Solitary necrotic nodule of the liver, a rare

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1 Original Article / Liver Clinical features of solitary necrotic nodule of the liver Yan-Ming Zhou, Bin Li, Feng Xu, Bin Wang, Dian-Qi Li, Peng Liu and Jia-Mei Yang Shanghai, China BACKGROUND: Solitary necrotic nodule of the liver is a rare nonmalignant lesion. The present study aimed to clarify the clinical features of the disease. METHOD: The medical records of 51 patients with histologically confirmed solitary necrotic nodule of the liver who received surgical resection at our institution were retrospectively reviewed. RESULTS: Solitary necrotic nodule of the liver was found mainly in males (68.6%, 35/51), and patients ranged in age from 5 to 69 years with a mean of Most of the patients (72.5%) had no significant symptoms, with negative results for the serum tumor markers alpha-fetoprotein, carbohydrate antigen 19-9 and carcinoembryonic antigen. The mean diameter of the nodule was 23 mm (range mm). Compared with ultrasonographic and computed tomography findings, the specific features of magnetic resonance imaging were more helpful for differential diagnosis of the disease. CONCLUSIONS: Solitary necrotic nodule of the liver is a rare nonmalignant lesion, showing no notable symptoms and potential complications. The pathological change of the disease is not significant over a lifetime. Conservative treatment and clinical follow-up are recommended. (Hepatobiliary Pancreat Dis Int 2008; 7: ) KEY WORDS: liver neoplasm; solitary necrotic nodule Author Affiliations: Department of Hepato-Biliary-Pancreato-Vascular Surgery, First Xiamen Hospital, Fujian Medical University, Xiamen , China (Zhou YM and Li B); Department of Special Treatment (Xu F, Li DQ, Liu P and Yang JM), and Department of Pathology (Wang B), Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai , China Corresponding Author: Jia-Mei Yang, MD, Department of Special Treatment, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai , China (Tel: ; Fax: ; yjm.1952@yahoo.com.cn) 2008, Hepatobiliary Pancreat Dis Int. All rights reserved. Introduction Solitary necrotic nodule of the liver, a rare nonmalignant lesion, was first described by Shepherd and Lee in 1983, [1] and comprises a central necrotic core enclosed by a hyalinized fibrotic capsule containing elastic fibres with inflammatory cells. Although there have been many studies reporting the etiology of the disease, [2-5] its clinical features are not well understood because of the rarity of cases. In the present study, we analyzed the medical records of 51 histologically confirmed cases of solitary necrotic nodule of the liver to clarify the clinical features of this disease. Methods From January 2005 to July 2007, 51 patients with solitary necrotic nodule of the liver underwent hepatic resection in the Eastern Hepatobiliary Surgery Hospital of the Second Military Medical University (Shanghai, China). The medical records of these patients were retrospectively reviewed. Serum hepatitis B surface antigen (HBsAg) and hepatitis C antibody were used as the positive markers of chronic viral hepatitis, and alpha-fetoprotein (AFP) >20 μg/l, carbohydrate antigen 19-9 (CA19-9) >37 U/ml and carcinoembryonic antigen (CEA) >10 μg/l as the positive tumor markers. All surgically excised specimens were fixed in formalin, embedded in paraffin for routine hematoxylin and eosin (HE) staining, and specifically stained with Grocott, Ziehl- Neelsen and periodic acid Schiff (PAS). Results Clinical findings Solitary necrotic nodule of the liver was found mainly in males (68.6%, 35/51), and patients ranged in age from 5 to 69 years with a mean of 45.3 years. Hepatobiliary Pancreat Dis Int,Vol 7,No 5 October 15,

