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INFECTIOUS DISEASE Update

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Presentation on theme: "INFECTIOUS DISEASE Update"— Presentation transcript:

1 INFECTIOUS DISEASE Update
Pediatric Cough; Dr. Theresa Kim A CPMC Regional CME Event INFECTIOUS DISEASE Update - Microbiome and Emerging Infections Saturday October 19, 2013

2 HPV UPDATE: Head and neck Carcinoma
Gerald Kangelaris, MD San Francisco Otolaryngology

3 No Financial Disclosures

4 Pediatric Cough; Dr. Theresa Kim
HPV In the media

5 Pediatric Cough; Dr. Theresa Kim
HPV In the media Long recognition of HPV involvement in cervical & anal cancers

6 Pediatric Cough; Dr. Theresa Kim
HPV In the media Increasing recognition oncogenic role in cancers of the upper respiratory tract

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CONCERNED PATIENTS

8 Pediatric Cough; Dr. Theresa Kim
Goals Describe HPV associated head & neck cancer Understand at-risk population Appreciate disease presentation Describe basics of treatment and outcomes Improve ability to counsel patients!

9 OUTLINE – hpv in head & neck carcinoma
Pediatric Cough; Dr. Theresa Kim OUTLINE – hpv in head & neck carcinoma Virology Epidemiology Carcinogenesis Presentation Treatment & Outcomes Future Directions

10 Pediatric Cough; Dr. Theresa Kim
Virology HPV dsDNA virus 100+ strains isolated 15 strains high risk Types 16 & 18 Genitals Anus Oropharynx Ubiquitous, nonenveloped double stranded DNA virus Classically associated with cutaneous and genital warts 100+ strains isolaged, with Types 16 & 18 accounting for largest percentage of cancers

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Virology Infects basal layer through microabrasions in the skin & mucous membranes Viral particles formed progressively as the basal cells differentiate are released when the cells reach the outer epithelium

12 Pediatric Cough; Dr. Theresa Kim
Virology In contrast to skin, the palatine & lingual tonsils contain cryptic invaginations that expose the basal epithelial cells, which are the preferred sites of HPV infection. May explain why see higher rates of HPV disease in the oropharynx compared to oral cavity, which is covered by thicker stratified squamous mucosa

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Virology Head & Neck Sites Palatine tonsil Tongue base

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epidemiology The recognition of HPV associated Oropharyngeal Cancers has been building since the early 2000s. This was one of the earliest studies to link the molecular evidence of HPV in cancer cells with an epidemiologic, causal role in carcinogenesis D’Souza G, Kreimer A, et al. Case-Control Study of Human Papillomavirus and Oropharyngeal Cancer. N Eng J Med 2007, 356:

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epidemiology Head and Neck Cancers Overall decreasing Oropharynx increasing OP Cancer Epidemic OP HPV (-) 2.0  1.0 per 100,000 OP HPV (+) 0.8  2.6 per 100,000 Overall rates of head & neck cancers decreasing in US & developed world - due to decreased rates of tobacco & alcohol use, which are estimated to account for >70% of these tumors in the US & europe. US cancer registry found incidence HPV (-) declined 50% from 1988 to HPV (+) increased by 225%. Most of increase occurred recently, with 5% annual increases from The proportion of OP cancers caused by HPV increased from 16.3% to 71.7% Similar findings in Europe If current trends continue, espiamated that by 2030 almost half of H&N cancers will be HPV(+) OP cancer, and by 2020 number of HPV(+) OP cancer will surpass numbers of cervical cancer Chaturvedi AK, Engels EA, et al. Human Papillomavirus and Rising Oropharyngeal Cancer Incidence in the United States. J Clin Onc (32):

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epidemiology Typical Head & Neck Cancer Patient Smoker, drinker, older >50, lower SES

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epidemiology HPV Oropharynx Cancer Patient Non-smoker, mild/moderate alcohol use, High marijuana exposure, younger age (<45), higher SES

