HPV Is Implicated in Esophageal Cancer

Detection of human papillomavirus DNA in cytologic specimens derived from esophageal precancer lesions and cancer. F Chang, O Shen, J Zhou, C Wang, D Wang, S Syrjänen, K Syrjänen. Scand J Gastroenterol 1990 Apr;25(4):383-388. 53 of 80 specimens (66.3%) from a high-risk area of China were positive for HPV.

Human papillomavirus involvement in esophageal precancerous lesions and squamous cell carcinomas as evidenced by microscopy and different DNA techniques. F Chang, S Syrjanen, Q Shen, L Wang, D Wang, K Syrjanen. Scand J Gastroenterol 1992 Jul;27(7):553-563. By light microscopy, HPV-suggestive lesions were found in 49.0% (25 of 51). By in situ hybridization, 43.1% (22 of 51) contained HPV DNA; and by PCR, DNA was found in three which were negative by ISH.

Infectious agents in the etiology of esophageal cancer. F Chang, S Syrjanen, L Wang, K Syrjanen. Gastroenterology 1992 Oct;103(4):1336-1348. Review.

Demonstration of human papillomavirus (HPV) type 30 in esophageal squamous-cell carcinomas by in situ hybridization (letter). F Chang, S Syrjänen, K Syrjänen. Int J Cancer 1993;55:171-173. HPV-30 was present in 8 (9.4%) of 85 HPV-positive esophageal carcinomas. "5 were infected with the HPV-30 as the single type, and 3 patients were co-infected with other HPV types, 1 with HPV 6/11 and 2 with HPV 16.... The original isolation of HPV 30 from a laryngeal squamous-cell carcinoma indicates that this virus can exert an oncogenic potential on epithelial cells. The identification of HPV 30 DNA in 2.2% (8/363) of esophageal squamous-cell carcinomas points to a causal role for this HPV type in the pathogenesis of esophageal carcinoma."

Screening for human papillomavirus infections in esophageal squamous cell carcinomas by in situ hybridization. F Chang, S Syrjanen, Q Shen, L Wang, K Syrjanen. Cancer 1993 Nov 1;72(9):2525-2530. 85 (23.4%) of esophageal squamous cell carcinomas from patients from a high-incidence area of China contained HPV DNA.

Human papillomavirus (HPV) infections in carcinogenesis of the upper aerodigestive tract. K Syrjanen & Kuopio Papillomavirus Research Group (S Syrjanen, R Mantyjarva, S Saarikoski, F Chang, S Parkkinen, M Yliskoski, T Nurmi, V Kataja, J Kellokoski, M Hippelainen, A Tervahauta, J Janne, L Albonen). Research proposal to the Council for Tobacco Research, estimated date 1993. "HPV infection in human esophagus was first suggested in 1982 by Syrjanen et al., who found that 40% (24/60) of esophageal squamous cell carcinomas presented with histological changes identical to those of genital (HPV-induced) condylomas.... These results have been confirmed by others demonstrating HPV-suggestive lesions, HPV antigens as well as HPV DNA sequences in esophageal squamous cell lesions." The Kuopio Papillomavirus Research Group's work was virtually the only research on infection as the fundamental cause of chronic disease that the CTR funded - and then they never used the data.

High prevalence of human papillomavirus in squamous cell carcinoma and matched normal esophageal mucosa: assessment by polymerase chain reaction. PO Fidalgo, ML Cravo, PP Chaves, CN Leitao, FC Mira. Cancer 1995 Nov 1;76(9):1522-1528. 8/16 (50%) were positive for HPV-16 and 3/16 (18.8%) were positive for HPV-18.

Detection of human papillomavirus in esophageal squamous cell carcinoma. L Suzuk, AE Noffsinger, YZ Hui, CM Fenoglio-Preiser. Cancer 1996 Aug 15;78(4):704-710. Out of 110 tumors, they did not find any HPV in any specimen by ISH or by PCR.

