hospital, Department of Otolaryngology - Head and Neck Surgery, 3800 Reservoir RD NW, Washington, D.C, 20007, USA. E-mail addresses: [email protected], [email protected] (E.H. Harley). https://doi.org/10.1016/j.pedeo.2019.100674 Received 9 September 2019; Received in revised form 15 November 2019; Accepted 22 November 2019 Available online 5 December 2019 2588-9109/© 2019 Elsevier Ltd. All rights reserved.
M.J. Bergman et al.
International Journal of Pediatric Otorhinolaryngology Case Reports 26 (2019) 100674
early childhood. It is the second most common solid tumor in children and accounts for 15% of pediatric cancer-related deaths. However, a 20 year review of the Surveillance, Epidemiology, and End. Results (SEER) database revealed neuroblastoma to be the most common malignancy in infants less than one year of age, at almost double the incidence of the second leading cancer—leukemia [1]. Neonatal malignancies are defined as those detected within the first 28 days of life and are very rare, accounting for only 2% of all pediatric cancers. The most common solid tumor to arise within the neonatal period is neuroblastoma. According to one study, 16% of infant neuro blastomas presented within the neonatal period and 41% were diag nosed within the first three months. The tumors have a slightly higher preponderance in males, with a male-to-female sex ratio of 1.2:1 [2]. Neuroblastoma is an embryonal malignancy derived from primordial neural crest cells and can originate anywhere within the sympathetic nervous system. Most primary neuroblastomas present as rapidly enlarging abdominal masses (47% adrenal, 24% abdomen/retro peritoneum); fewer tumors present in the thorax (15%) and even fewer still present in the pelvis (3%) or neck (3%) [3]. Neuroblastomas demonstrate a wide spectrum of histopathological differentiation and due to the variety of primary tumor sites, exhibit diverse biological, genetic, and clinical behavior. In the study by Alvi et al., nearly 25% of their 118 pediatric patients with neuroblastoma had primary or meta static head and neck involvement, with metastatic presentation being three times more prevalent [4]. Neuroblastoma generally has a good prognosis in neonates and infants less than one year. Occasionally, the tumor spontaneously regresses even in cases of metastatic disease. The outcome in children over 18 months of age is less promising, as their tumors often demonstrate more complex biology and require aggressive
Fig. 1. Left lateral neck mass (left) and (right) axial view MRA neck demon strating the left-sided neuroblastoma (blue star) displacing the trachea (green arrow) to the right and carotid bifurcation (red arrow) anteriorly at initial presentation. The patient’s upper extremity is observed anterior to his neck. A ¼ Anterior, P ¼ Posterior, L ¼ Left, R ¼ Right. (For interpretation of the ref erences to colour in this figure legend, the reader is referred to the Web version of this article.)
2. Discussion 2.1. Background and epidemiology With a peak age of onset at 18 months, neuroblastoma is a cancer of
Fig. 2. INSS table [22]. 2
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International Journal of Pediatric Otorhinolaryngology Case Reports 26 (2019) 100674
therapy [5]. More than 70% of neuroblastoma patients less than 18 months of age present with metastatic disease and less than 50% are cured despite intensive treatment and autologous bone marrow or stem cell rescue [6].
production. Inactivating mutations of this gene account for the other 5% of familial neuroblastomas. Alterations in PHOX2B are considered diagnostic in concordance with a presentation of congenital central hypoventilation syndrome (CCHS), a rare congenital breathing disorder [5]. Other genetic disorders that may occur together with neuroblas toma include Hirschsprung’s disease, Noonan syndrome, and neurofi bromatosis type 1 [5].
2.2. Etiology and genetics The etiology of neuroblastoma is unknown in most cases. Phenytoin, phenobarbitone, and alcohol use during pregnancy have been impli cated as potential risk factors, but no confirmations have been made. Some studies have reported increased risk in children conceived following assisted reproductive therapy; however, other studies failed to demonstrate a significant association between neuroblastoma and fertility treatment [7]. The vast majority of neuroblastomas arise as sporadic, solitary lesions. A small percentage (1–2%) of neuroblastomas occur as multiple primary tumors in the context of familial autosomal dominant inheritance patterns with incomplete penetrance [5]. The MYC-N transcription factor gene amplification, defined as the presence or absence of >10 copies per cell, is the principal indicator that defines high-risk neuroblastoma. Amplification of the MYC-N gene on the distal short arm of chromosome 2 (2p24) correlates with aggressive tumor behavior and poorer patient outcomes. and has thus served as a mainstay prognostic marker since its discovery in 1983 [8]. Overall, MYC-N is amplified in 20–25% of neuroblastoma primary tumors. Of the patients with MYC-N amplification, 40% are classified as high-risk while only 5–10% have low-stage disease. Recent advances have highlighted the importance of ALK and PHOX2B germline mutations, which account for approximately 80% of hereditary neuroblastoma. Activating mutations of anaplastic lym phoma kinase (ALK) account for 75% of these, which has prompted routine screening for this specific mutation in cases of familial neuro blastomas [5,6]. ALK amplifications are also found in 10% of sporadic neuroblastoma tumors. The ALK gene produces a receptor tyrosine ki nase involved in neuronal differentiation and when mutated or trans located, can result in constitutive cell growth and tumorigenesis. ALK mutations and rearrangements are found in a wide variety of types and as such, it has become a novel therapeutic target in recent years, including in clinical trials treating neuroblastoma [9]. The paired homeobox 2b gene (PHOX2B) is a critical regulator of sympathetic nervous system development and catecholamine
2.3. Clinical and otolaryngology-specific presentation As stated previously, neuroblastomas may present anywhere along the sympathetic chain and therefore express great heterogeneity in terms of clinical presentation. The most common location for neuro blastoma is within the abdomen (65%), with nearly half arising within the adrenal medulla [10]. Abdominal tumors present with abdominal distension and a palpable, firm, irregular mass. Pelvic tumors may also occur within the organs of Zuckerkandl and may alter bowel and bladder function due to spinal cord compression. Infants are more likely to have thoracic and cervical primary tumors than older children, and meta static disease is found in the majority of patients at the time of diagnosis [5,11,12]. Paraneoplastic syndromes can also occur and may be the first presentation of neuroblastoma. The two most common include vasoac tive intestinal polypeptide (VIP) hypersecretion leading to profuse, watery diarrhea, and opsoclonus-myoclonus ataxia (‘dancing eyes’ syndrome) resulting in fast, conjugate eye movements, synchronized muscle jerks, and behavioral change [5]. Primary head and neck neuroblastomas are very rare with a relative incidence of around 6%, while metastases to these sites are nearly three times more common [2]. Primary neuroblastoma of the neck presents as a palpable neck mass with signs and symptoms related to mass effect. Potential findings include respiratory compromise, vocal cord paralysis, and/or Horner syndrome, which presents with ipsilateral ptosis and miosis due to compression of the superior cervical sympathetic ganglion [2]. One study showed that in those with metastatic involvement of the head and neck, all had primary retroperitoneal neuroblastoma, and most had metastatic lesions within the craniofacial skeleton. Metastases to the periorbital bone and soft tissue is common and can result in ecchymosis, creating the characteristic “raccoon eyes” appearance seen in 30% of patients with metastatic neuroblastoma [2].
