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Hepatoblastoma presenting with focal nodular hyperplasia after treatment of neuroblastoma
Journal of Pediatric Surgery (2008) 43, 2297–2300
www.elsevier.com/locate/jpedsurg
Hepatoblastoma presenting with focal nodular hyperplasia after treatment of neuroblastoma Jordan R. Gutweiler a,1 , David C. Yu a,⁎,1 , Heung B. Kim a , Harry P. Kozakewich b , Karen J. Marcus c , Robert C. Shamberger a , Christopher B. Weldon a a
Department of Surgery, ChildrenTs Hospital Boston, Harvard Medical School, Boston, MA 02115, USA Department of Pathology, ChildrenTs Hospital Boston, Harvard Medical School, Boston, MA 02115, USA c Department of Radiation Oncology, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA b
Received 20 May 2008; revised 27 August 2008; accepted 27 August 2008
Key words: Focal nodular hyperplasia (FNH); Hepatoblastoma; Neuroblastoma
Abstract Focal nodular hyperplasia (FNH) is a benign, poorly understood hepatic tumor that is rare in children. Although there is no evidence for malignant degeneration, FNH can occur adjacent to a malignancy. Here, the case of a 4-year-old boy with a hepatic mass and history of stage IV neuroblastoma is presented. Initial imaging and core-needle biopsy were consistent with FNH. However, after left lateral segmentectomy, pathologic examination revealed a malignant tumor most consistent with small cell undifferentiated hepatoblastoma as well as 3 foci of FNH in the surrounding parenchyma. © 2008 Elsevier Inc. All rights reserved.
1. Case report A 4-year-old boy presented with a hepatic mass (2.3 × 2.3 × 2.2 cm) on surveillance computed tomographic (CT) imaging. He was diagnosed with stage IV neuroblastoma at 24 months of age. He was enrolled in National Cancer Institute (Bethesda, MD 20892, USA) clinical trial NCT00165139. Treatment included 7-drug chemotherapy (vincristine, cyclophosphamide, etoposide, cisplatin, carboplatin, melphalan, ifosfamide), granulocyte-colony stimulating factor and mesna (2427 months), surgical resection (age 27 months), tumor bed radiation (10.8 Gy, age 27-28 months), total body radiation (12
⁎ Corresponding author. Tel.: +1 617 355 2969; fax: +1 617 730 0918. E-mail address: [email protected] (D.C. Yu). 1 Co-first authors. 0022-3468/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.jpedsurg.2008.08.069
Gy, age 30 months), and double autologous bone marrow transplant (BMT) (age 28 and 30 months). Both the tumor bed and total body radiation courses included the liver in the irradiation field. After his transplant, he received pelvic radiation (age 28 months) subsequent to a bone scan demonstrating increased uptake. He was also receiving intermittent doses of monoclonal antibody 3F8. Core-needle biopsies of the adrenal primary tumor revealed a poorly differentiated neuroblastoma with a high mitotic-karyorhectic index unfavorable histological condition. The patient had been doing well without evidence of disease after cessation of treatment. The CT imaging was performed as part of routine surveillance (Fig. 1A, age 44 months). Three core-needle biopsy specimens of the liver mass were taken, and pathologic examination showed hepatic parenchyma with bands of fibrosis partially encircling hepatic nodules,
2298
J.R. Gutweiler et al.
Fig. 3 Histologic sample after left lateral segmentectomy (H&E stain, ×400) (diagnosis: hepatoblastoma). Arrow shows normal hepatocytes.
Fig. 1 Liver mass at presentation. A, CT image. B, Histologic sample from core-needle biopsy (H&E stain, ×100) diagnosed as consistent with FNH.
