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Motta G, Brandolini B, Di Meglio T, Allosso S, Mesolella M, Ricciardiello F, Bocchetti M, Testa D, Motta G. Challenges and Considerations in Diagnosing and Managing p16+-Related Oropharyngeal Squamous Cell Carcinoma (OPSCC) with Neck Metastasis: Implications of p16 Positivity, Tobacco Exposure, and De-Escalation Strategies. J Clin Med 2024; 13:6773. [PMID: 39597917 PMCID: PMC11595031 DOI: 10.3390/jcm13226773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Revised: 11/07/2024] [Accepted: 11/08/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND The incidence of patients showing neck metastasis and no obvious primary tumor at the initial diagnostic evaluation or neck cancer of unknown primary (NCUP) is rising. It is estimated that a relevant part of these tumors arises in the tonsillar crypts or base of the tongue and are p16+-related. However, today, the detection rate of the primary tumor is suboptimal. Identifying the primary tumor and its biomolecular characterization is essential since it influences the treatment administered, possibly reducing radiation fields and providing de-escalation to primary surgical management. However, p16 IHC (immunohistochemistry) might not be sufficient to diagnose HPV-related OPSCC. The other subset of patients discussed are the HPV-positive patients who have a history of tobacco exposure and/or p53 mutations. Possible factors that could negatively influence the outcomes of these patients are investigated and discussed below. So, this paper aims to analyze the diagnostic, bio-molecular, clinico-radiological, morphological, prognostic and therapeutical aspects of p16-positive OPSCC, highlighting the possible bias that can occur during the diagnostic and prognostic process. METHODS A narrative review was conducted to investigate the biases in the diagnostic and therapeutic process of two groups of patients: those who are p16-positive but HPV-negative patients, and those who are p16-positive and HPV-positive with exposure to traditional risk factors and/or p53 mutations. The keywords used for the literature research included the following: NCUP, OPSCC, p16IHC, HPV testing, p16 positive HPV negative OPSCC, p16 positive HPV positive OPSCC, tonsillectomy, tobacco exposure, p53 mutations, cystic neck metastasis, extranodal extension (ENE), radiotherapy, de-escalation and neck neck dissection. RESULTS HPV-positive OPSCC has specific clinico-radiological features. Bilateral tonsillectomy should be considered for the identification of the primary tumor. P16 IHC alone is not sufficient for diagnosing HPV-related OPSCC; additional detection methods are required. The role of tobacco exposure and p53 mutations should be investigated especially in cases of HPV-positive tumors. Extranodal extension (ENE) must be taken into consideration in the prognostic staging of HPV-positive tumors. Surgical primary treatment involving neck dissection (ND) and bilateral tonsillectomy followed by adjuvant radiation may represent the most appropriate approach for N3 cases. Diagnosis, prognosis and therapeutical implications must be addressed considering clinical, biomolecular and morphological aspects. At least today, the numerous biases that are still present influencing the diagnostic and prognostic process do not permit considering de-escalation protocols. CONCLUSIONS A precise and accurate diagnosis is required in order to adequately stage and manage p16+ OPSCC, particularly with neck metastasis. The role of tobacco exposure and/or p53 mutations must be considered not only in p16+ OPSCC but especially in HPV-positive OPSCC. Until a more accurate diagnosis is possible, ENE should be considered even in p16+HPV+ OPSCC. Primary surgery with unilateral ND and bilateral tonsillectomy might be the treatment of choice given the numerous diagnostic and prognostic pitfalls. Therefore, it is inappropriate and risky to propose de-escalation protocols in routine clinical practice due to the risk of undertreatment.
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Affiliation(s)
- Giovanni Motta
- ENT Unit, Department of Mental, Physical Health and Preventive Medicine, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy; (B.B.); (T.D.M.); (D.T.); (G.M.)
| | - Benedetta Brandolini
- ENT Unit, Department of Mental, Physical Health and Preventive Medicine, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy; (B.B.); (T.D.M.); (D.T.); (G.M.)
| | - Tonia Di Meglio
- ENT Unit, Department of Mental, Physical Health and Preventive Medicine, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy; (B.B.); (T.D.M.); (D.T.); (G.M.)
| | - Salvatore Allosso
- Otorhinolaryngology-Head and Neck Surgery Unit, Department of Neuroscience, Reproductive and Odontostomatological Sciences, University of Naples Federico II, 80138 Naples, Italy; (S.A.); (M.M.)
| | - Massimo Mesolella
- Otorhinolaryngology-Head and Neck Surgery Unit, Department of Neuroscience, Reproductive and Odontostomatological Sciences, University of Naples Federico II, 80138 Naples, Italy; (S.A.); (M.M.)
| | | | - Marco Bocchetti
- Department of Life and Health Sciences, Link Campus University, Via del Casale di San Pio V 44, 00165 Rome, Italy;
| | - Domenico Testa
- ENT Unit, Department of Mental, Physical Health and Preventive Medicine, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy; (B.B.); (T.D.M.); (D.T.); (G.M.)
| | - Gaetano Motta
- ENT Unit, Department of Mental, Physical Health and Preventive Medicine, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy; (B.B.); (T.D.M.); (D.T.); (G.M.)
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Masago K, Kuroda H, Sasaki E, Fujita Y, Fujita S, Horio Y, Endo M, Ishihara H, Hanai N, Matsushita H. Novel gene fusions in human oropharyngeal carcinoma. Cancer Genet 2024; 286-287:29-34. [PMID: 38971117 DOI: 10.1016/j.cancergen.2024.06.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 05/13/2024] [Accepted: 06/30/2024] [Indexed: 07/08/2024]
Abstract
Few reports have analyzed the fusion genes involved in carcinogenesis in the oropharynx, where the incidence of human papillomavirus-associated tumors is relatively low. The aim of this study was to identify novel driver fusion genes in patients with oropharyngeal cancer. The study enrolled fifty-seven patients who were diagnosed with oropharyngeal carcinoma. RNA sequencing data from fresh-frozen specimens were used to identify candidate fusion genes via the JAFFA, arriba, and STAR-Fusion pipelines. Candidate fusion genes were confirmed by direct sequencing. The expression level of a candidate fusion gene was compared to that of tumors without fusion genes. Finally, filtering was performed for driver genes using the annoFuse pipeline. In addition, the VIRTUS pipeline was used to analyze the presence of human papillomavirus in the tumors. We identified 5 (8.8 %) novel potential driver in-frame fusion genes, MKNK2::MOB3A, ICMT::RPS6KA3, ATP1B3::GRK7, CSNK2A1::KIF16B, and FGFR3::MAEA, and 1 (1.8 %) known in-frame fusion gene, FGFR3::TACC3, in 57 patients with pharyngeal carcinoma. Our results suggest that sporadic fusion genes may contribute to tumorigenesis in oropharyngeal carcinomas.
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Affiliation(s)
- Katsuhiro Masago
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan; Division of Translational Oncoimmunology, Aichi Cancer Research Institute, Nagoya, Japan.
| | - Hiroaki Kuroda
- Department of Respiratory Surgery, Aichi Cancer Center Hospital, Nagoya, Japan; Division of Translational Oncoimmunology, Aichi Cancer Research Institute, Nagoya, Japan; Department of Thoracic Surgery, Teikyo University Mizonokuchi Hospital, Kawasaki, Japan
| | - Eiichi Sasaki
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan
| | - Yasuko Fujita
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan
| | - Shiro Fujita
- Department of Respiratory Medicine, Kobe Central Hospital, Kobe, Japan
| | - Yoshitsugu Horio
- Department of Respiratory Medicine, Aichi Cancer Center Hospital, Nagoya, Japan; Division of Translational Oncoimmunology, Aichi Cancer Research Institute, Nagoya, Japan
| | - Motoyoshi Endo
- Department of Molecular Biology, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Hiromasa Ishihara
- Division of Translational Oncoimmunology, Aichi Cancer Research Institute, Nagoya, Japan
| | - Nobuhiro Hanai
- Department of Head and Neck Surgery, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Hirokazu Matsushita
- Division of Translational Oncoimmunology, Aichi Cancer Research Institute, Nagoya, Japan
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Duś-Ilnicka I, Hałoń A, Perra A, Radwan-Oczko M. HPV related p16 INK4A and HSV in benign and potentially malignant oral mucosa pathologies. BMC Oral Health 2024; 24:347. [PMID: 38500158 PMCID: PMC10949823 DOI: 10.1186/s12903-024-04105-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Accepted: 03/05/2024] [Indexed: 03/20/2024] Open
Abstract
BACKGROUND The association of Human Papilloma Virus (HPV) and Human Syncytial Virus (HSV) infection with inflammatory and potentially malignant disorders of the oral cavity (OPMD) is unknown. The aim of this cross-sectional study was to stablish the expression of the p16INK4A and HSV proteins, to test potential correlation between those parameters in biopsies from clinically diagnosed oral lesions. METHODS Immunochemical analysis of 211 formalin-fixed, paraffin-embedded (FFPE) blocks from 211 individuals was provided. The clinical diagnosis included in the research were Oral lichen planus (N = 30), Oral Leukoplakia (N = 13) Mucocele (N = 25), Erosion/ulceration/ inflammation of mucosa (N = 8), Overgrowth of mucosa (N = 135). RESULTS Two hundred eleven analyzed FFPE samples resulted with the median age of 58.5 years (the average age 54.0 years and SD ± 17 years). The female/male ratio was 2.3 (69.7% vs 30.3% respectively). All the samples positive for HSV also expressed p16INK4A (p = 0.000), that's showed various levels of association with the diverse clinical diagnosis reaching the higher level in OM 49.1% (29 positive samples) and OLP 30.5% (18). p16INK4A was associated with OLP at 30.5% (18), and fibroma 30.5%. HSV expression was mostly present in fibroma at 47.6% (10 positive samples). CONCLUSION HSV and p16INK4A positivity in relation to diagnosis of the biopsies showed statistically most often p16INK4A in OLP and fibroma. The results of co-expression of p16INK4A and HSV in mucocele and fibroma in oral mucosa suggest a cooperation between the molecular alterations induced by these two viruses. Squamous papilloma samples positive for p16INK4A were also positive for HSV, suggesting that the putative pro-oncogenic action of HSV could be an early event.
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Affiliation(s)
- Irena Duś-Ilnicka
- Oral Pathology Department, Faculty of Dentistry, Wroclaw Medical University, Ul. Krakowska 26, Wroclaw, 50-425, Poland.
| | - Agnieszka Hałoń
- Division of Clinical Pathology, Department of Clinical and Experimental Pathology, Wroclaw Medical University, Ul. Borowska 213, Wroclaw, Poland
| | - Andrea Perra
- Section of Pathology, Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria - Monserrato, Monserrato, Italy
| | - Małgorzata Radwan-Oczko
- Oral Pathology Department, Faculty of Dentistry, Wroclaw Medical University, Ul. Krakowska 26, Wroclaw, 50-425, Poland
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Ouh YT, Kim HY, Yi KW, Lee NW, Kim HJ, Min KJ. Enhancing Cervical Cancer Screening: Review of p16/Ki-67 Dual Staining as a Promising Triage Strategy. Diagnostics (Basel) 2024; 14:451. [PMID: 38396493 PMCID: PMC10888225 DOI: 10.3390/diagnostics14040451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 02/16/2024] [Accepted: 02/16/2024] [Indexed: 02/25/2024] Open
Abstract
Cervical cancer, primarily caused by high-risk human papillomavirus (HR-HPV) types 16 and 18, is a major global health concern. Persistent HR-HPV infection can progress from reversible precancerous lesions to invasive cervical cancer, which is driven by the oncogenic activity of human papillomavirus (HPV) genes, particularly E6 and E7. Traditional screening methods, including cytology and HPV testing, have limited sensitivity and specificity. This review explores the application of p16/Ki-67 dual-staining cytology for cervical cancer screening. This advanced immunocytochemical method allows for simultaneously detecting p16 and Ki-67 proteins within cervical epithelial cells, offering a more specific approach for triaging HPV-positive women. Dual staining and traditional methods are compared, demonstrating their high sensitivity and negative predictive value but low specificity. The increased sensitivity of dual staining results in higher detection rates of CIN2+ lesions, which is crucial for preventing cervical cancer progression. However, its low specificity may lead to increased false-positive results and unnecessary biopsies. The implications of integrating dual staining into contemporary screening strategies, particularly considering the evolving landscape of HPV vaccination and changes in HPV genotype prevalence, are also discussed. New guidelines and further research are necessary to elucidate the long-term effects of integrating dual staining into screening protocols.
