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• W2804621021 abstract "Primary hepatic leiomyosarcoma is a rare primary mesenchymal tumor of the liver requiring exclusion of any other primary site of origin and histological and immunohistochemical exclusion of other hepatic/extrahepatic tumors with spindle cell morphology. Only about 70 cases are reported in the English literature and many of these tumors have predisposing conditions in the form of immunosuppression or associated malignancies. The occurrence of this tumor in the immunocompetent individual is also known. Histomorphology of this tumor shows a spindle cell lesion which needs to be distinguished from other spindle cell lesions of this region. The main diagnostic challenge of this tumor lies in its rarity, lack of awareness and morphological mimickers in the given site. A complete range of immunohistochemical markers is required to distinguish the lesion from its close morphological mimickers. Here, we discuss a case of primary hepatic leiomyosarcoma in an adult female patient with detailed histomorphological differentials and respective immunoprofiles. Primary hepatic leiomyosarcoma is a rare primary mesenchymal tumor of the liver requiring exclusion of any other primary site of origin and histological and immunohistochemical exclusion of other hepatic/extrahepatic tumors with spindle cell morphology. Only about 70 cases are reported in the English literature and many of these tumors have predisposing conditions in the form of immunosuppression or associated malignancies. The occurrence of this tumor in the immunocompetent individual is also known. Histomorphology of this tumor shows a spindle cell lesion which needs to be distinguished from other spindle cell lesions of this region. The main diagnostic challenge of this tumor lies in its rarity, lack of awareness and morphological mimickers in the given site. A complete range of immunohistochemical markers is required to distinguish the lesion from its close morphological mimickers. Here, we discuss a case of primary hepatic leiomyosarcoma in an adult female patient with detailed histomorphological differentials and respective immunoprofiles. Primary hepatic leiomyosarcoma is a rare malignant tumor of the liver. It arises from the intrahepatic blood vessels, bile ducts or the ligamentum teres hepatis. There are approximately 70 cases reported in the English literature. Many of the reported cases of the primary hepatic leiomyosarcoma are associated with immunodeficiency conditions, other hepatic/systemic malignancies, EBV positivity or genetic diseases. The occurrence of primary hepatic leiomyosarcoma in an individual without any predisposing condition is also described in the literature. The diagnosis of this entity requires careful exclusion of the leiomyosarcoma in other commoner extrahepatic sites. Primary hepatic leiomyosarcoma often poses significant diagnostic challenge to the pathologists especially in the core biopsy because of the rarity of the entity, limited awareness among the clinicians, radiologists and pathologists and multiple differential diagnoses. Therefore, the histomorphology should be adequately supplemented by an extended immunohistochemistry panel. We report a case of primary hepatic leiomyosarcoma in an adult female patient without any known predisposing factor along with the detailed discussion of the histological differentials and immunomorphology. A 45-year-old female patient presented with dyspepsia and loss of weight for 6 months. The dyspepsia was partially unresponsive to the proton-pump inhibitor therapy. The patient was hypertensive and dyslipidemic and used to take telmisartan and atorvastatin respectively. The patient was a housemaker and did not have any addiction. There was no significant family