consistent with FNH, and no evidence of malignancy (Fig. 1B). No additional intervention was taken at that time. The CT imaging of the abdomen was repeated 2 months later showing interval growth (3.2 × 3.0 × 2.6 cm, Fig. 2), and a
new core-needle biopsy specimen was taken (not shown). Pathologic examination then showed an undifferentiated spindle cell tumor. Subsequently, the patient underwent a left lateral segmentectomy (age 48 months). Pathologic examination revealed a malignant tumor most consistent with small cell, undifferentiated hepatoblastoma (Fig. 3). Tumor cells were immunopositive for vimentin, cytokeratin, Wilms tumor 1, antigen and β-catenin. Ultrastructural features included basal lamina, tonofilaments, and desmosomes. Three foci of FNH were also seen in the resection specimen. Chemotherapy was started consisting of vincristine, cisplatin, and 5-fluorouracil. One month after resection, 2 new liver masses were seen on CT imaging (Fig. 4A/B). A wedge resection of segment 5 and a core-needle biopsy of segment 4 were obtained. Pathologic examination of each specimen was consistent with FNH (Fig. 4C). The chemotherapy regimen was completed after the second resection. No subsequent growth of the residual lesion or appearance of new lesions has been observed since, and the patient has been cancer-free for more than 2 years.
2. Discussion
Fig. 2
Liver mass 2 months after initial biopsy (CT image).
Primary hepatic tumors are rare in the pediatric population with an incidence of 0.4 to 1.9 per million children annually [1]. Of these tumors, 57% are malignant and 43% are benign with FNH representing 2% of all lesions [2]. Focal nodular hyperplasia is a benign lesion that has never been demonstrated to have malignant potential. Although the etiology of FNH is unclear, it has been hypothesized that focal circulatory disturbances cause arterial and portal venous thrombosis. Subsequent vascular recanalization and reperfusion may lead to hepatocyte proliferation and the development of FNH [3-5].
Hepatoblastoma with focal nodular hyperplasia
Fig. 4 Computed tomographic scan images showing new lesion in segments 4 (A) and 5 (B) after left lateral segmentectomy. C, Biopsy (H&E stain, ×20) (diagnosis: FNH). Arrows indicate the border of FNH and normal liver.
Focal nodular hyperplasia varies in size from a few millimeters to more than 15 cm in diameter and may be single or multiple [1,6,7]. Focal nodular hyperplasia is a well-circumscribed, lobulated lesion lacking a true capsule
2299 but often surrounded by thin fibrous tissue. On gross examination, FNH often has a central stellate scar. Microscopically, the central scar and the radiating septa contain bile ducts, blood vessels, and lymphocytes surrounded by proliferating nodules of hepatocytes [8]. Okada et al [6] have proposed a management algorithm for children with FNH. Their scheme calls for solitary hepatic lesions to be imaged with either CT or magnetic resonance. After imaging, a symptomatic FNH is resected. Conversely, an asymptomatic FNH would have to be subjected to biopsy to confirm diagnosis and then followed with ultrasound. Lesions with an uncertain nature that enlarge or that becomes symptomatic are resected. The occurrence of FNH in patients after they have completed therapy for other malignancy is well documented. Case studies have described FNH in patients subsequent to chemotherapy, radiotherapy, and BMT for both solid and hematogenous cancers [4]. A review of ultrasound records of pediatric cancer patients after treatment recorded a 0.45% incidence of FNH, which is a 225-fold greater incidence than found in the general pediatric population [9]. Secondary malignancies are not an uncommon sequela of advanced stage neuroblastoma. In a recent large study of long-term complications after treatment of stage III to IV neuroblastoma, Laverdiere et al [10] reported a 6% incidence of secondary cancers. Secondary malignancies are also well reported in the adult population after BMT [11,12]. One study of 467 patients with Hodgkin's disease documented 18 (4%) secondary cancers after BMT [12]. Secondary malignancies are also common after radiation therapy. Data from the Childhood Cancer Survivor Study indicate that 83% of patients with secondary malignancies had radiation as part of their treatment; of those, 82% occurred in the radiation field [13]. Ishimura et al [14] recently reported a case of a 13-year-old boy who developed a malignant liver tumor with features of both hepatoblastoma and hepatocellular carcinoma 10 years after chemotherapy and BMT for aplastic anemia. Although there is no evidence in the literature for malignant degeneration of FNH, there are reports of FNH occurring simultaneously with hepatocellular carcinoma [15,16]. The case presented here is an interesting combination of a secondary hepatoblastoma most likely occurring adjacent to a posttherapy FNH. Even with CT images and a core-needle biopsy consistent with FNH, this lesion was observed very closely. Rapid interval growth, unusual for an FNH, dictated resection of the lesion. Most likely, the initial core-needle biopsy was of tissue adjacent to the hepatoblastoma. When 2 additional hepatic lesions were subsequently encountered, resection was again the treatment of choice. Because the segment 5 lesion was superficial, it was resected. However, the segment 4 lesion was not amenable to resection so definitive biopsy was performed guided by intraoperative sonography. Fortunately, neither lesion was malignant.
