Human Papillomavirus and Head and Neck Cancer. Ed Stelow, MD

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1 Human Papillomavirus and Head and Neck Cancer Ed Stelow, MD

2 No conflict of interest Declaration

3 Cancer 1974

4 Lancet Oncol 2016; 17: e477-8

5 JAMA 1984; 252: 1857

6 JAMA 1988;259(13):

7 Clin Cancer Res 1996; 2:

8 Clin Cancer Res 1996; 2:

9 Am J Pathol 1998; 152:

10 Am J Pathol 1998; 152:

11 J Natl Cancer Inst 2000; 92:

12 What They Did 253 HN SCC, PCR, SB, ISH for HPV and PCR for p53 Compared results to clinical data and outcomes

13 What They Found Found HPV in 62 (25%) of cases localized by ISH to tumor nuclei 90% HPV 16 Southern blot showed DNA integration Oropharynx (55%) and poor tumor grade (non-keratinizing) assoc with HPV 59% decrease risk of death when controlled for stage, grade, age and smoking status

14 What They Found

15 Causation? Correlation established with known causation of cervical cancer Temporal relationship Experiments

16 NEJM 2007; 356:

17 Sexual behavior also linked to oral HPV without a tumor

18 JAMA 2012; 307:

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20 J Clin Oncol 2011; 29:

21 J Clin Oncol 2011; 29:

22 J Clin Oncol 2011; 29:

23 Prognosis and p16 (Oropharynx) Hazard Ratios Study N OS PFS DFS Weinberger et al Reimers et al Shi et al Ang et al Lewis et al Rischen et al

24 NEJM 2010;363:

25 Other Hot Spot Am J Surg Pathol 2010; 34; e15-24

26 Head Neck Pathol 2014; 8:

27 SINONASAL Am J Surg Pathol 2013; 37:

28 Virchows Archives 2015; 467:

29 P16 performance Antibody fx (Roche vs. Pharmingen) Staining pattern (generally dichotomous) Site dependent

30 P16 Performance Varies with Histology, e,g, Sinonasal Cases 3/25 keratinizing SCCs positive for p16; None were HR-Positive 34/57 non-keratinizing SCCs positive for p16; 19 were HR-HPV positive

31 Morphology Alone AJSP 2016; 40:

32 Current Practice Prognosis most use p16; Site of origin for neck metastasis? Trial / therapy change HPV type specific demands

33 p16 p16 Y ISH N VS Y VS PCR or p16 PCR PCR

34 Arch Pathol Lab Med 2016; 140:

35 RNA SCOPE Am J Surg Pathol 2012; 36: View RNA Am J Surg Pathol 2015; 39:

36 Br J Cancer 2013; 108;

37 NEW WHO OROPHARYNX 5. Tumours of the oropharynx (BOT, Tonsils, Adenoids) Introduction (including cytology) Squamous cell carcinoma B. Squamous cell carcinoma, HPV A. Squamous cell carcinoma, HPV- 263 HPV detection. It is highly desirable to confirm the presence of high risk HPV in the tumour. The virus can be detected by molecular assays (e.g. in situ hybridization, PCR-based assays) performed singly or in combination. Diffuse immunoreactivity for p16 is a reliable surrogate marker for the presence of high risk HPV in oropharyngeal carcinomas, and may serve as a stand alone test for HPV status in tumours with appropriate morphology arising at this site. HPV testing of a lymph node metastasis is also used for tumour localization: positivity points to the oropharynx as the most likely primary site even in the absence of a clinically or radiographically detectable oropharyngeal mass. When the HPV testing is not available, oropharyngeal squamous cell carcinoma can be diagnosed as "squamous cell carcinoma, HPV status unknown", or "squamous cell carcinoma, HPV status not tested, morphologically highly suggestive of HPV association" if the tumor shows the characteristic non-keratinizing morphology.

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42 Papillary SCC Site p16 OP 70% Oral 14% Larynx 14% Am J Surg Pathol 2013; 37: Am J Surg Pathol 2009; 33:

43 Undifferentiated Carcinoma Broad Differential Diagnosis In the oropharynx it s almost always HPV Mod Pathol 2011: 24: Am J Surg Pathol: 2010; 34: 800-5

44 Small Cell Carcinoma or other High-Grade Neuroendocrine Carcinoma In the oropharynx, often related to HPV 5/9; 2/4 Sometimes in the sinonasal tract 1/6; 1/3 AJSP 2011; 35: AJSP 2013; 37: AJSP 2016; 40: 471-8

45 Adeno / Adenosquamous Oropharynx (2/3), Sinonasal (1/3), Other (0/12) Head Neck Pathol 2011; 5:

46 Ciliated

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48 Basaloid SCC Oropharynx 9/12 Other 0/16 Hum Pathol 2010; 41:

49 Spindle Cell / Sarcomatoid SCC All Cases 1-2/31 Oropharynx 0/5 Head Neck Pathol 2013; 7: 250-7

50 Keratinizing SCC p16 Oropharynx 7/54 Am J Surg Pathol 2014; 38:

51 Other Morphologies Combinations of above Tumors resembling salivary gland tumors replete with myoepithelial differentiation (e.g., Sinonasal HPV-related adenoid cystic-like carcinoma)

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53 p16

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55 HPV-Related Adenoid Cystic-Like Carcinoma yo; F:M=2:1 Cribriform and tubular growth with inconspicuous ducts 62% with squamous dysplasia Sarcomatoid features in about 10% including with chondroid differentiation 59% HPV 33 40% recurrence; 7% metastases; No deaths

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62 Takeaway: Morphology and HPV Site trumps growth pattern For the most part, p16/hpv status confers a better prognosis (except for with small cell carcinoma)

63 Other Questions Can HPV-Associated SCCs actually be treated differently (e.g., less radiation, etc.)?? Will this go away as suddenly as it developed??

64 Current ASTRO Recommendations

65 De-escalation Decreasing radiation (less than 70-Gy) Less toxic radio-sensitizing agents (less cisplatin; cisplatin to cetuximab; etc.) Trans-oral robotic surgery

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67 Take Home 70-80% of orophayngeal SCC now secondary to HR-HPV (90% type 16) 40% of non-keratinizing SCC of the sinonasal tract secondary to HR-HPV Currently it is only recommended to find status of oropharyngeal SCC, and p16 IHC is considered acceptable for this

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