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Neuroblastoma metastasis to bone requiring differentiation from septic arthritis of the hip. Report of 2 cases
Journal of Orthopaedic Science xxx (2016) 1e4
Contents lists available at ScienceDirect
Journal of Orthopaedic Science journal homepage: http://www.elsevier.com/locate/jos
Case Report
Neuroblastoma metastasis to bone requiring differentiation from septic arthritis of the hip. Report of 2 cases Toru Nishiwaki a, Shinichi Uchikawa b, Hiroshi Kusakabe c, Atsuhito Seki b, Yoshitaka Eguchi b, Shinichiro Takayama b, Yoshiaki Toyama a, Masaya Nakamura a, Morio Matsumoto a, Arihiko Kanaji a, * a
Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan Division of Orthopedics, Department of Surgical Subspecialties, National Children's Medical Center, National Center for Child Health and Development, Tokyo, Japan c Department of Orthopedic Surgery, Fujita Health University School of Medicine, Banbuntane Houtokukai Hospital, Nagoya, Japan b
a r t i c l e i n f o Article history: Received 16 October 2015 Received in revised form 11 August 2016 Accepted 9 September 2016 Available online xxx
1. Introduction Neuroblastoma is the most common malignant solid tumor occurring in childhood, and may manifest with a wide variety of early symptoms. It is not rare for the early symptoms to be orthopedic symptoms, and for the patient to be examined first by an orthopedic surgeon; however orthopedic surgeons often find it difficult to make the diagnosis. In this paper we present two cases of bone metastasis from a neuroblastoma that required differentiation from septic arthritis of the hip. We discuss aspects of the diagnosis that require attention in patients who exhibit manifestations resembling those of septic arthritis of the hip. We present the cases herein after obtaining informed consent for publication of the data from the patients' parents.
* Corresponding author. Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Tokyo, Japan. Fax: þ81 3 3353 6597. E-mail address: [email protected] (A. Kanaji).
2. Reports of the cases 2.1. Case 1 A 4-year-old girl was brought to the hospital with the complaint of pain in the right hip in the absence of any obvious precipitating cause. She was diagnosed as having transient synovitis of the hip by an orthopedic practitioner and advised rest at home. Soon thereafter, she developed fever (temperature 38 C), septic arthritis of the hip was suspected, and the child was referred to our institution for further assessment and treatment. At the first visit, the child measured 105 cm in height and weighed 16 kg. General physical examination revealed fever (temperature 37.8 C), and examination of the hip joints revealed swelling and tenderness of the right hip joint. Blood hematology and biochemistry tests revealed evidence of an inflammatory reaction and mild anemia; the laboratory test results were as follows: WBC 11.09 103/ml, RBC 411 104/ml, Hb 11.2 g/dl, Na 136 mEq/l, Cl 101 mEq/l, K 4.5 mEq/l, GOT 37 IU/l, GPT 9 IU/l, BUN 9.6 mg/dl, Cre 0.21 mg/dl, UA 5.1 mg/dl, and CRP 6.3 mg/dl. A plain radiograph of the hip joint showed widening of the joint space of the right hip, with no other abnormalities (Fig. 1). Arthrocentesis yielded cloudy, yellowish-colored joint fluid, and the patient was diagnosed as having septic arthritis of the hip. However contrast-enhanced MRI showed bilateral multiple bone marrow lesions in the pelvis and proximal femur in addition to hydrarthrosis, which were suspected as bone metastases from a malignant tumor (Fig. 2). Under the suspected diagnosis of septic arthritis of the hip, metastases from a malignant tumor, or a combination of both, we performed an open washout of the joint and at the same time conducted a thorough examination of the bone marrow lesions. Cultures of the arthrocentesis fluid and joint fluid obtained intraoperatively yielded negative results, and no tumor cells were detected in the joint fluid; however, the WBC count of the joint fluid was elevated to 55.9 103/ml. CT of the abdomen was
http://dx.doi.org/10.1016/j.jos.2016.09.004 0949-2658/© 2016 Published by Elsevier B.V. on behalf of The Japanese Orthopaedic Association.