Fig. 3. INRG table [19]. 3
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International Journal of Pediatric Otorhinolaryngology Case Reports 26 (2019) 100674
2.4. Imaging
2.9. INGR risk-stratification and outcomes
For any neonate, infant, or child presenting with an abdominal mass, ultrasound is typically the initial imaging method. MRI is used in cases of paravertebral and pelvic masses, while radiographs are unfavorable due to the risks associated with radiation exposure [5]. Iodine-123 MIBG scintigraphy uptake is seen in 90% of neuroblastomas [13] and may have prognostic significance for response to chemotherapy in children over one year of age with metastatic disease [14]. Stage 4S neuroblas toma should have negative MIBG in the bone marrow (Fig. 2).
The very low-risk and low-risk groups have similar five-year survival and treatment modalities and have been grouped together for the pur pose of this paper. Low risk groups are defined as 1) localized tumors without MYC-N amplification or chromosomal abnormalities 2) meta static disease with hyperdiploid DNA but without MYC-N amplification 3) Stage 4S without MYC-N amplification or chromosomal abnormalities [17]. Around 70% of neonatal neuroblastomas fall into this category; however, only 30% of all neuroblastomas are low risk, as older patients typically have higher-staged tumors. Low-risk staging has an excellent five-year survival of 95–100% [21]. Surgery alone is indicated for all localized, resectable tumors. In cases of inaccessible primary tumors, it is acceptable to monitor with serial MRIs due to the high likelihood of spontaneous regression. Carboplatin-based chemotherapy is the treat ment of choice if unresectable and symptomatic [21]. If segmental chromosomal abnormalities are present, chemotherapy is given for almost all low-risk grades irrespective of symptoms. The intermediate-risk group involves patients that are 1) localized tumor with 11q aberration or poorly differentiated tumor grade 2) metastatic disease with diploid chromosomes [19]. Intermediate-risk tumors account for 25% of neonatal neuroblastomas and 20% of all neuroblastomas. The prognosis is very good, with 85–95% five-year survival in most studies [21]. The initial treatment is four to eight courses of carboplatin-based and doxorubicin-based conventional chemotherapy. For patients with unfavorable tumor histology, local radiotherapy and 13-cis-retinoic acid can also be administered. The high-risk group is defined as 1) any tumor with MYCN amplifi cation 2) Stage 4S with 11q aberration [17]. This group makes accounts for 5% of neonatal and 50% of all neuroblastomas. It has a 30–40% 5-year survival and patients with MYC-N amplification have a 30% two-year survival [21]. Modern high-risk treatment regimens include beginning with five to six cycles of induction chemotherapy followed by surgery. Patients are then given high-dose consolidation therapy with autologous hematopoietic stem-cell rescue and irradiation. Finally, post-consolidation therapy is used to treat minimal residual disease. Unique to the neonatal patient, however, is that surgery is associated with more morbidity compared to older patients and should be avoided or at least delayed until age older than one year.
2.5. Pathology Glial fibrillary acidic protein (GFAP) staining is specific for glial cells and is positive in normally-functioning astrocytes and ependymal cells. It can stain positively in neuroblastomas, but usually only those that are grade I and well-differentiated [15]. S100 are low-molecular weight proteins that were originally discovered in neuronal tissue but are pre sent in many cell types [16]. Neuroblastomas demonstrate variable expression of S100, staining positively in approximately half of tumors [15]. While less important for diagnostic purposes, S100 positivity may be a favorable prognostic indicator in neuroblastoma [17]. For the purpose of staging, tumor cell ploidy and the presence/absence of 11q aberrations are also assessed [17]. Neuroblastic tumor pathology is comprised of three types: neuro blastomas and the more mature ganglioneuroblastomas and ganglio neuromas. The latter two are rare in infancy as the maturation process takes time to occur spontaneously in vivo. Classically, neuroblastomas histology present as small round blue cell tumor and Homer-Wright pseudorosettes [18]. 2.6. Laboratory testing Homovanillic acid (HVA) and vanillylmandelic acid (VMA) are uri nary catecholamine metabolites that are elevated in more than 90% of all neuroblastomas. HMA and VMA are raised in only 33% of neonatal neuroblastomas, making them less reliable diagnostic markers in this age group [5]. Some general tumor markers that may be useful in initial workup, but are not specific to neuroblastoma, include lactate dehy drogenase, ferritin, and neuron-specific enolase [5].