2 Hepatobiliary & Pancreatic Diseases International There was only one pediatric patient, a 5-year-old girl. Most patients (72.5%) presented no symptoms and were found incidentally at health check-ups or examinations for other diseases. Intermittent abdominal pain or discomfort was reported in 11 patients, malaise in 2 and fever in 1. The course of disease ranged from 2 to 13 months. HBsAg was positive in 8 patients (15.6%). None of the 51 patients was positive for anti-hcv. Routine blood, urine and stool results were within the normal ranges. Normal liver function was normal found in 47 patients, elevated alanine aminotransferase ( U/L) in 3, and elevated aspartate aminotransferase ( U/L) in 4. There was no significant abnormality in renal function and electrolytes. Serum AFP, CA19-9 and CEA were within normal limits in all patients. Concurrent hepatic cysts were found in 4 patients, gallbladder stones in 3, and gallbladder polyps in 1. Imaging findings Ultrasonography was performed in all 51 patients, of whom 49 (96.1%) had hypoechoes with unclear margins of the lesions, and 2 (3.9%) had hyperechoes. All the 51 patients had heterogeneous echoes. Dynamic computed tomography (CT) scans were performed in 23 patients. Unenhanced CT scans showed hypodense lesions with unclear margins in all patients. CT enhancement showed that the periphery of the lesion was slightly enhanced during the arterial phase in 8 patients (34.8%), strongly enhanced during the portal phase in 1 (4.3%), and no significant enhancement in any phase in 15 (65.2%) (Fig. 1). Magnetic resonance imaging (MRI) was performed in 21 patients. The T1-weighted signal intensity was low in all of them (100%), and the T2-weighted signal intensity was slightly high in 19 (90.5%). High cordlike and spot signal intensities were seen in the central area in 6 patients (28.6%). Gadolinium-enhanced results showed no enhancement during the different phases in 11 patients (52.3%). The periphery of the lesions was slightly enhanced in 10 patients (47.6%) during the arterial phase, and in 2 (9.5%) during the portal phase. The lesions became hypointense with a well-demarcated border against the liver parenchyma during the portal and delayed phases in 19 patients (90.5%) (Fig. 2). Based on the clinical manifestations, histories, laboratory and imaging findings, only 4 (7.8%) of the 51 patients were preoperatively suspected to have solitary necrotic nodule of the liver, 16 (31.4%) to have peripheral cholangiocarcinoma, 4 (7.8%) to have hepatocellular carcinoma, and 2 (3.9%) to have Fig. 1. Unenhanced CT scan demonstrating a hypodense nodule with unclear margins in the right lobe of the liver (black arrow) (A). Enhanced scan showing that the periphery of nodule was slightly enhanced in the arterial phase (B), and markedly enhanced in the portal phase (C), whereas there was a washout of the contrast in the delayed phase (D). Fig. 2. T1-weighted MRI scan showing a nodule with hypointensity in the left lobe of the liver (white arrow) (A), while T2-weighted images demonstrating a slightly hyperintense nodule with a high spot signal intensity in the central area (B). An enhanced scan showing that the nodule was slightly peripherally enhanced on the arterial phase (C), and became hypointense with a well-demarcated border in the portal phase (D). metastatic liver tumors. Endoscopy of the upper digestive tract, fibrocolonoscopy, head CT, chest CT, abdominal CT and bone scanning did not find any tumor in other parts of the body. The nature of the other patients was not defined. All of the patients underwent hepatectomy with tumor resection. Operative modalities included resection of the left lateral lobe in 3 patients, and irregular liver resection in the others. 486 Hepatobiliary Pancreat Dis Int,Vol 7,No 5 October 15,2008

3 Clinical features of solitary necrotic nodule of the liver Fig. 3. A: HE staining showing amorphous necrosis surrounded by a fibrotic capsule, with infiltration by inflammatory cells (original magnification 200); B: No abnormality was seen in the surrounding liver tissue (original magnification 200). Pathologic study By observation of the gross specimens, primary lesions were found in the right lobe in 43 patients (84.3%), and in the left lobe in 8 (15.7%). Single nodules were found in 36 patients, two nodules in 4, and three nodules in 1. The lesions were found under the superficial capsule in 44 patients (86.3%), and in the liver parenchyma in 7 (13.7%). The mean diameter of the nodules was 23 mm (range mm). The white-gray or yellow cut surface of the nodules, had a clear border with the surrounding liver tissue, indicating capsular formation in 6 patients. Small cyst cavities were present in 8 nodules. Microscopically, the pathological changes of the 51 patients showed a typical picture of solitary necrotic nodules of the liver. It was composed of a central necrotic core and a peripheral fibrotic capsule with inflammatory cells, including