Please cite this article in press as: Nishiwaki T, et al., Neuroblastoma metastasis to bone requiring differentiation from septic arthritis of the hip. Report of 2 cases, Journal of Orthopaedic Science (2016), http://dx.doi.org/10.1016/j.jos.2016.09.004
2
T. Nishiwaki et al. / Journal of Orthopaedic Science xxx (2016) 1e4
Fig. 3. Case 1. A solid para-adrenal tumor is visible (arrowhead). Fig. 1. Case 1. A 4-year-old girl. Plain radiographic view. Widening of the articular space is seen in the right hip joint.
performed as part of the investigation of the bone marrow lesions, which revealed a solid para-adrenal tumor (Fig. 3). Biopsy of the tumor led to the diagnosis of neuroblastoma, and the pelvic lesions were concluded as being metastases. Urine tests for VMA (urinary VMA) and HVA (urinary HVA) performed three days after the open washout revealed elevated levels of the metabolites to 98.55 mg/g Cr and 80.91 mg/g Cr, respectively. The patient was 4 years old, and immunohistochemical analysis of the tumor revealed amplification of the N-myc gene. A diagnosis of stage IV disease was made, with a predicted poor prognosis. Tumor resection with lymph node dissection was performed, with chemotherapy, radiation therapy, and autologous hematopoietic stem cell transplantation. Despite the treatments, the tumor progressed and after 29 months from her initial visit to our institution, the patient passed away. 2.2. Case 2 A 14-month-old girl child was brought to an orthopedic practitioner with high fever (temperature over 38 C). Laboratory tests revealed evidence of an inflammatory reaction, with a WBC count of 17.7 103/ml and serum CRP value of 4.5 mg/dl. She was treated with an antibiotic, and the clinical course was monitored. Two weeks later, she developed reduced active movements of the right hip, septic arthritis of the hip was suspected, and the patient was referred to our institution for further assessment and treatment.
At the first visit, the child measured 76.5 cm in height and weighed 9.8 kg. General physical examination revealed fever (temperature 37.5 C), and examination of the hip joints revealed swelling and decreased active motions of the right hip joint. Unilateral narrowing of the palpebral fissure of unknown etiology was noted, which had reportedly been noticed since 4 months of age. Blood hematology and biochemistry tests revealed anemia, liver dysfunction and mild inflammatory reaction; the laboratory results were as follows: WBC 9.47 103/ml, RBC 3.45 104/ml, Hb 9.2 g/dl, Na 140 mEq/l, Cl 102/mEq, K 4.2 mEq/l, GOT 123 IU/l, GPT 198 IU/l, BUN 7.9 mg/dl, Cre 0.18 mg/dl, and CRP 2.0 mg/dl. No abnormal findings were seen on a plain radiograph of the hips (Fig. 4). Ultrasound examination of the joint also did not show any evidence of joint effusion. On the basis of the findings of a narrowed palpebral fissure, anemia, and our previous experience of Case 1, we suspected bone metastases from a neuroblastoma. Contrast-enhanced MRI revealed multiple bone marrow lesions in the pelvis in addition to mild effusion of the right hip joint (Fig. 5). A plain chest radiograph revealed a mediastinal tumor (Fig. 6), and pleural fluid cytology led to the diagnosis of neuroblastoma. Urine tests for VMA (urinary VMA) and HVA (urinary HVA) performed at the initial visit of the child to our institution revealed elevated levels of the metabolites of 22.14 mg/g Cr and 41.29 mg/g Cr, respectively. Although the child was diagnosed as having stage IV disease, since she was relatively young and amplification of the N-myc gene was not detected, the prognosis appeared to be better than that of
Fig. 2. Case 1. MRI T2WI (a), CE (b). The T2WI shows fluid accumulation in the right hip joint, and abnormal shadows are visible in the shaft of the left femur. Contrast MRI shows enhanced bone marrow lesions in both femurs, the bony pelvis, and the spine.
Please cite this article in press as: Nishiwaki T, et al., Neuroblastoma metastasis to bone requiring differentiation from septic arthritis of the hip. Report of 2 cases, Journal of Orthopaedic Science (2016), http://dx.doi.org/10.1016/j.jos.2016.09.004
T. Nishiwaki et al. / Journal of Orthopaedic Science xxx (2016) 1e4
Fig. 4. Case 2. A 14-month-old girl. Plain radiography view of the hip joint. There are no abnormal findings.
Case 1 reported above. Chemotherapy was administered, however, and after one year of treatment, the mediastinal tumor showed no difference in size, and MIBG scintigraphy still revealed uptake, although it was decreased. The child is currently under treatment with retinoic acid.