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Affiliation(s)
| | | | | | | | | | - Kyung-Jin Min
- Department of Obstetrics and Gynecology, Korea University Ansan Hospital, Ansan-si 15355, Gyeonggi-do, Republic of Korea; (Y.-T.O.); (H.Y.K.); (K.W.Y.); (N.-W.L.); (H.-J.K.)
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Janecka-Widła A, Majchrzyk K, Mucha-Małecka A, Słonina D, Biesaga B. Prognostic potential of Akt, pAkt(Ser473) and pAkt(Thr308) immunoreactivity in relation to HPV prevalence in head and neck squamous cell carcinoma patients. Pathol Res Pract 2021; 229:153684. [PMID: 34839095 DOI: 10.1016/j.prp.2021.153684] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Revised: 10/29/2021] [Accepted: 11/03/2021] [Indexed: 10/19/2022]
Abstract
BACKGROUND The prognosis of squamous cell carcinoma of head and neck (HNSCC) patients remains relatively poor over the last years. Tobacco, alcohol and active human papillomavirus (HPV) infection are involved in HNSCC development. Akt is a serine-threonine protein kinase with main phosphorylation sites at Thr308 and Ser473, which are critical to generate a high level of Akt activity. MATERIALS AND METHODS The aim of the study was to compare the expression and prognostic potential of total Akt and its 2 phosphorylated forms - pAkt(Ser473) and pAkt(Thr308) in relation to HPV status in HNSCC patients. The expression levels of proteins were assessed immunohistochemically. To select independent prognostic factors univariate and multivariate analyses with Cox proportional regression model were performed. RESULTS Among HNSCC with active HPV16 infection significantly more tumors with high Akt (67.86%, p = 0.026) and low pAkt(Ser473) (64.29%, p = 0.000) expressions were found as compared to those with HPV negativity, while there was no significant difference in the pAkt(Thr308) expression level between HPV positive and negative tumors (p = 0.359). In the whole group of HNSCC patients independent favorable prognostic factors were low T stage, low pAkt(Thr308) expression, HPV16 active infection presence (for OS and DFS) and female gender (for OS only). CONCLUSIONS Our results indicate an important role of pAkt(Thr308) as prognostic biomarker for HNSCC patients. There is a high probability that using Akt inhibitors would improve therapeutical benefits and treatment effectiveness, especially in HNSCC patients with high expression of pAkt.
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Affiliation(s)
- Anna Janecka-Widła
- Department of Tumour Pathology, Maria Sklodowska-Curie National Research Institute of Oncology, Cracow Branch, Garncarska 11, 31-115 Cracow, Poland.
| | - Kaja Majchrzyk
- Department of Tumour Pathology, Maria Sklodowska-Curie National Research Institute of Oncology, Cracow Branch, Garncarska 11, 31-115 Cracow, Poland
| | - Anna Mucha-Małecka
- Department of Radiotherapy, Maria Sklodowska-Curie National Research Institute of Oncology, Cracow Branch, Garncarska 11, 31-115 Cracow, Poland
| | - Dorota Słonina
- Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Wybrzeże Armii Krajowej 15, 44-102 Gliwice, Poland
| | - Beata Biesaga
- Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Wybrzeże Armii Krajowej 15, 44-102 Gliwice, Poland
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Pakdel F, Farhadi A, Pakdel T, Andishe-Tadbir A, Alavi P, Behzad-Behbahani A, Ashraf MJ. The frequency of high-risk human papillomavirus types, HPV16 lineages, and their relationship with p16 INK4a and NF-κB expression in head and neck squamous cell carcinomas in Southwestern Iran. Braz J Microbiol 2021; 52:195-206. [PMID: 33169334 PMCID: PMC7966695 DOI: 10.1007/s42770-020-00391-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 10/17/2020] [Indexed: 12/14/2022] Open
Abstract
High-risk human papillomaviruses (hr-HPVs) are the key risk factors implicated in the development of a significant proportion of head and neck squamous cell carcinomas (HNSCCs). We aimed to investigate the distribution of hr-HPV types and HPV16 lineages in a sample of patients with HNSCC and the possible association between HPV status and the expression of P16INK4A and NF-κB in Iranian HNSCC patients. We examined 108 formalin-fixed, paraffin-embedded (FFPE) histologically confirmed primary SCC tissue specimens of different head and neck anatomical sites. HPV types and HPV16 lineages were determined by nested PCR and overlapping nested PCR assays, respectively, followed by gene sequencing and phylogenetic analysis. The expression of p16INK4a and NF-κB was evaluated by immunohistochemistry. Twenty-five (23.1%) HNSCC tissue specimens were tested positive for HPV infection. The most prevalent HPV type was HPV-16, followed by HPV18 and HPV11. HPV16 variants belonged to the lineage A and lineage D which were further sorted into sublineages A1, A2, and D2. A significant association between HPV status and p16INK4a immunoreactivity was observed in more than 76% of the HPV-related HNSCCs (P < 0.0001). The overexpression of p16INK4a and cytoplasmic NF-κB was more common in low-grade HNSCC tumors. Our data highlights that HPV16, in particular the A2 sublineage, followed by A1 and D2 sublineages are the major agents associated with HNSCCs in Iran. Based on HPV16 predominance and its lineage distribution pattern, it seems that the prophylactic vaccines developed for cervical cancer prevention could also be applicable for the prevention of HPV-related HNSCCs in our population.
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Affiliation(s)
- Fatemeh Pakdel
- Diagnostic Laboratory Sciences and Technology Research Center, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Oral and Maxillofacial Pathology, School of Dentistry, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ali Farhadi
- Diagnostic Laboratory Sciences and Technology Research Center, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Tahereh Pakdel
- Diagnostic Laboratory Sciences and Technology Research Center, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Azadeh Andishe-Tadbir
- Oral and Dental Disease Research Center, School of Dentistry, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Parnian Alavi
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Abbas Behzad-Behbahani
- Diagnostic Laboratory Sciences and Technology Research Center, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad J Ashraf
- Department of Pathology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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Zhou L. Concerns about human papillomavirus-associated oropharyngeal cancer detection methods. Oral Oncol 2021; 116:105143. [PMID: 33468408 DOI: 10.1016/j.oraloncology.2020.105143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 12/07/2020] [Accepted: 12/08/2020] [Indexed: 11/17/2022]
Affiliation(s)
- Lei Zhou
- Department of Otorhinolaryngology-Head and Neck Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo 315000, China.
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Janecka-Widła A, Mucha-Małecka A, Majchrzyk K, Halaszka K, Przewoźnik M, Słonina D, Biesaga B. Active HPV infection and its influence on survival in head and neck squamous-cell cancer. J Cancer Res Clin Oncol 2020; 146:1677-1692. [PMID: 32372145 PMCID: PMC7256081 DOI: 10.1007/s00432-020-03218-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 04/11/2020] [Indexed: 01/04/2023]
Abstract
Purpose HPV is involved in the development of some head and neck squamous-cell carcinomas (HNSCC). It was suggested that only transcriptionally active virus can induce carcinogenesis, therefore, the aim of our study was to analyze the frequency of active HPV infection, virus type, and its prognostic role in HNSCC patients. Methods Status of active HPV infection was assessed for 155 HNSCC patients based on p16 expression and HPV DNA presence. Univariate and multivariate analyses with Cox proportional regression model were performed to select independent prognostic factors. Results Active HPV infection was detected in 20.65% of patients. We identified 16.0, 40.9 and 1.7% of HPV positive oral cavity, oropharyngeal, and laryngeal cancer cases, respectively. HPV16 was dominant (81.25%) followed by HPV35 (9.38%) and double infections with HPV16 and 35 (6.25%) or HPV35 and 18 (3.12%). Patients with active HPV infection demonstrated significantly higher survival than HPV negative ones (OS 80.89% vs. 37.08%, p = 0.000; DFS 93.0% vs. 53.35%, p = 0.000, respectively). Longer OS and DFS were maintained for infected patients when oropharyngeal and non-oropharyngeal cases were analyzed separately. Interestingly, all patients infected with other than HPV16 types survived 5 years without cancer progression. In the analyzed group of 155 patients the strongest independent favourable prognostic factor for both OS and DFS was HPV presence. Conclusions High prevalence of HPV-driven HNSCC (mostly within oropharynx) was detected, with HPV16 type the most frequent, followed by HPV35 and HPV18. The presence of active HPV infection improved survival of both oropharyngeal and non-oropharyngeal cancer patients and should be taken into account in treatment planning.
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Affiliation(s)
- Anna Janecka-Widła
- Department of Tumour Pathology, Maria Sklodowska-Curie Institute - Oncology Center, Cracow Branch, Cracow, Poland.
| | - Anna Mucha-Małecka
- Department of Radiotherapy, Maria Sklodowska-Curie Institute - Oncology Center, Cracow Branch, Cracow, Poland
| | - Kaja Majchrzyk
- Department of Tumour Pathology, Maria Sklodowska-Curie Institute - Oncology Center, Cracow Branch, Cracow, Poland
| | - Krzysztof Halaszka
- Department of Tumour Pathology, Maria Sklodowska-Curie Institute - Oncology Center, Cracow Branch, Cracow, Poland
| | - Marcin Przewoźnik
- Department of Tumour Pathology, Maria Sklodowska-Curie Institute - Oncology Center, Cracow Branch, Cracow, Poland
| | - Dorota Słonina
- Department of Tumour Pathology, Maria Sklodowska-Curie Institute - Oncology Center, Cracow Branch, Cracow, Poland.,Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie Institute - Oncology Center, Gliwice Branch, Gliwice, Poland
| | - Beata Biesaga
- Department of Tumour Pathology, Maria Sklodowska-Curie Institute - Oncology Center, Cracow Branch, Cracow, Poland.,Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie Institute - Oncology Center, Gliwice Branch, Gliwice, Poland
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Devaraja K, Aggarwal S, Verma SS, Gupta SC. Clinico-pathological peculiarities of human papilloma virus driven head and neck squamous cell carcinoma: A comprehensive update. Life Sci 2020; 245:117383. [PMID: 32007572 DOI: 10.1016/j.lfs.2020.117383] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 01/17/2020] [Accepted: 01/28/2020] [Indexed: 01/11/2023]
Abstract
AIMS The current article provides a detailed account of the current understanding of molecular and clinico-pathological aspects of Human papilloma virus (HPV) driven head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS The literature review included most of the landmark trials and clinical studies related to the HPV driven HNSCC. KEY FINDINGS HPV positive HNSCC differ distinctly from HPV negative tobacco-related HNSCC, especially in oropharyngeal region. Therefore, the American joint committee on cancer`s latest manual for classification and staging of cancer suggests a separate staging system for HPV positive oropharyngeal cancers. Despite the younger patients being affected and the high propensity for cervical metastasis, the HPV positive oropharyngeal cancers respond much better to the treatment. The association with wild type TP53 and low EGFR expression confers the favorable prognosis in HPV driven HNSCC. Since the association is not universal, we suggest checking for p53 and EGFR expression status before considering de-intensification of therapy. In addition, the presence of matted lymph nodes and five or more nodes could mean relatively poorer prognosis, and are not suitable for de-intensification of therapy. The same is also true probably with higher T stage and co-existing tobacco use. The methods for the detection of p16, HPV DNA, HPV E6/E7 mRNA, anti-E6/E7 antibodies, in tissue, in serum and in saliva of patients, along with their clinical implications are also discussed. SIGNIFICANCE This article provides latest developments on the HPV driven HNSCC. 'Diagnosis of transcriptionally active HPV infection,' 'Modalities for surveillance,' 'Implication of de-escalation of therapy' are some of the critical issues that could serve the medical, the research as well as the patient communities.
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Affiliation(s)
- K Devaraja
- Department of Otorhinolaryngology and Head and Neck surgery, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Udupi, Karnataka, 576104, India.
| | - Sadhna Aggarwal
- Department of Biotechnology, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Sumit Singh Verma
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, 221 005, India
| | - Subash Chandra Gupta
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, 221 005, India.