Serologic association between human papillomavirus type 16 infection and esophageal cancer in Shaanxi Province, China. C Han, G Qiao, NL Hubbert, L Li, C Sun, Y Wang, M Yan, D Xu, Y Li, DR Lowy, JT Schiller. J Natl Cancer Inst 1996 Oct 16;88(20):1467-1471. "24% of the cancer patients were seropositive compared with 7% of the control subjects, yielding a sex- and age-adjusted OR of 4.5 (95% CI = 1.8-11.9). In general, the OR for esophageal cancer increased with increasing HPV16 seroreactivity."

p53 overexpression and human papillomavirus (HPV) infection in oesophageal squamous cell carcinomas derived from a high-incidence area in China. F Chang, S Syrjanen, L Wang, Q Shen, K Syrjanen. Anticancer Res 1997 Jan-Feb;17(1B):709-715.

Absence of human papillomavirus-16 and -18 DNA and Epstein-Barr virus DNA in esophageal squamous cell carcinoma. S Mizobuchi, H Sakamoto, Y Tachimori, H Kato, H Watanabe, M Terada. Jpn J Clin Oncol 1997 Feb;27(1):1-5. HPV DNA sequences were found in 3/36 patients (8.3%).

Low prevalence of human papillomavirus infection in esophageal squamous cell carcinomas from North America: analysis by a highly sensitive and specific polymerase chain reaction-based approach. JR Turner, LH Shen, CP Crum, PJ Dean, RD Odze. Hum Pathol 1997 Feb;28(2):174-178. Harvard Medical School researchers found only 1/51 (2%) HPV-positive ESCCs.

Human papillomavirus infection in esophageal carcinomas: a study of 121 lesions using multiple broad-spectrum polymerase chain reactions and literature review. M Poljak, A Cerar, K Seme. Hum Pathol 1998 Mar;29(3):266-271. They found no HPV in 121 ESCCs.

Infection of human papillomavirus (HPV) and Epstein-Barr virus (EBV) and p53 expression in human esophageal carcinoma. A Khurshid, N Kazuya, I Hanae, I Manabu. J Pak Med Assoc 1998 May;48(5):138-142. "HPV and EBV DNA were found in 25% and 0% of normal esophageal tissues and in 63% and 7% of esophageal carcinoma specimens, respectively."

Human papillomavirus involvement in esophageal carcinogenesis in the high-incidence area of China. A study of 700 cases by screening and type-specific in situ hybridization. F Chang, S Syrjanen, Q Shen, M Cintorino, R Santopietro, P Tosi, K Syrjanen. Scand J Gastroenterol 2000 Feb;35(2):123-130. "Of the 700 esophageal carcinomas, 118 (16.9%) were shown to contain HPV DNA sequences by screening ISH... Notably, 60.2% of the HPV-positive lesions contained DNA sequences other than HPV types 6, 11, 16, 18, 30, and 53."

Evaluation of HPV, CMV, HSV and EBV in esophageal squamous cell carcinomas from a high-incidence area of China. F Chang, S Syrjanen, Q Shen, M Cintorino, R Santopietro, P Tosi, K Syrjanen. Anticancer Res 2000 Sep-Oct;20(5C):3935-3940. HPV DNA sequences found in 17/101 (16.8%) of carcinomas. The three herpesviruses were not detected.

Human papillomavirus type 16 is an important infectious factor in the high incidence of esophageal cancer in Anyang area of China. T Li, Z-M Lu, K-N Chen, M Guo, H-P Xing, Q Mei, H-H Yang, JF Lechner, Y Ke. Carcinogenesis 2001 Jun;22(6):929-934. "Esophageal carcinoma is one of the major cancers in China. The area of Anyang is located at the foot of Tai Hang Mountain in Henan province and has the highest incidence and mortality of esophageal cancer in China. Extensive investigations on natural geographic environment, life habits and trace elements in the diet have failed to establish the etiology of esophageal cancer in this district." In volunteers, 72% in the high incident village and 37% in the low incident village were infected, mainly by HPV-16.