histiocytes, plasma cells and lymphocyte infiltration (Fig. 3A). No abnormality was seen in the surrounding liver tissue (Fig. 3B). Grocott, Ziehl-Neelsen and PAS staining did not reveal any bacterial, fungal or parasitic infection. Surgical outcome All patients recovered well postoperatively and were discharged from the hospital uneventfully. Follow-up for 6-27 months did not find recurrence in any patients. Discussion Solitary necrotic nodule of the liver is a rare nontumorous pathological condition. Since it was first described in 5 cases by Shepherd and Lee in 1983, [1] there have been no more than 100 cases reported in the English literature. [2-14] To our knowledge, our report presents the largest series from one institution. The etiology and pathogenesis of solitary necrotic nodule of the liver remain unclear. It has been [4, 5] postulated to be related to parasitic infection, trauma, [1] and sclerosing hemangiomas. [3] No parasitic infection or vascular lesion was found in our 51 patients. This finding is consistent with the idea that the pathogenesis of solitary necrotic nodule of the [4, 13, 16] liver is multifactorial. An overview of 68 cases of solitary necrotic nodule of the liver [1-14] reveals that the disease is predominant in males (57.4%, 39/68), with a median age of 62 years and a mean age of 57.5 (range 27-85). Of the 68 cases, 59 (86.7%) were primary lesions located in the right lobe and 9 (13.3%) in the left lobe. Sixtyone (89.7%) of the cases were solitary nodules, and 7 had 2 or more nodules. The nodules were under the superficial capsule in 60 cases (88.2%), and in the liver parenchyma in 8 (11.8%). The mean diameter of the nodules was 14 mm (range 2-85 mm), and 75% were <20 mm, while only one case was >35 mm. Most patients had no significant symptoms. The results of laboratory examination were within the normal range, except that serum CA19-9 and CEA levels were slightly elevated in 2 cases. [9, 12] There was no case of elevated AFP and complicated viral hepatitis. In the present series, the clinical manifestations were similar to those reported previously, but the age at which the disease occurred was younger; the possible reason being that all patients included in the present study were surgical patients without a single case of autopsy. No previous study has reported pediatric patients with this disease. We encountered a 5-year-old girl who underwent ultrasonography because of feeling weak for one week. She was admitted to our hospital because of a space-occupying lesion in the right lobe of the liver. Why solitary necrotic nodules of the liver are rare in children may be due to their benign nature without significant overt symptoms. In addition, the frequency of health check-ups for children is far lower than that for adults. Interestingly, the positive rate of HBsAg in our series was 15.6%, which is higher than the 9.09% in the general Chinese population. [15] This is supposed to be a mere coincidence, and there is no etiological connection between them. Solitary necrotic nodules of the liver are by no means solitary, but they are multiple. Some researchers preferred to "fibrosing [3, 4, 16] necrotic nodule" for this disease. Since the disease lacks characteristic clinical manifestations and laboratory markers, radiological image examination is important for its preoperative diagnosis. Ultrasonography was performed in all our 51 patients, of whom 49 had hypoechoes of unclear Hepatobiliary Pancreat Dis Int,Vol 7,No 5 October 15,

4 Hepatobiliary & Pancreatic Diseases International margins and two had hyperechoes; all of them showed heterogeneous echoes. Unenhanced CT scans showed hypodense lesions with unclear margins in all patients. Most lesions were not enhanced in the various phases because of homogeneity of coagulative necrosis. Slight enhancement was seen in the arterial and portal phases in the periphery of the lesions in a small number of patients, probably because there was infiltration of inflammatory cells in the surrounding tissue, and because diffusion of the contrast medium was slow in the wide extracellular spaces, and its clearance was also slow. Ultrasonographic and CT findings lack specificity for the disease, [8] but MRI is relatively more valuable for the diagnosis. [9] On the T1-weighted images, the lesions showed hypointensity, indicating fluid collection, a