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Sabu A, Mouli NVR, Tejaswini N, Rohit V, Nishitha G, Uppala D. Human Papillomavirus Detection in Oropharyngeal Squamous Cell Carcinoma Using p16 Immunohistochemistry. Int J Appl Basic Med Res 2019; 9:212-216. [PMID: 31681545 PMCID: PMC6822319 DOI: 10.4103/ijabmr.ijabmr_221_18] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Revised: 03/29/2019] [Accepted: 08/25/2019] [Indexed: 12/03/2022] Open
Abstract
Introduction: Oral cancer ranks third among all cancers in the Indian population with approximately 45% of call cancer cases in India being diagnosed as oral cancer, among which 20%–50% of the cases are observed to be associated with human papillomavirus (HPV) infection. Aim: This study aims to detect and evaluate the presence of p16 in oropharyngeal squamous cell carcinoma (OPSCC) patients using immunohistochemistry (IHC). Materials and Methods: This study was based on samples collected from 21 patients with primary OPSCC who were diagnosed and treated during the period of December 2017–March 2018. Inclusion criteria were complete clinicopathologic data, adequate clinical follow-up, and availability of sufficient paraffin-embedded tumor material. HPV immunoreactivity was further investigated by means of IHC using p16 as a marker. Results: IHC results revealed p16 positivity in six OPSCC cases. There was no statistically significant association of the p16 positivity of HPV with the age, gender, or site. Conclusion: Our results suggest that IHC-based detection of p16 provides a suboptimal prognostic information if not combined with detection of HPV DNA. Although p16 expression and HPV DNA infection are correlated with HPV-associated OPSCCs, neither of the tests alone is the optimal method for HPV status detection.
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Affiliation(s)
- Annetmary Sabu
- Interns, GITAM Dental College and Hospital, Visakhapatnam, Andhra Pradesh, India
| | - N V Ratna Mouli
- Interns, GITAM Dental College and Hospital, Visakhapatnam, Andhra Pradesh, India
| | - N Tejaswini
- Interns, GITAM Dental College and Hospital, Visakhapatnam, Andhra Pradesh, India
| | - V Rohit
- Interns, GITAM Dental College and Hospital, Visakhapatnam, Andhra Pradesh, India
| | - G Nishitha
- Interns, GITAM Dental College and Hospital, Visakhapatnam, Andhra Pradesh, India
| | - Divya Uppala
- Department of Oral and Maxillofacial Pathology, GITAM Dental College and Hospital, Visakhapatnam, Andhra Pradesh, India
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Guo Y, Ahn MJ, Chan A, Wang CH, Kang JH, Kim SB, Bello M, Arora RS, Zhang Q, He X, Li P, Dechaphunkul A, Kumar V, Kamble K, Li W, Kandil A, Cohen EEW, Geng Y, Zografos E, Tang PZ. Afatinib versus methotrexate as second-line treatment in Asian patients with recurrent or metastatic squamous cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 3): an open-label, randomised phase III trial. Ann Oncol 2019; 30:1831-1839. [PMID: 31501887 PMCID: PMC6927323 DOI: 10.1093/annonc/mdz388] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Treatment options are limited for patients with recurrent or metastatic squamous cell carcinoma of the head and neck (HNSCC) following progression after first-line platinum-based therapy, particularly in Asian countries. PATIENTS AND METHODS In this randomised, open-label, phase III trial, we enrolled Asian patients aged ≥18 years, with histologically or cytologically confirmed recurrent/metastatic HNSCC following first-line platinum-based therapy who were not amenable for salvage surgery or radiotherapy, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0/1. Patients were randomised (2 : 1) to receive oral afatinib (40 mg/day) or intravenous methotrexate (40 mg/m2/week), stratified by ECOG performance status and prior EGFR-targeted antibody therapy. The primary end point was progression-free survival (PFS) assessed by an independent central review committee blinded to treatment allocation. RESULTS A total of 340 patients were randomised (228 afatinib; 112 methotrexate). After a median follow-up of 6.4 months, afatinib significantly decreased the risk of progression/death by 37% versus methotrexate (hazard ratio 0.63; 95% confidence interval 0.48-0.82; P = 0.0005; median 2.9 versus 2.6 months; landmark analysis at 12 and 24 weeks, 58% versus 41%, 21% versus 9%). Improved PFS was complemented by quality of life benefits. Objective response rate was 28% with afatinib and 13% with methotrexate. There was no significant difference in overall survival. The most common grade ≥3 drug-related adverse events were rash/acne (4% with afatinib versus 0% with methotrexate), diarrhoea (4% versus 0%), fatigue (1% versus 5%), anaemia (<1% versus 5%) and leukopenia (0% versus 5%). CONCLUSIONS Consistent with the phase III LUX-Head & Neck 1 trial, afatinib significantly improved PFS versus methotrexate, with a manageable safety profile. These results demonstrate the efficacy and feasibility of afatinib as a second-line treatment option for certain patients with recurrent or metastatic HNSCC. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01856478.
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Affiliation(s)
- Y Guo
- Department of Medical Oncology, Shanghai East Hospital, Tongji University, Shanghai, China.
| | - M-J Ahn
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - A Chan
- State Key Laboratory in Translational Oncology, The Chinese University of Hong Kong, Hong Kong, China
| | - C-H Wang
- Department of Medical Oncology, Chang Gung Memorial Hospital at Keelung, Keelung, Taiwan
| | - J-H Kang
- The Catholic University of Korea, Seoul St. Mary's Hospital, Seoul
| | - S-B Kim
- Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - M Bello
- Department of Oncology, St Luke's Medical Center, Quezon City, Philippines
| | - R S Arora
- Department Oncology, Sujan Surgical Cancer Hospital and Amravati Cancer Foundation, Amravati, India
| | - Q Zhang
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - X He
- Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Science, Beijing
| | - P Li
- West China Hospital, Sichuan University, Chengdu, China
| | - A Dechaphunkul
- Division of Medical Oncology, Prince of Songkla University, Songkhla, Thailand
| | - V Kumar
- Department of Surgical Oncology, King George's Medical University, Lucknow
| | - K Kamble
- Department of Medicine, Government Medical College and Hospital, Nagpur, India
| | - W Li
- Department of Hematology and Oncology, First Hospital Affiliated to Jilin University, Jilin, China
| | - A Kandil
- Internal Medicine, Alexandria University Hospital, Alexandria, Egypt
| | - E E W Cohen
- Department of Medicine, University of California, San Diego, USA
| | - Y Geng
- Biostatistics, Boehringer Ingelheim (China) Investment Co., Ltd, China
| | - E Zografos
- Clinical Development and Medical Affairs, Boehringer Ingelheim Ltd, Bracknell, Berkshire, UK
| | - P Z Tang
- Department of Oncology, Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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12
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Sudhakaran A, Hallikeri K, Babu B. p16 as an independent marker for detection of high-risk HPV in oral submucous fibrosis and oral squamous cell carcinoma. INDIAN J PATHOL MICR 2019; 62:523-528. [PMID: 31611434 DOI: 10.4103/ijpm.ijpm_838_18] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Background An alarming increase in incidence of high-risk human papillomavirus (HPV) positive tumors in head and neck squamous cell carcinoma (HNSCC) by 25% and 70% in oropharyngeal HNSCC cannot be ignored. The early oncogenes of HPV, E6, and E7 play a key role in carcinogenesis. HPV associated tumors have a better clinical outcome and a favorable prognosis. The p16 expression has high concordance with other methods of HPV detection, ascertaining p16 as a surrogate marker for HPV. Objective To assess the immunohistochemical expression of p16 in oral submucous fibrosis (OSF) and oral squamous cell carcinoma (OSCC) with and without coexistent OSF as a marker for high-risk HPV detection. Materials and. Methods Tissue blocks of 70 cases including normal, OSF, OSCC with and without OSF were subjected to IHC staining with a p16INK4A monoclonal antibody. (Biogenex, San Roman). The p16 expression was noted according to percent positivity and pattern. The data were tabulated, statistically analyzed using the Chi-square test and the P value was assessed. Results The percentage of p16 positive cells raised from normal to OSF to OSCC with and without OSF. In addition, a shift from nuclear to cytoplasmic expression from normal to OSCC was noted with a statistical significance (P < 0.001). However, no statistical significance was established with any clinicopathologic parameters except age (P = 0.012) and habits (P= 0.023). Conclusion The presence of HPV using p16 was not detected in OSF but was positive in OSCC. Altered pattern of expression from normal to OSF to OSCC indicates promising use of p16 as a diagnostic marker.
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Affiliation(s)
- Archana Sudhakaran
- Department of Oral and Maxillofacial Pathology, SDM College of Dental Sciences and Hospital, Dharwad, Bangalore, Karnataka, India
| | - Kaveri Hallikeri
- Department of Oral and Maxillofacial Pathology, SDM College of Dental Sciences and Hospital, Dharwad, Bangalore, Karnataka, India
| | - Biji Babu
- Department of Oral and Maxillofacial Pathology, SDM College of Dental Sciences and Hospital, Dharwad, Bangalore, Karnataka, India
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13
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Palve V, Bagwan J, Krishnan NM, Pareek M, Chandola U, Suresh A, Siddappa G, James BL, Kekatpure V, Kuriakose MA, Panda B. Detection of High-Risk Human Papillomavirus in Oral Cavity Squamous Cell Carcinoma Using Multiple Analytes and Their Role in Patient Survival. J Glob Oncol 2019; 4:1-33. [PMID: 30398949 PMCID: PMC7010445 DOI: 10.1200/jgo.18.00058] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
PURPOSE Accurate detection of human papillomavirus (HPV) in oral cavity squamous cell carcinoma (OSCC) is essential to understanding the role of HPV in disease prognosis and management of patients. We used different analytes and methods to understand the true prevalence of HPV in a cohort of patients with OSCC with different molecular backgrounds, and we correlated HPV data with patient survival. METHODS We integrated data from multiple analytes (HPV DNA, HPV RNA, and p16), assays (immunohistochemistry, polymerase chain reaction [PCR], quantitative PCR [qPCR], and digital PCR), and molecular changes (somatic mutations and DNA methylation) from 153 patients with OSCC to correlate p16 expression, HPV DNA, and HPV RNA with HPV incidence and patient survival. RESULTS High prevalence (33% to 58%) of HPV16/18 DNA did not correlate with the presence of transcriptionally active viral genomes (15%) in tumors. Eighteen percent of the tumors were p16 positive and only 6% were both HPV DNA and HPV RNA positive. Most tumors with relatively high copy number HPV DNA and/or HPV RNA, but not with HPV DNA alone (irrespective of copy number), were wild-type for TP53 and CASP8 genes. In our study, p16 protein, HPV DNA, and HPV RNA, either alone or in combination, did not correlate with patient survival. Nine HPV-associated genes stratified the virus-positive from the virus-negative tumor group with high confidence ( P < .008) when HPV DNA copy number and/or HPV RNA were considered to define HPV positivity, and not HPV DNA alone, irrespective of copy number ( P < .2). CONCLUSION In OSCC, the presence of both HPV RNA and p16 is rare. HPV DNA alone is not an accurate measure of HPV positivity and therefore may not be informative. HPV DNA, HPV RNA, and p16 do not correlate with patients' outcome.
