Current diagnostic strategies for undifferentiated tumours of the nasal cavities and paranasal sinuses

Histopathology

Volumn 59, Issue 6, 2011, Pages 1034-1045

  Franchi, Alessandro ^a   Palomba, Annarita ^b   Cardesa, Antonio ^c  

^a UNIVERSITY OF FLORENCE   (Italy)

^b CAREGGI UNIVERSITY HOSPITAL   (Italy)

^c UNIVERSITY OF BARCELONA   (Spain)

Author keywords

Diagnosis; Electron microscopy; Immunohistochemistry; Molecular biology; Nasal cavity; Paranasal sinuses; Undifferentiated tumours

Indexed keywords

CD45 ANTIGEN; CD99 ANTIGEN; CHROMOGRANIN; CYTOKERATIN; DESMIN; EPITHELIAL MEMBRANE ANTIGEN; LYMPHOCYTE SURFACE MARKER; MYOGENIN; PROTEIN P16; PROTEIN P63; PROTEIN S 100; SYNAPTOPHYSIN; SYNDECAN 1;

ADENOID CYSTIC CARCINOMA; CANCER DIAGNOSIS; CARCINOMA; CHONDROSARCOMA; CYLINDRICAL CELL CARCINOMA; DIFFERENTIAL DIAGNOSIS; ELECTRON MICROSCOPY; EPSTEIN BARR VIRUS; ESTHESIONEUROBLASTOMA; EWING SARCOMA; FLUORESCENCE IN SITU HYBRIDIZATION; GRANULOCYTIC SARCOMA; HISTIOCYTIC SARCOMA; HISTOGENESIS; HUMAN; IMMUNOHISTOCHEMISTRY; LIGHT CHAIN; LYMPHOMA; MELANOMA; MESENCHYME CHONDROSARCOMA; MIDLINE CARCINOMA; MOLECULAR BIOLOGY; NASOPHARYNGEAL TYPE UNDIFFERENTIATED CARCINOMA; NEUROENDOCRINE TUMOR; NOSE TUMOR; PARANASAL SINUS TUMOR; PLASMACYTOMA; PRIORITY JOURNAL; PROGNOSIS; PROTEIN EXPRESSION; REVIEW; RHABDOMYOSARCOMA; SINONASAL B CELL LYMPHOMA; SINONASAL MELANOMA; SINONASAL UNDIFFERENTIATED CARCINOMA; SMALL CELL NEUROENDOCRINE CARCINOMA; SQUAMOUS CELL CARCINOMA; SYNOVIAL SARCOMA; TUMOR CLASSIFICATION; UNDIFFERENTIATED CARCINOMA;

HUMANS; NASAL CAVITY; NOSE NEOPLASMS; PARANASAL SINUS NEOPLASMS;

HUMAN HERPESVIRUS 4;

EID: 84855967810     PISSN: 03090167     EISSN: 13652559     Source Type: Journal    
DOI: 10.1111/j.1365-2559.2011.03813.x     Document Type: Review

References (99)