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epidemiology HPV (+) OPSCC as Sexually Transmitted Disease Presence of HPV in Oral Samples Increases With… Being sexually active Early age sexual activity Increasing # oral sex partners Increasing # vaginal & anal sex partners Male No difference if hetero- or homosexual/bisexual Having sex – prevalence 0.9% NO, 7.5 YES% (PR 8.69) Oral sex partners – 0 3.5%, 21.5% PR 6.12 >20 partners Vaginal sex partners – 0 1.4%, PR >20 partners Early age oral sex – 9.0% if <18, 5.9 if >18 PR 0.66 if >18 yo Men ~10% versus 3.6% women, adjusted PR 2.33 PR 2.33 Gillison ML, Broutian T, et al. Prevalence of Oral HPV Infection in the United States, J Am Med Assoc (7):

19 Pediatric Cough; Dr. Theresa Kim
epidemiology HPV (+) OPSCC as Sexually Transmitted Disease Presence of HPV in Oral Samples… Having sex – prevalence 0.9 NO, 7.5 YES Oral sex partners – 0 3.5%, 21.5% 20+ Vaginal sex partners – 0 1.4%, Early age oral sex – 9.0% if <18, 5.9 if >18 Men ~10% versus 3.6% women, adjusted PR 2.33 Gillison ML, Broutian T, et al. Prevalence of Oral HPV Infection in the United States, J Am Med Assoc (7):

20 Pediatric Cough; Dr. Theresa Kim
epidemiology HPV (+) OPSCC as Sexually Transmitted Disease HPV (+) vs. HPV (-) OPSCC Lifetime # Oral Sex Partners 0 partners OR 1.0 1-5 partners OR 3.8 6+ partners OR 8.6 Lifetime # Vaginal Sex Partners 0-5 partners OR 1.0 6-25 partners OR 2.7 26+ partners OR 4.2 D’Souza G, Kreimer A, et al. Case-Control Study of Human Papillomavirus and Oropharyngeal Cancer. N Eng J Med 2007, 356:

21 Pediatric Cough; Dr. Theresa Kim
epidemiology HPV (+) OPSCC HPV (-) OPSCC Younger (<50 years) Older (>60 years) Never / Mild Smoker Heavy Smoker Mild / Mod Alcohol Heavy Alcohol High Sexual Exposure Low Sexual Exposure Higher Socioeconomic Status Lower Socioeconomic Status Increasing Incidence Decreasing Incidence Role of tobacco on HPV(+) tumors is unclear, some studies suggesting an increased risk, other suggesting no association Median tobacco use is less among HPV(+) than (-), more than half of HPV(+) OPSCC have history of tobacco use

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Carcinogenesis Six non-structural proteins Two viral oncoproteins E6 and E7 E6 and E7 increased activity in high-risk HPV strains HPV DNA Two capsid proteins, L1 and L2

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Carcinogenesis E6 Degradation of tumor suppressor p53 Prevents apoptosis E7 Loss of retinoblastoma (Rb) tumor suppressor Accumulates p16 Pushes cells from G1  S phase Degredation of p53 causes loss of programmed cell death in response to genetic mutations P16 inhibits cell cycle progression through cyclin D1 and CDK4/CDK6 mediated-events

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presentation Palatine or Lingual Tonsil Location

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presentation Symptoms Painful oral lesion Dysphagia or odynophagia Bleeding Asymmetry Trismus Otalgia Hypoesthesia Asymptomatic!