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Affiliation(s)
- Vinayak Palve
- Vinayak Palve, Jamir Bagwan, Neeraja M. Krishnan, Manisha Pareek, Udita Chandola, and Binay Panda, Ganit Labs, Institute of Bioinformatics and Applied Biotechnology; Amritha Suresh, Gangotri Siddappa, Bonney L. James, and Moni Abraham Kuriakose, Mazumdar Shaw Centre for Translational Cancer Research; and Vikram Kekatpure and Moni Abraham Kuriakose, Mazumdar Shaw Medical Centre, Bangalore; Neeraja M. Krishnan and Binay Panda, Ganit Labs Foundation, Delhi, India
| | - Jamir Bagwan
- Vinayak Palve, Jamir Bagwan, Neeraja M. Krishnan, Manisha Pareek, Udita Chandola, and Binay Panda, Ganit Labs, Institute of Bioinformatics and Applied Biotechnology; Amritha Suresh, Gangotri Siddappa, Bonney L. James, and Moni Abraham Kuriakose, Mazumdar Shaw Centre for Translational Cancer Research; and Vikram Kekatpure and Moni Abraham Kuriakose, Mazumdar Shaw Medical Centre, Bangalore; Neeraja M. Krishnan and Binay Panda, Ganit Labs Foundation, Delhi, India
| | - Neeraja M Krishnan
- Vinayak Palve, Jamir Bagwan, Neeraja M. Krishnan, Manisha Pareek, Udita Chandola, and Binay Panda, Ganit Labs, Institute of Bioinformatics and Applied Biotechnology; Amritha Suresh, Gangotri Siddappa, Bonney L. James, and Moni Abraham Kuriakose, Mazumdar Shaw Centre for Translational Cancer Research; and Vikram Kekatpure and Moni Abraham Kuriakose, Mazumdar Shaw Medical Centre, Bangalore; Neeraja M. Krishnan and Binay Panda, Ganit Labs Foundation, Delhi, India
| | - Manisha Pareek
- Vinayak Palve, Jamir Bagwan, Neeraja M. Krishnan, Manisha Pareek, Udita Chandola, and Binay Panda, Ganit Labs, Institute of Bioinformatics and Applied Biotechnology; Amritha Suresh, Gangotri Siddappa, Bonney L. James, and Moni Abraham Kuriakose, Mazumdar Shaw Centre for Translational Cancer Research; and Vikram Kekatpure and Moni Abraham Kuriakose, Mazumdar Shaw Medical Centre, Bangalore; Neeraja M. Krishnan and Binay Panda, Ganit Labs Foundation, Delhi, India
| | - Udita Chandola
- Vinayak Palve, Jamir Bagwan, Neeraja M. Krishnan, Manisha Pareek, Udita Chandola, and Binay Panda, Ganit Labs, Institute of Bioinformatics and Applied Biotechnology; Amritha Suresh, Gangotri Siddappa, Bonney L. James, and Moni Abraham Kuriakose, Mazumdar Shaw Centre for Translational Cancer Research; and Vikram Kekatpure and Moni Abraham Kuriakose, Mazumdar Shaw Medical Centre, Bangalore; Neeraja M. Krishnan and Binay Panda, Ganit Labs Foundation, Delhi, India
| | - Amritha Suresh
- Vinayak Palve, Jamir Bagwan, Neeraja M. Krishnan, Manisha Pareek, Udita Chandola, and Binay Panda, Ganit Labs, Institute of Bioinformatics and Applied Biotechnology; Amritha Suresh, Gangotri Siddappa, Bonney L. James, and Moni Abraham Kuriakose, Mazumdar Shaw Centre for Translational Cancer Research; and Vikram Kekatpure and Moni Abraham Kuriakose, Mazumdar Shaw Medical Centre, Bangalore; Neeraja M. Krishnan and Binay Panda, Ganit Labs Foundation, Delhi, India
| | - Gangotri Siddappa
- Vinayak Palve, Jamir Bagwan, Neeraja M. Krishnan, Manisha Pareek, Udita Chandola, and Binay Panda, Ganit Labs, Institute of Bioinformatics and Applied Biotechnology; Amritha Suresh, Gangotri Siddappa, Bonney L. James, and Moni Abraham Kuriakose, Mazumdar Shaw Centre for Translational Cancer Research; and Vikram Kekatpure and Moni Abraham Kuriakose, Mazumdar Shaw Medical Centre, Bangalore; Neeraja M. Krishnan and Binay Panda, Ganit Labs Foundation, Delhi, India
| | - Bonney L James
- Vinayak Palve, Jamir Bagwan, Neeraja M. Krishnan, Manisha Pareek, Udita Chandola, and Binay Panda, Ganit Labs, Institute of Bioinformatics and Applied Biotechnology; Amritha Suresh, Gangotri Siddappa, Bonney L. James, and Moni Abraham Kuriakose, Mazumdar Shaw Centre for Translational Cancer Research; and Vikram Kekatpure and Moni Abraham Kuriakose, Mazumdar Shaw Medical Centre, Bangalore; Neeraja M. Krishnan and Binay Panda, Ganit Labs Foundation, Delhi, India
| | - Vikram Kekatpure
- Vinayak Palve, Jamir Bagwan, Neeraja M. Krishnan, Manisha Pareek, Udita Chandola, and Binay Panda, Ganit Labs, Institute of Bioinformatics and Applied Biotechnology; Amritha Suresh, Gangotri Siddappa, Bonney L. James, and Moni Abraham Kuriakose, Mazumdar Shaw Centre for Translational Cancer Research; and Vikram Kekatpure and Moni Abraham Kuriakose, Mazumdar Shaw Medical Centre, Bangalore; Neeraja M. Krishnan and Binay Panda, Ganit Labs Foundation, Delhi, India
| | - Moni Abraham Kuriakose
- Vinayak Palve, Jamir Bagwan, Neeraja M. Krishnan, Manisha Pareek, Udita Chandola, and Binay Panda, Ganit Labs, Institute of Bioinformatics and Applied Biotechnology; Amritha Suresh, Gangotri Siddappa, Bonney L. James, and Moni Abraham Kuriakose, Mazumdar Shaw Centre for Translational Cancer Research; and Vikram Kekatpure and Moni Abraham Kuriakose, Mazumdar Shaw Medical Centre, Bangalore; Neeraja M. Krishnan and Binay Panda, Ganit Labs Foundation, Delhi, India
| | - Binay Panda
- Vinayak Palve, Jamir Bagwan, Neeraja M. Krishnan, Manisha Pareek, Udita Chandola, and Binay Panda, Ganit Labs, Institute of Bioinformatics and Applied Biotechnology; Amritha Suresh, Gangotri Siddappa, Bonney L. James, and Moni Abraham Kuriakose, Mazumdar Shaw Centre for Translational Cancer Research; and Vikram Kekatpure and Moni Abraham Kuriakose, Mazumdar Shaw Medical Centre, Bangalore; Neeraja M. Krishnan and Binay Panda, Ganit Labs Foundation, Delhi, India
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Lechner M, Chakravarthy AR, Walter V, Masterson L, Feber A, Jay A, Weinberger PM, McIndoe RA, Forde CT, Chester K, Kalavrezos N, O'Flynn P, Forster M, Jones TM, Vaz FM, Hayes DN, Fenton TR. Frequent HPV-independent p16/INK4A overexpression in head and neck cancer. Oral Oncol 2018; 83:32-37. [DOI: 10.1016/j.oraloncology.2018.06.006] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2018] [Revised: 05/13/2018] [Accepted: 06/04/2018] [Indexed: 10/14/2022]
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15
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Grønhøj C, Jensen DH, Dehlendorff C, Marklund L, Wagner S, Mehanna H, Munck-Wikland E, Ramqvist T, Näsman A, Wittekindt C, Würdemann N, Sharma SJ, Gattenlöhner S, Kiss K, Andersen E, Spruce R, Batis N, Robinson M, Harrington K, Winter S, Jones TM, Klussmann JP, Dalianis T, Friborg J, von Buchwald C. Development and external validation of nomograms in oropharyngeal cancer patients with known HPV-DNA status: a European Multicentre Study (OroGrams). Br J Cancer 2018; 118:1672-1681. [PMID: 29795309 PMCID: PMC6008433 DOI: 10.1038/s41416-018-0107-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Revised: 03/02/2018] [Accepted: 04/12/2018] [Indexed: 01/28/2023] Open
Abstract
BACKGROUND The proxy marker for human papillomavirus (HPV), p16, is included in the new AJCC 8th/UICC 8th staging system, but due to incongruence between p16 status and HPV infection, single biomarker evaluation could lead to misallocation of patients. We established nomograms for overall survival (OS) and progression-free survival (PFS) in patients with oropharyngeal squamous cell carcinoma (OPSCC) and known HPV-DNA and p16 status, and validated the models in cohorts from high- and low-prevalent HPV countries. METHODS Consecutive OPSCC patients treated in Denmark, 2000-2014 formed the development cohort. The validation cohorts were from Sweden, Germany, and the United Kingdom. We developed nomograms by applying a backward-selection procedure for selection of variables, and assessed model performance. RESULTS In the development cohort, 1313 patients, and in the validation cohorts, 344 German, 503 Swedish and 463 British patients were included. For the OS nomogram, age, gender, combined HPV-DNA and p16 status, smoking, T-, N-, and M-status and UICC-8 staging were selected, and for the PFS nomogram the same variables except UICC-8 staging. The nomograms performed well in discrimination and calibration. CONCLUSIONS Our nomograms are reliable prognostic methods in patients with OPSCC. Combining HPV DNA and p16 is essential for correct prognostication. The nomograms are available at www.orograms.org .
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Affiliation(s)
- Christian Grønhøj
- Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - David H Jensen
- Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Christian Dehlendorff
- Statistics and Pharmacoepidemiology, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Linda Marklund
- Department of Clinical Science and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden
| | - Steffen Wagner
- Department of Otorhinolaryngology, Head and Neck Surgery, University of Giessen, Giessen, Germany
| | - Hisham Mehanna
- Head and Neck Studies and Education (InHANSE), University of Birmingham, Birmingham, UK
| | - Eva Munck-Wikland
- Department of Clinical Science and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden
| | - Torbjörn Ramqvist
- Department of Clinical Science and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden
| | - Anders Näsman
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Claus Wittekindt
- Department of Otorhinolaryngology, Head and Neck Surgery, University of Giessen, Giessen, Germany
| | - Nora Würdemann
- Department of Otorhinolaryngology, Head and Neck Surgery, University of Giessen, Giessen, Germany
| | - Shachi Jenny Sharma
- Department of Otorhinolaryngology, Head and Neck Surgery, University of Giessen, Giessen, Germany
| | | | - Katalin Kiss
- Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Elo Andersen
- Department of Oncology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Rachel Spruce
- Head and Neck Studies and Education (InHANSE), University of Birmingham, Birmingham, UK
| | - Nikos Batis
- Head and Neck Studies and Education (InHANSE), University of Birmingham, Birmingham, UK
| | - Max Robinson
- Centre for Oral Health Research, Newcastle University, Newcastle, UK
| | - Kevin Harrington
- The Institute of Cancer Research/The Royal Marsden NIHR Biomedical Research Centre, London, UK
| | - Stuart Winter
- Department of Otorhinolaryngology, Head and Neck Surgery, Nuffield Department of Medicine, Oxford, UK
| | - Terence M Jones
- Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Jens Peter Klussmann
- Department of Otorhinolaryngology, Head and Neck Surgery, University of Giessen, Giessen, Germany
| | - Tina Dalianis
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Jeppe Friborg
- Department of Oncology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Christian von Buchwald
- Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
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A dualistic model of primary anal canal adenocarcinoma with distinct cellular origins, etiologies, inflammatory microenvironments and mutational signatures: implications for personalised medicine. Br J Cancer 2018; 118:1302-1312. [PMID: 29700411 PMCID: PMC5959925 DOI: 10.1038/s41416-018-0049-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 02/05/2018] [Accepted: 02/07/2018] [Indexed: 12/19/2022] Open
Abstract
Background Primary adenocarcinoma of the anal canal is a rare and aggressive gastrointestinal disease with unclear pathogenesis. Because of its rarity, no clear clinical practice guideline has been defined and a targeted therapeutic armamentarium has yet to be developed. The present article aimed at addressing this information gap by in-depth characterising the anal glandular neoplasms at the histologic, immunologic, genomic and epidemiologic levels. Methods In this multi-institutional study, we first examined the histological features displayed by each collected tumour (n = 74) and analysed their etiological relationship with human papillomavirus (HPV) infection. The intratumoural immune cell subsets (CD4, CD8, Foxp3), the expression of immune checkpoints (PD-1, PD-L1), the defect in mismatch repair proteins and the mutation analysis of multiple clinically relevant genes in the gastrointestinal cancer setting were also determined. Finally, the prognostic significance of each clinicopathological variable was assessed. Results Phenotypic analysis revealed two region-specific subtypes of anal canal adenocarcinoma. The significant differences in the HPV status, density of tumour-infiltrating lymphocytes, expression of immune checkpoints and mutational profile of several targetable genes further supported the separation of these latter neoplasms into two distinct entities. Importantly, anal gland/transitional-type cancers, which poorly respond to standard treatments, displayed less mutations in downstream effectors of the EGFR signalling pathway (i.e., KRAS and NRAS) and demonstrated a significantly higher expression of the immune inhibitory ligand-receptor pair PD-1/PD-L1 compared to their counterparts arising from the colorectal mucosa. Conclusions Taken together, the findings reported in the present article reveal, for the first time, that glandular neoplasms of the anal canal arise by HPV-dependent or independent pathways. These etiological differences leads to both individual immune profiles and mutational landscapes that can be targeted for therapeutic benefits.