2300
3. Conclusion Traditionally, FNH has been defined as a benign lesion without malignant potential. Unfortunately, because of its rarity in children, the etiology, natural history, and outcome of FNH remains poorly understood in the pediatric population. Although FNH is a common posttherapy liver mass, secondary hepatic malignancies are also documented. This combined with the possibility of malignancy occurring concomitantly with FNH makes evaluation of liver masses in this population very difficult. However, it demonstrates the need to closely observe a patient with suspected FNH, if nonoperative management is the treatment course of choice. Also, in cases such as of this patient, with a high-risk or suspicious lesion, even a biopsy diagnostic of benign disease does not necessarily rule out malignancy. Hence, continued surveillance and a high index of suspicion must be used in treating these patients.
References [1] Reymond D, Plaschkes J, Luthy A, et al. Focal nodular hyperplasia of the liver in children: review of follow-up and outcome. J Pediatr Surg 1995;30(11):1590-3. [2] Greenberg M, Filler RM. Hepatic tumors. In: Pizzo PA, Poplack DG, editors. Principles and practice of pediatric oncology. Philadelphia, Pa: Lippincott; 1989. p. 569-82. [3] Evans JE, Dick R, Sherlock S. Focal nodular hyperplasia of the liver. B J Surg 1980;67:175-7. [4] Joyner BL, Goyal RK, Newman B, et al. Focal nodular hyperplasia of the liver: a sequela of tumor therapy. Pediatr Radiol 2005;35:1234-9.
J.R. Gutweiler et al. [5] Kumagai H, Masuda T, Oikawa H, et al. Focal nodular hyperplasia of the liver: direct evidence of circulatory disturbances. J Gastroenterol Hepatol 2000;15:1344-7. [6] Okada T, Sasaki F, Kamiyama T, et al. Management and algorithm for focal nodular hyperplasia of the liver in children. Eur J Pediatr Surg 2006;16:235-40. [7] Nichols FC, Van Heerden JA, Weiland LH. Benign liver tumors. Surg Clin North Am 1989;69:297-314. [8] Makhlouf HR, Abdul-Al HM, Goodman ZD. Diagnosis of focal nodular hyperplasia of the liver by needle biopsy. HUM PATHOL 2005; 36:1210-6. [9] Icher-De Bouyn C, Leclere J, Raimondo G, et al. Hepatic focal nodular hyperplasia in children previously treated for a solid tumor: incidence risk factors and outcome. Cancer 2003;97:3107-13. [10] Laverdiere C, Cheung NKV, Kushner BH, et al. Long-term complication in survivors of advanced stage neuroblastoma. Pediatr Blood Cancer 2005;45:324-32. [11] Andre M, Henry-Amar M, Blaise D, et al. Treatment-related deaths and second cancer risk after autologous stem-cell transplantation for Hodgkin's disease. Blood 1998;92:1933-40. [12] Witherspoon RP, Fisher LD, Schoch G, et al. Secondary cancers after bone marrow transplantation for leukemia or aplastic anemia. N Engl J Med 1989;321:784-9. [13] Bassal M, Mertens AC, Taylor L, et al. Risk of selected subsequent carcinomas in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol 2006;24: 476-83. [14] Ishimura M, Ohga S, Nagatoshi Y, et al. Malignant hepatic tumor occurring 10 yrs after a histocompatible sibling donor bone marrow transplantation for severe aplastic anemia. Pediatr Transplantation 2007;11:945-9. [15] Zhang SH, Cong WM, Wu MC. Focal nodular hyperplasia with concomitant hepatocellular carcinoma: a case report and clonal analysis. J Clin Pathol 2004;57:556-9. [16] Langrehr JM, Pfitzmann R, Hermann M, et al. Hepatocellular carcinoma in association with hepatic focal nodular hyperplasia. Acta Radiol 2006;47:340-4.
