Reporting HPV related carcinomas of the head and neck. dr. Nina Zidar Institute of Pathology Faculty of Medicine University of Ljubljana Slovenia

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1 Reporting HPV related carcinomas of the head and neck dr. Nina Zidar Institute of Pathology Faculty of Medicine University of Ljubljana Slovenia

2 Conflict of interest/funding X None Company: Product royalties Paid consultant Research support

3 Outline HPV in oropharyngeal SCC Diagnosing HPV infection Reporting HPV-pos. SCC HPV in variants of SCC HPV in other locations of the head & neck

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5 HPV-positive squamous cell carcinoma of the oropharynx

6 Characteristics HPV-positive SCC HPV-negative SCC Median age years years Risk factors Sexual behaviour Smoking and alcohol abuse Lymph node metastases Frequently cystic Uncommonly cystic Postulated origin Reticulated epithelium of invaginated crypts Surface epithelium Dysplasia Rare Often present Morphology Commonly non-keratinizing Conventional SCC Grading Not applicable Applicable p16 immunohistochemistry Positive Negative Overall survival (3 years) 82% 57% El-Naggar AK, Chan JKC, Grandis JR, Takata T, Slootweg PJ, eds. WHO Classification of Head and Neck Tumours. 4 th ed. IARC: Lyon; 2017

7 HPV-pos. SCC of the oropharynx HPV16 (85%), 18, 31, 33, 35, 39, 45, 51, 52, 56, 59, 68, 69, 73, % in US to % in some European countries at a younger age weaker association with tobacco and alcohol abuse associated with sexual behavior palatine or lingual tonsils, non-keratinizing morphology early metastases to regional lymph nodes enhanced sensitivity to irradiation treatment better overall survival: 82% for HPV+ vs 57% for HPV neg Ang KK, Harris J, Wheeler R et al. HPV and survival of patients with oropharyngeal cancer. N Engl J Med 2010; 363: 24-35

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12 Cystic nodal metastases

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14 Diagnosis of HPV-related carcinoma

15 Diagnosis of HPV-related carcinoma p16 INK4 overexpression + expression of high risk HPV E6/E7 mrna

16 Method Advantages Disadvantages PCR for HPV DNA PCR for E6/E7 mrna ISH for E6/E7 mrna DNA in situ hybridization RNA in situ hybridization p16 immunohistochemistry Highly sensitive Highly sensitive Highly specific Highly sensitive Highly specific Highly specific Highly sensitive Highly specific Highly sensitive Inexpensive Does not distinguish relevant from irrelevant infections Risk of cross contamination Technically demanding Fresh frozen tissue Confirms transcriptionally active HPV, visualization in tissue, FFPE Not sensitive at low copy number Limited experience, not optimized to run on automated platforms Not highly specific for HPV Bishop JA, Lewis JS, Rocco JW, Faquin WC. HPV-related squamous cell carcinoma of the head and neck: An update on testing in routine pathology practice. Sem Diagn Pathol 2015; 32: Bishop JA, Ma X-J, Wang H et al. Detection of transcriptionally active high-risk HPV in patients with head and neck SCC as visualised by novel E6/E7 mrna in situ hybridization method. Am J Surg Pathol 2012; 36:

17 p16 E6/E7 mrna ISH

18 Alos L, Hakim A, Larque AB, de la Oliva J, Rodriguez- Carunchio L, Caballero M, Nadal A, Marti C, Guimera N, Fernandez-Figueras MT, Quint W, Ordi J. p16 overexpression in high-grade neuroendocrine carcinomas of the head and neck: potential diagnostic pitfall with HPV-related carcinomas. Virch Arch 2016: 469:

19 Reporting carcinoma of the oropharynx

20 Reporting oropharyngeal carcinoma oral SCC and oropharyngeal SCC separated oropharynx: HPV-pos, HPVneg SCC recommendations how to report them

21 How to report oropharyngeal SCC SCC, HPV-positive: palatine or lingual tonsils, p16 overexpression and/or evidence of HPV SCC, HPV status unknown: none of the recommended tests are available SCC, HPV not tested, morphology highly suggestive of HPV association: nonkeratinizing morphology