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Human papillomavirus infection is not associated with laryngeal squamous cell carcinoma in Taiwan. JOURNAL OF MICROBIOLOGY, IMMUNOLOGY, AND INFECTION = WEI MIAN YU GAN RAN ZA ZHI 2018; 53:79-86. [PMID: 29500045 DOI: 10.1016/j.jmii.2018.02.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Revised: 11/27/2017] [Accepted: 02/05/2018] [Indexed: 01/05/2023]
Abstract
BACKGROUND/PURPOSE To examine whether the prevalence rate of human papillomavirus (HPV) infection in Taiwanese patients with primary laryngeal squamous cell carcinoma (LSCC) is different from that in those with a vocal polyp (VP) or vocal fold leukoplakia (VFL). METHODS This prospective cohort study recruited 41 consecutive patients with primary LSCC and 27 and 20 patients with VP and VFL, respectively. The HPV L1 gene in surgical specimens was detected using polymerase chain reaction. High-risk HPV DNA in tissue microarray specimens was detected using in situ hybridization. Expression of p16INK4a in tissue microarray specimens was determined through immunohistochemistry. RESULTS The prevalence of HPV L1 DNA in the LSCC group was equivalent to that in the VP and VFL groups (7.3% vs. 7.4% vs. 10.0%; P = 0.929; effect size = 0.20). High-risk HPV DNA detected using in situ hybridization was relatively rare in all groups (2.6% vs. 5.3% vs. 0.0%; P = 0.636; effect size = 0.81). The prevalence of p16INK4a positivity was significantly lower in the LSCC group than in the VP and VFL groups (5.1% vs. 58.8% vs. 14.3%; P < 0.001). Multivariate analysis results revealed that age ≥65 years (adjusted odds ratio, 4.09; 95% confidence interval, 1.21-13.91; P = 0.024) and p16INK4a positivity (adjusted odds ratio, 0.10; 95% confidence interval, 0.02-0.53; P = 0.006) were LSCC risk factors. CONCLUSION HPV infection is uncommon in Taiwanese patients with LSCC and seems not to be associated with an increased LSCC risk. Larger sample size is warranted for further study.
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18
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Lafaurie GI, Perdomo SJ, Buenahora MR, Amaya S, Díaz-Báez D. Human papilloma virus: An etiological and prognostic factor for oral cancer? ACTA ACUST UNITED AC 2018; 9:e12313. [DOI: 10.1111/jicd.12313] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Accepted: 10/17/2017] [Indexed: 12/26/2022]
Affiliation(s)
- Gloria I. Lafaurie
- Unit of Basic Oral Investigation, School of Dentistry, El Bosque University; Bogotá Colombia
| | - Sandra J. Perdomo
- Unit of Basic Oral Investigation, School of Dentistry, El Bosque University; Bogotá Colombia
| | - María R. Buenahora
- Unit of Oral Clinical Epidemiology; School of Dentistry, El Bosque University; Bogotá Colombia
| | - Sandra Amaya
- School of Dentistry, University of Valle; Cali Colombia
| | - David Díaz-Báez
- Unit of Basic Oral Investigation, School of Dentistry, El Bosque University; Bogotá Colombia
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Almangush A, Heikkinen I, Mäkitie AA, Coletta RD, Läärä E, Leivo I, Salo T. Prognostic biomarkers for oral tongue squamous cell carcinoma: a systematic review and meta-analysis. Br J Cancer 2017; 117:856-866. [PMID: 28751758 PMCID: PMC5589992 DOI: 10.1038/bjc.2017.244] [Citation(s) in RCA: 150] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2016] [Revised: 05/02/2017] [Accepted: 07/03/2017] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Identifying informative prognostic biomarkers for oral tongue squamous cell carcinoma (OTSCC) is of great importance in order to better predict tumour behaviour and to guide treatment planning. Here, we summarise existing evidence regarding immunohistochemical prognostic biomarkers for OTSCC. METHODS A systematic search of the literature was performed using the databases of Scopus, Ovid Medline, Web of Science and Cochrane Library. All studies which had investigated the prognostic significance of immunohistochemical biomarkers in OTSCC during the period from 1985 to 2015 were retrieved. For the five most often evaluated biomarkers a random-effects meta-analysis on overall survival was performed, including those studies that provided the necessary statistical results. RESULTS A total of 174 studies conducted during the last three decades were found, and in these 184 biomarkers were evaluated for the prognostication of OTSCC. The five biomarkers most frequently assessed were p53, Ki-67, p16, VEGFs and cyclin D1. In the meta-analyses, the most promising results of the prognostic power for OTSCC were obtained for cyclin D1. For studies of VEGF A and C the results were equivocal, but the pooled analysis of VEGF A separately showed it to be a useful prognosticator for OTSCC. There was no sufficient evidence to support p53, Ki-67 and p16 as prognostic biomarkers for OTSCC. Limitations in the quality of the published studies (e.g., small cohorts, lack of compliance with REMARK guidelines) are widespread. CONCLUSIONS Numerous biomarkers have been presented as useful prognosticators for OTSCC, but the quality of the conduct and reporting of original studies is overall unsatisfactory which does not allow reliable conclusions. The value of two biomarkers (VEGF-A and cyclin D1) should be validated in a multicentre study setting following REMARK guidelines.
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Affiliation(s)
- Alhadi Almangush
- Department of Pathology, University of Helsinki, Helsinki, Finland
- Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, Finland
- Institute of Dentistry, University of Misurata, Misurata, Libya
| | - Ilkka Heikkinen
- Department of Pathology, University of Helsinki, Helsinki, Finland
- Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, Finland
| | - Antti A Mäkitie
- Department of Otorhinolaryngology- Head and Neck Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Ricardo D Coletta
- Department of Oral Diagnosis, School of Dentistry, State University of Campinas, Piracicaba, São Paulo, Brazil
| | - Esa Läärä
- Department of Mathematical Sciences and Statistics, University of Oulu, Oulu, Finland
| | - Ilmo Leivo
- Department of Pathology, University of Turku, Turku, Finland
| | - Tuula Salo
- Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, Finland
- Department of Pathology, HUSLAB, Helsinki University Hospital, Helsinki, Finland
- Department of Diagnostics and Oral Medicine, Research Group of Cancer Research and Translational Medicine, Medical Faculty, University of Oulu, Oulu, Finland
- Medical Research Center, Oulu University Hospital, Oulu, Finland
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20
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Skillington SA, Kallogjeri D, Lewis JS, Piccirillo JF. Prognostic Importance of Comorbidity and the Association Between Comorbidity and p16 in Oropharyngeal Squamous Cell Carcinoma. JAMA Otolaryngol Head Neck Surg 2017; 142:568-75. [PMID: 27077485 DOI: 10.1001/jamaoto.2016.0347] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
IMPORTANCE Comorbidity affects the prognosis of patients with cancer through the direct effects of the comorbid illness and by influencing the patients' ability to tolerate treatment and mount a host response. However, the prognostic importance of comorbidity in oropharyngeal squamous cell carcinoma is not well characterized in the era of human papillomavirus infection. OBJECTIVE To determine the prognostic importance of comorbidity in both p16-positive and p16-negative oropharyngeal squamous cell carcinoma and to explore the relationship between comorbidity and p16. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study of 305 patients at a single tertiary referral center diagnosed as having oropharyngeal squamous cell carcinoma between June 1996 and June 2010, but without a history of head and neck cancer or distant metastasis at time of diagnosis. The data were analyzed from August 1, 2014, through April 30, 2015. EXPOSURES Patients were grouped according to p16 status. MAIN OUTCOMES AND MEASURES Overall survival, defined as the time from diagnosis to death from any cause. Disease-free survival, defined as the time from diagnosis to either death from any cause or the first documented local, regional, or distant recurrence. RESULTS Of the 305 patients who met eligibility criteria, 230 were p16-positive, 70 were p16-negative, and 5 were not evaluable for p16 status. The final cohort of 300 patients had a mean (SD) age of 56.3 (9.3) years and 262 (87%) were male. In Kaplan-Meier analysis, the 5-year overall survival rates were 71% (95% CI, 65%-76%) for 232 patients with no comorbidity to mild comorbidity and 49% (95% CI, 36%-61%) for 63 patients with moderate to severe comorbidity. In multivariate Cox proportional hazards analysis, moderate to severe comorbidity was associated with an increased risk of death from any cause (adjusted hazards ratio [aHR], 1.52 [95% CI, 0.99-2.32]) and increased risk of death or recurrence (aHR, 1.71 [95% CI, 1.13-2.59]). After stratifying by p16 status and controlling for other variables, moderate to severe comorbidity was significantly associated with increased risk of death from any cause among p16-negative patients (aHR, 1.90 [95% CI, 1.03-3.50]) but not among p16-positive patients (aHR, 1.11 [95% CI, 0.61-2.02]). CONCLUSIONS AND RELEVANCE Comorbidity is important to consider when assessing the prognosis of patients with oropharyngeal squamous cell carcinoma and is of greater prognostic value in p16-negative than p16-positive cancer.
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Affiliation(s)
- S Andrew Skillington
- Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine in St Louis, St Louis, Missouri
| | - Dorina Kallogjeri
- Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine in St Louis, St Louis, Missouri
| | - James S Lewis
- Department of Pathology and Immunology, Washington University School of Medicine in St Louis, St Louis, Missouri3Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Jay F Piccirillo
- Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine in St Louis, St Louis, Missouri4Editor, JAMA Otolaryngology-Head & Neck Surgery
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21
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Skillington SA, Kallogjeri D, Lewis JS, Piccirillo JF. The Role of Adjuvant Chemotherapy in Surgically Managed, p16-Positive Oropharyngeal Squamous Cell Carcinoma. JAMA Otolaryngol Head Neck Surg 2017; 143:253-259. [PMID: 27918781 DOI: 10.1001/jamaoto.2016.3353] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Importance Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) has a favorable prognosis, and p16 immunohistochemistry is a surrogate marker of high-risk HPV infection and strong prognosticator. Given this favorable prognosis, treatment de-escalation for p16-positive OPSCC is now being considered with the goal of decreasing treatment-associated morbidity without compromising tumor control. The role of adjuvant chemotherapy in this setting is becoming increasingly unclear. Objective To compare survival between surgically managed patients with p16-positive OPSCC who received adjuvant chemoradiotherapy and patients who received adjuvant radiotherapy alone. Design, Setting, and Participants This was a cohort study of patients with OPSCC diagnosed from June 1996 to June 2010, with follow-up through December 2014, at a single tertiary referral center. One hundred ninety-five surgically managed, p16-positive patients without a history of head and neck cancer or distant metastasis at time of diagnosis were included. Exposures Patients were dichotomized into adjuvant radiotherapy and adjuvant chemoradiotherapy groups. Main Outcomes and Measures Overall survival was the primary outcome, and disease-free survival was the secondary outcome. Propensity-weighted multivariate Cox proportional hazards analysis was conducted to quantify the effect of adjuvant chemotherapy on survival. Results The study included 195 patients with p16-positive, surgically managed OPSCC. Median duration of follow-up was 87 months (interquartile range, 68-116 months). Ninety patients received adjunct chemoradiotherapy (mean age, 54.3 years), 88 patients received adjuvant radiotherapy (mean age, 56.4 years), and 17 patients received surgery alone. The 5-year overall survival rate for patients who received adjuvant chemoradiotherapy was 82% (95% CI, 73%-90%) and 84% (95% CI, 76%-91%) for patients who received adjuvant radiotherapy alone. The 5-year disease-free survival rate for patients who received adjuvant chemoradiotherapy was 79% (95% CI, 71%-88%) and 79% (95% CI, 70%-88%) for patients who received radiotherapy alone. After weighting cases by the inverse probability of receiving adjuvant chemotherapy and controlling for age, comorbidity, smoking, pathological T stage, and pathological N stage, the receipt of adjuvant chemotherapy was not significantly associated with disease-free survival (adjusted hazard ratio, 0.91; 95% CI, 0.59-1.42) but was associated with a statistically insignificant yet clinically meaningful increase in all-cause mortality (adjusted hazard ratio, 1.46; 95% CI, 0.91-2.33). Conclusions and Relevance Among patients with p16-positive OPSCC managed surgically with adjuvant radiotherapy, the addition of adjuvant chemotherapy provided no additional disease-free survival benefit and was associated with worse overall survival. These results should help inform future clinical trials aiming to deescalate treatment for p16-positive patients.