totally necrotic lesion, or a lesion consisting solely of fibrous tissue. On the T2-weighted images, most lesions showed slight hyperintensity, indicating dense fibrous tissue. [9] In some patients, liquidation due to coagulative necrosis, cord-like and higher spot signal intensity were seen in the central area on T2-weighted images. In about half of the patients who underwent MRI scan, slight enhancement was seen during the arterial phase in the periphery. Most of the lesions were hypointense with a well-demarcated border seen against the liver parenchyma in the portal and delayed phases. Therefore, combining our findings with reviews of the literature, [6, 9, 11] the specific features of MRI imaging are very helpful for differential diagnosis of the disease if taken in the context of the clinical findings. Most cases of the disease were found accidentally by autopsy, operation, or radiological investigation. [1-5] Recently, more cases of solitary necrotic nodules of the liver have been misdiagnosed as hepatic malignancies including cholangiocarcinoma or hepatic metastasis. [7-13] Hence, distinguishing solitary necrotic nodules of the liver from cholangiocarcinoma and metastatic liver tumors is almost in clinical practice. T2-weighted MRI of the latter two diseases shows hyperintensity against the liver parenchyma, and dynamic MRI enhancement shows a slight gradual enhancement in the unclear periphery of the lesions. In contrast, there is no enhancement or slight enhancement in the periphery of the lesions for the former. In some cases of metastatic hepatic tumor, the center looks typically like a "bull's eye" because of necrosis of the central portion, which presents as small round hyperintensities on T2-weighted MRI. In contrast, necrosis of solitary necrotic nodule of the liver presents as spot or cord-like hyperintensity. Of the previous 29 cases of solitary necrotic nodule of the liver that were misdiagnosed as liver metastatic tumors, 23 (79.3%) were complicated with various primary tumors. [7-13] Therefore a history of primary tumors is important for preoperative misdiagnosis. Hepatocellular carcinoma, cavernous hemangioma, hepatocellular adenoma and focal nodular hyperplasia of the liver are pathological factors for rich blood supply, so it is not very difficult to differentiate them from solitary necrotic nodules of the liver. The natural history of solitary fibrous nodule is unclear. Since the specimens surgically excised and found by autopsy are small in size, we presume that the pathological change of the disease is not significant over a lifetime. There has been only one reported case where the lesion expanded quickly from 30 to 80 mm within a short period and was excised surgically after being misinterpreted as a malignant tumor. [12] We therefore suggest that solitary necrotic nodule of the liver should be treated conservatively and followed up, and for those that expand quickly within a short period and whose nature cannot be defined, surgery can be considered. Funding: None. Ethical approval: Not needed. Contributors: ZYM wrote the first draft. All authors contributed to the intellectual context and approved the final version. YJM is the guarantor. Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. References 1 Shepherd NA, Lee G. Solitary necrotic nodules of the liver simulating hepatic metastases. J Clin Pathol 1983;36: Berry CL. Solitary "necrotic nodule" of the liver: a probable pathogenesis. J Clin Pathol 1985;38: Sundaresan M, Lyons B, Akosa AB. 'Solitary' necrotic nodules of the liver: an aetiology reaffirmed. Gut 1991;32: Tsui WM, Yuen RW, Chow LT, Tse CC. Solitary necrotic nodule of the liver: parasitic origin? J Clin Pathol 1992;45: Clouston AD, Walker NI, Prociv P. Parasitic origin of a solitary necrotic nodule of the liver. J Clin Pathol 1993;46: Alfieri S, Carriero C, Doglietto GB, Pacelli F, Crucitti F. Solitary necrotic nodule of the liver: diagnosis and treatment. Hepatogastroenterology 1997;44: De Luca M, Luigi B, Formisano C, Formato A, De Werra C, Cappuccio M, et al. Solitary necrotic nodule of the liver misinterpreted as malignant lesion: considerations on two cases. J Surg Oncol 2000;74: Yoon KH, Yun KJ, Lee JM, Kim CG. Solitary necrotic 488 Hepatobiliary Pancreat Dis Int,Vol 7,No 5 October 15,2008

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