Unresectable VIP‐secreting neuroblastoma: Efficacy of debulking and steroids for symptom control
Unresectable VIP‐secreting neuroblastoma: Efficacy of debulking and steroids for symptom control
复制标题
不可切除的 VIP 分泌神经母细胞瘤：减瘤和类固醇对症状控制的功效
作者：
P. Kabalan;A. Gifford;D. Ziegler
致编辑：神经母细胞瘤是一种源自自主神经系统胚胎细胞的恶性肿瘤一小部分患者有副肿瘤综合征2 - 4，包括血管活性肠肽（VIP）相关的分泌性腹泻VIP诱导平滑肌松弛，刺激水、电解质和胰腺碳酸氢盐的分泌，导致严重的水样腹泻、低钾血症、缺氯血症、高血糖和高钙血症。出现时的VIP分泌通常与分化良好和局部肿瘤有关，在完全切除后具有良好的长期预后然而，VIP分泌综合征可导致难治性分泌性腹泻5,6和严重的全身症状。不可切除的VIP分泌性肿瘤的治疗尚未明确。在这里，我们描述了一个患有vip分泌神经母细胞瘤的儿童，该肿瘤不可切除，对标准化疗无反应，并引起严重的全身症状。部分减脂手术和类固醇治疗后症状得到控制。一名11个月大的女性表现为发育不良和严重腹泻，持续10周。入院时，她体重不足3百分，低血压，严重脱水，腹部内有肿块。计算机断层扫描显示，腰椎和骶椎骨上部前有一个广泛的腹膜后肿块，使腹主动脉下部远离椎体，包围了髂总动脉的起源和近端，因此不适合手术切除。metaiodobenzyguanidine （MIBG）扫描显示肿瘤明显，尿儿茶酚胺升高。电解质紊乱伴低钠血症和严重低钾血症。开放性活检显示为NMYC非扩增、分化良好的神经母细胞瘤，未累及骨髓，符合III期、中度风险、vip分泌神经母细胞瘤。化疗按照A3961方案开始治疗中危神经母细胞瘤。给予卡铂、依托泊苷、环磷酰胺和阿霉素2个周期治疗，无改善使用环磷酰胺和拓扑替康进行单周期高风险治疗试验，无反应。尝试洛哌丁胺和奥曲肽治疗腹泻，但没有临床效果。患者出现临床恶化，持续腹泻大于30 mL/kg/天，电解质丢失和代谢性酸中毒，这些特征似乎与潜在的VIP分泌有关。下一步是肿瘤减体积手术，切除85%的肿瘤，留下大量残余肿瘤（图1）。残余肿瘤尺寸为6.1 × 2.0 × 3.6 cm，诊断时为7.7 × 4.4 × 9.3 cm。组织病理学与活检诊断一致。手术后患者的临床状况立即得到改善，腹泻量显著减少，全身症状得到缓解。然而，由于腹泻量持续减少，术后影像学显示明显残留肿瘤，我们试验了6个疗程的维甲酸分化治疗和1个疗程的口服非甾体类药物。未观察到任何反应，患者保持良好，但持续出现稀便，水样便。在并发呼吸道病毒感染期间，患者开始使用皮质类固醇，并立即完全停止腹泻，持续了2个月。随后，她的腹泻复发，但在随后的几年中持续缓慢改善。她现在已经7年了，她的腹泻已经完全消除。她的残余肿瘤在减体积手术后没有改变大小，但已变得不那么强烈，表明正在进行分化。vip相关性腹泻的代谢后果可能使诱导化疗复杂化，难以控制，如本例。生长抑素是一种有效的治疗方法，以控制腹泻与VIP分泌胰腺肿瘤在成人。然而，有限的病例报告表明，它可能对神经母细胞瘤无效切除VIP分泌性神经母细胞瘤和神经节神经瘤显示腹泻在数小时内消退。然而，对于不可切除的肿瘤，尚无明确的治疗途径。在Bourdeaut等人的系列研究中，4名患有不可切除肿瘤的儿童接受了新辅助化疗，但没有发现腹泻的改善我们的病例支持这样的建议，即在治疗不可切除的肿瘤时应及早考虑肿瘤减容。据报道，皮质类固醇对成人VIP分泌性胰腺肿瘤有益处。Cooperman等人描述了一名65岁患有良性VIP分泌胰岛细胞瘤的男性患者，每天口服10mg强的松可控制腹泻11我们的患者接受了皮质类固醇治疗，并经历了vip相关腹泻的突然和长期改善，提示可能在该疾病中起作用。在随后的几年中，腹泻的进一步逐渐消退，以及mib摄取的减少，表明分泌vip的神经母细胞瘤已经分化良好，随着分化的继续，它们的分泌可能会减少。本病例提示，在不可切除的vip分泌神经母细胞瘤的治疗早期应考虑减积，以控制vip相关的腹泻和代谢并发症。类固醇
To the Editor: Neuroblastoma is a malignant tumour arising from embryonal cells of the autonomic nervous system.1 A small percentage of patients have paraneoplastic syndromes2–4 including vasoactive intestinal peptide (VIP) associated secretory diarrhoea.5,6 VIP induces smooth muscle relaxation, stimulating the secretion of water, electrolytes and pancreatic bicarbonate leading to severe watery diarrhoea, hypokalaemia, achlorhydria, hyperglycaemia and hypercalcemia.6–8 VIP secretion at presentation is usually associated with well-differentiated and localised tumours with excellent longtermoutcomes following complete resection.8 However, the syndrome of VIP secretion can lead to intractable secretory diarrhoea5,6 and severe systemic symptoms. The management of unresectable VIP secreting tumours has not beenwell defined. Here, we describe a child with a VIP-secreting neuroblastoma that was unresectable, non-responsive to standard chemotherapy, and caused severe systemic symptoms. The control of symptoms was achieved after partial debulking surgery and steroid therapy. An 11-month-old female presented with failure to thrive and profound diarrhoea for 10 weeks. On presentation, she weighed less than the 3rd centile, was hypotensive, severely dehydrated and had an intra-abdominal mass. Computed tomography showed an extensive retroperitoneal mass located anterior to the lumbar and upper sacral spine that displaced the lower portion of the abdominal aorta away from the vertebral bodies and encased the origins and proximal portions of both common iliac arteries, and was therefore not amenable to surgical resection. The tumour was avid on metaiodobenzyguanidine (MIBG) scan and urine catecholamine was raised. Electrolytes were deranged with hyponatraemia and severe hypokalaemia. Open biopsy demonstrated an NMYC non-amplified, well-differentiated neuroblastoma,with no bonemarrow involvement, consistent with a Stage III, intermediate risk, VIP-secreting neuroblastoma. Chemotherapy was commenced as per A3961 