Case presentation of severe papillomatosis of the larynx in non sexually active male teenager and discussion of biopsy finding of severe dysplasia and possible formation of laryngeal cancer

1. HPV and Laryngeal CarcinomaHPV and Laryngeal Carcinoma
• Is there a relationship ?Is there a relationship ?
• Are HPV High/Low Risk DNA Probes ReliableAre HPV High/Low Risk DNA Probes Reliable
and useful ?and useful ?
• Is there a prognostic relationship ?Is there a prognostic relationship ?
• Should severe dysplasia be treated ?Should severe dysplasia be treated ?
• Is there a role for XRT for HPV associatedIs there a role for XRT for HPV associated
severe dysplasia or is it contra-indicated ?severe dysplasia or is it contra-indicated ?

2. HistoryHistory
• 20 yr old male, non-drinker,20 yr old male, non-drinker,
• smoked 5 cigarettes day for 2 yrssmoked 5 cigarettes day for 2 yrs
until 1/1/2 years ago.until 1/1/2 years ago.
• 3 month history of worsening hoarse voice3 month history of worsening hoarse voice
• ODQ: poor diet frequent heart burn &ODQ: poor diet frequent heart burn &
frequent throat clearingfrequent throat clearing

3. Examination FindingsExamination Findings
• In -office: laryngoscopy ant 2/3 TVC bilateral papillomaIn -office: laryngoscopy ant 2/3 TVC bilateral papilloma
• 4/08 Vocal cord stripping: Condyloma and focal4/08 Vocal cord stripping: Condyloma and focal
moderate dysplasiamoderate dysplasia
• 7/16 recurrence with a larger papilloma anterior & L>R7/16 recurrence with a larger papilloma anterior & L>R
• 7/17 Vocal cord stripping: L mass mostly within the7/17 Vocal cord stripping: L mass mostly within the
ventricle above the L TVCventricle above the L TVC
• Pathology: Focal moderate to severe dysplasiaPathology: Focal moderate to severe dysplasia
• DNA probe ‘ Low Risk Positive’, ‘High Risk Negative’DNA probe ‘ Low Risk Positive’, ‘High Risk Negative’

4. Examination FindingsExamination Findings
• 9/10/08: No masses seen with thickening9/10/08: No masses seen with thickening
R TVCR TVC

5. Larynx PapillomaLarynx Papilloma
• The most common benign laryngeal neoplasmThe most common benign laryngeal neoplasm
• No sex predilectionNo sex predilection
• Changes in phonation, dyspnea, cough, stridorChanges in phonation, dyspnea, cough, stridor
• HPV types 6 and 11HPV types 6 and 11
• Juvenile type:multiple,rapid growth/recurrenceJuvenile type:multiple,rapid growth/recurrence
• Adult type: more often single, recurs less often,Adult type: more often single, recurs less often,
less likely to spreadless likely to spread

6. DNA ProbeDNA Probe
• DNA-EIA/immunofluorescence/Southern Blot/RIA:DNA-EIA/immunofluorescence/Southern Blot/RIA:
• ‘‘High Risk’ Oncogenic HPVHigh Risk’ Oncogenic HPV 16, 18, 31, 33, 35, 52 &5816, 18, 31, 33, 35, 52 &58
16/18/31/33/35/39/45/51/52/56/58/59/6816/18/31/33/35/39/45/51/52/56/58/59/68
• ‘‘Low Risk’ Non - oncogenicLow Risk’ Non - oncogenic 66& 11& 11
6/11/42/43/446/11/42/43/44
• Oncogene of HPV 16:Oncogene of HPV 16:
• E6E6 targets p53 tumor suppressor gene and this leads totargets p53 tumor suppressor gene and this leads to
ubiquitination and degradationubiquitination and degradation
• E7E7 targets the pRb and this leads to a reduced expression, E7 alsotargets the pRb and this leads to a reduced expression, E7 also
enhances expression of Bcl-2 and reduces Bak by reducing proteinenhances expression of Bcl-2 and reduces Bak by reducing protein
stabilitystability