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presentation Present with firm, indurated, unilateral tumor

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presentation Palpation of tongue base is important, but difficult – gag reflex, circumvallate papillae

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presentation Differential Diagnosis Infectious Benign lesions Neoplastic Inflammatory Infectious – tonsillitis, peritonsillar abscess Benign lesions – mucus cysts of tonsil, non-neoplastic papillomas Neoplastic – lymphoma, salivary tumors Inflammatory – apthous ulcers, lichen planus

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presentation Palpation of tongue base is important, but difficult – gag reflex, circumvallate papillae

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presentation

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presentation High Rates Nodal Metastases Often Tumor Undetectable at Primary Site Very classic presentation is asymptomatic patient with rapidly growing neck mass Unclear pathophysiology. Theories include differential growth rates from primary to metastatic disease (more aggressive subtype), better access to nutrition with neck vessels, immune phenomenon with control at primary site, CYSTIC neck mass

32 Pediatric Cough; Dr. Theresa Kim
presentation Consider HPV(+) OPSCC Neck mass persisting for 4+ weeks, unresponsive to medical therapy Upper jugular chain Firm, discrete, mobile, nontender May be asymptomatic & non-visible at primary site! Persistent OP sore throat 4+ weeks, unresponsive to medical therapy Tonsillar asymmetry, otalgia Advanced disease Dysphagia, pharyngeal bleeding, trismus, voice changes

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presentation Workup FNA neck mass US guidance may improve yield in cystic masses Imaging Contrast enhanced CT / MRI neck CXR OHNS evaluation Fiberoptic nasopharyngoscopy Exam under anesthesia, biopsies

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TREATMENT & OUTCOME Treatment Options Concurrent chemoradiation Surgery with adjuvant radiation, +/- chemotherapy Concurrent chemoradiation, generally with platinum based chemothereutics Surgery possible for small T stage tumors

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TREATMENT & OUTCOME Improved survival in HPV (+) OPSCC tumors First study to demonstrate HPV seropositivity as an independent risk factor in survival outcomes Retrospective study of pts with advanced Stage III & IV OP tumors (HPV+ 206, HPV- 117) 3 year overall survival 82.4% versus 57.1% 58% risk reduction in risk of death (HR .42 to .27) after adjustments for age, race, tumor & nodal stage, and tobacco exposure Ang KK, Harris J, et al. Human Papillomavirus and Survival of Patients with Oropharyngeal Cancer.N Eng J Med (1):24-35.

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TREATMENT & OUTCOME Improved survival in HPV (+) OPSCC tumors 53% better overall survival 74% better disease specific survival Improvements in progression free survival, disease free survival O’Rorke MA, Ellison MV, et al. Human Papillomavirus Related Head and Neck Cancer Survival: A Systematic Review and Meta-Analysis. Oral Oncology :

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TREATMENT & OUTCOME Mechanisms for Improved Outcomes Lack of field cancerization Increased sensitivity to radiation therapy Degraded wild-type p53, not mutations Immune response Suggestions that HPV positive cells may induce a more effective cytotoxic immne response improving clearance rates

38 Pediatric Cough; Dr. Theresa Kim
Future directions De-intensification strategies Lower dose of radiation therapy Targeted chemotherapeutics Surgery with de-escalation of adjuvant treatment Current studies examining the following Exchanging targeted chemotherapeutics (e.g., cetuximab, a monoclonal antibody versus epidermal growth factors receptor EGFR) TLM or TORS Goal is to reduce the long-term morbidity of head & neck cancer treatment: dysphagia, xerostomia, mucositis, radiation induced cancers WHILE PRESERVING THE SURVIVAL BENEFITS. Particularly important in this YOUNG patient population

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Future directions Vaccination HPV vaccines vs. high risk subtypes 6, 11, 16, 18

40 Pediatric Cough; Dr. Theresa Kim
Future directions Vaccination United States Advisory Committee on Immunization Practices (ACIP) recommends the bivalent or quadrivalent HPV vaccines for females aged 11 to 12 for the prevention of cervical, vaginal, and vulvar cancer and the related precursor lesions caused by the HPV types targeted by these vaccines 36]. The ACIP also recommends the quadrivalent HPV vaccine for the prevention of anal cancer and its precursor lesions, and genital warts in females

41 Pediatric Cough; Dr. Theresa Kim
Future directions Vaccination Controversy. Postliscensure data has been consistent with preliscensure trials, and overall safe. Rates of adverse affects really no different than any other vaccine and have not been attributed to the vaccine specifically. Have seen increased rates of syncope and VTE in high-risk individuals


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