www.elsevier.com/locate/jpedsurg
Hepatoblastoma presenting with focal nodular hyperplasia after treatment of neuroblastoma Jordan R. Gutweiler a,1 , David C. Yu a,⁎,1 , Heung B. Kim a , Harry P. Kozakewich b , Karen J. Marcus c , Robert C. Shamberger a , Christopher B. Weldon a a
Department of Surgery, ChildrenTs Hospital Boston, Harvard Medical School, Boston, MA 02115, USA Department of Pathology, ChildrenTs Hospital Boston, Harvard Medical School, Boston, MA 02115, USA c Department of Radiation Oncology, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA b
Received 20 May 2008; revised 27 August 2008; accepted 27 August 2008
Key words: Focal nodular hyperplasia (FNH); Hepatoblastoma; Neuroblastoma
Abstract Focal nodular hyperplasia (FNH) is a benign, poorly understood hepatic tumor that is rare in children. Although there is no evidence for malignant degeneration, FNH can occur adjacent to a malignancy. Here, the case of a 4-year-old boy with a hepatic mass and history of stage IV neuroblastoma is presented. Initial imaging and core-needle biopsy were consistent with FNH. However, after left lateral segmentectomy, pathologic examination revealed a malignant tumor most consistent with small cell undifferentiated hepatoblastoma as well as 3 foci of FNH in the surrounding parenchyma. © 2008 Elsevier Inc. All rights reserved.
1. Case report A 4-year-old boy presented with a hepatic mass (2.3 × 2.3 × 2.2 cm) on surveillance computed tomographic (CT) imaging. He was diagnosed with stage IV neuroblastoma at 24 months of age. He was enrolled in National Cancer Institute (Bethesda, MD 20892, USA) clinical trial NCT00165139. Treatment included 7-drug chemotherapy (vincristine, cyclophosphamide, etoposide, cisplatin, carboplatin, melphalan, ifosfamide), granulocyte-colony stimulating factor and mesna (2427 months), surgical resection (age 27 months), tumor bed radiation (10.8 Gy, age 27-28 months), total body radiation (12
⁎ Corresponding author. Tel.: +1 617 355 2969; fax: +1 617 730 0918. E-mail address: [email protected] (D.C. Yu). 1 Co-first authors. 0022-3468/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.jpedsurg.2008.08.069
Gy, age 30 months), and double autologous bone marrow transplant (BMT) (age 28 and 30 months). Both the tumor bed and total body radiation courses included the liver in the irradiation field. After his transplant, he received pelvic radiation (age 28 months) subsequent to a bone scan demonstrating increased uptake. He was also receiving intermittent doses of monoclonal antibody 3F8. Core-needle biopsies of the adrenal primary tumor revealed a poorly differentiated neuroblastoma with a high mitotic-karyorhectic index unfavorable histological condition. The patient had been doing well without evidence of disease after cessation of treatment. The CT imaging was performed as part of routine surveillance (Fig. 1A, age 44 months). Three core-needle biopsy specimens of the liver mass were taken, and pathologic examination showed hepatic parenchyma with bands of fibrosis partially encircling hepatic nodules,
2298
J.R. Gutweiler et al.
Fig. 3 Histologic sample after left lateral segmentectomy (H&E stain, ×400) (diagnosis: hepatoblastoma). Arrow shows normal hepatocytes.
Fig. 1 Liver mass at presentation. A, CT image. B, Histologic sample from core-needle biopsy (H&E stain, ×100) diagnosed as consistent with FNH.