[Causal association between human papilloma virus infection and head and neck and esophageal squamous cell carcinoma]. Z Szentirmay, I Szántó, I Bálint, K Pólus, E Remenár, L Tamás, G Szentkúti, Z Melegh, P Nagy, M Kásler. Magy Onkol 2002;46(1):35-41. "Overall, HPV sequences were detected in 61 of 150 specimens. HPV DNA sequences were detected in 16/32 specimens in the oropharyngeal region, in 13/36 specimens in larynx and 32/82 specimens in esophagus. Papillomas contained only the episomal form of HPV 16.In the esophagus, the most common type was HPV 73. In all specimens examined, HPV 6/11 (4/150), HPV 16 (23/150), HPV 35 (1/150), HPV 45 (1/150), HPV 54 (1/150), HPV 58 (1/150), HPV 61 (1/150), HPV 66 (1/150), HPV 68 (2/150), HPV 70 (3/150), HPV 72 (1/150), HPV 73 (16/150), double HPV infection (2/150), and unidentified HPV type (4/150) was detected. Interestingly, HPV was found in all verrucous carcinomas and in 18/22 basaloid squamous cell carcinomas."

HPV infections and esophageal cancer. KJ Syrjanen. J Clin Pathol 2002;55(10):721-728. Review. "To date, 239 oesophageal squamous cell papillomas have been analysed in 29 separate studies using different HPV detection methods, with HPV being detected in 51 (21.3%) cases. Many more squamous cell carcinomas have been analysed: of the 1485 squamous cell carcinomas analysed by in situ hybridisation, 22.9% were positive for HPV DNA, as were 15.2% of the 2020 cases tested by the polymerase chain reaction."

Detection of human papillomavirus in esophageal carcinoma. ZY Shen, SP Hu, LC Lu, CZ Tang, ZS Kuang, SP Zhong, Y Zeng. J Med Virol 2002 Nov;68(3):412-416. In 176 esophageal cancer patients, high-risk HPV types were more prevalent in cancerous tissues than in precancerous or normal tissue.

Expression of p21/WAF-1, status of apoptosis and p53 mutation in esophageal squamous cell carcinoma with HPV infection. M Hasegawa, I Ohoka, K Yamazaki, K Hanami, I Sugano, T Nagao, A Asoh, N Wada, K Nagao, Y Ishida. Pathol Int 2002 Jul;52(7):442-450. 20/48 (42%) of ESCCs were HPV-positive by PCR.

E6/E7 genes of human papilloma virus type 18 induced immortalization of human fetal esophageal epithelium. ZY Shen, S Cen, LY Xu, WJ Cai, MH Chen, J Shen, Y Zeng. Oncol Rep 2003;10:1431–1436.

Viral load of HPV in esophageal squamous cell carcinoma. HX Si, SW Tsao, CS Poon, LD Wang, YC Wong, AL Cheung. Int J Cancer 2003 Feb 10;103(4):496-500. "HPV infection was detected in 2-22.2% of samples. Infection with HPV-16 was again shown to be more common than that with HPV-18 among Chinese ESCC patients. The copy number of HPV-16 in these ESCC cases ranged from < or =1 to 157 copies/genome equivalent, with 65% of samples harboring fewer than 10 copies/genome equivalent. The median copy number of HPV-18 was 4.9/genome equivalent."

[Expression of HPV16-E6 and E7 oncoproteins in squamous cell carcinoma tissues of esophageal cancer and non-cancer tissues]. CL Xu, XL Qian, XS Zhou, QZ Zhao, YC Li. Ai Zheng 2004 Feb;23(2):165-168. "HPV16-E6 and E7 oncoproteins were determined using immunohistochemical staining in normal mucosa tissues (70 cases), dysplasia tissues (43 cases), and carcinoma tissues (18 cases). RESULTS: The positive rates of HPV16-E6 in the tissues of normal mucosa, dysplasia, and carcinoma of esophagus patients were 59.3%, 88.4%, and 83.3%,respectively; the positive rates of HPV16-E7 protein were 62.1%, 90.7%, and 88.9%, respectively. The positive rates of HPV16-E6 and E7 in dysplasia and carcinoma of esophagus were significantly higher than those in normal mucosa (P< 0.05). Double expression of HPV16-E6 and E7 in normal mucosa was 25.7%, while in dysplasia and carcinoma were 88.3% and 83.3%, respectively. CONCLUSION: HPV16-E6 and E7 are highly associated with esophageal squamous cell carcinogenesis. And cooperation of HPV16-E6 and E7 may play an important role in genesis of esophageal squamous carcinoma."