3. Discussion Neuroblastoma is a malignant tumor of childhood that is derived from the neural crest cells, and arises from the adrenal medulla or sympathetic nerve ganglia, and produces catecholamines. The incidence of neuroblastoma is 10.2 cases per million children under 15 years of age, and it is the most commonly encountered extracranial malignant tumor in children [1]. In 40% of cases, the disease is diagnosed in children younger than one year of age. The most common age of occurrence of septic arthritis of the hip is also around one year of age. The clinical and biological prognostic factors reported until date are the age at the time of diagnosis, the disease stage, presence/ absence of amplification of the N-myc gene, histological class, and tumor cell DNA ploidy. Neuroblastoma with bone metastasis in children 1 year of age or older is classified as stage IV disease according to the International Neuroblastoma Staging System (INSS), and the prognosis is poor, with 5-year survival rates of 20e60% [2]. Presence/absence of amplification of the N-myc gene is a prognostic
3
Fig. 6. Case 2. Plain radiograph of the chest. A superior mediastinal tumor is visible at the upper left.
factor independent of the stage and age, and presence of amplification of this gene is strongly correlated with rapid stage progression and a poor outcome [3]. Children with neuroblastoma often present with vague initial symptoms, which could arise from the primary focus itself, from distant metastases, or even be caused by the catecholamine metabolites released from the tumor [1]. Aston et al. assessed the early presentations of 109 cases of neuroblastoma [4]. Hip pain was the initial presenting symptom in approximately 8.3% of all cases, making it the third most common presenting symptom of this tumor, and metastasis to the pelvis was not unusual. When nonspecific symptoms, such as limping, were included, the proportion of patients presenting with orthopedic symptoms increased to 18%. According to one report, presentation to an orthopedic surgeon first because of orthopedic-related symptoms delayed the diagnosis of neuroblastoma by an average of three months [5]. Therefore, orthopedic surgeons treating children must be aware that patients with neuroblastoma could first present to their service, and neuroblastoma should be included in the differential diagnosis of pain and limping in children. Transient synovitis of the hip is the most common cause of hip pain in infants, with septic arthritis not being uncommon either. In their report, Aston et al. incised and drained the hip in three cases of neuroblastoma, under the assumption that the patients had septic arthritis [4]. It can be difficult to differentiate between septic
Fig. 5. Case 2. MRI T2 WI (a), CE (b). High signal intensity area is present in the fascia around the right hip joint on the T2WI, and a bone marrow lesion showing a bone enhancement effect is observed in the left ilium. Very slight fluid accumulation is observed in the right hip joint.
Please cite this article in press as: Nishiwaki T, et al., Neuroblastoma metastasis to bone requiring differentiation from septic arthritis of the hip. Report of 2 cases, Journal of Orthopaedic Science (2016), http://dx.doi.org/10.1016/j.jos.2016.09.004
4
T. Nishiwaki et al. / Journal of Orthopaedic Science xxx (2016) 1e4
arthritis and metastases arising from neuroblastoma in these cases, even if bone lesions are seen on plain radiographs since they may be interpreted as evidence of osteomyelitis associated with septic arthritis of the hip. Although the definitive diagnosis of septic arthritis of the hip is based on a positive culture of the hip aspirate, not all cases of septic arthritis show positive results of culture [6]. Wong et al. reported collecting clear, straw-colored fluid from a case of neuroblastoma presenting with hip pain, which was initially diagnosed as a case of transient synovitis [7]. The possibility of metastasis to the pelvis from a neuroblastoma must be considered in cases of suspected septic arthritis of the hip, in which joint fluid cultures yield negative results and the response to conventional treatment is poor. Additional tests that may assist in the diagnosis are urine tests for vanillylmandelic acid (urinary VMA) and homovanillic acid (urinary HVA), which show elevated levels of these metabolites in about 90% of all cases of neuroblastoma. Urinary VMA and urinary HVA were elevated in both of our cases reported here, proving as useful adjuncts in the diagnosis of neuroblastoma. Hip pain is very common in childhood, so when should neuroblastoma be considered as a diagnosis? Patients with metastasis to the pelvis often show manifestations of disease spread outside the pelvis too. If such