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Affiliation(s)
- S Andrew Skillington
- Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine in St Louis, St Louis, Missouri
| | - Dorina Kallogjeri
- Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine in St Louis, St Louis, Missouri
| | - James S Lewis
- Department of Pathology and Immunology, Washington University School of Medicine in St Louis, St Louis, Missouri3Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Jay F Piccirillo
- Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine in St Louis, St Louis, Missouri4Editor, JAMA Otolaryngology-Head & Neck Surgery, Chicago, Illinois
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22
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Application of p16 Immunohistochemistry and RNA In Situ Hybridization in the Classification of Adenoid Basal Tumors of the Cervix. Int J Gynecol Pathol 2017; 35:82-91. [PMID: 26352551 DOI: 10.1097/pgp.0000000000000221] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Our understanding of adenoid basal tumors of the cervix has evolved over time. Most of the proliferations referred to as adenoid basal carcinoma have a clinically benign course--leading some to suggest the term "adenoid basal epithelioma." However, rarely, these may be associated with invasive carcinomas. These tumors have been etiologically linked with high-risk human papillomavirus (HR-HPV) infection. Here, we investigate the use of p16 immunohistochemistry and HR-HPV RNA in situ hybridization (ISH) in the classification of adenoid basal tumors of the cervix. Seventeen cases of adenoid basal tumors of the cervix were included. The patients' age ranged from 19 to 79 yr (average, 59 yr). p16 immunostain was performed on all cases and RNA ISH was performed in 4 cases with available formalin-fixed paraffin-embedded tissue. There were 11 low-grade tumors, 5 frankly invasive carcinomas, and 1 with histologic features that were intermediate between the former 2 categories. p16 immunostain was negative or showed patchy cytoplasmic staining in the low-grade tumors and was strongly and diffusely positive in the invasive carcinomas. HR-HPV RNA ISH was negative in the 3 low-grade tumors and was positive in 1 case of invasive carcinoma including the adenoid basal component. Distinct p16 immunostaining and HR-HPV RNA ISH patterns exist between low-grade adenoid basal tumors and invasive adenoid basal carcinomas. Our study indicates that p16 immunostaining and HR-HPV RNA ISH can be employed as useful ancillary tools in differentiating between noninvasive and invasive adenoid basal tumors along with careful histopathologic evaluation.
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23
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Pastrez PRA, Mariano VS, da Costa AM, Silva EM, Scapulatempo-Neto C, Guimarães DP, Fava G, Neto SAZ, Nunes EM, Sichero L, Villa LL, Syrjanen KJ, Longatto-Filho A. The Relation of HPV Infection and Expression of p53 and p16 Proteins in Esophageal Squamous Cells Carcinoma. J Cancer 2017; 8:1062-1070. [PMID: 28529620 PMCID: PMC5436260 DOI: 10.7150/jca.17080] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 12/23/2016] [Indexed: 12/13/2022] Open
Abstract
GOAL: To investigate the HPV prevalence and characterize the expression of potential molecular surrogate markers of HPV infection in esophageal squamous cell carcinoma. MATERIALS AND METHODS: The prevalence of HPV in individuals with and without esophageal cancer (EC) was determined by using multiplex PCR; p16 and p53 protein levels were assessed by immunohistochemistry (IHC). RESULTS: High-risk HPV (hr-HPV) was found in the same frequency (13.8%) in esophageal squamous cell carcinoma (ESCC) and in healthy individuals. The p53 expression was positive in 67.5% of tumor tissue, 20.0% of adjacent non-tumoral tissue and 1.8% of normal esophageal tissue. p16 was positive in 11.6% of esophageal cancer cases and 4.7% of adjacent non-tumoral tissue. p16 was undetectable among control group samples. p53 and p16 levels were not significantly associated with the HPV status. CONCLUSIONS: These results suggest that hr-HPV types are not associated with the development of ESCC and that p53 and p16 protein expression have no relationship with HPV infection in normal or cancerous esophagus.
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Affiliation(s)
- Paula Roberta Aguiar Pastrez
- Teaching and Research Institute, Molecular Oncology Research Center, Barretos Cancer Hospital - Pio XII Foundation, Brazil
| | - Vânia Sammartino Mariano
- Teaching and Research Institute, Molecular Oncology Research Center, Barretos Cancer Hospital - Pio XII Foundation, Brazil
| | - Allini Mafra da Costa
- Teaching and Research Institute, Molecular Oncology Research Center, Barretos Cancer Hospital - Pio XII Foundation, Brazil
| | - Estela Maria Silva
- Teaching and Research Institute, Molecular Oncology Research Center, Barretos Cancer Hospital - Pio XII Foundation, Brazil
| | - Cristovam Scapulatempo-Neto
- Teaching and Research Institute, Molecular Oncology Research Center, Barretos Cancer Hospital - Pio XII Foundation, Brazil
| | - Denise Peixoto Guimarães
- Teaching and Research Institute, Molecular Oncology Research Center, Barretos Cancer Hospital - Pio XII Foundation, Brazil.,Department of Endoscopy, Barretos Cancer Hospital - Pio XII Foundation, Brazil
| | - Gilberto Fava
- Department of Endoscopy, Barretos Cancer Hospital - Pio XII Foundation, Brazil
| | | | - Emily Montosa Nunes
- Molecular Biology Laboratory, Center for Translational Research in Oncology, Instituto do Câncer do Estado de São Paulo - ICESP, São Paulo, Brazil
| | - Laura Sichero
- Molecular Biology Laboratory, Center for Translational Research in Oncology, Instituto do Câncer do Estado de São Paulo - ICESP, São Paulo, Brazil
| | - Luisa Lina Villa
- Molecular Biology Laboratory, Center for Translational Research in Oncology, Instituto do Câncer do Estado de São Paulo - ICESP, São Paulo, Brazil.,Department of Radiology and Oncology, School of Medicine, University of São Paulo, Brazil
| | - Kari Juhani Syrjanen
- Teaching and Research Institute, Molecular Oncology Research Center, Barretos Cancer Hospital - Pio XII Foundation, Brazil.,Department of Clinical Research - Biohit Oyj, Finland
| | - Adhemar Longatto-Filho
- Teaching and Research Institute, Molecular Oncology Research Center, Barretos Cancer Hospital - Pio XII Foundation, Brazil.,Medical Laboratory of Medical Investigation (LIM) 14.Department of Pathology, Faculty of Medicine, University of São Paulo, Brazil.,Research Institute of Life and Health Sciences (ICVS), University of Minho, Braga, Portugal.,ICVS / 3B's - Associated Laboratory to the Government of Portugal, Braga / Guimarães, Portugal
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24
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Herfs M, Longuespée R, Quick CM, Roncarati P, Suarez-Carmona M, Hubert P, Lebeau A, Bruyere D, Mazzucchelli G, Smargiasso N, Baiwir D, Lai K, Dunn A, Obregon F, Yang EJ, Pauw ED, Crum CP, Delvenne P. Proteomic signatures reveal a dualistic and clinically relevant classification of anal canal carcinoma. J Pathol 2017; 241:522-533. [DOI: 10.1002/path.4858] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Revised: 11/21/2016] [Accepted: 11/30/2016] [Indexed: 12/11/2022]
Affiliation(s)
- Michael Herfs
- Laboratory of Experimental Pathology, GIGA-Cancer; University of Liège; Liège Belgium
| | - Rémi Longuespée
- Mass Spectrometry Laboratory, Systems Biology and Chemical Biology, GIGA-Research; University of Liège; Liège Belgium
| | - Charles M Quick
- Department of Pathology; University of Arkansas for Medical Sciences; Little Rock AR USA
| | - Patrick Roncarati
- Laboratory of Experimental Pathology, GIGA-Cancer; University of Liège; Liège Belgium
| | - Meggy Suarez-Carmona
- Laboratory of Experimental Pathology, GIGA-Cancer; University of Liège; Liège Belgium
| | - Pascale Hubert
- Laboratory of Experimental Pathology, GIGA-Cancer; University of Liège; Liège Belgium
| | - Alizée Lebeau
- Laboratory of Experimental Pathology, GIGA-Cancer; University of Liège; Liège Belgium
| | - Diane Bruyere
- Laboratory of Experimental Pathology, GIGA-Cancer; University of Liège; Liège Belgium
| | - Gabriel Mazzucchelli
- Mass Spectrometry Laboratory, Systems Biology and Chemical Biology, GIGA-Research; University of Liège; Liège Belgium
| | - Nicolas Smargiasso
- Mass Spectrometry Laboratory, Systems Biology and Chemical Biology, GIGA-Research; University of Liège; Liège Belgium
| | - Dominique Baiwir
- Mass Spectrometry Laboratory, Systems Biology and Chemical Biology, GIGA-Research; University of Liège; Liège Belgium
- GIGA Proteomic Facility; University of Liège; Liège Belgium
| | - Keith Lai
- Department of Pathology; University of Arkansas for Medical Sciences; Little Rock AR USA
| | - Andrew Dunn
- Department of Pathology; University of Arkansas for Medical Sciences; Little Rock AR USA
| | - Fabiola Obregon
- Department of Pathology; University of Arkansas for Medical Sciences; Little Rock AR USA
| | - Eric J Yang
- Department of Pathology, Division of Women's and Perinatal Pathology, Brigham and Women's Hospital; Harvard Medical School; Boston MA USA
| | - Edwin De Pauw
- Mass Spectrometry Laboratory, Systems Biology and Chemical Biology, GIGA-Research; University of Liège; Liège Belgium
| | - Christopher P Crum
- Department of Pathology, Division of Women's and Perinatal Pathology, Brigham and Women's Hospital; Harvard Medical School; Boston MA USA
| | - Philippe Delvenne
- Laboratory of Experimental Pathology, GIGA-Cancer; University of Liège; Liège Belgium
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25
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Khanal S, Trainor PJ, Zahin M, Ghim SJ, Joh J, Rai SN, Jenson AB, Shumway BS. Histologic variation in high grade oral epithelial dysplasia when associated with high-risk human papillomavirus. Oral Surg Oral Med Oral Pathol Oral Radiol 2017; 123:566-585. [PMID: 28407985 DOI: 10.1016/j.oooo.2017.01.008] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Revised: 01/05/2017] [Accepted: 01/10/2017] [Indexed: 01/05/2023]
Abstract
OBJECTIVES Reported cytologic alterations associated with high-risk human papillomavirus (HR-HPV) in oral epithelial dysplasia (HPV-OED) need further characterization. STUDY DESIGN Archival cases of high-grade oral epithelial dysplasia (hgOED) (N = 38) were assigned a cytologic score (CS) based on the average number of mitotic, karyorrhectic, and apoptotic cells per high-power field. Three groups were then generated on the basis of increasing CS: Focal (group 1, N = 14), Intermediate (group 2, N = 12), and Diffuse (group 3, N = 12). Polymerase chain reaction-based HPV genotyping and p16 immunohistochemistry were performed. RESULTS HR-HPV was found significantly more in group 3 (83.3%) compared with groups 1 and 2 (group 1&2; 42.9% and 41.7%, respectively; P = .047). HPV16 predominated in HR-HPV-positive cases (90.5%). By location, the tongue or the floor of mouth was associated with all groups (P = .04). Increasing CS was associated with a slightly younger age (P = .04) and increased expression of p16 (P = .005). CS and p16 expression were not sensitive but were highly specific predictors for HR-HPV presence. Based on limited follow-up information, HPV-OED does not differ in clinical aggressiveness compared with conventional OED. CONCLUSIONS Increased CS in hgOED is strongly associated with HR-HPV (mostly HPV16) and p16 expression. CS and p16 expression are specific predictors of HR-HPV presence. Further molecular study and long-term follow-up of HPV-OED are needed.