7. HPV and Larynx CarcinomaHPV and Larynx Carcinoma
Pol Merkur LekarskiPol Merkur Lekarski.. 2005 Sep;19(111):291-32005 Sep;19(111):291-3
10% normal mucosa n=50 vrs larynx ca 36% n=7210% normal mucosa n=50 vrs larynx ca 36% n=72
European Journal of CancerEuropean Journal of Cancer..1999; 35 (5): 825 - 8321999; 35 (5): 825 - 832
58% with larynx ca + high risk HPV,58% with larynx ca + high risk HPV,
Yet only 26% individual tumor cells harbour HPVYet only 26% individual tumor cells harbour HPV
AnnAnn Otol Rhinol LaryngolOtol Rhinol Laryngol..2000 Nov;109(11):1069-762000 Nov;109(11):1069-76
+HPV:25% larynx ca & 30% leukoplakia,+HPV:25% larynx ca & 30% leukoplakia,
increased risk for Ca if HPV + & smoking and ETOH.increased risk for Ca if HPV + & smoking and ETOH.
Control +HPV 16% ( typically 1-10% other studies)Control +HPV 16% ( typically 1-10% other studies)
Clinical Cancer Research.. 2003; 9:2620-26262003; 9:2620-2626
Matched pair analysis HPV seropositivity assoc with 7 fold increase in SCCHN.Matched pair analysis HPV seropositivity assoc with 7 fold increase in SCCHN.
When combined with cigarette smoking was greater than the additive riskWhen combined with cigarette smoking was greater than the additive risk

8. HPV and Larynx CarcinomaHPV and Larynx Carcinoma
Journal of Laryngology & Otology 1996; 110:75-77
Larynx ca 11 yrs after papillomatosis found HPV 18+
Current Opinion in Otolaryng & Head & Neck Surg 2004;12(2):88-92, April 2004
3-7% risk malignant transformation of laryngel pappiloma:
smoking and irradiation cofactors
Clin Otolaryngol&Allied Sciences 2004;29(4):301-306
Marked heterogenicity in methods used to detect HPV and frequency with
which it is detected
NEJM May 2007- BOT/Tonsillar Ca 9 times increased risk if more than 6 oral sex
partners in a lifetime, if HPV positive 32 x risk of Ca vrs 3x smoking, 2.5 drinking

9. Severe larynx dysplasia & XRT ?Severe larynx dysplasia & XRT ?
• Previously verrucous ca larynx contraindaictionPreviously verrucous ca larynx contraindaiction
for XRTfor XRT
• Little info on XRT for severe dysplasiaLittle info on XRT for severe dysplasia
• XRT controls 94% of T1A larynx lesionsXRT controls 94% of T1A larynx lesions
• Other treatment modalities:Other treatment modalities:
– InterferonInterferon
– Nebulized Imiquinone ( Aldara ) ?Nebulized Imiquinone ( Aldara ) ?
– Gardesil or TA-HPV Vaccine ?Gardesil or TA-HPV Vaccine ?
– INF chemotherapyINF chemotherapy

10. Severe larynx dysplasia & XRT ?Severe larynx dysplasia & XRT ?
• Previously verrucous ca larynx contraindaictionPreviously verrucous ca larynx contraindaiction
for XRTfor XRT
• Little info on XRT for severe dysplasiaLittle info on XRT for severe dysplasia
• XRT controls 94% of T1A larynx lesionsXRT controls 94% of T1A larynx lesions
• Other treatment modalities:Other treatment modalities:
– InterferonInterferon
– Nebulized Imiquinone ( Aldara ) ?Nebulized Imiquinone ( Aldara ) ?
– Gardesil or TA-HPV Vaccine ?Gardesil or TA-HPV Vaccine ?
– INF chemotherapyINF chemotherapy