manifestations as an abdominal mass or paralysis of various nerves are present, thorough general examination should be undertaken. When they compared cases of septic arthritis of the hip and cases of neuroblastoma in which the patients complained of hip pain due to pelvic metastasis, Aston et al. found that anemia tended to be more severe in cases of neuroblastoma. They suggested that measurement of the hemoglobin values is useful for the differential diagnosis [8]. In our Case 2, the hemoglobin value of 9.2 g/dl indicated severe anemia, and this combined with the observation of ptosis in the patient led us to suspect this may not be a routine case of septic arthritis. When anemia is also present in cases that exhibit manifestations such as fever and hip pain which suggests septic arthritis of the hip, the possible presence of bone marrow disease, such as bone metastasis by a malignant tumor, must also be considered. There have been no reports of the concomitant development of neuroblastoma and septic arthritis of the hip, but this is always a concern in patients such as Case 1, because of the impending chemotherapy. Kiess et al. reported a case of concomitant neuroblastoma and femoral osteomyelitis, and stated that the difference in accumulation between MIBG scintigraphy and bone scintigraphy is helpful in the differential diagnosis, since there is increased activity on both scans in patients with metastatic lesions, but increased activity only on bone scans in patients with septic lesions [9]. However, some tumor lesions and metastatic lesions do not show increased uptake on MIBG scintigraphy. Furthermore, when the metastatic lesion and the osteomyelitis lesion are intermingled homogeneously at the same site instead of forming a mosaic, diagnosis by scintigraphy is difficult. In both cases, increased
uptake in the hip was detected by MIBG at the same site as that observed on enhanced MRI. However in Case 1, leukocytosis was observed in the joint fluid. We thought it impossible to rule out septic arthritis of the hip and elected to treat the patient for septic arthritis before commencing chemotherapy. The cause of inflammation and synovitis in the absence of infection is unclear, and to the best of our knowledge, no reports of neuroblastomas secreting inflammatory cytokines have been reported. Pathological fractures due to metastasis may be a cause of inflammation in the hip joint. Methods to rule out concomitant infection such as septic arthritis and osteomyelitis will be necessary in the future, so that the start of cancer chemotherapy is not delayed in cases of neuroblastoma with a poor prognosis. Hip pain caused by bone metastasis from a neuroblastoma is uncommon, however, early diagnosis and treatment are important. The presence of an abdominal mass, nerve palsies and anemia should raise the suspicion of bone metastasis from neuroblastoma. Urinary VMA, urinary HVA, enhanced MRI, MIBG scintigraphy, and bone scintigraphy are useful adjuncts for making the diagnosis of neuroblastoma. Conflict of interest There are no conflicts of interest related to the manuscript. Acknowledgments We would like to thank Dr. Joshua Lee of London Bridge Hospital for his assistance with the preparation of this manuscript. References [1] Maris JM, Hogarty MD, Bagatell R, Cohn SL. Neuroblastoma. Lancet 2007 Jun 23;369(9579):2106e20. [2] Schmidt ML, Lukens JN, Seeger RC, Brodeur GM, Shimada H, Gerbing RB, Stram DO, Perez C, Haase GM, Matthay KK. Biologic factors determine prognosis in infants with stage IV neuroblastoma: a prospective Children's Cancer Group study. J Clin Oncol 2000 Mar;18(6):1260e8. [3] Nakagawara A, Ikeda K, Tsuda T, Higashi K. N-myc oncogene amplification and prognostic factors of neuroblastoma in children. J Pediatr Surg 1987 Oct;22(10): 895e8. [4] Aston Jr JW. Pediatric update #16. The orthopaedic presentation of neuroblastoma. Orthop Rev 1990 Oct;19(10):929e32. [5] Trapani S, Grisolia F, Simonini G, Calabri GB, Falcini F. Incidence of occult cancer in children presenting with musculoskeletal symptoms: a 10-year survey in a pediatric rheumatology unit. Semin Arthritis Rheum 2000 Jun;29(6):348e59. [6] Lyon RM, Evanich JD. Culture-negative septic arthritis in children. J Pediatr Orthop 1999 SepeOct;19(5):655e9. [7] Wong M, Chung CH, Ngai WK. Hip pain and childhood malignancy. Hong Kong Med J 2002 Dec;8(6):461e3. [8] Laug WE, Siegel SE, Shaw KN, Landing B, Baptista J, Gutenstein M. Initial urinary catecholamine metabolite concentrations and prognosis in neuroblastoma. Pediatrics 1978 Jul;62(1):77e83. [9] Kiess W, Leisner B, Haas R. Coincidence of infectious osteomyelitis and disseminated neuroblastoma: a diagnostic dilemma solved by scintigraphic imaging. J Cancer Res Clin Oncol 1985 Jul;110(1):85e6.