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Affiliation(s)
- Sujita Khanal
- James Graham Brown Cancer Center, Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY, USA
| | - Patrick J Trainor
- Research Associate, Biostatistics Shared Facility, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Maryam Zahin
- Postdoctoral Associate, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Shin-Je Ghim
- Assistant Professor, Department of Medicine, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Joongho Joh
- Assistant Professor, Department of Medicine, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Shesh N Rai
- Professor, Wendell Cherry Chair in Clinical Trial Research; Director, Biostatistics Shared Facility, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Alfred Bennett Jenson
- Senior scientist, Professor of Vaccinology, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Brian S Shumway
- Associate Professor, Oral and Maxillofacial Pathology, Department of Surgical and Hospital Dentistry, University of Louisville School of Dentistry, Louisville, KY, USA.
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26
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Smitha T, Mohan CV, Hemavathy S. Prevalence of human papillomavirus16 DNA and p16 INK4a protein in oral squamous cell carcinoma: A systematic review and meta-analysis. J Oral Maxillofac Pathol 2017; 21:76-81. [PMID: 28479691 PMCID: PMC5406823 DOI: 10.4103/jomfp.jomfp_248_16] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Accepted: 01/11/2017] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND AND AIM Indian patients with oral squamous cell carcinoma (OSCC) are etiologically associated with the use of tobacco and alcohol; yet, a proportion of tumors that may harbor human papillomavirus (HPV) infections cannot be neglected. The following meta-analysis was conducted to address the association of p16INK4a and HPV DNA with OSCC. In addition, the study also provides the updated prevalence of HPV-induced OSCC. MATERIALS AND METHODS Literature survey was performed using databases such as PubMed with the help of the following keywords - "HPV infection," "oral squamous cell carcinoma," "p16INK4a," "HPV DNA," "E6," "E7," "L1," "L2" and "LCR." Proportion method was performed to derive the forest plot using MedCalc statistical software version 16.4.3. RESULTS Among 145 research articles, 33 articles were selected for further analysis, in which 13 articles were related to HPV DNA detection in tissues, 11 articles detected the overexpression of p16INK4a and nine articles reported the detection of both HPV DNA and p16INK4a expression. Meta-analysis revealed significant heterogeneity (P < 0.0001) among the articles. Overall, the study consisted of 3339 patients with OSCC, among which 559 patients were diagnosed with the presence of HPV16 DNA with a random proportion of 20.1% at 95% confidence interval (CI) (13.9-27.1, P < 0.0001). Overexpression of p16INK4a protein was observed in 709 patients with a random proportion of 25.4% at 95% CI (14.3-38.3, P < 0.0001). CONCLUSION HPV DNA and expression of p16INK4a was suggested as gold standard for the detection of HPV infection in many cases of cancers. Frequency of HPV infection is significantly higher in patients with OSCC as identified through the detection of HPV DNA and p16INK4a expression. Even though the association of HPV infection has been established in head and neck cancer, this review could further the establishment of molecular level interaction of HPV in patients with oral cancer.
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Affiliation(s)
- T Smitha
- Department of Oral Pathology, VS Dental College and Hospital, Bengaluru, Karnataka, India
| | - C V Mohan
- Dental Care and Research Centre, Bengaluru, Karnataka, India
| | - S Hemavathy
- Department of Oral Pathology, Sri Rajiv Gandhi College of Dental Science, Bengaluru, Karnataka, India
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27
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Larsen CG, Jensen DH, Carlander ALF, Kiss K, Andersen L, Olsen CH, Andersen E, Garnæs E, Cilius F, Specht L, von Buchwald C. Novel nomograms for survival and progression in HPV+ and HPV- oropharyngeal cancer: a population-based study of 1,542 consecutive patients. Oncotarget 2016; 7:71761-71772. [PMID: 27708214 PMCID: PMC5342120 DOI: 10.18632/oncotarget.12335] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Accepted: 09/12/2016] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND No study has combined tumour and clinical covariates for survival to construct an individual risk-profile for overall survival (OS), time to progression (TTP), and survival after progression (SAP) in patients with HPV+ and HPV- oropharyngeal squamous cell carcinoma (OPSCC). Based on the largest-to-date, unselected, population-based cohort of patients diagnosed with OPSCC, we performed a comprehensive analysis of long-term OS, TTP, and SAP and constructed novel nomograms to evaluate patients' prognoses. RESULTS At a median follow-up of 4.0 years (range: 0.8-15.8 yrs.), 690 deaths were recorded. The 5-year OS, TTP, and SAP for the HPV+/p16+ subgroup were 77%, 82%, and 33, vs. 30%, 66%, and 6% for the HPV-/p16- group (P < 0.01). 376 patients failed to maintain disease control with a median TTP of 13 months in the HPV+/p16+ subgroup vs. 8.5 months in the HPV-/p16- subgroup (P < 0.05). HPV combined with p16 status remained one of the most informative covariates in the final Cox regression model for OS, TTP, and SAP. METHODS We included all patients diagnosed with OPSCC (n = 1,542) between 2000-2014 in Eastern Denmark. Survival rates were estimated by the Kaplan-Meier method. A multivariate Cox regression model was used to construct predictive, internally validated nomograms. CONCLUSION The HPV+/p16+ subgroup had improved OS, TTP, and SAP compared with other combinations of HPV and p16 after adjusting for covariates. Nomograms were constructed for 1-, 5- and 10-year survival probability. Models may aid patients and clinicians in their clinical decision making as well as in counselling, research, and trial design.
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Affiliation(s)
- Christian Grønhøj Larsen
- Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - David H. Jensen
- Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Amanda-Louise Fenger Carlander
- Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Katalin Kiss
- Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Luise Andersen
- Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | | | - Elo Andersen
- Department of Oncology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Emilie Garnæs
- Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Finn Cilius
- Centre for Genomic Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Lena Specht
- Department of Oncology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Christian von Buchwald
- Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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p53 expression but not p16(INK4A) correlates with human papillomavirus-associated esophageal squamous cell carcinoma in Kazakh population. Infect Agent Cancer 2016; 11:19. [PMID: 27076841 PMCID: PMC4830030 DOI: 10.1186/s13027-016-0065-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Accepted: 03/15/2016] [Indexed: 12/20/2022] Open
Abstract
Background p16INK4A expression has been used as a surrogate marker for human papillomavirus (HPV) infection in cervical cancer and head and neck cancer. p53 has also been reported as a feasible marker to identify HPV-positive oropharyngeal carcinoma and penile lesions. This study aimed to investigate p16INK4A and p53 expression levels and their correlation with HPV status and clinical parameters in Kazakh patients with esophageal squamous cell carcinoma. Methods Immunohistochemical expression of p16INK4A and p53 were evaluated in 163 cases of esophageal squamous cell carcinoma in Kazakh patients. The presence of HPV DNA was detected by polymerase chain reaction. Results p16INK4A-positive expression was detected in 19.0 % of patients, and its expression was significantly correlated with a lower frequency of lymph node metastasis (p = 0.038). By contrast no significant association was found between p16INK4A-positive expression and HPV status (correlation coefficient = -0.062, p = 0.499). p16INK4A-positive expression did not affect the odds of tumors being HPV positive (odds ratio [OR] = 0.727 with 95 % confidence interval [CI] = 0.288–1.836). The sensitivity of p16INK4A-positive expression as an HPV marker was 0.164, with a specificity of 0.788 and a positive predictive value of 0.391. p53-positive expression was present in 88.3 % of all cases. Although no significant correlation with available clinical parameters was found, a significantly inverse correlation was observed between p53 expression and HPV status (correlation coefficient = -0.186, p = 0.039). Moreover, p53-positive expression decreased the odds of tumors being HPV positive (OR = 0.292 with 95 % CI = 0.086–0.990). The sensitivity of p53-negative expression as an HPV marker was 0.179, with a specificity of 0.940 and a positive predictive value of 0.714. The overall HPV prevalence was high (45.5 %) in Kazakh patients, with no significant association between HPV positivity and available clinical parameters or combined p16INK4A/p53 expression. Conclusions p16INK4A-positive expression was associated with lymph node metastasis. Results indicate that p53-negative expression and not p16INK4A-positive expression may be used as a marker for HPV status in ESCC; however, this finding requires further studies for validation.
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p16 cutoff in head and neck squamous cell carcinoma: correlation between tumor and patient characteristics and outcome. Int J Biol Markers 2016; 31:e44-52. [PMID: 26481441 DOI: 10.5301/jbm.5000175] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/17/2015] [Indexed: 11/20/2022]
Abstract
BACKGROUND p16 has been indicated as a suitable surrogate biomarker of HPV infection. The prognosis of p16-positive oropharynx tumors (OTs) of squamous cell carcinoma (SCC) histology is better than that of p16-negative tumors. METHODS We analyzed 209 samples of head and neck SCC to establish a predictive cutoff for p16 and determine the role of p16 positivity in OTs versus non-OTs. We compared the outcomes of tumors harboring any percentage of p16-positive cells (≥1%) with those of p16-negative OTs. We then considered 3 cutoffs (10%, 50% and 70% positive cells) to evaluate the outcome of OTs/non-OTs with similar p16 expression and p16-positive versus p16-negative tumors stratified by patient age. RESULTS p16-negative tumors among OTs and non-OTs were 29% and 49%, respectively (p = 0.0054). The cumulative distribution showed that the positive values were located around 2 focus points: 2% and 96%. Subgroup analysis showed that only OTs occurred in young patients (aged <65 years) and that there was a ≥70% gain in survival in cases with p16-positive cells. CONCLUSIONS p16 positivity influences outcome only in young patients and OTs (p = 0.048).
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McDowell LJ, Young RJ, Johnston ML, Tan TJ, Kleid S, Liu CS, Bressel M, Estall V, Rischin D, Solomon B, Corry J. p16-positive lymph node metastases from cutaneous head and neck squamous cell carcinoma: No association with high-risk human papillomavirus or prognosis and implications for the workup of the unknown primary. Cancer 2016; 122:1201-8. [PMID: 26881928 DOI: 10.1002/cncr.29901] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Revised: 12/18/2015] [Accepted: 12/28/2015] [Indexed: 12/19/2022]
Abstract
BACKGROUND The incidence of p16 overexpression and the role of human papillomavirus (HPV) in cutaneous head and neck squamous cell carcinoma (cHNSCC) are unclear. METHODS One hundred forty-three patients with cHNSCC lymph node metastases involving the parotid gland were evaluated for p16 expression by immunohistochemistry. The detection of 18 high-risk HPV subtypes was performed with HPV RNA in situ hybridization for a subset of 59 patients. The results were correlated with clinicopathological features and outcomes. RESULTS The median follow-up time was 5.3 years. No differences were observed in clinicopathological factors with respect to the p16 status. p16 was positive, weak, and negative in 45 (31%), 21 (15%), and 77 cases (54%), respectively. No high-risk HPV subtypes were identified, regardless of the p16 status. The p16 status was not prognostic for overall (hazard ratio, 1.08; 95% confidence interval [CI], 0.85-1.36; P = .528), cancer-specific (hazard ratio, 1.12; 95% CI, 0.77-1.64; P = .542), or progression-free survival (hazard ratio, 1.03; 95% CI, 0.83-1.29; P = .783). Distant metastasis-free survival, freedom from locoregional failure, and freedom from local failure were also not significantly associated with the p16 status. CONCLUSIONS p16 positivity is common but not prognostic in cHNSCC lymph node metastases. High-risk HPV subtypes are not associated with p16 positivity and do not appear to play a role in this disease. HPV testing, in addition to the p16 status in the unknown primary setting, may provide additional information for determining a putative primary site.