1. Barnes L, Brandwein M, Som PM. Disease of the nasal cavities, paranasal sinuses and nasopharynx. In Barnes L ed. Surgical pathology of the head and neck, 2nd edn. New York: Marcel Dekker, 2001; 439-555.
2. Franchi A, Miligi L, Palomba A, Giovannetti L, Santucci M. Sinonasal carcinomas: recent advances in molecular and phenotypic characterization and their clinical implications. Crit. Rev. Oncol. Hematol. 2010; Epub ahead of print.
3. Mills SE, Fechner RE. 'Undifferentiated' neoplasms of the sinonasal region: differential diagnosis based on clinical, light microscopic, immunohistochemical, and ultrastructural features. Semin. Diagn. Pathol. 1989; 6; 316-328.
4. Cordes B, Williams MD, Tirado Y et al. Molecular and phenotypic analysis of poorly differentiated sinonasal neoplasms: an integrated approach for early diagnosis and classification. Hum. Pathol. 2009; 40; 283-292.
5. Wenig BM. Undifferentiated malignant neoplasms of the sinonasal tract. Arch. Pathol. Lab. Med. 2009; 133; 699-712.
6. Rosenthal DI, Barker JL, El-Naggar AK et al. Sinonasal malignancies with neuroendocrine differentiation. Patterns of failure according to the histologic phenotype. Cancer 2004; 101; 2567-2573.
7. Dulguerov P, Jacobsen MS, Allal AS, Lehmann W, Calcaterra T. Nasal and paranasal sinus carcinoma: are we making progress? A series of 220 patients and a systematic review. Cancer 2001; 92; 3012-3029.
8. Lin EM, Sparano A, Spalding A et al. Sinonasal undifferentiated carcinoma: a 13-year experience at a single institution. Skull Base 2010; 20; 61-67.
9. Frierson HF, Mills SE, Fechner RE, Taxy JB, Levine PA. Sinonasal undifferentiated carcinoma. An aggressive neoplasm derived from Schneiderian epithelium and distinct from olfactory neuroblastoma. Am. J. Surg. Pathol. 1986; 10; 771-779.
10. Helliwell TR, Yeoh LH, Stell PM. Anaplastic carcinoma of the nose and paranasal sinuses. Light microscopy, immunohistochemistry, and clinical correlation. Cancer 1986; 58; 2038-2045.
11. Stewart FM, Lazarus HM, Levine PA, Stewart KA, Tabbara IA, Spaulding CA. High-dose chemotherapy and autologous marrow transplantation for esthesioneuroblastoma and sinonasal undifferentiated carcinoma. Am. J. Clin. Oncol. 1989; 12; 217-221.
12. Houston GD, Gillies E. Sinonasal undifferentiated carcinoma: a distinctive clinicopathologic entity. Adv. Anat. Pathol. 1999; 6; 317-323.
13. Gorelick J, Ross D, Marentette L, Blaivas M. Sinonasal undifferentiated carcinoma: case series and review of the literature. Neurosurgery 2000; 47; 750-754.
14. Cerilli LA, Holst VA, Brandwein MS, Stoler MH, Mills SE. Sinonasal undifferentiated carcinoma. Immunohistochemical profile and lack of EBV association. Am. J. Surg. Pathol. 2001; 25; 156-163.
15. Jeng YM, Sung MT, Fang CL et al. Sinonasal undifferentiated carcinoma and nasopharyngeal-type undifferentiated carcinoma. Two clinically, biologically, and histopathologically distinct entities. Am. J. Surg. Pathol. 2002; 26; 371-376.
16. Franchi A, Moroni M, Massi D, Paglierani M, Santucci M. Sinonasal undifferentiated carcinoma, nasopharyngeal-type undifferentiated carcinoma, and keratinizing and nonkeratinizing squamous cell carcinoma express different cytokeratin patterns. Am. J. Surg. Pathol. 2002; 26; 1597-1604.
17. Bourne TD, Bellizzi AM, Stelow EB et al. p63 expression in olfactory neuroblastoma and other small cell tumors of the sinonasal tract. Am. J. Clin. Pathol. 2008; 130; 213-218.
18. Chapman-Fredricks J, Jorda M, Gomez-Fernandez C. A limited immunohistochemical panel helps differentiate small cell epithelial malignancies of the sinonasal cavity and nasopharynx. Appl. Immunohistochem. Mol. Morphol. 2009; 17; 207-210.