Please cite this article in press as: Nishiwaki T, et al., Neuroblastoma metastasis to bone requiring differentiation from septic arthritis of the hip. Report of 2 cases, Journal of Orthopaedic Science (2016), http://dx.doi.org/10.1016/j.jos.2016.09.004
Contents lists available at ScienceDirect
Journal of Orthopaedic Science journal homepage: http://www.elsevier.com/locate/jos
Case Report
Neuroblastoma metastasis to bone requiring differentiation from septic arthritis of the hip. Report of 2 cases Toru Nishiwaki a, Shinichi Uchikawa b, Hiroshi Kusakabe c, Atsuhito Seki b, Yoshitaka Eguchi b, Shinichiro Takayama b, Yoshiaki Toyama a, Masaya Nakamura a, Morio Matsumoto a, Arihiko Kanaji a, * a
Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan Division of Orthopedics, Department of Surgical Subspecialties, National Children's Medical Center, National Center for Child Health and Development, Tokyo, Japan c Department of Orthopedic Surgery, Fujita Health University School of Medicine, Banbuntane Houtokukai Hospital, Nagoya, Japan b
a r t i c l e i n f o Article history: Received 16 October 2015 Received in revised form 11 August 2016 Accepted 9 September 2016 Available online xxx
1. Introduction Neuroblastoma is the most common malignant solid tumor occurring in childhood, and may manifest with a wide variety of early symptoms. It is not rare for the early symptoms to be orthopedic symptoms, and for the patient to be examined first by an orthopedic surgeon; however orthopedic surgeons often find it difficult to make the diagnosis. In this paper we present two cases of bone metastasis from a neuroblastoma that required differentiation from septic arthritis of the hip. We discuss aspects of the diagnosis that require attention in patients who exhibit manifestations resembling those of septic arthritis of the hip. We present the cases herein after obtaining informed consent for publication of the data from the patients' parents.
* Corresponding author. Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Tokyo, Japan. Fax: þ81 3 3353 6597. E-mail address: [email protected] (A. Kanaji).
2. Reports of the cases 2.1. Case 1 A 4-year-old girl was brought to the hospital with the complaint of pain in the right hip in the absence of any obvious precipitating cause. She was diagnosed as having transient synovitis of the hip by an orthopedic practitioner and advised rest at home. Soon thereafter, she developed fever (temperature 38 C), septic arthritis of the hip was suspected, and the child was referred to our institution for further assessment and treatment. At the first visit, the child measured 105 cm in height and weighed 16 kg. General physical examination revealed fever (temperature 37.8 C), and examination of the hip joints revealed swelling and tenderness of the right hip joint. Blood hematology and biochemistry tests revealed evidence of an inflammatory reaction and mild anemia; the laboratory test results were as follows: WBC 11.09 103/ml, RBC 411 104/ml, Hb 11.2 g/dl, Na 136 mEq/l, Cl 101 mEq/l, K 4.5 mEq/l, GOT 37 IU/l, GPT 9 IU/l, BUN 9.6 mg/dl, Cre 0.21 mg/dl, UA 5.1 mg/dl, and CRP 6.3 mg/dl. A plain radiograph of the hip joint showed widening of the joint space of the right hip, with no other abnormalities (Fig. 1). Arthrocentesis yielded cloudy, yellowish-colored joint fluid, and the patient was diagnosed as having septic arthritis of the hip. However contrast-enhanced MRI showed bilateral multiple bone marrow lesions in the pelvis and proximal femur in addition to hydrarthrosis, which were suspected as bone metastases from a malignant tumor (Fig. 2). Under the suspected diagnosis of septic arthritis of the hip, metastases from a malignant tumor, or a combination of both, we performed an open washout of the joint and at the same time conducted a thorough examination of the bone marrow lesions. Cultures of the arthrocentesis fluid and joint fluid obtained intraoperatively yielded negative results, and no tumor cells were detected in the joint fluid; however, the WBC count of the joint fluid was elevated to 55.9 103/ml. CT of the abdomen was
http://dx.doi.org/10.1016/j.jos.2016.09.004 0949-2658/© 2016 Published by Elsevier B.V. on behalf of The Japanese Orthopaedic Association.