history. An Upper Gastrointestinal Endoscopy (UGIE) was performed revealing patchy hyperemia in the antrum and the antral biopsy did not reveal any H. pylori. The complete blood count was as follows; Hemoglobin 13.5 g/dL, Platelet 473,000/μL and total leukocyte count 8500/μL. The liver function test, renal function test and the thyroid function tests of the patient were within normal limits. The serum albumin was 4 g/dL (normal 3.5–5 g/dL) and serum IgG was 1.4 g/dL (normal 0.7–1.6 g/dL). The serum total cholesterol/triglyceride/HDL (high density lipoprotein)/LDL (low density lipoprotein) was 155/189/48/69 mg/dL. The HbA1c was 6 and the serum α-fetoprotein (AFP) and Carcinoembryonic Antigen (CEA) levels were within normal limits (AFP – 1.72 ng/mL; normal range 0–10 ng/mL and CEA – 1.06 ng/mL; normal range 0–3 ng/mL). The serum CA-19-9 was mildly elevated (98 U/mL; normal range 0–37 U/mL). The serum HBsAg, Anti-HBc (total), HCV and HIV serology were non reactive. An Ultrasonography (USG) of the abdomen was performed in view of the dyspepsia which revealed a large heteroechoic lesion in the segment IV, V and VI of the liver measuring 11.3 cm × 7.4 cm with cystic areas within the mass. A Triple Phasic Computed Tomography (TPCT) showed a large heterogeneously enhancing lesion arising from IV, V and VI with large exophytic component in subhepatic space which shows arterial hypervascularity and wash-out in the portal venous phase (Figure 1a) . Rest of the liver was normal in the outline and the spleen was normal. There was no evidence of background cirrhosis. The diameter of the portal vein was 11 mm and there was no ascites. Contrast Enhanced Magnetic Resonance Imaging (CEMRI) revealed large multilobulated, well-marginated solid cystic lesion from the liver with large exophytic component in the subhepatic region which was hypointense in TIW and mildly hyperintense in T2W image. Mild diffusion restriction was also seen. Dehiscence of one of the cystic components was noted with the leakage of the fluid into the peritoneal cavity. Gall bladder was seen separately (Figure 1b). On dynamic post contrast enhancement, the solid component of the lesion showed arterial hypervascularity and gradually became isointense to liver parenchyma on delayed sequences. The Positron Emission Tomography – Computed Tomography (PET-CT) revealed this mass to be a low-Fluorodeoxyglucose (FDG) avid mass. Fine Needle Aspiration Cytology (FNAC) was performed revealing predominantly blood and few scattered benign hepatocytes. A liver biopsy was performed with a clinical suspicion of hepatocellular adenoma. The liver biopsy was composed of a single linear core measuring 1.4 cm. The whole of the core was composed of the tumor tissue and no native liver parenchyma was present in the core. The tumor cells were arranged in diffuse sheets and vague short fascicles with the formation of whorls around the small arterioles. Individual tumor cells were spindle shaped with relatively monomorphic nuclear morphology. The nuclei were hyperchromatic with predominantly blunt edges, inconspicuous nucleoli and the cytoplasm was eosinophilic to clear containing multiple tiny vacuoles (Figure 2a–c ). There was no fat vacuole associated with the tumor. No bile or eosinophilic hyaline globule was noted. Occasional mitotic figure was seen. Morphologically, a number of possibilities were considered including Gastrointestinal Stromal Tumor (GIST), primary hepatic leiomyosarcoma, solitary fibrous tumor, malignant peripheral nerve sheath tumor, hepatic angiomyolipoma, sarcomatoid hepatocellular carcinoma and metastatic malignant melanoma. An immunohistochemical panel comprising of c-kit (CD117) (Figure 2d), CD34 (Figure 2e), S100, HMB45, Melan-A, desmin, Heppar-1, arginase and CD56 was negative ruling out almost all