19. MacMillan C, Kapadia SB, Finkelstein SD et al. Lymphoepithelial carcinoma of the larynx and hypopharynx: study of eight cases with relationship to Epstein-Barr virus (EBV) and p53 gene alterations, and review of the literature. Hum. Pathol. 1996; 27; 1172-1179.
20. Ferlito A, Weiss LM, Rinaldo A et al. Lymphoepithelial carcinoma of the larynx, hypopharynx, and trachea. Ann. Otol. Rhinol. Laryngol. 1997; 106; 437-444.
21. Singhi AD, Stelow EB, Mills SE, Westra WH. Lymphoepithelial-like carcinoma of the oropharynx: a morphologic variant of HPV-related head and neck carcinoma. Am. J. Surg. Pathol. 2010; 34; 800-805.
22. Maxwell JH, Kumar B, Feng FY et al. HPV-positive/p16-positive/EBV-negative nasopharyngeal carcinoma in white North Americans. Head Neck 2010; 32; 562-567.
23. Perez-Ordonez B, Caruana SM, Huvos AG, Shah JP. Small cell neuroendocrine carcinoma of the nasal cavity and paranasal sinuses. Hum. Pathol. 1998; 29; 826-832.
24. Chen CL, Hsu MM. Second primary epithelial malignancy of nasopharynx and nasal cavity after successful curative radiation therapy of nasopharyngeal carcinoma. Hum. Pathol. 2000; 31; 227-232.
25. Wang CP, Hsieh CY, Chang YL et al. Postirradiated neuroendocrine carcinoma of the sinonasal tract. Laryngoscope 2008; 118; 804-809.
26. Franchi A, Sardi I, Cetica V et al. Pediatric sinonasal neuroendocrine carcinoma after treatment of retinoblastoma. Hum. Pathol. 2009; 40; 750-755.
27. Weinreb I, Perez-Ordonez B. Non-small cell neuroendocrine carcinoma of the sinonasal tract and nasopharynx. Report of 2 cases and review of the literature. Head Neck Pathol. 2007; 1; 21-26.
28. Morice WG, Ferreiro JA. Distinction of basaloid squamous cell carcinoma from adenoid cystic and small cell undifferentiated carcinoma by immunohistochemistry. Hum. Pathol. 1998; 29; 609-612.
29. French CA, Kutok JL, Faquin WC et al. Midline carcinoma of children and young adults with NUT rearrangement. J. Clin. Oncol. 2004; 22; 4135-4139.
30. French CA, Ramirez CL, Kolmakova J et al. BRD-NUT oncoproteins: a family of closely related nuclear proteins that block epithelial differentiation and maintain the growth of carcinoma cells. Oncogene 2008; 27; 2237-2242.
31. Stelow EB, Bellizzi AM, Taneja K et al. NUT rearrangement in undifferentiated carcinomas of the upper aerodigestive tract. Am. J. Surg. Pathol. 2008; 32; 828-834.
32. Hsieh MS, French CA, Liang CW, Hsiao CH. NUT midline carcinoma: case report and review of the literature. Int. J. Surg. Pathol. 2009; Epub ahead of print.
33. Mertens F, Wiebe T, Adlercreutz C, Mandahl N, French CA. Successful treatment of a child with t(15;19)-positive tumor. Pediatr. Blood Cancer 2007; 49; 1015-1017.
34. Engleson J, Soller M, Panagopoulos I, Dahlén A, Dictor M, Jerkeman M. Midline carcinoma with t(15;19) and BRD4-NUT fusion oncogene in a 30-year-old female with response to docetaxel and radiotherapy. BMC Cancer 2006; 6; 69.
35. French CA. Demystified molecular pathology of NUT midline carcinomas. J. Clin. Pathol. 2010; 63; 492-496.
36. Haack H, Johnson LA, Fry CJ et al. Diagnosis of NUT midline carcinoma using a NUT-specific monoclonal antibody. Am. J. Surg. Pathol. 2009; 33; 984-991.
37. Stelow EB, French CA. Carcinomas of the upper aerodigestive tract with rearrangement of the nuclear protein of the testis (NUT) gene (NUT midline carcinomas). Adv. Anat. Pathol. 2009; 16; 92-96.
38. El-Mofty SK, Lu DW. Prevalence of high-risk human papillomavirus DNA in nonkeratinizing (cylindrical cell) carcinoma of the sinonasal tract: a distinct clinicopathologic and molecular disease entity. Am. J. Surg. Pathol. 2005; 29; 1367-1372.