Please cite this article in press as: Nishiwaki T, et al., Neuroblastoma metastasis to bone requiring differentiation from septic arthritis of the hip. Report of 2 cases, Journal of Orthopaedic Science (2016), http://dx.doi.org/10.1016/j.jos.2016.09.004
2
T. Nishiwaki et al. / Journal of Orthopaedic Science xxx (2016) 1e4
Fig. 3. Case 1. A solid para-adrenal tumor is visible (arrowhead). Fig. 1. Case 1. A 4-year-old girl. Plain radiographic view. Widening of the articular space is seen in the right hip joint.
performed as part of the investigation of the bone marrow lesions, which revealed a solid para-adrenal tumor (Fig. 3). Biopsy of the tumor led to the diagnosis of neuroblastoma, and the pelvic lesions were concluded as being metastases. Urine tests for VMA (urinary VMA) and HVA (urinary HVA) performed three days after the open washout revealed elevated levels of the metabolites to 98.55 mg/g Cr and 80.91 mg/g Cr, respectively. The patient was 4 years old, and immunohistochemical analysis of the tumor revealed amplification of the N-myc gene. A diagnosis of stage IV disease was made, with a predicted poor prognosis. Tumor resection with lymph node dissection was performed, with chemotherapy, radiation therapy, and autologous hematopoietic stem cell transplantation. Despite the treatments, the tumor progressed and after 29 months from her initial visit to our institution, the patient passed away. 2.2. Case 2 A 14-month-old girl child was brought to an orthopedic practitioner with high fever (temperature over 38 C). Laboratory tests revealed evidence of an inflammatory reaction, with a WBC count of 17.7 103/ml and serum CRP value of 4.5 mg/dl. She was treated with an antibiotic, and the clinical course was monitored. Two weeks later, she developed reduced active movements of the right hip, septic arthritis of the hip was suspected, and the patient was referred to our institution for further assessment and treatment.
At the first visit, the child measured 76.5 cm in height and weighed 9.8 kg. General physical examination revealed fever (temperature 37.5 C), and examination of the hip joints revealed swelling and decreased active motions of the right hip joint. Unilateral narrowing of the palpebral fissure of unknown etiology was noted, which had reportedly been noticed since 4 months of age. Blood hematology and biochemistry tests revealed anemia, liver dysfunction and mild inflammatory reaction; the laboratory results were as follows: WBC 9.47 103/ml, RBC 3.45 104/ml, Hb 9.2 g/dl, Na 140 mEq/l, Cl 102/mEq, K 4.2 mEq/l, GOT 123 IU/l, GPT 198 IU/l, BUN 7.9 mg/dl, Cre 0.18 mg/dl, and CRP 2.0 mg/dl. No abnormal findings were seen on a plain radiograph of the hips (Fig. 4). Ultrasound examination of the joint also did not show any evidence of joint effusion. On the basis of the findings of a narrowed palpebral fissure, anemia, and our previous experience of Case 1, we suspected bone metastases from a neuroblastoma. Contrast-enhanced MRI revealed multiple bone marrow lesions in the pelvis in addition to mild effusion of the right hip joint (Fig. 5). A plain chest radiograph revealed a mediastinal tumor (Fig. 6), and pleural fluid cytology led to the diagnosis of neuroblastoma. Urine tests for VMA (urinary VMA) and HVA (urinary HVA) performed at the initial visit of the child to our institution revealed elevated levels of the metabolites of 22.14 mg/g Cr and 41.29 mg/g Cr, respectively. Although the child was diagnosed as having stage IV disease, since she was relatively young and amplification of the N-myc gene was not detected, the prognosis appeared to be better than that of
Fig. 2. Case 1. MRI T2WI (a), CE (b). The T2WI shows fluid accumulation in the right hip joint, and abnormal shadows are visible in the shaft of the left femur. Contrast MRI shows enhanced bone marrow lesions in both femurs, the bony pelvis, and the spine.
Please cite this article in press as: Nishiwaki T, et al., Neuroblastoma metastasis to bone requiring differentiation from septic arthritis of the hip. Report of 2 cases, Journal of Orthopaedic Science (2016), http://dx.doi.org/10.1016/j.jos.2016.09.004
T. Nishiwaki et al. / Journal of Orthopaedic Science xxx (2016) 1e4
Fig. 4. Case 2. A 14-month-old girl. Plain radiography view of the hip joint. There are no abnormal findings.
Case 1 reported above. Chemotherapy was administered, however, and after one year of treatment, the mediastinal tumor showed no difference in size, and MIBG scintigraphy still revealed uptake, although it was decreased. The child is currently under treatment with retinoic acid.