the possibilities. Smooth Muscle Antigen (SMA) showed diffuse strong cytoplasmic positivity in all the tumor cells (Figure 2f). The relevant internal controls and the external controls were in order. An EBER-ISH (Epstein Barr Encoded RNA-In Situ Hybridization) was performed which was negative with positive external control (Figure 2g). A diagnosis of primary hepatic leiomyosarcoma was rendered. On thorough search, no uterine or extrahepatic primary was identified. The patient was started on doxorubicin-based chemotherapy and was healthy till date (5 months post-diagnosis). The mesenchymal malignancies contribute to only 1–2% of the primary hepatic malignancies, hepatocellular carcinoma and cholangiocarcinoma forming the major bulk.1Shivathirthan N. Kita J. Iso Y. et al.Primary hepatic leiomyosarcoma: case report and literature review.World J Gastrointest Oncol. 2011; 3: 148-152Crossref PubMed Google Scholar Moreover, most of the primary hepatic mesenchymal malignancies are vascular tumors namely angiosarcoma and epithelioid hemangioendothelioma. Primary hepatic leiomyosarcoma is a rare mesenchymal malignancy of the liver with an incidence of 6–16% of the primary hepatic mesenchymal malignancies.2Iida T. Maeda T. Amari Y. Yurugi T. Tsukamoto Y. Nakajima F. Primary hepatic leiomyosarcoma in a patient with autosomal dominant polycystic kidney disease.CEN Case Rep. 2017; 6: 74-78Crossref PubMed Google Scholar, 3Weitz J. Klimstra D.S. Cymes K. et al.Management of primary liver sarcomas.Cancer. 2007; 109: 1391-1396Crossref PubMed Scopus (138) Google Scholar The diagnosis of this entity requires exclusion of a primary site namely genitourinary tract (especially gynaecologic tract in female patients), retroperitoneum, gastrointestinal tract or any other site. Moreover, the diagnosis should be made after the exclusion of other commoner entities by means of the histomorphology and immunohistochemistry. The pathologist should also be aware of this rare entity for a confident diagnosis. Primary hepatic leiomyosarcoma arises from the smooth muscle cells present in the intrahepatic vessels, bile ducts or ligamentum teres.4Han J.H. Park Y.N. Jung W.H. Chi H.S. Park C. A case with sarcomatoid hepatocellular carcinoma.Yonsei Med J. 1998; 39: 390-394Crossref PubMed Scopus (19) Google Scholar Most of the reported cases of primary hepatic leiomyosarcoma are associated with immunocompromised state like AIDS, post-renal and liver transplant recipient, coexisting primary or secondary hepatic/extrahepatic malignancy or multiple synchronous malignancies including both Hodgkin's and non-Hodgkin lymphoma, EBV positivity with or without AIDS, hepatitis C virus related cirrhosis, autosomal dominant polycystic kidney disease, predisposing genetic conditions like retinoblastoma or neurofibromatosis and drug (thorotrast) usage.1Shivathirthan N. Kita J. Iso Y. et al.Primary hepatic leiomyosarcoma: case report and literature review.World J Gastrointest Oncol. 2011; 3: 148-152Crossref PubMed Google Scholar, 2Iida T. Maeda T. Amari Y. Yurugi T. Tsukamoto Y. Nakajima F. Primary hepatic leiomyosarcoma in a patient with autosomal dominant polycystic kidney disease.CEN Case Rep. 2017; 6: 74-78Crossref PubMed Google Scholar, 4Han J.H. Park Y.N. Jung W.H. Chi H.S. Park C. A case with sarcomatoid hepatocellular carcinoma.Yonsei Med J. 1998; 39: 390-394Crossref PubMed Scopus (19) Google Scholar, 5Hamed M.O. Roberts K.J. Merchant W. Lodge J.P. Contemporary management and classification of hepatic leiomyosarcoma.HPB (Oxford). 2015; 17: 362-367Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar, 6Giakoustidis D. Giakoustidis A. Goulopoulos T. Arabatzi N. Kainantidis A. Zaraboukas T. Primary gigantic leiomyosarcoma of the liver treated with portal vein embolization and liver resection.Ann Hepatobiliary Pancreat Surg. 2017; 21: 228-231Crossref PubMed Google Scholar, 7Takehara K. Aoki H. Takehara Y. Yamasaki R. Tanakaya K. Takeuchi H. Primary hepatic leiomyosarcoma with liver metastasis of rectal cancer.World J Gastroenterol. 