22 How to report oropharyngeal HPVpos. SCC no grading no in situ carcinoma (no Tis) extranodal extension (ENE) not included in ptnm for HPV-pos. SCC prognostic significance of ENE? number of pos. nodes (N1 4, N2 > 4)

23 HPV-pos. variants of squamous cell carcinoma

24 HPV in variants of SCC papillary SCC lymphoepithelial carcinoma adenosquamous carcinoma spindle cell carcinoma pleomorphic/giant cell carcinoma basaloid SCC El-Mofty SK. HPV-related head and neck squamous cell carcinoma variants. Sem Diagn Pathol 2015; 32:23-31

25 HPV positivity in variants of SCC Location: oropharynx > sinonasal tract > larynx, hypopharynx and oral cavitiy

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28 Prognostic significance of HPV in SCC variants limited number of cases favourable prognosis? report them as HPV-pos. or HPV-neg.

29 Two exceptions: neuroendocrine carcinoma verrucous carcinoma

30 Small cell (neuroendocrine) carcinoma small cell morphology + HPV + neuroendocrine markers often associated with SCC widespread dissemination poor survival separate entity not variant of HPV-pos. oropharyngeal carcinoma Bishop JA, Westra WH. HPV-related small cell carcinoma of the oropharynx. Am J Surg Pathol 2011; 35:

31 Large cell neuroendocrine carcinoma NEC of the head and neck even if HPV-pos. behaves aggressively as their HPV-neg counterparts.

32 Verrucous carcinoma

33 Verrucous carcinoma is not related to infection with HPV!

34 HPV-related carcinoma of the sinonasal tract

35 HPV and carcinoma of the sinonasal tract 2 nd most common location of head & neck HPV in % of tumours HPV 16, 18, 31, 33 non-keratinizing sinonasal SCC (41%) keratinizing sinonasal SCC (5%)

36 In contrast to the oropharynx, HPV positivity in the sinonasal SCC is not regarded as a separate tumor entity as it is in the oropharynx, largely because it lacks clinical and pathologic distinctness (Stelow, Bishop. Head Neck Pathol 2017; 11: 3-15).

37 HPV and carcinoma of the sinonasal tract papillary SCC (80% HPV positive) basaloid SCC (45% HPV positive) adenosquamous carcinoma SNUC small cell carcinoma

38 Prognostic significance of HPV positivity in sinonasal carcinoma???

39 A trend towards an improved survival for HPV-pos. sinonasal tumours Alos L, Moyano S, Nadal A et al. HPV are identified in a subgroup of sinonasal squamous cell carcinomas with favorable outcome. Cancer 2009; 115: Bishop JA, Guo TW, Smith DF et al. HPV-related carcinomas of the sinonasal tract. Am J Surg Pathol 2013; 37: Laco J, Sieglová K, Vošmiková H et al. The presence of highrisk HPV E6/E7 mrna transcripts in a subset of sinonasal carcinomas is evidence of involvement of HPV in its etiopathogenesis. Virchows Arch 2015; 467:405-15

40 New entity of HPV-related sinonasal carcinoma

41 HPV-related sinonasal carcinoma with adenoid cystic-like features basaloid cells, arranged in nests with cribriform and microcystic architecture squamous dysplasia of the surface epithelium lacks myb gene rearrangements p16 pos. and HPV, mostly type 33 limited number of reported cases, variable morphology and unknown prognostic significance WHO 2017: provisional entity

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43 HPV-related carcinoma of the larynx and oral cavity

44 Prevalence of HPV in oral and laryngeal SCC: <4% Overall survival was significantly higher for patients with HPV-pos. versus HPV-neg. non-oropharyngeal SCC.

45 HPV in the larynx

46 Conclusions 1. Hot spots for HPV: oropharynx and sinonasal tract 2. HPV pos: better prognosis in oropharyngeal carcinoma, in sinonasal carcinoma? 3. SCC variants: HPV-pos. or HPV-neg., prognosis? 4. Report variants as HPV-pos. or HPV-neg. 5. Two exceptions: - neuroendocrine carcinoma: poor prognosis - verrucous carcinoma: not related to HPV

47 Thank you for your attention! Svečinske gorice, Slovenija