3. Discussion Neuroblastoma is a malignant tumor of childhood that is derived from the neural crest cells, and arises from the adrenal medulla or sympathetic nerve ganglia, and produces catecholamines. The incidence of neuroblastoma is 10.2 cases per million children under 15 years of age, and it is the most commonly encountered extracranial malignant tumor in children [1]. In 40% of cases, the disease is diagnosed in children younger than one year of age. The most common age of occurrence of septic arthritis of the hip is also around one year of age. The clinical and biological prognostic factors reported until date are the age at the time of diagnosis, the disease stage, presence/ absence of amplification of the N-myc gene, histological class, and tumor cell DNA ploidy. Neuroblastoma with bone metastasis in children 1 year of age or older is classified as stage IV disease according to the International Neuroblastoma Staging System (INSS), and the prognosis is poor, with 5-year survival rates of 20e60% [2]. Presence/absence of amplification of the N-myc gene is a prognostic
3
Fig. 6. Case 2. Plain radiograph of the chest. A superior mediastinal tumor is visible at the upper left.
factor independent of the stage and age, and presence of amplification of this gene is strongly correlated with rapid stage progression and a poor outcome [3]. Children with neuroblastoma often present with vague initial symptoms, which could arise from the primary focus itself, from distant metastases, or even be caused by the catecholamine metabolites released from the tumor [1]. Aston et al. assessed the early presentations of 109 cases of neuroblastoma [4]. Hip pain was the initial presenting symptom in approximately 8.3% of all cases, making it the third most common presenting symptom of this tumor, and metastasis to the pelvis was not unusual. When nonspecific symptoms, such as limping, were included, the proportion of patients presenting with orthopedic symptoms increased to 18%. According to one report, presentation to an orthopedic surgeon first because of orthopedic-related symptoms delayed the diagnosis of neuroblastoma by an average of three months [5]. Therefore, orthopedic surgeons treating children must be aware that patients with neuroblastoma could first present to their service, and neuroblastoma should be included in the differential diagnosis of pain and limping in children. Transient synovitis of the hip is the most common cause of hip pain in infants, with septic arthritis not being uncommon either. In their report, Aston et al. incised and drained the hip in three cases of neuroblastoma, under the assumption that the patients had septic arthritis [4]. It can be difficult to differentiate between septic
Fig. 5. Case 2. MRI T2 WI (a), CE (b). High signal intensity area is present in the fascia around the right hip joint on the T2WI, and a bone marrow lesion showing a bone enhancement effect is observed in the left ilium. Very slight fluid accumulation is observed in the right hip joint.
Please cite this article in press as: Nishiwaki T, et al., Neuroblastoma metastasis to bone requiring differentiation from septic arthritis of the hip. Report of 2 cases, Journal of Orthopaedic Science (2016), http://dx.doi.org/10.1016/j.jos.2016.09.004
4
T. Nishiwaki et al. / Journal of Orthopaedic Science xxx (2016) 1e4
arthritis and metastases arising from neuroblastoma in these cases, even if bone lesions are seen on plain radiographs since they may be interpreted as evidence of osteomyelitis associated with septic arthritis of the hip. Although the definitive diagnosis of septic arthritis of the hip is based on a positive culture of the hip aspirate, not all cases of septic arthritis show positive results of culture [6]. Wong et al. reported collecting clear, straw-colored fluid from a case of neuroblastoma presenting with hip pain, which was initially diagnosed as a case of transient synovitis [7]. The possibility of metastasis to the pelvis from a neuroblastoma must be considered in cases of suspected septic arthritis of the hip, in which joint fluid cultures yield negative results and the response to conventional treatment is poor. Additional tests that may assist in the diagnosis are urine tests for vanillylmandelic acid (urinary VMA) and homovanillic acid (urinary HVA), which show elevated levels of these metabolites in about 90% of all cases of neuroblastoma. Urinary VMA and urinary HVA were elevated in both of our cases reported here, proving as useful adjuncts in the diagnosis of neuroblastoma. Hip pain is very common in childhood, so when should neuroblastoma be considered as a diagnosis? Patients with metastasis to the pelvis often show manifestations of disease spread outside the pelvis too. If such manifestations as an abdominal mass or paralysis of various nerves are present, thorough general examination should be undertaken. When