consistent with FNH, and no evidence of malignancy (Fig. 1B). No additional intervention was taken at that time. The CT imaging of the abdomen was repeated 2 months later showing interval growth (3.2 × 3.0 × 2.6 cm, Fig. 2), and a
new core-needle biopsy specimen was taken (not shown). Pathologic examination then showed an undifferentiated spindle cell tumor. Subsequently, the patient underwent a left lateral segmentectomy (age 48 months). Pathologic examination revealed a malignant tumor most consistent with small cell, undifferentiated hepatoblastoma (Fig. 3). Tumor cells were immunopositive for vimentin, cytokeratin, Wilms tumor 1, antigen and β-catenin. Ultrastructural features included basal lamina, tonofilaments, and desmosomes. Three foci of FNH were also seen in the resection specimen. Chemotherapy was started consisting of vincristine, cisplatin, and 5-fluorouracil. One month after resection, 2 new liver masses were seen on CT imaging (Fig. 4A/B). A wedge resection of segment 5 and a core-needle biopsy of segment 4 were obtained. Pathologic examination of each specimen was consistent with FNH (Fig. 4C). The chemotherapy regimen was completed after the second resection. No subsequent growth of the residual lesion or appearance of new lesions has been observed since, and the patient has been cancer-free for more than 2 years.
2. Discussion
Fig. 2
Liver mass 2 months after initial biopsy (CT image).
Primary hepatic tumors are rare in the pediatric population with an incidence of 0.4 to 1.9 per million children annually [1]. Of these tumors, 57% are malignant and 43% are benign with FNH representing 2% of all lesions [2]. Focal nodular hyperplasia is a benign lesion that has never been demonstrated to have malignant potential. Although the etiology of FNH is unclear, it has been hypothesized that focal circulatory disturbances cause arterial and portal venous thrombosis. Subsequent vascular recanalization and reperfusion may lead to hepatocyte proliferation and the development of FNH [3-5].
Hepatoblastoma with focal nodular hyperplasia
Fig. 4 Computed tomographic scan images showing new lesion in segments 4 (A) and 5 (B) after left lateral segmentectomy. C, Biopsy (H&E stain, ×20) (diagnosis: FNH). Arrows indicate the border of FNH and normal liver.
Focal nodular hyperplasia varies in size from a few millimeters to more than 15 cm in diameter and may be single or multiple [1,6,7]. Focal nodular hyperplasia is a well-circumscribed, lobulated lesion lacking a true capsule
2299 but often surrounded by thin fibrous tissue. On gross examination, FNH often has a central stellate scar. Microscopically, the central scar and the radiating septa contain bile ducts, blood vessels, and lymphocytes surrounded by proliferating nodules of hepatocytes [8]. Okada et al [6] have proposed a management algorithm for children with FNH. Their scheme calls for solitary hepatic lesions to be imaged with either CT or magnetic resonance. After imaging, a symptomatic FNH is resected. Conversely, an asymptomatic FNH would have to be subjected to biopsy to confirm diagnosis and then followed with ultrasound. Lesions with an uncertain nature that enlarge or that becomes symptomatic are resected. The occurrence of FNH in patients after they have completed therapy for other malignancy is well documented. Case studies have described FNH in patients subsequent to chemotherapy, radiotherapy, and BMT for both solid and hematogenous cancers [4]. A review of ultrasound records of pediatric cancer patients after treatment recorded a 0.45% incidence of FNH, which is a 225-fold greater incidence than found in the general pediatric population [9]. Secondary malignancies are not an uncommon sequela of advanced stage neuroblastoma. In a recent large study of long-term complications after treatment of stage III to IV neuroblastoma, Laverdiere et al [10] reported a 6% incidence of secondary cancers. Secondary malignancies are also well reported in the adult population after BMT [11,12]. One study of 467 patients with Hodgkin's disease documented 18 (4%) secondary cancers after BMT [12]. Secondary malignancies are also common after radiation therapy. Data from the Childhood Cancer Survivor Study indicate that 83% of patients with secondary malignancies had radiation as part of their treatment; of those, 82% occurred in the radiation field [13]. Ishimura et al [14] recently reported a case of a 13-year-old boy who developed a malignant liver tumor with features of both hepatoblastoma and hepatocellular carcinoma 10 years after chemotherapy and BMT for aplastic anemia. Although there is no evidence in the literature for malignant degeneration of FNH, there are reports of FNH occurring simultaneously with hepatocellular carcinoma [15,16]. The case presented here is an interesting combination of a secondary hepatoblastoma most likely occurring adjacent to a posttherapy FNH. Even with CT images and a core-needle biopsy consistent with FNH, this lesion was observed very closely. Rapid interval growth, unusual for an FNH, dictated resection of the lesion. Most likely, the initial core-needle biopsy was of tissue adjacent to the hepatoblastoma. When 2 additional hepatic lesions were subsequently encountered, resection was again the treatment of choice. Because the segment 5 lesion was superficial, it was resected. However, the segment 4 lesion was not amenable to resection so definitive biopsy was performed guided by intraoperative sonography. Fortunately, neither lesion was malignant.