2012; 18: 5479-5484Crossref PubMed Scopus (8) Google Scholar, 8Ross J.S. Del Rosario A. Bui H.X. Sonbati H. Solis O. Primary hepatic leiomyosarcoma in a child with the acquired immunodeficiency syndrome.Hum Pathol. 1992; 23: 69-72Crossref PubMed Scopus (79) Google Scholar, 9Fujita H. Kiriyama M. Kawamura T. et al.Primary hepatic leiomyosarcoma in a woman after renal transplantation: report of a case.Surg Today. 2002; 32: 446-449Crossref PubMed Scopus (21) Google Scholar, 10Giuliante F. Sarno G. Ardito F. Pierconti F. Primary hepatic leiomyosarcoma in a young man after Hodgkin's disease: diagnostic pitfalls and therapeutic challenge.Tumori. 2009; 95: 374-377Crossref PubMed Scopus (11) Google Scholar, 11Brichard B. Smets F. Sokal E. et al.Unusual evolution of an Epstein-Barr virus-associated leiomyosarcoma occurring after liver transplantation.Pediatr Transplant. 2001; 5: 365-369Crossref PubMed Scopus (57) Google Scholar, 12Tsuji M. Takenaka R. Kashihara T. Hadama T. Terada N. Mori H. Primary hepatic leiomyosarcoma in a patient with hepatitis C virus-related liver cirrhosis.Pathol Int. 2000; 50: 41-47Crossref PubMed Scopus (19) Google Scholar, 13Abdelli N. Thiefin G. Diebold M.D. Bouche O. Aucouturier J.P. Zeitoun P. Primary leiomyosarcoma of the liver 37 years after successful treatment of hereditary retinoblastoma.Gastroenterol Clin Biol. 1996; 20: 502-505PubMed Google Scholar, 14Kinoshita A. Sakon M. Monden M. et al.Triple synchronous malignant tumors. Hepatic leiomyosarcoma, splenic hemangiosarcoma and sigmoid colon cancer. Case report.Acta Chir Scand. 1988; 154: 477-479PubMed Google Scholar, 15Maruta K. Sonoda Y. Saigo R. Yoshioka T. Fukunaga H. A patient with von Recklinghausen's disease associated with polymyositis, asymptomatic pheochromocytoma, and primary hepatic leiomyosarcoma.Nihon Ronen Igakkai Zasshi. 2004; 41: 339-343Crossref PubMed Scopus (4) Google Scholar, 16Shurbaji M.S. Olson J.L. Kuhajda F.P. Thorotrast-associated hepatic leiomyosarcoma and cholangiocarcinoma in a single patient.Hum Pathol. 1987; 18: 524-526Crossref PubMed Scopus (11) Google Scholar Multifactorial etiology can also be present. Nevertheless, primary hepatic leiomyosarcoma in a patient without any predisposing condition has also been described in literature. Matthaei et al. and Shamseddine et al. and other authors demonstrated adult to young adult patients with primary hepatic leiomyosarcoma without any such known predisposing conditions.1Shivathirthan N. Kita J. Iso Y. et al.Primary hepatic leiomyosarcoma: case report and literature review.World J Gastrointest Oncol. 2011; 3: 148-152Crossref PubMed Google Scholar, 6Giakoustidis D. Giakoustidis A. Goulopoulos T. Arabatzi N. Kainantidis A. Zaraboukas T. Primary gigantic leiomyosarcoma of the liver treated with portal vein embolization and liver resection.Ann Hepatobiliary Pancreat Surg. 2017; 21: 228-231Crossref PubMed Google Scholar, 17Matthaei H. Krieg A. Schmelzle M. et al.Long-term survival after surgery for primary hepatic sarcoma in adults.Arch Surg. 2009; 144 (discussion 44): 339-344Crossref PubMed Scopus (47) Google Scholar, 18Shamseddine A. Faraj W. Mukherji D. El Majzoub N. Khalife M. Soubra A. Unusually young age distribution of primary hepatic leiomyosarcoma: case series and review of the adult literature.World J Surg Oncol. 2010; 8: 56Crossref PubMed Scopus (17) Google Scholar Similarly, the occurrence of primary hepatic leiomyosarcoma in infants has also been reported.19Surendrababu N.R. Rao A. Samuel R. Primary hepatic leiomyosarcoma in an infant.Pediatr Radiol. 