Esophageal squamous cell cancer in patients with head and neck cancer: Prevalence of human papillomavirus DNA sequences. EM de Villiers, K Gunst, H Stein, H Scherubl. Int J Cancer 2004 Mar 20;109(2):253-258. They found a high prevalence of "low-risk" HPV types in ESCC.

p53 polymorphism in human papillomavirus-associated Kazakh's esophageal cancer in Xinjiang, China. XM Lu, YM Zhang, RY Lin, XH Liang, YL Zhang, X Wang, Y Zhang, Y Wang, H Wen H. World J Gastroenterol 2004 Oct 1;10(19):2775-2778. 55 of 104 esophageal squamous cell carcinomas were positive for HPV16 E6.

p53 gene mutation and human papillomavirus (HPV) infection in esophageal carcinoma from three different endemic geographic regions of India. S Katiyar, S Hedau, N Jain, P Kar, MS Khuroo, J Mohanta, S Kumar, V Gopalkrishna, N Kumar, BC Das. Cancer Lett 2005 Jan 31;218(1):69-79. "Out of a total of 101 biopsy specimens of carcinoma esophagus analysed, the frequency of HPV was found to be the highest 14/32 (44%) in Dibrugarh followed by 33% (11/33) in Kashmir, but, interestingly, no high-risk HPV could be detected in New Delhi patients who showed the highest frequency (30.6%) of p53 mutation as against only 12.5% in Dibrugarh and 6.1% in Kashmir."

Evaluation of the prevalence of human papillomavirus and Epstein-Barr virus in esophageal squamous cell carcinomas. ID Lyronis, S Baritaki, I Bizakis, M Tsardi, DA Spandidos. Int J Biol Markers 2005 Jan-Mar;20(1):5-10. 17/30 (56%) of ESCC were positive for HPV, versus 6/27 (22.2%) normal samples (p < 0.001). All were negative for EBV.

Human papillomavirus infection in Egyptian esophageal carcinoma: correlation with p53, p21, mdm2, C-erbB2 and impact on survival. AA Bahnassy, AR Zekri, S Abdallah, AM El-Shehaby, GM Sherif. Pathol Int 2005 Feb;55(2):53-62. Human papillomavirus was detected in 54% of tumors and in 24% of normal tissues, of 50 patients with esophageal cancer.

Human papillomavirus in squamous cell carcinoma of esophagus in a high-risk population. M Farhadi, Z Tahmasebi, S Merat, F Kamangar, D Nasrollahzadeh, R Malekzadeh. World J Gastroenterol 2005 Feb 28;11(8):1200-1203. 14/38 (36.8%) of ESCCs were positive for the HPV L1 gene, versus 5/38 (13.2%) of controls. Fewer cases and controls were positive for HPV-18 E6/E7 gene.

The relationship between HPV16 and expression of CD44v6, nm23H1 in esophageal squamous cell carcinoma. WK Liu, YL Chu, F Zhang, P Chen, F Cheng, H Wang, YY Jia, TY Ma. Arch Virol 2005 May;150(5):991-1001. 24 of 40 (60%) esophageal squamous cell carcinomas were positive for the HPV16 E6 gene in Shaanxi Province of China, a high-incidence area.

LMP7/TAP2 gene polymorphisms and HPV infection in esophageal carcinoma patients from a high incidence area in China. B Cao, X Tian, Y Li, P Jiang, T Ning, H Xing, Y Zhao, C Zhang, X Shi, D Chen, Y Shen, Y Ke. Carcinogenesis 2005 Jul;26(7):1280-1284. "HPV16 and 18 were identified by PCR. HPV infection was found in 207 cases (78.11%) and 203 controls (56.86%). Among the 207 HPV positive patients, HPV16 and/or 18 DNA was found in 186 individuals including 175 infected by HPV16 alone, 4 infected by HPV18 alone and 7 infected by both types. In the control group, among the 203 HPV positive individuals, 181 were infected by HPV16 and/or 18 including 178 infected by HPV16, 4 infected by HPV18 and 1 infected by both HPV16 and 18." For HPV types 16 and/or 18, OR = 2.33 (95% CI = 1.66–3.27, P < 0.0001) [low due to the high rate of infection in controls -cast.] "No significant differences between cases and controls in cigarette smoking and alcohol consumption were found."