2.10. Case conclusion Our patient was INSS stage 2A, defined as a localized tumor with incomplete gross excision and no spread to ipsilateral lymph nodes (Fig. 2). The tumor was non-metastatic with poorly-differentiated pa thology and negative MYC-N amplification, making it low risk INRG L2. Given the poor differentiation of the tumor, it was not surprising that GFAP staining was negative on immunohistochemistry. S100 staining is only positive in approximately 50% of neuroblastomas so our patient’s negative staining is likely insignificant. Interestingly, our patient’s I-123 scan showed no uptake despite histologically confirmed neuroblastoma. PET and MRI imaging modalities were then used for metastatic evalu ation, all of which were negative. Even though the tumor was low risk on staging, his tumor was clinically high risk due to airway compromise. Chemotherapy was indicated as life-saving treatment. As stated above, the patient had a good response to therapy, with significant reduction in tumor size. One and a half years after completion of chemotherapy, the patient was developing well, although he was still dependent on his gastrostomy for feeds. He had a residual left-sided Horner syndrome and a persistent but non-palpable neck mass on imaging. As the patient was stable and the tumor was in remission, he was followed clinically without a secondlook biopsy or surgical intervention.
2.7. Staging The International Neuroblastoma Risk Group (INRG) classification is a staging system based on imaging criteria to determine the extent of disease through absence or presence of image-defined risk factors (Fig. 3). The system was created through analyses of data collected on more than 8800 patients diagnosed between 1990 and 2002 in North American, Europe, Japan, and Australia [19]. Stage M indicates the presence of disseminated disease, analogous to INSS stage 4. Risk stratification through the INRG places patients into low, intermediate, or high-risk groups. 2.8. Stage 4S classification Stage 4S (‘S’ stands for ‘special’) neuroblastoma is a unique stage specific to neuroblastoma. It is defined as children under 12 months with localized primary stage 1 or 2 tumor with metastatic involvement limited to the liver, bone marrow without cortical involvement, or skin [19]. For imaging, stage 4S neuroblastoma should have negative MIBG in the bone marrow (Fig. 2). Stage 4S neuroblastoma is low stage as most patients will experience spontaneous remission of their primary and metastatic disease without the need for therapeutic intervention [20]. 4
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International Journal of Pediatric Otorhinolaryngology Case Reports 26 (2019) 100674
3. Conclusion
[8] A.M. Davidoff, Neuroblastoma, Semin. Pediatr. Surg. 21 (1) (2012) 2–14, https:// doi.org/10.1053/j.sempedsurg.2011.10.009. [9] R. Chiarle, C. Voena, C. Ambrogio, R. Piva, G. Inghirami, The anaplastic lymphoma kinase in the pathogenesis of cancer, Nat. Rev. Cancer 8 (1) (2008) 11–23, https:// doi.org/10.1038/nrc2291. [10] J.M. Maris, M.D. Hogarty, R. Bagatell, S.L. Cohn, Neuroblastoma seminar, Lancet 369 (2007) 2106–2120, https://doi.org/10.1016/S0140-6736(07)60983-0. [11] S.G. DuBois, Y. Kalika, J.N. Lukens, et al., Metastatic sites in stage IV and IVS neuroblastoma correlate with age, tumor biology, and survival, J. Pediatr. Hematol. Oncol. 21 (3) (1999) 181–189, https://doi.org/10.1097/00043426199905000-00005. [12] S.E. Sharp, M.J. Gelfand, B.L. Shulkin, Pediatrics: diagnosis of neuroblastoma, Semin. Nucl. Med. 41 (5) (2011) 345–353, https://doi.org/10.1053/j. semnuclmed.2011.05.001. [13] S.E. Sharp, A.T. Trout, B.D. Weiss, M.J. Gelfand, MIBG in neuroblastoma diagnostic imaging and therapy, RadioGraphics 36 (1) (2016) 258–278, https://doi.org/ 10.1148/rg.2016150099. [14] A.F. Jacobson, H. Deng, J. Lombard, H.J. Lessig, R.R. Black, 123I-metaiodobenzylguanidine scintigraphy for the detection of neuroblastoma and pheochromocytoma: results of a meta-analysis, J. Clin. Endocrinol. Metab. 95 (6) (2010) 2596–2606, https://doi.org/10.1210/jc.2009-2604. [15] D. Schmidt, W. Keil, D. Harms, Neuron-specific enolase, protein S-100, neurofilaments, glial fibrillary acidic protein and vimentin as markers for cytodifferentiation in neuroblastoma, in: Progress in Surgical Pathology, Springer Berlin Heidelberg, 1988, pp. 33–39, https://doi.org/10.1007/978-3-662-12820-6_ 3. [16] P.H. Kuberappa, B.S. Bagalad, A. Ananthaneni, M.A. Kiresur, G.V. Srinivas, Certainty of S100 from physiology to pathology, J. Clin. Diagn. Res. 10 (6) (2016) ZE10–ZE15, https://doi.org/10.7860/JCDR/2016/17949.8022. [17] H. Shimada, C. Aoyama, T. Chiba, W.A. Newton, Prognostic subgroups for undifferentiated neuroblastoma: immunohistochemical study with anti-S-100 protein antibody, Hum. Pathol. 16 (5) (1985) 471–476, https://doi.org/10.1016/ S0046-8177(85)80085-X. [18] G.J. Lonergan, C.M. Schwab, E.S. Suarez, C.L. Carlson, From the archives of the AFIP - neuroblastoma, ganglioneuroblastoma, and ganglioneuroma: radiologicpathologic correlation, RadioGraphics 22 (4) (2002) 911–934, https://doi.org/ 10.1148/radiographics.22.4.g02jl15911. [19] S.L. Cohn, A.D.J. Pearson, W.B. London, et al., The International Neuroblastoma Risk Group (INRG) classification system: an INRG task force report, J. Clin. Oncol. 27 (2) (2009) 289–297, https://doi.org/10.1200/JCO.2008.16.6785. [20] J. Moppett, I. Haddadin, A.B. Foot, Neonatal neuroblastoma, Arch. Dis. Child. Fetal Neonatal Ed. 81 (2) (1999) F134–F137, https://doi.org/10.1136/fn.81.2.f134. [21] N.R. Pinto, M.A. Applebaum, S.L. Volchenboum, et al., Advances in risk classification and treatment strategies for neuroblastoma, J. Clin. Oncol. 33 (27) (2015) 3008–3017, https://doi.org/10.1200/JCO.2014.59.4648. [22] PDQ Pediatric Treatment Editorial Board, Neuroblastoma treatment (PDQ®): health professional version. 2019 Jun 4, in: PDQ Cancer Information Summaries [Internet], National Cancer Institute (US), Bethesda (MD), 2002. Table 3. The International Neuroblastoma Staging System (INSS), https://www.ncbi.nlm.nih. gov/books/NBK65747/table/CDR0000062786__725/.