protocol for intermediate risk neuroblastoma. Two cycles consisting of carboplatin, etoposide, cyclophosphamide and doxorubicin were administered without improvement.9 A single cycle of high-risk therapy was trialled using cyclophosphamide and topotecanwithout response. Loperamide and octreotide were tried to manage the diarrhoea without clinical benefit. The patient experienced clinical deterioration with persistent diarrhoea greater than 30 mL/kg/day, electrolyte loss and metabolic acidosis, features that appeared to be related to the underlying VIP secretion. Tumour debulking surgery was the next step where 85% of the tumour was resected, with a significant residual bulk of tumour remaining (Figure 1). The residual tumour measured 6.1 × 2.0 × 3.6 cm compared with 7.7 × 4.4 × 9.3 cm at diagnosis. The histopathology was consistent with the diagnostic biopsy. The patient's clinical status improved immediately following the operation with a dramatic reduction in the volume of diarrhoea and resolution of systemic symptoms. However, due to persistence of reduced volume of diarrhoea, and significant residual tumour on post-operative imaging, six courses of retinoic differentiation therapy and a course of oral non-steroidal were trialled. No response was observed, and the patient remained well but with persistent loose, watery stools. During an intercurrent respiratory viral infection corticosteroids were commenced, with an immediate and complete cessation of her diarrhoea, which lasted for 2 months. Her diarrhoea then recurred but continued to slowly improve over the subsequent years. She is now 7 years after diagnosis and her diarrhoea has completely resolved.Her residual tumour has not changed in size since the debulking operation, but has become less MIBG avid, suggesting ongoing differentiation. The metabolic consequences of VIP-associated diarrhoea may complicate induction chemotherapy and be difficult to manage, as in this case. Somatostatin is an effective treatment to control diarrhoea associated with VIP secreting pancreatic tumours in adults. However, limited case reports suggest that it may not be effective in neuroblastoma.10 Resection of both VIP secreting neuroblastoma and ganglioneuroma demonstrate a resolution of diarrhoea within hours. However, there is no clear treatment pathway for unresectable tumours. In the series from Bourdeaut et al., four children with unresectable tumours received neoadjuvant chemotherapy, but no improvement in diarrhoea was seen.5 Our case supports the suggestion that tumour debulking should be considered early in the management of unresectable tumours. Corticosteroids have been reported to be of benefit in adults with VIP secreting pancreatic tumours. Cooperman et al. described control of diarrhoea in a 65-year-old man with a benign VIP secreting pancreatic islet cell tumour on 10 mg of oral prednisone a day.11 Our patient received corticosteroids and experienced a sudden and prolonged improvement in VIP-related diarrhoea, suggesting a possible role in this disease. The further gradual resolution of diarrhoea over subsequent years, alongwith reducedMIBGuptake, suggests thatVIPsecreting neuroblastomas, which are already well differentiated, may reduce their secretion as differentiation continues. This case indicates that debulking should be considered early in themanagement of unresectable VIP-secreting neuroblastoma to control VIP-associated diarrhoea and metabolic complications. Steroid
DOI：
10.1056/nejmoa1001527
发表时间：
2010-09-30
期刊：
The New England journal of medicine
影响因子：
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作者：
Baker DL;Schmidt ML;Cohn SL;Maris JM;London WB;Buxton A;Stram D;Castleberry RP;Shimada H;Sandler A;Shamberger RC;Look AT;Reynolds CP;Seeger RC;Matthay KK;Children’s Oncology Group
通讯作者：
Children’s Oncology Group