Detection of human papillomavirus DNA in squamous cell carcinoma of the esophagus by auto-nested PCR. AP Souto Damin, AP Guedes Frazzon, D de Carvalho Damin, H Beck Biehl, L Abruzzi de Oliveira, R Auler, C Marroni, CO Alexandre. Dis Esophagus 2006;19(2):64-68. In 165 paraffin-embedded specimens, "HPV DNA was detected in 26 esophageal carcinomas (15.75%), but in none of the benign esophageal specimens (P < 0.05). Out of the 26 positive cases, 24 were HPV-16 and one was HPV-18. One tumor contained both HPV-16 and -18 DNA. Positive PCR results were confirmed by the amplified viral sequences."

Evidence of human papilloma virus infection and its epidemiology in esophageal squamous cell carcinoma. PF Yao, GC Li, J Li, HS Xia, XL Yang, HY Huang, YG Fu, RQ Wang, XY Wang, JW Sha. World J Gastroenterol 2006 Mar 7;12(9):1352-1355. "IHC revealed that the positive rate of PV was 75.0%, 68.18% and 72.5% respectively while the HPV (16/18-E6) positive rate was 45.0%, 36.36%, 37.5%, respectively in esophageal carcinoma tissue specimens from Henan emigrants, the local citizens and patients in Hubei Cancer Hospital. The PV and HPV (16/18-E6) were negative in all normal esophageal mucosa specimens.... In situ hybridization showed that the HPV (16/18) DNA positive rate was 30.0%, 31.8%, 25.0%, respectively in the 3 groups of samples. No positive hybridization signal was found in 40 normal esophageal mucosa specimens."

High-risk human papilloma virus (HPV) and survival in patients with esophageal carcinoma: a pilot study. M Dreilich, M Bergqvist, M Moberg, D Brattstrom, I Gustavsson, S Bergstrom, A Wanders, P Hesselius, G Wagenius, U Gyllensten. BMC Cancer 2006 Apr 18;6:94. 100 patients with esophageal carcinoma investigated for HPV types 16, 18, 31, 33, 39, 45, 52, 58, and 67."HPV 16 was detected in 16% of the patients; no other HPV type was detected. HPV 16 infection had no significant effect on survival (p = 0.72)."

[HPV-infection in esophageal cancer as possible predictive factor after neoadjuvant therapy] B Gabor, A Imdahl, L Gyorgy, O Pal. Magy Seb 2006 Apr;59(2):97-104. 6 of 26 [23%] of oesophageal cancers had HPV-16 or -18.

Relationship between HPV16/18 E6 and 53, 21WAF1, MDM2, Ki67 and cyclin D1 expression in esophageal squamous cell carcinoma: comparative study by using tissue microarray technology. ZL Qi, X Huo, XJ Xu, B Zhang, MG Du, HW Yang, LK Zheng, J Li, ZY Shen. Exp Oncol 2006 Sep;28(3):235-240. "In ESCC samples, 18.3% (11/60) were revealed HPV16/18 E6 positive by IHC, while 40.0% (24/60) HPV positive by ISH; HPV16/18 E6 expression was significantly higher than that of control samples."

No association between HPV infection and the neoplastic progression of esophageal squamous cell carcinoma: result from a cross-sectional study in a high-risk region of China. GF Gao, MJ Roth, WQ Wei, CC Abnet, F Chen, N Lu, FH Zhao, XQ Li, GQ Wang, PR Taylor, QJ Pan, W Chen, SM Dawsey, YL Qiao. Int J Cancer 2006 Sep 15;119(6):1354-1359. 702 subjects. "A multivalent HPV hybridization probe, Digene Hybrid Capture II (Gaithersburg, MD), which recognizes high-risk types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68, was used to determine the HPV infection status of the cytologic specimens...Using a cutpoint of > or =3.0 pg/ml of HPV DNA to define a positive test, HPV positivity was identified in 13% (61/475) of subjects without squamous dysplasia, 8% (8/102) with mild dysplasia, 7% (6/83) with moderate dysplasia, 16% (6/38) with severe dysplasia and zero (0/4) with invasive ESCC."

Human papillomavirus in esophageal squamous cell carcinoma in Colombia and Chile. A Castillo, E Aguayo, C Koriyama, M Torres, E Carrascal, A Corvalan, JP Roblero, C Naquira, M Palma, C Backhouse, J Argandona, T Itoh, K Shuyama, Y Eizuru, S Akiba. World J Gastroenterol 2006 Oct 14;12(38):6188-6192. HPV types 16 and 18 were detected in 21 of 73 ESCC specimens (29%), by PCR with GP5+/GP6+ primer and confirmed by Southern blot.