While rare, neuroblastomas can and do present in the head and neck region during infancy with a variety of factors determining the complexity of each patient’s situation. A more favorable prognosis is seen in patients younger than 18 months with non-metastatic or stage 4S tumors that are MYC-N negative and without segmental chromosomal anomalies. Risk stratification is highly correlated with overall prognosis and is used to determine treatment modalities. Infant neuroblastoma which presents as low or intermediate risk has excellent progression-free and overall survival [21]. However, neonates with high-risk disease and MYC-N amplification have poorer prognosis, which is similar to trends found in older patients [6]. Financial disclosure The authors have no financial interests related to this project. Declaration of competing interest The authors have no conflicts of interest to disclose. References [1] L.A.G. Ries, M.A. Smith, J.G. Gurney, M. Linet, T. Tamra, J.L.B.G. Young (Eds.), Cancer Incidence and Survival Among Children and Adolescents: United States SEER Program, 1975. http://www-seer.ims.nci.nih.gov. (Accessed 14 November 2019). [2] S. Dhir, K. Wheeler, Early human development neonatal neuroblastoma, Early Hum. Dev. 86 (10) (2010) 601–605, https://doi.org/10.1016/j. earlhumdev.2010.08.019. [3] J.L. Grosfeld, Risk-based management: current concepts of treating malignant solid tumors of childhood, J. Am. Coll. Surg. 189 (4) (1999) 407–425, https://doi.org/ 10.1016/s1072-7515(99)00167-2. [4] S. Alvi, O. Karadaghy, M. Manalang, R. Weatherly, Clinical manifestations of neuroblastoma with head and neck involvement in children, Int. J. Pediatr. Otorhinolaryngol. 97 (2017) 157–162, https://doi.org/10.1016/j. ijporl.2017.04.013. [5] J.P.H. Fisher, D.A. Tweddle, Neonatal neuroblastoma, Semin. Fetal Neonatal Med. 17 (4) (2012) 207–215, https://doi.org/10.1016/j.siny.2012.05.002. [6] G.M. Brodeur, J. Pritchard, F. Berthold, et al., Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment, J. Clin. Oncol. 11 (8) (1993) 1466–1477, https://doi.org/10.1200/JCO.1993.11.8.1466. [7] M. Neelanjana, A. Sabaratnam, Malignant conditions in children born after assisted reproductive technology, Obstet. Gynecol. Surv. 63 (10) (2008) 669–676, https:// doi.org/10.1097/OGX.0b013e318181a9f0.
5
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology Case Reports journal homepage: http://www.elsevier.com/locate/PEDEO
Case Report
Neonatal neuroblastoma in otolaryngology: A case and literature review Maxwell J. Bergman a, Navin R. Prasad b, Caitlin M. Brumfiel b, Earl H. Harley Jr. b, * a b
Department of Otolaryngology - Head & Neck Surgery, Ohio State University Wexner Medical Center, Columbus, OH, 43212, USA Department of Otolaryngology - Head & Neck Surgery, Medstar Georgetown University Hospital, Washington, DC, 20007, USA
A R T I C L E I N F O
A B S T R A C T
Keywords: Neuroblastoma Airway Pediatric Treatment Outcomes
A male born at 35 2/7 weeks gestation was found at one week of life to have a left-sided neck mass following a period of prolonged respiratory distress. The mass was associated with elevated urine catecholamine metabolites levels, and upon subsequent biopsy and PET scan was diagnosed as a stage 2A risk group L2 neuroblastoma. The patient was treated with four cycles of chemotherapy, and the residual tumor became stable in size several months after conclusion of chemotherapy. This differs from the classic presentation of neuroblastoma, which is a rapidly enlarging abdominal mass in a less than 2-year-old child. In this article, we detail the management of this patient and review the epidemiology, genetics, typical and otolaryngology-specific presentations, diagnosis, and treatment of neonatal neuroblastomas. Our review models the current understanding of neuroblastoma pa thology in the neonatal population for the perspective of otolaryngology.