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Affiliation(s)
- Lachlan J McDowell
- Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Richard J Young
- Research Division, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Meredith L Johnston
- Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Tze-Jian Tan
- Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Stephen Kleid
- Division of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Chen S Liu
- Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Mathias Bressel
- Centre for Biostatistics and Clinical Trials, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Vanessa Estall
- Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Australia.,University of Melbourne, Parkville, Australia
| | - Danny Rischin
- University of Melbourne, Parkville, Australia.,Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Benjamin Solomon
- Research Division, Peter MacCallum Cancer Centre, Melbourne, Australia.,University of Melbourne, Parkville, Australia.,Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - June Corry
- Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Australia.,University of Melbourne, Parkville, Australia
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Sannigrahi MK, Singh V, Sharma R, Panda NK, Radotra BD, Khullar M. Detection of active human papilloma virus-16 in head and neck cancers of Asian North Indian patients. Oral Dis 2015; 22:62-8. [DOI: 10.1111/odi.12382] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2015] [Revised: 10/01/2015] [Accepted: 10/06/2015] [Indexed: 12/17/2022]
Affiliation(s)
- MK Sannigrahi
- Department of Otolaryngology; Post Graduate Institute of Medical Education and Research (PGIMER); Chandigarh India
| | - V Singh
- Department of Otolaryngology; Post Graduate Institute of Medical Education and Research (PGIMER); Chandigarh India
| | - R Sharma
- Department of Experimental Medicine and Biotechnology; PGIMER; Chandigarh India
| | - NK Panda
- Department of Otolaryngology; Post Graduate Institute of Medical Education and Research (PGIMER); Chandigarh India
| | - BD Radotra
- Department of Histopathology; PGIMER; Chandigarh India
| | - M Khullar
- Department of Experimental Medicine and Biotechnology; PGIMER; Chandigarh India
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Shapiro KA, McGuone D, Deshpande V, Sadow PM, Stemmer-Rachamimov A, Staley KJ. Failure to detect human papillomavirus in focal cortical dysplasia type IIb. Ann Neurol 2015; 78:63-7. [DOI: 10.1002/ana.24422] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Revised: 04/07/2015] [Accepted: 04/09/2015] [Indexed: 12/21/2022]
Affiliation(s)
- Kevin A. Shapiro
- Department of Neurology; University of California; San Francisco San Francisco CA
| | | | | | | | | | - Kevin J. Staley
- Neurology; Massachusetts General Hospital and Harvard Medical School; Boston MA
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Wang H, Zhang Z, Sun R, Lin H, Gong L, Fang M, Hu WH. HPV Infection and Anemia Status Stratify the Survival of Early T2 Laryngeal Squamous Cell Carcinoma. J Voice 2015; 29:356-62. [DOI: 10.1016/j.jvoice.2014.08.016] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Accepted: 08/25/2014] [Indexed: 12/21/2022]
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Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial. Lancet Oncol 2015; 16:583-94. [PMID: 25892145 DOI: 10.1016/s1470-2045(15)70124-5] [Citation(s) in RCA: 288] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (HNSCC) progressing after first-line platinum regimens have a poor prognosis and few treatment options. Afatinib, an irreversible ERBB family blocker, has shown efficacy in a phase 2 study in this setting. We aimed to assess the efficacy and safety of afatinib compared with methotrexate as second-line treatment in patients with recurrent or metastatic HNSCC progressing on or after platinum-based therapy. METHODS In this open-label, phase 3, randomised controlled trial conducted in 101 centres in 19 countries, we enrolled patients aged 18 years or older with histologically or cytologically confirmed HNSCC that was recurrent, metastatic, or both who had progressed on or after first-line platinum-based therapy, were not amenable for salvage surgery or radiotherapy, and who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Previous treatment with more than one systemic regimen in this setting was not allowed; previous treatment with EGFR-targeted antibody therapy (but not EGFR-targeted tyrosine-kinase inhibitors) was allowed. We randomly assigned eligible patients in a 2:1 ratio to receive oral afatinib (40 mg/day) or intravenous methotrexate (40 mg/m(2) per week), stratified by ECOG performance status and previous EGFR-targeted antibody therapy for recurrent or metastatic disease. Randomisation was done centrally with an interactive voice or web-based response system. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. The primary endpoint was progression-free survival as assessed by an independent, central imaging review committee. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01345682. FINDINGS Between Jan 10, 2012, and Dec 12, 2013, we enrolled 483 patients and randomly assigned 322 to afatinib and 161 to methotrexate. After a median follow-up of 6·7 months (IQR 3·1-9·0), progression-free survival was longer in the afatinib group than in the methotrexate group (median 2·6 months [95% CI 2·0-2·7] for the afatinib group vs 1·7 months [1·5-2·4] for the methotrexate group; hazard ratio [HR] 0·80 [95% CI 0·65-0·98], p=0·030). The most frequent grade 3 or 4 drug-related adverse events were rash or acne (31 [10%] of 320 patients in the afatinib group vs none of 160 patients in the methotrexate group), diarrhoea (30 [9%] vs three [2%]), stomatitis (20 [6%] vs 13 [8%]), fatigue (18 [6%] vs five [3%]), and neutropenia (1 [<1%] vs 11 [7%]); serious adverse events occurred in 44 (14%) of afatinib-treated patients and 18 (11%) of methotrexate-treated patients. INTERPRETATION Afatinib was associated with significant improvements in progression-free survival and had a manageable safety profile. These findings provide important new insights into the treatment of this patient population and support further investigations with irreversible ERBB family blockers in HNSCC. FUNDING Boehringer Ingelheim.
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Young RJ, Urban D, Angel C, Corry J, Lyons B, Vallance N, Kleid S, Iseli TA, Solomon B, Rischin D. Frequency and prognostic significance of p16(INK4A) protein overexpression and transcriptionally active human papillomavirus infection in laryngeal squamous cell carcinoma. Br J Cancer 2015; 112:1098-104. [PMID: 25688737 PMCID: PMC4366899 DOI: 10.1038/bjc.2015.59] [Citation(s) in RCA: 76] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2014] [Revised: 11/18/2014] [Accepted: 01/19/2015] [Indexed: 12/30/2022] Open
Abstract
Background: Human papillomavirus (HPV) infection is a powerful prognostic biomarker in a subset of head and neck squamous cell carcinomas, specifically oropharyngeal cancers. However, the role of HPV in non-oropharyngeal sites, such as the larynx, remains unconfirmed. Methods: We evaluated a cohort of 324 laryngeal squamous cell carcinoma (LSCC) patients for the expression of p16INK4A (p16) protein by immunohistochemistry (IHC) and for high-risk HPV E6 and E7 mRNA transcripts by RNA in situ hybridisation (ISH). p16 expression and HPV status were correlated with clinicopathological features and outcomes. Results: Of 307 patients assessable for p16 IHC, 20 (6.5%) were p16 positive. Females and node-positive patients were more likely to be p16 positive (P<0.05). There were no other significant clinical or demographic differences between p16-positive and -negative cases. There was no difference in overall survival (OS) between p16-positive and -negative patients with 2-year survival of 79% in each group (HR=0.83, 95% CI 0.36–1.89, P=0.65). There was no statistically significant difference in failure-free survival (FFS) with 2-year FFS of 79% and 66% for p16-positive and -negative patients, respectively (HR=0.60, 95% CI 0.26–1.36, P=0.22). Only seven cases were found to be HPV RNA ISH positive, all of which were p16 IHC positive. There was no statistically significant difference in OS between patients with HPV RNA ISH-positive tumours compared with -negative tumours with 2-year survival of 86% and 71%, respectively (HR=0.76, 95% CI 0.23–2.5, P=0.65). The 2-year FFS was 86% and 59%, respectively (HR=0.62, 95% CI 0.19–2.03, P=0.43). Conclusions: p16 overexpression is infrequent in LSCC and the proportion of cases with high-risk HPV transcripts is even lower. There are no statistically significant correlations between p16 IHC or HPV RNA ISH status and OS or disease outcomes.
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Affiliation(s)
- R J Young
- 1] Research Division, Peter MacCallum Cancer Centre, Melbourne, Australia [2] Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
| | - D Urban
- 1] Research Division, Peter MacCallum Cancer Centre, Melbourne, Australia [2] Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - C Angel
- 1] Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia [2] Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - J Corry
- Department of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - B Lyons
- Department of Surgery, St Vincent's Hospital, Melbourne, Australia
| | - N Vallance
- Department of Otorhinolaryngology, Monash Medical Centre, Melbourne, Australia
| | - S Kleid
- Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - T A Iseli
- Department of Surgery, Melbourne University, Royal Melbourne Hospital, Melbourne, Australia
| | - B Solomon
- 1] Research Division, Peter MacCallum Cancer Centre, Melbourne, Australia [2] Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia [3] Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - D Rischin
- 1] Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia [2] Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia
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Murao K, Yoshioka R, Kubo Y. Human papillomavirus infection in Bowen disease: Negative p53 expression, not p16INK4aoverexpression, is correlated with human papillomavirus-associated Bowen disease. J Dermatol 2014; 41:878-84. [DOI: 10.1111/1346-8138.12613] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Accepted: 07/31/2014] [Indexed: 01/10/2023]
Affiliation(s)
- Kazutoshi Murao
- Department of Dermatology; Institute of Health Biosciences; University of Tokushima Graduate School; Tokushima Japan
| | - Rika Yoshioka
- Department of Dermatology; Institute of Health Biosciences; University of Tokushima Graduate School; Tokushima Japan
| | - Yoshiaki Kubo
- Department of Dermatology; Institute of Health Biosciences; University of Tokushima Graduate School; Tokushima Japan
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Woods RSR, O’Regan EM, Kennedy S, Martin C, O’Leary JJ, Timon C. Role of human papillomavirus in oropharyngeal squamous cell carcinoma: A review. World J Clin Cases 2014; 2:172-193. [PMID: 24945004 PMCID: PMC4061306 DOI: 10.12998/wjcc.v2.i6.172] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2014] [Revised: 04/21/2014] [Accepted: 05/19/2014] [Indexed: 02/05/2023] Open
Abstract
Human papillomavirus (HPV) has been implicated in the pathogenesis of a subset of oropharyngeal squamous cell carcinoma. As a result, traditional paradigms in relation to the management of head and neck squamous cell carcinoma have been changing. Research into HPV-related oropharyngeal squamous cell carcinoma is rapidly expanding, however many molecular pathological and clinical aspects of the role of HPV remain uncertain and are the subject of ongoing investigation. A detailed search of the literature pertaining to HPV-related oropharyngeal squamous cell carcinoma was performed and information on the topic was gathered. In this article, we present an extensive review of the current literature on the role of HPV in oropharyngeal squamous cell carcinoma, particularly in relation to epidemiology, risk factors, carcinogenesis, biomarkers and clinical implications. HPV has been established as a causative agent in oropharyngeal squamous cell carcinoma and biologically active HPV can act as a prognosticator with better overall survival than HPV-negative tumours. A distinct group of younger patients with limited tobacco and alcohol exposure have emerged as characteristic of this HPV-related subset of squamous cell carcinoma of the head and neck. However, the exact molecular mechanisms of carcinogenesis are not completely understood and further studies are needed to assist development of optimal prevention and treatment modalities.
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Wang H, Sun R, Lin H, Hu WH. P16INK4A as a surrogate biomarker for human papillomavirus-associated oropharyngeal carcinoma: consideration of some aspects. Cancer Sci 2013; 104:1553-9. [PMID: 24344719 DOI: 10.1111/cas.12287] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2013] [Revised: 09/03/2013] [Accepted: 09/11/2013] [Indexed: 12/21/2022] Open
Abstract
Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinomas (OPSCCs) frequently show different clinical and pathological features, which tend to be younger age, better performance status, less tobacco and alcohol consumption, more poorly differentiated histopathology, but usually with better treatment response and prognosis compared with HPV-negative OPSCCs. In tumor tissue, HPV infection is closely correlated with p16(INK4A) expression, which has been suggested to be a surrogate biomarker of HPV infection. However, there is diversity of sensitivity and specificity about p16(INK4A) in surrogate detection of HPV status. Herein, we summarize the current knowledge and note some aspects for consideration concerning p16(INK4A) as a surrogate biomarker for HPV-associated OPSCC.
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Affiliation(s)
- Hongzhi Wang
- Sun Yat-sen University Cancer Center, Guangdong, China; State Key Laboratory of Oncology in South China, Guangdong, China; Collaborative Innovation Center for Cancer Medicine, Guangdong, China
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