2300
3. Conclusion Traditionally, FNH has been defined as a benign lesion without malignant potential. Unfortunately, because of its rarity in children, the etiology, natural history, and outcome of FNH remains poorly understood in the pediatric population. Although FNH is a common posttherapy liver mass, secondary hepatic malignancies are also documented. This combined with the possibility of malignancy occurring concomitantly with FNH makes evaluation of liver masses in this population very difficult. However, it demonstrates the need to closely observe a patient with suspected FNH, if nonoperative management is the treatment course of choice. Also, in cases such as of this patient, with a high-risk or suspicious lesion, even a biopsy diagnostic of benign disease does not necessarily rule out malignancy. Hence, continued surveillance and a high index of suspicion must be used in treating these patients.
References [1] Reymond D, Plaschkes J, Luthy A, et al. Focal nodular hyperplasia of the liver in children: review of follow-up and outcome. J Pediatr Surg 1995;30(11):1590-3. [2] Greenberg M, Filler RM. Hepatic tumors. In: Pizzo PA, Poplack DG, editors. Principles and practice of pediatric oncology. Philadelphia, Pa: Lippincott; 1989. p. 569-82. [3] Evans JE, Dick R, Sherlock S. Focal nodular hyperplasia of the liver. B J Surg 1980;67:175-7. [4] Joyner BL, Goyal RK, Newman B, et al. Focal nodular hyperplasia of the liver: a sequela of tumor therapy. Pediatr Radiol 2005;35:1234-9.
J.R. Gutweiler et al. [5] Kumagai H, Masuda T, Oikawa H, et al. Focal nodular hyperplasia of the liver: direct evidence of circulatory disturbances. J Gastroenterol Hepatol 2000;15:1344-7. [6] Okada T, Sasaki F, Kamiyama T, et al. Management and algorithm for focal nodular hyperplasia of the liver in children. Eur J Pediatr Surg 2006;16:235-40. [7] Nichols FC, Van Heerden JA, Weiland LH. Benign liver tumors. Surg Clin North Am 1989;69:297-314. [8] Makhlouf HR, Abdul-Al HM, Goodman ZD. Diagnosis of focal nodular hyperplasia of the liver by needle biopsy. HUM PATHOL 2005; 36:1210-6. [9] Icher-De Bouyn C, Leclere J, Raimondo G, et al. Hepatic focal nodular hyperplasia in children previously treated for a solid tumor: incidence risk factors and outcome. Cancer 2003;97:3107-13. [10] Laverdiere C, Cheung NKV, Kushner BH, et al. Long-term complication in survivors of advanced stage neuroblastoma. Pediatr Blood Cancer 2005;45:324-32. [11] Andre M, Henry-Amar M, Blaise D, et al. Treatment-related deaths and second cancer risk after autologous stem-cell transplantation for Hodgkin's disease. Blood 1998;92:1933-40. [12] Witherspoon RP, Fisher LD, Schoch G, et al. Secondary cancers after bone marrow transplantation for leukemia or aplastic anemia. N Engl J Med 1989;321:784-9. [13] Bassal M, Mertens AC, Taylor L, et al. Risk of selected subsequent carcinomas in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol 2006;24: 476-83. [14] Ishimura M, Ohga S, Nagatoshi Y, et al. Malignant hepatic tumor occurring 10 yrs after a histocompatible sibling donor bone marrow transplantation for severe aplastic anemia. Pediatr Transplantation 2007;11:945-9. [15] Zhang SH, Cong WM, Wu MC. Focal nodular hyperplasia with concomitant hepatocellular carcinoma: a case report and clonal analysis. J Clin Pathol 2004;57:556-9. [16] Langrehr JM, Pfitzmann R, Hermann M, et al. Hepatocellular carcinoma in association with hepatic focal nodular hyperplasia. Acta Radiol 2006;47:340-4.