2006; 36: 366Crossref PubMed Scopus (3) Google Scholar, 20Tsai P.S. Yeh T.C. Shih S.L. Primary hepatic leiomyosarcoma in a 5-month-old female infant.Acta Radiol Short Rep. 2013; 2 (2047981613498722)PubMed Google Scholar We have searched the Pubmed with the search options like “primary hepatic leiomyosarcoma”, “primary liver leiomyosarcoma” and “liver sarcoma” and “India” to find out the reported cases of primary hepatic leiomyosarcoma from India. However, we could find only one case of primary hepatic leiomyosarcoma from India reported by Surendrababu et al.19Surendrababu N.R. Rao A. Samuel R. Primary hepatic leiomyosarcoma in an infant.Pediatr Radiol. 2006; 36: 366Crossref PubMed Scopus (3) Google Scholar The case reported by Surendrababu et al. occurred in an infant. Hence, the index case appears to be the second case of primary hepatic leiomyosarcoma from India and the first Indian case of adult primary hepatic leiomyosarcoma. The histomorphological differential should include the commoner entities and other hepatic tumors that can have spindle cell morphology. The morphological differentials are wide and relevant immunohistochemistry is required to rule out other possibilities. The spindle cell type of Gastrointestinal Stromal Tumor (GIST) should be the first differential diagnosis in all such cases and GIST must be ruled out before a confident diagnosis of leiomyosarcoma. Morphologically, GIST can be epithelioid or spindle cell type and the spindle cell type mimics leiomyosarcoma. The subtle morphological clues of leiomyosarcoma could be deep eosinophilic cytoplasm and blunt ended nuclei instead of relatively pale eosinophilic cytoplasm and spindle shaped nuclei in GIST. GIST can commonly show the presence of intracytoplasmic pinocytic vacuoles although leiomyosarcoma can also show the presence of such vacuoles. CD117 (c-kit) and DOG1 positivity necessarily suggests a diagnosis of GIST and SMA (Smooth Muscle Actin) positivity with CD117 negativity favors the possibility of a tumor of smooth muscle origin. Solitary fibrous tumor (SFT) can arise from the adjacent soft tissue and infiltrate the liver or can rarely occur de novo.21Dey B. Gochhait D. Kaushal G. Barwad A. Pottakkat B. Solitary fibrous tumor of the liver: a rare tumor in a rarer location.Rare Tumors. 2016; 8: 6403Crossref PubMed Scopus (5) Google Scholar The SFT shows a patternless pattern with variable deposition of the collagen and prominent angulated hemangiopericytomatous blood vessels. CD34 positivity and SMA negativity is the key immunological feature of SFT unlike the index case. Angiosarcoma is the commonest primary hepatic sarcoma and morphologically shows variable shaped vascular spaces and solid areas lined by mitotically active atypical endothelial cells that express CD34, CD31 and other vascular markers like Factor VIII related antigen or Fli-1. These malignant endothelial cells can show variable cytomorphology ranging from spindle cells to epithelioid cells and immunohistochemistry is often required. Malignant Peripheral Nerve Sheath Tumor (MPNST) shows variable patterns including fascicular arrangement and commonly shows wavy/kinky nuclear morphology with pale cytoplasm. S100 is positive in about half of the MPNST but SMA is almost always negative. Hepatic Angiomyolipoma (HAML) is a rare benign mesenchymal tumor of the liver. Malignant HAML can also occur in the liver and is an extremely rare entity. The histomorphology of the HAML shows a variable admixture of the spindle shaped cells with smooth muscle differentiation, adipocytes and vessels.22Du S. Li Y. Mao Y. et al.Diagnosis and treatment of hepatic angiomyolipoma.Hepatobiliary Surg Nutr. 2012; 1: 19-24PubMed Google Scholar However, it is important to note that the adipocytes can be absent in a core biopsy and the absence of the adipocytes