they compared cases of septic arthritis of the hip and cases of neuroblastoma in which the patients complained of hip pain due to pelvic metastasis, Aston et al. found that anemia tended to be more severe in cases of neuroblastoma. They suggested that measurement of the hemoglobin values is useful for the differential diagnosis [8]. In our Case 2, the hemoglobin value of 9.2 g/dl indicated severe anemia, and this combined with the observation of ptosis in the patient led us to suspect this may not be a routine case of septic arthritis. When anemia is also present in cases that exhibit manifestations such as fever and hip pain which suggests septic arthritis of the hip, the possible presence of bone marrow disease, such as bone metastasis by a malignant tumor, must also be considered. There have been no reports of the concomitant development of neuroblastoma and septic arthritis of the hip, but this is always a concern in patients such as Case 1, because of the impending chemotherapy. Kiess et al. reported a case of concomitant neuroblastoma and femoral osteomyelitis, and stated that the difference in accumulation between MIBG scintigraphy and bone scintigraphy is helpful in the differential diagnosis, since there is increased activity on both scans in patients with metastatic lesions, but increased activity only on bone scans in patients with septic lesions [9]. However, some tumor lesions and metastatic lesions do not show increased uptake on MIBG scintigraphy. Furthermore, when the metastatic lesion and the osteomyelitis lesion are intermingled homogeneously at the same site instead of forming a mosaic, diagnosis by scintigraphy is difficult. In both cases, increased
uptake in the hip was detected by MIBG at the same site as that observed on enhanced MRI. However in Case 1, leukocytosis was observed in the joint fluid. We thought it impossible to rule out septic arthritis of the hip and elected to treat the patient for septic arthritis before commencing chemotherapy. The cause of inflammation and synovitis in the absence of infection is unclear, and to the best of our knowledge, no reports of neuroblastomas secreting inflammatory cytokines have been reported. Pathological fractures due to metastasis may be a cause of inflammation in the hip joint. Methods to rule out concomitant infection such as septic arthritis and osteomyelitis will be necessary in the future, so that the start of cancer chemotherapy is not delayed in cases of neuroblastoma with a poor prognosis. Hip pain caused by bone metastasis from a neuroblastoma is uncommon, however, early diagnosis and treatment are important. The presence of an abdominal mass, nerve palsies and anemia should raise the suspicion of bone metastasis from neuroblastoma. Urinary VMA, urinary HVA, enhanced MRI, MIBG scintigraphy, and bone scintigraphy are useful adjuncts for making the diagnosis of neuroblastoma. Conflict of interest There are no conflicts of interest related to the manuscript. Acknowledgments We would like to thank Dr. Joshua Lee of London Bridge Hospital for his assistance with the preparation of this manuscript. References [1] Maris JM, Hogarty MD, Bagatell R, Cohn SL. Neuroblastoma. Lancet 2007 Jun 23;369(9579):2106e20. [2] Schmidt ML, Lukens JN, Seeger RC, Brodeur GM, Shimada H, Gerbing RB, Stram DO, Perez C, Haase GM, Matthay KK. Biologic factors determine prognosis in infants with stage IV neuroblastoma: a prospective Children's Cancer Group study. J Clin Oncol 2000 Mar;18(6):1260e8. [3] Nakagawara A, Ikeda K, Tsuda T, Higashi K. N-myc oncogene amplification and prognostic factors of neuroblastoma in children. J Pediatr Surg 1987 Oct;22(10): 895e8. [4] Aston Jr JW. Pediatric update #16. The orthopaedic presentation of neuroblastoma. Orthop Rev 1990 Oct;19(10):929e32. [5] Trapani S, Grisolia F, Simonini G, Calabri GB, Falcini F. Incidence of occult cancer in children presenting with musculoskeletal symptoms: a 10-year survey in a pediatric rheumatology unit. Semin Arthritis Rheum 2000 Jun;29(6):348e59. [6] Lyon RM, Evanich JD. Culture-negative septic arthritis in children. J Pediatr Orthop 1999 SepeOct;19(5):655e9. [7] Wong M, Chung CH, Ngai WK. Hip pain and childhood malignancy. Hong Kong Med J 2002 Dec;8(6):461e3. [8] Laug WE, Siegel SE, Shaw KN, Landing B, Baptista J, Gutenstein M. Initial urinary catecholamine metabolite concentrations and prognosis in neuroblastoma. Pediatrics 1978 Jul;62(1):77e83. [9] Kiess W, Leisner B, Haas R. Coincidence of infectious osteomyelitis and disseminated neuroblastoma: a diagnostic dilemma solved by scintigraphic imaging. J Cancer Res Clin Oncol 1985 Jul;110(1):85e6.
Please cite this article in press as: Nishiwaki T, et al., Neuroblastoma metastasis to bone requiring differentiation from septic arthritis of the hip. Report of 2 cases, Journal of Orthopaedic Science (2016), http://dx.doi.org/10.1016/j.jos.2016.09.004