1. Case A male born at 35 2/7 weeks gestation was initially transferred to Medstar Georgetown University Hospital (MGUH) at 12 hours of life due to worsening respiratory status requiring intubation, surfactant admin istration, and ventilation. Pregnancy was complicated by preeclampsia and premature rupture of membranes. He was stabilized and transferred to an outside hospital but transferred back to MGUH one week later due to persistent desaturations and increased work of breathing. Significant swelling of the left side of the infant’s neck was noted at that time and there was concern that mass effect was causing the respiratory distress. Family history was negative for neonatal masses or malignancy. Physical exam revealed a firm mass present over the left lateral neck, as well as left-sided miosis concerning for Horner syndrome. The patient was initially treated with methylprednisolone for what was presumed to be a hemangioma. Magnetic resonance angiography (MRA) of the neck showed a 3.1� 3.4 � 3.4 cm, well-defined, solid, heterogeneous mass with internal vascularity and microcalcifications (Fig. 1). The mass was noted to have multiple hyperechoic areas consistent with necrosis and to displace, but not invade, the common carotid, internal jugular vein, and trachea. Ultrasound-guided biopsy results revealed a small round blue cell tumor with diffuse, strong immunoreactivity for chromogranin and synaptophysin, confirming the diagnosis of neuroblastoma, while
negative for MYC-N, GFAP, and S100. Subsequent MRI and PET scans were negative for metastases. Bilateral bone marrow biopsy showed no marrow involvement by the neuroblastoma. Iodine-123 meta iodo benzylguanidine (MIBG) scan showed no radiotracer accumulation, even in the site of the primary mass. The tumor was diagnosed as a stage 2A neuroblastoma per the International Neuroblastoma Staging System (INSS; Fig. 2); the risk group was L2 per the International Neuroblas toma Risk Group (INRG) Pretreatment Classification Schema (Fig. 3). Repeat ultrasound a week later demonstrated an increased size of the mass. The tumor was deemed unresectable due to its location and chemotherapy was initiated with etoposide, carboplatin, and filgrastim. Urine catecholamines were monitored weekly and downtrended with treatment. A subsequent cycle of chemotherapy included cyclophos phamide and doxorubicin in addition to the aforementioned agents. Imaging studies after the second cycle showed a 62% reduction in tumor size, and repeat PET showed no areas of radiotracer accumulation other than in the left neck lesion. During chemotherapy, the patient was unable to tolerate oral feeds due to impaired swallowing and was fed exclusively through nasogastric tube and subsequent gastrostomy tube. He was discharged after his fourth cycle of chemotherapy with significantly decreased size of the left neck neuroblastoma on MRI and normalized urine catecholamines. Repeat PET scans after finishing chemotherapy showed no residual uptake by the primary tumor and no detectable metastatic sites.
* Corresponding author. Medstar Georgetown University Hospital, Department of Otolaryngology - Head and Neck Surgery, 3800 Reservoir RD NW, Washington, D.C, 20007, USA. E-mail addresses: [email protected], [email protected] (E.H. Harley). https://doi.org/10.1016/j.pedeo.2019.100674 Received 9 September 2019; Received in revised form 15 November 2019; Accepted 22 November 2019 Available online 5 December 2019 2588-9109/© 2019 Elsevier Ltd. All rights reserved.
M.J. Bergman et al.
International Journal of Pediatric Otorhinolaryngology Case Reports 26 (2019) 100674
early childhood. It is the second most common solid tumor in children and accounts for 15% of pediatric cancer-related deaths. However, a 20 year review of the Surveillance, Epidemiology, and End. Results (SEER) database revealed neuroblastoma to be the most common malignancy in infants less than one year of age, at almost double the incidence of the second leading cancer—leukemia [1]. Neonatal malignancies are defined as those detected within the first 28 days of life and are very rare, accounting for only 2% of all pediatric cancers. The most common solid tumor to arise within the neonatal period is neuroblastoma. According to one study, 16% of infant neuro blastomas presented within the neonatal period and 41% were diag nosed within the first three months. The tumors have a slightly higher preponderance in males, with a male-to-female sex ratio of 1.2:1 [2]. Neuroblastoma is an embryonal malignancy derived from primordial neural crest cells and can originate anywhere within the sympathetic nervous system. Most primary neuroblastomas present as rapidly enlarging abdominal masses (47% adrenal, 24% abdomen/retro peritoneum); fewer tumors present in the thorax (15%) and even fewer still present in the pelvis (3%) or neck (3%) [3]. Neuroblastomas demonstrate a wide spectrum of histopathological differentiation and due to the variety of primary tumor sites, exhibit diverse biological, genetic, and clinical behavior. In the study by Alvi et al., nearly 25% of their 118 pediatric patients with neuroblastoma had primary or meta static head and neck involvement, with metastatic presentation being three times more prevalent [4]. Neuroblastoma generally has a good prognosis in neonates and infants less than one year. Occasionally, the tumor spontaneously regresses even in cases of metastatic disease. The outcome in children over 18 months of age is less promising, as their tumors often demonstrate more complex biology and require aggressive
Fig. 1. Left lateral neck mass (left) and (right) axial view MRA neck demon strating the left-sided neuroblastoma (blue star) displacing the trachea (green arrow) to the right and carotid bifurcation (red arrow) anteriorly at initial presentation. The patient’s upper extremity is observed anterior to his neck. A ¼ Anterior, P ¼ Posterior, L ¼ Left, R ¼ Right. (For interpretation of the ref erences to colour in this figure legend, the reader is referred to the Web version of this article.)
2. Discussion 2.1. Background and epidemiology With a peak age of onset at 18 months, neuroblastoma is a cancer of
Fig. 2. INSS table [22]. 2
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therapy [5]. More than 70% of neuroblastoma patients less than 18 months of age present with metastatic disease and less than 50% are cured despite intensive treatment and autologous bone marrow or stem cell rescue [6].
production. Inactivating mutations of this gene account for the other 5% of familial neuroblastomas. Alterations in PHOX2B are considered diagnostic in concordance with a presentation of congenital central hypoventilation syndrome (CCHS), a rare congenital breathing disorder [5]. Other genetic disorders that may occur together with neuroblas toma include Hirschsprung’s disease, Noonan syndrome, and neurofi bromatosis type 1 [5].