does not necessarily rule out a possibility of the HAML. Moreover, SMA is also positive in these spindle cells. However, unlike the index case, the spindle cells in HAML also show immunopositivity for Melan-A ruling out a possibility of HAML. Primary Sarcomatous Hepatocellular Carcinoma (PSHCC) and metastatic malignant melanoma are the two non-mesenchymal liver tumors that can mimic a leiomyosarcoma. PSHCC is a rare tumor with both sarcomatous and well to moderately differentiated hepatocellular component. Only the sarcomatous component may be sampled in a core biopsy and the sarcomatous component may show Heppar-1 negativity. However, arginase can be positive in the sarcomatous component and it is unlikely to show strong and diffuse SMA positivity.23Mitra S. Gupta S. Dahiya D. Saikia U.N. A rare case of primary sarcomatous hepatocellular carcinoma without previous anticancer therapy.J Clin Exp Hepatol. 2017; 7: 378-384Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar Metastatic malignant melanoma can adopt variable cytomorphology including spindle shaped tumor cells in diffuse sheets. The cells usually show vesicular chromatin, prominent nucleoli and intracytoplasmic melanin pigment may also be seen. These cells show Melan-A and S100 positivity and SMA negativity. Importantly, CD117 positivity can be seen in melanoma although the other features need to be taken into account to prevent its misdiagnosis as GIST.24Pilloni L. Bianco P. Difelice E. et al.The usefulness of c-Kit in the immunohistochemical assessment of melanocytic lesions.Eur J Histochem. 2011; 55: e20Crossref PubMed Scopus (21) Google Scholar The immunohistochemistry of the hepatic tumors with spindle cell morphology are discussed in Table 1.Table 1Immunohistochemical Comparison of the Spindle Cell Tumors of the Liver.ImmunomarkersSite of positivityPrimary hepatic leiomyosarcomaGastrointestinal stromal tumorSolitary fibrous tumorAngiosarcomaMalignant peripheral nerve sheath tumorHepatic angiomyolipomaPrimary sarcomatous hepatocellular carcinomaMetastatic melanomaSMACytoplasmic+++−−−−+++−−CD117Membranocytoplasmic−+++−−−−−+/−CD34Cytoplasmic−+/−++++++−−−−CD31Cytoplasmic−−−+++−−−−S100Nucleocytoplasmic−−−−++/−−−+++HMB45Cytoplasmic−−−−−+++−+++ArginaseCytoplasmic−−−−−−Could be ++− Open table in a new tab The treatment modality for primary hepatic leiomyosarcoma is not standardized due to the rarity of the lesion. However, most of the authorities employed surgical resection with or without chemotherapy. There is no standard chemotherapeutic regimen and most people had employed a doxorubicin or docetaxel based therapy. The role of liver transplantation is controversial and liver transplantation is usually not recommended. Despite all these measures, the prognosis of primary hepatic leiomyosarcoma is poor.17Matthaei H. Krieg A. Schmelzle M. et al.Long-term survival after surgery for primary hepatic sarcoma in adults.Arch Surg. 2009; 144 (discussion 44): 339-344Crossref PubMed Scopus (47) Google Scholar, 18Shamseddine A. Faraj W. Mukherji D. El Majzoub N. Khalife M. Soubra A. Unusually young age distribution of primary hepatic leiomyosarcoma: case series and review of the adult literature.World J Surg Oncol. 2010; 8: 56Crossref PubMed Scopus (17) Google Scholar This case represents a rare tumor of the liver in an adult female patient and the histomorphological differential with detailed discussion of the immunological features. An awareness of this entity among the pathologists, high index of suspicion and adequate immunohistochemistry is required for the correct diagnosis." @default.
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• W2804621021 title "Primary Hepatic Leiomyosarcoma: Histopathologist's Perspective of a Rare Case" @default.
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