39. Alos L, Moyano S, Nadal A et al. Human papilloma viruses are identified in a subgroup of sinonasal squamous cell carcinomas with favorable outcome. Cancer 2009; 115; 2701-2709.
40. Wieneke JA, Thompson LD, Wenig BM. Basaloid squamous cell carcinoma of the sinonasal tract. Cancer 1999; 85; 841-854.
41. Begum S, Westra WH. Basaloid squamous cell carcinoma of the head and neck is a mixed variant that can be further resolved by HPV status. Am. J. Surg. Pathol. 2008; 32; 1044-1050.
42. Chernock RD, Lewis JS Jr, Zhang Q, El-Mofty SK. Human papillomavirus-positive basaloid squamous cell carcinomas of the upper aerodigestive tract: a distinct clinicopathologic and molecular subtype of basaloid squamous cell carcinoma. Hum. Pathol. 2010; 41; 1016-1023.
43. Nagao T, Gaffey TA, Serizawa H et al. Dedifferentiated adenoid cystic carcinoma: a clinicopathologic study of 6 cases. Mod. Pathol. 2003; 16; 1265-1272.
44. Emanuel P, Wang B, Wu M, Burstein DE. p63 Immunohistochemistry in the distinction of adenoid cystic carcinoma from basaloid squamous cell carcinoma. Mod. Pathol. 2005; 18; 645-650.
45. Batsakis JG, Regezi JA, Solomon AR, Rice DH. The pathology of head and neck tumors: mucosal melanomas. Head Neck Surg. 1982; 4; 404-418.
46. Franquemont DW, Mills SE. Sinonasal malignant melanoma. A clinicopathologic and immunohistochemical study of 14 cases. Am. J. Clin. Pathol. 1991; 96; 689-697.
47. Lund V. Malignant melanoma of the nasal cavity and paranasal sinuses. J. Laryngol. Otol. 1982; 96; 347-355.
48. Zak FG, Lawson W. The presence of melanocytes in the nasal cavity. Ann. Otol. Rhinol. Laryngol. 1974; 83; 515-519.
49. Fernandez PL, Cardesa A, Bombì JA, Palacin A, Traserra J. Malignant sinonasal epithelioid schwannoma. Virchows Arch. A Pathol. Anat. Histopathol. 1993; 423; 401-405.
50. Prasad ML, Jungbluth AA, Iversen K, Huvos AG, Busam KJ. Expression of melanocytic differentiation markers in malignant melanomas of the oral and sinonasal mucosa. Am. J. Surg. Pathol. 2001; 25; 782-787.
51. Thompson LD, Wieneke JA, Miettinen M. Sinonasal tract and nasopharyngeal melanomas: a clinicopathologic study of 115 cases with a proposed staging system. Am. J. Surg. Pathol. 2003; 27; 594-611.
52. Coli A, Giacomini PG, Bigotti G et al. Aberrant neurofilament protein and synaptophysin expression in malignant melanoma of the nasal cavity. Histopathology 2004; 44; 193-195.
53. Eyden B, Pandit D, Banerjee SS. Malignant melanoma with neuroendocrine differentiation: clinical, histological, immunohistochemical and ultrastructural features of three cases. Histopathology 2005; 47; 402-409.
54. Lee H, Torres FX, McLean SA, Chen R, Lee MW. Immunophenotypic heterogeneity of primary sinonasal melanoma with aberrant expression of neuroendocrine markers and calponin. Appl. Immunohistochem. Mol. Morphol. 2011; 19; 48-53.
55. Min KW. Usefulness of electron microscopy in the diagnosis of "small" round cell tumors of the sinonasal region. Ultrastruct. Pathol. 1995; 19; 347-363.
56. Mills SE, Frierson HF. Olfactory neuroblastoma. A clinicopathologic study of 21 cases. Am. J. Surg. Pathol. 1985; 9; 317-327.
57. Dulguerov P, Allal AS, Calcaterra TC. Esthesioneuroblastoma: a meta analysis and review. Lancet Oncol. 2001; 2; 683-690.
58. Kane AJ, Sughrue ME, Rutkowski MJ et al. Posttreatment prognosis of patients with esthesioneuroblastoma. J. Neurosurg. 2010; 113; 340-351.
59. Frierson HF, Ross GW, Mills SE, Frankfurter A. Olfactory neuroblastoma. Additional immunohistochemical characterization. Am. J. Clin. Pathol. 1990; 94; 547-553.
60. Devaney K, Wenig BM, Abbondanzo SL. Olfactory neuroblastoma and other round cell lesions of the sinonasal region. Mod. Pathol. 1996; 9; 658-663.