2.2. Etiology and genetics The etiology of neuroblastoma is unknown in most cases. Phenytoin, phenobarbitone, and alcohol use during pregnancy have been impli cated as potential risk factors, but no confirmations have been made. Some studies have reported increased risk in children conceived following assisted reproductive therapy; however, other studies failed to demonstrate a significant association between neuroblastoma and fertility treatment [7]. The vast majority of neuroblastomas arise as sporadic, solitary lesions. A small percentage (1–2%) of neuroblastomas occur as multiple primary tumors in the context of familial autosomal dominant inheritance patterns with incomplete penetrance [5]. The MYC-N transcription factor gene amplification, defined as the presence or absence of >10 copies per cell, is the principal indicator that defines high-risk neuroblastoma. Amplification of the MYC-N gene on the distal short arm of chromosome 2 (2p24) correlates with aggressive tumor behavior and poorer patient outcomes. and has thus served as a mainstay prognostic marker since its discovery in 1983 [8]. Overall, MYC-N is amplified in 20–25% of neuroblastoma primary tumors. Of the patients with MYC-N amplification, 40% are classified as high-risk while only 5–10% have low-stage disease. Recent advances have highlighted the importance of ALK and PHOX2B germline mutations, which account for approximately 80% of hereditary neuroblastoma. Activating mutations of anaplastic lym phoma kinase (ALK) account for 75% of these, which has prompted routine screening for this specific mutation in cases of familial neuro blastomas [5,6]. ALK amplifications are also found in 10% of sporadic neuroblastoma tumors. The ALK gene produces a receptor tyrosine ki nase involved in neuronal differentiation and when mutated or trans located, can result in constitutive cell growth and tumorigenesis. ALK mutations and rearrangements are found in a wide variety of types and as such, it has become a novel therapeutic target in recent years, including in clinical trials treating neuroblastoma [9]. The paired homeobox 2b gene (PHOX2B) is a critical regulator of sympathetic nervous system development and catecholamine
2.3. Clinical and otolaryngology-specific presentation As stated previously, neuroblastomas may present anywhere along the sympathetic chain and therefore express great heterogeneity in terms of clinical presentation. The most common location for neuro blastoma is within the abdomen (65%), with nearly half arising within the adrenal medulla [10]. Abdominal tumors present with abdominal distension and a palpable, firm, irregular mass. Pelvic tumors may also occur within the organs of Zuckerkandl and may alter bowel and bladder function due to spinal cord compression. Infants are more likely to have thoracic and cervical primary tumors than older children, and meta static disease is found in the majority of patients at the time of diagnosis [5,11,12]. Paraneoplastic syndromes can also occur and may be the first presentation of neuroblastoma. The two most common include vasoac tive intestinal polypeptide (VIP) hypersecretion leading to profuse, watery diarrhea, and opsoclonus-myoclonus ataxia (‘dancing eyes’ syndrome) resulting in fast, conjugate eye movements, synchronized muscle jerks, and behavioral change [5]. Primary head and neck neuroblastomas are very rare with a relative incidence of around 6%, while metastases to these sites are nearly three times more common [2]. Primary neuroblastoma of the neck presents as a palpable neck mass with signs and symptoms related to mass effect. Potential findings include respiratory compromise, vocal cord paralysis, and/or Horner syndrome, which presents with ipsilateral ptosis and miosis due to compression of the superior cervical sympathetic ganglion [2]. One study showed that in those with metastatic involvement of the head and neck, all had primary retroperitoneal neuroblastoma, and most had metastatic lesions within the craniofacial skeleton. Metastases to the periorbital bone and soft tissue is common and can result in ecchymosis, creating the characteristic “raccoon eyes” appearance seen in 30% of patients with metastatic neuroblastoma [2].
Fig. 3. INRG table [19]. 3
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2.4. Imaging
2.9. INGR risk-stratification and outcomes
For any neonate, infant, or child presenting with an abdominal mass, ultrasound is typically the initial imaging method. MRI is used in cases of paravertebral and pelvic masses, while radiographs are unfavorable due to the risks associated with radiation exposure [5]. Iodine-123 MIBG scintigraphy uptake is seen in 90% of neuroblastomas [13] and may have prognostic significance for response to chemotherapy in children over one year of age with metastatic disease [14]. Stage 4S neuroblas toma should have negative MIBG in the bone marrow (Fig. 2).
The very low-risk and low-risk groups have similar five-year survival and treatment modalities and have been grouped together for the pur pose of this paper. Low risk groups are defined as 1) localized tumors without MYC-N amplification or chromosomal abnormalities 2) meta static disease with hyperdiploid DNA but without MYC-N amplification 3) Stage 4S without MYC-N amplification or chromosomal abnormalities [17]. Around 70% of neonatal neuroblastomas fall into this category; however, only 30% of all neuroblastomas are low risk, as older patients typically have higher-staged tumors. Low-risk staging has an excellent five-year survival of 95–100% [21]. Surgery alone is indicated for all localized, resectable tumors. In cases of inaccessible primary tumors, it is acceptable to monitor with serial MRIs due to the high likelihood of spontaneous regression. Carboplatin-based chemotherapy is the treat ment of choice if unresectable and symptomatic [21]. If segmental chromosomal abnormalities are present, chemotherapy is given for almost all low-risk grades irrespective of symptoms. The intermediate-risk group involves patients that are 1) localized tumor with 11q aberration or poorly differentiated tumor grade 2) metastatic disease with diploid chromosomes [19]. Intermediate-risk tumors account for 25% of neonatal neuroblastomas and 20% of all neuroblastomas. The prognosis is very good, with 85–95% five-year survival in most studies [21]. The initial treatment is four to eight courses of carboplatin-based and doxorubicin-based conventional chemotherapy. For patients with unfavorable tumor histology, local radiotherapy and 13-cis-retinoic acid can also be administered. The high-risk group is defined as 1) any tumor with MYCN amplifi cation 2) Stage 4S with 11q aberration [17]. This group makes accounts for 5% of neonatal and 50% of all neuroblastomas. It has a 30–40% 5-year survival and patients with MYC-N amplification have a 30% two-year survival [21]. Modern high-risk treatment regimens include beginning with five to six cycles of induction chemotherapy followed by surgery. Patients are then given high-dose consolidation therapy with autologous hematopoietic stem-cell rescue and irradiation. Finally, post-consolidation therapy is used to treat minimal residual disease. Unique to the neonatal patient, however, is that surgery is associated with more morbidity compared to older patients and should be avoided or at least delayed until age older than one year.