Frequency of human papillomavirus infection in oesophageal squamous cell carcinoma in Iranian patients. AE Far, A Aghakhani, R Hamkar, A Ramezani, HF Pishbigar, S Mirmomen, MR Roshan, S Vahidi, V Shahnazi, Z Deljoodokht. Scand J Infect Dis 2007;39(1):58-62. 140 cases of oesophageal squamous cell carcinoma analyzed by PCR. "...50.7% were female and 49.3% were male, aged between 20 and 81 y. 33 tumour specimens (23.6%) and 12 (8.6%) non-involved tumour margins were HPV positive. From HPV positive tumour cases 36% were positive in tumour margins. The HPV positive cases were 21.7% male and 25.3% female. There is no correlation between presence and types of HPV with patients' gender and age. The frequency of HPV subtypes in tumoural regions was as follows: HPV-16, 60.6%; HPV-18, 30.3%; HPV-33, 6.1%; and HPV-31, 3%. We found only HPV-16 in tumour margins. Our results are consistent with HPV studies conducted in other high-risk areas for ESCC and provided further evidence to support a causal association of HPV infection with ESCC."

Human papillomavirus in high- and low-risk areas of oesophageal squamous cell carcinoma in China. K Shuyama, A Castillo, F Aguayo, Q Sun, N Khan, C Koriyama, S Akiba. Br J Cancer 2007 May 21;96(10):1554-1559. 26 oesophageal squamous cell carcinomas from Gansu, 33 from Shandong. "HPV DNA was detected in 17 cases (65%) in Gansu, where ESCC incidence is much higher than in Shandong, where HPV was positive in two samples (6%). HPV genotypes 16 and 18 were detected in 79 and 16% of HPV-positive samples, respectively."

p53 Codon 72 polymorphism, loss of heterozygosity and high-risk human papillomavirus infection in a low-incidence German esophageal squamous cell carcinoma patient cohort. A Pantelis, D Pantelis, P Ruemmele, A Hartmann, F Hofstaedter, R Buettner, F Bootz, R Stoehr. Oncol Rep 2007 May;17(5):1243-1248. 53 cases screened for high-risk HPV infection (HPV 16 and 18) with primer specific PCR and confirmed by sequencing. "Of 53 (17%) samples, 9 showed HPV 16 or 18 infection. We found no association between p53 codon 72 genotypes and increasing HPV infection rates."

Mechanisms

The genetic events of HPV-immortalized esophageal epithelium cells. ZY Shen, LY Xu, XH Chen, WJ Cai, J Shen, JY Chen, TH Huang, Y Zeng. Int J Mol Med 2001 Nov;8(5):537-542. Changes of chromosomes, telomere length, telomerase activity and certain gene expressions in epithelial cells from embryonic esophagus induced by genes E6E7 of HPV type 18, cultivated without co-carcinogens.

A possible role for JC virus

Detection of JC virus DNA sequences and expression of viral T antigen and agnoprotein in esophageal carcinoma. L Del Valle, MK White, S Enam, SP Oviedo, MQ Bromer, RM Thomas, HP Parkman, K Khalili. Cancer 2005 Feb 1;103(3):516-527. "Using immunohistochemistry, JCV T antigen was detected in 10 of 19 carcinomas (53%), agnoprotein was detected in 8 carcinomas (42%), p53 tumor suppressor was detected in 11 carcinomas (58%), and beta-catenin was detected in 4 carcinomas (21%). Zero of 51 normal, benign, and premalignant esophageal samples expressed viral proteins. Laser-capture microdissection verified the presence and specificity of JCV DNA sequences. beta-Catenin and p53 were colocalized with JCV T-antigen in the nuclei of neoplastic cells."

See also:

Confounding By Infection - why studies that don't include full detection of HPV (and other causal infections) are defective, and falsely blame smoking and other non-causal associations.

The Lie That p53 Mutations Are the Mechanism Behind Lung Cancer - this is because p53 mutations happen after maligancy has occurred, and the point is relevant to other cancers as well.

cast 01-13-08