61. Argani P, Perez-Ordonez B, Xiao H, Caruana SM, Huvos AG, Ladanyi M. Olfactory neuroblastoma is not related to the Ewing family of tumours. Absence of EWS/FLI1 gene fusion and MIC2 expression. Am. J. Surg. Pathol. 1998; 22; 391-398.
62. Allam A, El-Husseiny G, Khafaga Y et al. Ewing's sarcoma of the head and neck: a retrospective analysis of 24 cases. Sarcoma 1999; 3; 11-15.
63. Raney RB, Asmar L, Vassilopoulou-Sellin R et al. Late complications of therapy in 213 children with localized, nonorbital soft-tissue sarcoma of the head and neck: a descriptive report from the Intergroup Rhabdomyosarcoma Studies (IRS)-II and -III. IRS Group of the Children's Cancer Group and the Pediatric Oncology Group. Med. Pediatr. Oncol. 1999; 33; 362-371.
64. Windfuhr JP. Primitive neuroectodermal tumour of the head and neck: incidence, diagnosis and management. Ann. Otol. Rhinol. Laryngol. 2004; 113; 533-543.
65. Whaley JT, Indelicato DJ, Morris CG et al. Ewing tumors of the head and neck. Am. J. Clin. Oncol. 2010; 33; 321-326.
66. Weidner N, Tjoe J. Immunohistochemical profile of monoclonal antibody O13: antibody that recognizes glycoprotein p30/32MIC2 and is useful in diagnosing Ewing's sarcoma and peripheral neuroepithelioma. Am. J. Surg. Pathol. 1994; 18; 486-494.
67. Llombart-Bosch A, Machado I, Navarro S et al. Histological heterogeneity of Ewing's sarcoma/PNET: an immunohistochemical analysis of 415 genetically confirmed cases with clinical support. Virchows Arch. 2009; 455; 397-411.
68. Kapadia SB, Barnes L, Deutsch M. Non-Hodgkin's lymphoma of the nose and paranasal sinuses: a study of 17 cases. Head Neck Surg. 1981; 3; 490-499.
69. Harbo G, Grau C, Bundgaard T et al. Cancer of the nasal cavity and paranasal sinuses. A clinico-pathological study of 277 patients. Acta Oncol. 1997; 36; 45-50.
70. Abbondanzo SL, Wenig BM. Non-Hodgkin's lymphoma of the sinonasal tract. A clinicopathologic and immunophenotypic study of 120 cases. Cancer 1995; 75; 1281-1291.
71. Oprea C, Cainap C, Azoulay R et al. Primary diffuse large B-cell non-Hodgkin lymphoma of the paranasal sinuses: a report of 14 cases. Br. J. Haematol. 2005; 131; 468-471.
72. Campo E, Cardesa A, Alos L et al. Non-Hodgkin's lymphomas of nasal cavity and paranasal sinuses. An immunohistochemical study. Am. J. Clin. Pathol. 1991; 96; 184-190.
73. Chan JK. Natural killer cell neoplasms. Anat. Pathol. 1998; 3; 77-145.
74. Cheung MM, Chan JK, Lau WH et al. Primary non-Hodgkin's lymphoma of the nose and nasopharynx: clinical features, tumor immunophenotype, and treatment outcome in 113 patients. J. Clin. Oncol. 1998; 16; 70-77.
75. Siu LL, Chan V, Chan JK, Wong KF, Liang R, Kwong YL. Consistent patterns of allelic loss in natural killer cell lymphoma. Am. J. Pathol. 2000; 157; 1803-1809.
76. Gaal K, Sun NCJ, Hernandez AM, Arber DA. Sinonasal NK/T-cell lymphomas in the United States. Am. J. Surg. Pathol. 2000; 24; 1511-1517.
77. Harabuchi Y, Takahara M, Kishibe K, Moriai S, Nagato T, Ishii H. Nasal natural killer (NK)/T-cell lymphoma: clinical, histological, virological, and genetic features. Int. J. Clin. Oncol. 2009; 14; 181-190.
78. Liu Q, Ohshima K, Sumie A, Suzushima H, Iwasaki H, Kikuchi M. Nasal CD56 positive small round cell tumors. Differential diagnosis of hematological, neurogenic, and myogenic neoplasms. Virchows Arch. 2001; 438; 271-279.
79. Castro EB, Lewis JS, Strong EW. Plasmacytoma of paranasal sinuses and nasal cavity. Arch. Otolaryngol. 1973; 97; 326-329.
80. Abemayor E, Canalis RF, Greenberg P, Wortham DG, Rowland JP, Sun NC. Plasma cell tumors of the head and neck. J. Otolaryngol. 1988; 17; 376-381.