2.5. Pathology Glial fibrillary acidic protein (GFAP) staining is specific for glial cells and is positive in normally-functioning astrocytes and ependymal cells. It can stain positively in neuroblastomas, but usually only those that are grade I and well-differentiated [15]. S100 are low-molecular weight proteins that were originally discovered in neuronal tissue but are pre sent in many cell types [16]. Neuroblastomas demonstrate variable expression of S100, staining positively in approximately half of tumors [15]. While less important for diagnostic purposes, S100 positivity may be a favorable prognostic indicator in neuroblastoma [17]. For the purpose of staging, tumor cell ploidy and the presence/absence of 11q aberrations are also assessed [17]. Neuroblastic tumor pathology is comprised of three types: neuro blastomas and the more mature ganglioneuroblastomas and ganglio neuromas. The latter two are rare in infancy as the maturation process takes time to occur spontaneously in vivo. Classically, neuroblastomas histology present as small round blue cell tumor and Homer-Wright pseudorosettes [18]. 2.6. Laboratory testing Homovanillic acid (HVA) and vanillylmandelic acid (VMA) are uri nary catecholamine metabolites that are elevated in more than 90% of all neuroblastomas. HMA and VMA are raised in only 33% of neonatal neuroblastomas, making them less reliable diagnostic markers in this age group [5]. Some general tumor markers that may be useful in initial workup, but are not specific to neuroblastoma, include lactate dehy drogenase, ferritin, and neuron-specific enolase [5].
2.10. Case conclusion Our patient was INSS stage 2A, defined as a localized tumor with incomplete gross excision and no spread to ipsilateral lymph nodes (Fig. 2). The tumor was non-metastatic with poorly-differentiated pa thology and negative MYC-N amplification, making it low risk INRG L2. Given the poor differentiation of the tumor, it was not surprising that GFAP staining was negative on immunohistochemistry. S100 staining is only positive in approximately 50% of neuroblastomas so our patient’s negative staining is likely insignificant. Interestingly, our patient’s I-123 scan showed no uptake despite histologically confirmed neuroblastoma. PET and MRI imaging modalities were then used for metastatic evalu ation, all of which were negative. Even though the tumor was low risk on staging, his tumor was clinically high risk due to airway compromise. Chemotherapy was indicated as life-saving treatment. As stated above, the patient had a good response to therapy, with significant reduction in tumor size. One and a half years after completion of chemotherapy, the patient was developing well, although he was still dependent on his gastrostomy for feeds. He had a residual left-sided Horner syndrome and a persistent but non-palpable neck mass on imaging. As the patient was stable and the tumor was in remission, he was followed clinically without a secondlook biopsy or surgical intervention.
2.7. Staging The International Neuroblastoma Risk Group (INRG) classification is a staging system based on imaging criteria to determine the extent of disease through absence or presence of image-defined risk factors (Fig. 3). The system was created through analyses of data collected on more than 8800 patients diagnosed between 1990 and 2002 in North American, Europe, Japan, and Australia [19]. Stage M indicates the presence of disseminated disease, analogous to INSS stage 4. Risk stratification through the INRG places patients into low, intermediate, or high-risk groups. 2.8. Stage 4S classification Stage 4S (‘S’ stands for ‘special’) neuroblastoma is a unique stage specific to neuroblastoma. It is defined as children under 12 months with localized primary stage 1 or 2 tumor with metastatic involvement limited to the liver, bone marrow without cortical involvement, or skin [19]. For imaging, stage 4S neuroblastoma should have negative MIBG in the bone marrow (Fig. 2). Stage 4S neuroblastoma is low stage as most patients will experience spontaneous remission of their primary and metastatic disease without the need for therapeutic intervention [20]. 4
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3. Conclusion
[8] A.M. Davidoff, Neuroblastoma, Semin. Pediatr. Surg. 21 (1) (2012) 2–14, https:// doi.org/10.1053/j.sempedsurg.2011.10.009. [9] R. Chiarle, C. Voena, C. Ambrogio, R. Piva, G. Inghirami, The anaplastic lymphoma kinase in the pathogenesis of cancer, Nat. Rev. Cancer 8 (1) (2008) 11–23, https:// doi.org/10.1038/nrc2291. [10] J.M. Maris, M.D. Hogarty, R. Bagatell, S.L. Cohn, Neuroblastoma seminar, Lancet 369 (2007) 2106–2120, https://doi.org/10.1016/S0140-6736(07)60983-0. [11] S.G. DuBois, Y. Kalika, J.N. Lukens, et al., Metastatic sites in stage IV and IVS neuroblastoma correlate with age, tumor biology, and survival, J. Pediatr. Hematol. Oncol. 21 (3) (1999) 181–189, https://doi.org/10.1097/00043426199905000-00005. [12] S.E. Sharp, M.J. Gelfand, B.L. Shulkin, Pediatrics: diagnosis of neuroblastoma, Semin. Nucl. Med. 41 (5) (2011) 345–353, https://doi.org/10.1053/j. semnuclmed.2011.05.001. [13] S.E. Sharp, A.T. Trout, B.D. Weiss, M.J. Gelfand, MIBG in neuroblastoma diagnostic imaging and therapy, RadioGraphics 36 (1) (2016) 258–278, https://doi.org/ 10.1148/rg.2016150099. [14] A.F. Jacobson, H. Deng, J. Lombard, H.J. Lessig, R.R. Black, 123I-metaiodobenzylguanidine scintigraphy for the detection of neuroblastoma and pheochromocytoma: results of a meta-analysis, J. Clin. Endocrinol. Metab. 95 (6) (2010) 2596–2606, https://doi.org/10.1210/jc.2009-2604. [15] D. Schmidt, W. Keil, D. Harms, Neuron-specific enolase, protein S-100, neurofilaments, glial fibrillary acidic protein and vimentin as markers for cytodifferentiation in neuroblastoma, in: Progress in Surgical Pathology, Springer Berlin Heidelberg, 1988, pp. 33–39, https://doi.org/10.1007/978-3-662-12820-6_ 3. [16] P.H. Kuberappa, B.S. Bagalad, A. Ananthaneni, M.A. Kiresur, G.V. Srinivas, Certainty of S100 from physiology to pathology, J. Clin. Diagn. Res. 10 (6) (2016) ZE10–ZE15, https://doi.org/10.7860/JCDR/2016/17949.8022. [17] H. Shimada, C. Aoyama, T. Chiba, W.A. Newton, Prognostic subgroups for undifferentiated neuroblastoma: immunohistochemical study with anti-S-100 protein antibody, Hum. Pathol. 16 (5) (1985) 471–476, https://doi.org/10.1016/ S0046-8177(85)80085-X. [18] G.J. Lonergan, C.M. Schwab, E.S. Suarez, C.L. Carlson, From the archives of the AFIP - neuroblastoma, ganglioneuroblastoma, and ganglioneuroma: radiologicpathologic correlation, RadioGraphics 22 (4) (2002) 911–934, https://doi.org/ 10.1148/radiographics.22.4.g02jl15911. [19] S.L. Cohn, A.D.J. Pearson, W.B. London, et al., The International Neuroblastoma Risk Group (INRG) classification system: an INRG task force report, J. Clin. Oncol. 27 (2) (2009) 289–297, https://doi.org/10.1200/JCO.2008.16.6785. [20] J. Moppett, I. Haddadin, A.B. Foot, Neonatal neuroblastoma, Arch. Dis. Child. Fetal Neonatal Ed. 81 (2) (1999) F134–F137, https://doi.org/10.1136/fn.81.2.f134. [21] N.R. Pinto, M.A. Applebaum, S.L. Volchenboum, et al., Advances in risk classification and treatment strategies for neuroblastoma, J. Clin. Oncol. 33 (27) (2015) 3008–3017, https://doi.org/10.1200/JCO.2014.59.4648. [22] PDQ Pediatric Treatment Editorial Board, Neuroblastoma treatment (PDQ®): health professional version. 2019 Jun 4, in: PDQ Cancer Information Summaries [Internet], National Cancer Institute (US), Bethesda (MD), 2002. Table 3. The International Neuroblastoma Staging System (INSS), https://www.ncbi.nlm.nih. gov/books/NBK65747/table/CDR0000062786__725/.
While rare, neuroblastomas can and do present in the head and neck region during infancy with a variety of factors determining the complexity of each patient’s situation. A more favorable prognosis is seen in patients younger than 18 months with non-metastatic or stage 4S tumors that are MYC-N negative and without segmental chromosomal anomalies. Risk stratification is highly correlated with overall prognosis and is used to determine treatment modalities. Infant neuroblastoma which presents as low or intermediate risk has excellent progression-free and overall survival [21]. However, neonates with high-risk disease and MYC-N amplification have poorer prognosis, which is similar to trends found in older patients [6]. Financial disclosure The authors have no financial interests related to this project. Declaration of competing interest The authors have no conflicts of interest to disclose. References [1] L.A.G. Ries, M.A. Smith, J.G. Gurney, M. Linet, T. Tamra, J.L.B.G. Young (Eds.), Cancer Incidence and Survival Among Children and Adolescents: United States SEER Program, 1975. http://www-seer.ims.nci.nih.gov. (Accessed 14 November 2019). [2] S. Dhir, K. Wheeler, Early human development neonatal neuroblastoma, Early Hum. Dev. 86 (10) (2010) 601–605, https://doi.org/10.1016/j. earlhumdev.2010.08.019. [3] J.L. Grosfeld, Risk-based management: current concepts of treating malignant solid tumors of childhood, J. Am. Coll. Surg. 189 (4) (1999) 407–425, https://doi.org/ 10.1016/s1072-7515(99)00167-2. [4] S. Alvi, O. Karadaghy, M. Manalang, R. Weatherly, Clinical manifestations of neuroblastoma with head and neck involvement in children, Int. J. Pediatr. Otorhinolaryngol. 97 (2017) 157–162, https://doi.org/10.1016/j. ijporl.2017.04.013. [5] J.P.H. Fisher, D.A. Tweddle, Neonatal neuroblastoma, Semin. Fetal Neonatal Med. 17 (4) (2012) 207–215, https://doi.org/10.1016/j.siny.2012.05.002. [6] G.M. Brodeur, J. Pritchard, F. Berthold, et al., Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment, J. Clin. Oncol. 11 (8) (1993) 1466–1477, https://doi.org/10.1200/JCO.1993.11.8.1466. [7] M. Neelanjana, A. Sabaratnam, Malignant conditions in children born after assisted reproductive technology, Obstet. Gynecol. Surv. 63 (10) (2008) 669–676, https:// doi.org/10.1097/OGX.0b013e318181a9f0.
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