81. Navarrete ML, Quesada P, Pellicer M, Ruiz C. Extramedullary nasal plasmacytoma. J. Laryngol. Otol. 1991; 105; 41-43.
82. Aguilera NS, Kapadia SB, Nalesnik MA, Swerdlow SH. Extramedullary plasmacytoma of the head and neck: use of paraffin sections to assess clonality with insitu hybridization, growth fraction, and the presence of Epstein-Barr virus. Mod. Pathol. 1995; 8; 503-508.
83. Bachar G, Goldstein D, Brown D et al. Solitary extramedullary plasmacytoma of the head and neck-long-term outcome analysis of 68 cases. Head Neck 2008; 30; 1012-1019.
84. Prades JM, Alaani A, Mosnier JF, Dumollard JM, Martin C. Granulocytic sarcoma of the nasal cavity. Rhinology 2002; 40; 159-161.
85. Gorman M, Ahmed KA, Pallera A, Samant S. Granulocytic sarcoma of the nasal cavity: a case report. Ear Nose Throat J. 2009; 88; 1210-1212.
86. Roth MJ, Medeiros LJ, Elenitoba-Johnson K, Kuchnio M, Jaffe ES, Stetler-Stevenson M. Extramedullary myeloid cell tumors. An immunohistochemical study of 29 cases using routinely fixed and processed paraffin-embedded tissue sections. Arch. Pathol. Lab. Med. 1995; 119; 790-798.
87. Menasce LP, Banerjee SS, Beckett E, Harris M. Extra-medullary myeloid tumour (granulocytic sarcoma) is often misdiagnosed: a study of 26 cases. Histopathology 1999; 34; 391-398.
88. Pileri SA, Grogan TM, Harris NL et al. Tumours of histiocytes and accessory dendritic cells: an immunohistochemical approach to classification from the International Lymphoma Study Group based on 61 cases. Histopathology 2002; 41; 1-29.
89. Hornick JL, Jaffe ES, Fletcher CD. Extranodal histiocytic sarcoma: clinicopathologic analysis of 14 cases of a rare epithelioid malignancy. Am. J. Surg. Pathol. 2004; 28; 1133-1144.
90. Knott PD, Gannon FH, Thompson LD. Mesenchymal chondrosarcoma of the sinonasal tract: a clinicopathological study of 13 cases with a review of the literature. Laryngoscope 2003; 113; 783-790.
91. Wehrli BM, Huang W, De Crombrugghe B, Ayala AG, Czerniak B. Sox9, a master regulator of chondrogenesis, distinguishes mesenchymal chondrosarcoma from other small blue round cell tumors. Hum. Pathol. 2003; 34; 263-269.
92. Fanburg-Smith JC, Auerbach A, Marwaha JS, Wang Z, Rushing EJ. Reappraisal of mesenchymal chondrosarcoma: novel morphologic observations of the hyaline cartilage and endochondral ossification and beta-catenin, Sox9, and osteocalcin immunostaining of 22 cases. Hum. Pathol. 2010; 41; 653-662.
93. Callender TA, Weber RS, Janjan N et al. Rhabdomyosarcoma of the nose and paranasal sinuses in adults and children. Otolaryngol. Head Neck Surg. 1995; 112; 252-257.
94. Herrmann BW, Sotelo-Avila C, Eisenbeis JF. Pediatric sinonasal rhabdomyosarcoma: three cases and a review of the literature. Am. J. Otolaryngol. 2003; 24; 174-180.
95. Hicks J, Flaitz C. Rhabdomyosarcoma of the head and neck in children. Oral Oncol. 2002; 38; 450-459.
96. Chan JK, Ng HK, Wan KY, Tsao SY, Leung TW, Tse KC. Clear cell rhabdomyosarcoma of the nasal cavity and paranasal sinuses. Histopathology 1989; 14; 391-399.
97. Harb WJ, Luna MA, Patel SR, Ballo MT, Roberts DB, Sturgis EM. Survival in patients with synovial sarcoma of the head and neck: association with tumor location, size, and extension. Head Neck 2007; 29; 731-740.
98. Al-Daraji W, Lasota J, Foss R, Miettinen M. Synovial sarcoma involving the head. Analysis of 36 cases with predilection to the parotid and temporal regions. Am. J. Surg. Pathol. 2009; 33; 1494-1503.
99. Finke NM, Lae ME, Lloyd RV, Gehani SK, Nascimento AG. Sinonasal desmoplastic small round cell tumor: a case report. Am. J. Surg. Pathol. 2002; 26; 799-803.