1. Extracapsular Extension in Oropharyngeal Carcinoma: The HPV Era
Thomas J. Gal, MD, MPH, FACS
Professor, Division of Head and Neck Oncology
Department of Otolaryngology
University of Kentucky
Lexington, KY

2. Thank You As a clinical researcher, I rely on your efforts
SEER
NCDB
Internal research
Kentucky Cancer Registry
Markey Cancer Center

3. Why me? Professor, Division of Head and Neck Oncology
Masters of Public Health
University of Washington
Cancer Epidemiology
Over 50 publication in Otolaryngology
Skull base
Maxillofacial trauma
Head and Neck Oncology
Microvascular reconstruction
Most meaningful work comes from database analysis
Your work counts!

4. Topic Today Oropharyngeal Carcinoma Extracapsular Spread
Extranodal Extension
Extracapsular Extension
Extranodal Extension (ENE) considered best nomenclature

5. Impact of Extranodal Extension
Decreased survival
Increased risk of distant metastatic disease
More aggressive pathology
More aggressive therapy
More aggressive chemotherapy

6. ENE has profound effect on prognosis in Head & Neck Cancer
Evidence supports ENE as adverse prognostic factor
Most evidence from pathologic examination of nodes
Pathology includes distinction between microscopic and macroscopic
Inclusion of ENE in N category
P16- Oropharynx and unknown primary and hypopharynx
Oral cavity
Larynx
Skin
Salivary gland
Nasal cavity and paranasal sinus
Terminology for extension outside lymph nodes
ENE is the preferred wording
Not extracapsular spread/extension or extranodal involvement

7. Clinical Staging
Stringent criteria required to permit ENE(+) diagnosis
Unambiguous evidence of gross ENE on clinical exam
Invasion of skin
Infiltration of musculature or dense tethering to adjacent structures
Nerve invasion with dysfunction
Cranial nerve
Brachial plexus
Sympathetic trunk
Phrenic Nerve
Supported by strong radiographic evidence
Radiographic evidence alone is insufficient
If in doubt, assign ENE(-)

8. Pathologic Staging Clearly defined pathological ENE(+) based on
Tumor present within confines of node AND
Extending through the node capsule
Into surrounding connective tissue
With or without associated stromal reaction
ENE (+) may be classified as
ENEmi for microscopic ENE ≤ 2mm
ENEma for major ENE ≥2mm
If in doubt, assign ENE (-)

9. ENE- N Characteristic 8th Edition
Clinical
Any ENE is N3b
Pathologic
ENE either Minor (≤2mm) or Major (≥2mm) increases N by one step

10. ENE (-)

11. ENE (+)

12. Clinical ENE (+)

13. ENE (-)

14. Extranodal Extension: Why has this changed?
Human Papillomavirus (HPV)
Distinct pathologic entity
Non-smokers
Younger
Viral
Favorable treatment profile
Treatment De-escalation?
No significant change in risk for smoking-related “garden variety” head and neck cancer
But what about this?

20. More aggressive surgical management of primary site disease
More access to minimally invasive approaches
Failure to change therapeutic approaches because of aggressive appearance of neck disease
Nodal disease (any?) not the same in HPV-related oropharynx cancer
So why is ENE still significant?
Does the extent of extranodal extension allow us to modify therapy?
Clinical versus microscopic ENE?

21. SEER

22. SEER DATA 2008 We thought we were on to something
THEY BASHED THE MANUSCRIPT!
SEER doesn’t have chemo data
No delineation of HPV disease
Completely counter to current knowledge at the time
FLAT EARTH?
Predates actual awareness of HPV epidemic
Testing
Predates attempts to change therapy based on disease

23. Markey Cancer Center NCI designation Access to NCDB Chemo data
HPV from 2010

24. Current Data NCDB 2010-2015 Includes HPV All treatment data
Chemotherapy

25. NCDB
Nationwide clinical surveillance data set that includes approximately 70% of all newly diagnosed malignancies.
It includes all cancer cases treated at American College of Surgeons Commissions on Cancer (CoC) accredited hospitals in the US
Access requires NCI status

26. Methods Squamous Cell Carcinoma of the Oropharynx Demographics
Specifically tonsil, base of tongue
Demographics
AJCC 7th Edition Staging
Treatment categorized
Surgery alone
Surgery with adjuvant radiotherapy±chemotherapy
No treatment
Unknown

27. Methods
Patients treated with surgery as the initial treatment modality
Primary Site
Neck
Salvage surgery excluded
Excluded patients with surgery only for primary site or only for neck
Evidence of primary site surgery
Margins, PNI, LVI, etc.
AND lymph nodes examined

28. Methods Node negative Node (+), ENE (-) Node (+), ENE (+)
Clinical
Microscopic/Pathologic
To review, ENE (+) may be classified as
ENEmi for microscopic ENE ≤ 2mm
ENEma for major ENE ≥2mm

29. Methods Descriptive Analysis Survival Analysis
Cox proportional hazards models

30. Results 2010-2015 66,106 patients White Male Age 50-64
41.9% (27,663) HPV+
42.2% HPV unknown

31. Primary Surgery+/- Adjuvant Therapy
Entire Cohort
Primary Surgery+/- Adjuvant Therapy
N=66,106
N=16,845
Gender
Male
54,099 (81.8%)
13640 (81.0%)
Female
12007 (18.2%)
3205 (19.0%)
Age
20-49
8,566 (13.0%)
2,910 (17.3%)
50-64
36,100 (54.6%)
9,641 (57.2%)
65-74
15,148 (22.9%)
3,290 (19.5%)
75+
6,292 (9.5%)
1,004 (6.0%)
Race
White
59,200 (89.6%)
15,543 (92.3%)
Black
5,025 (7.6%)
816 (4.8%)
Other
1,305 (2.0%)
336 (2.0%)
Unknown
576 (0.9%)
150 (0.9%)
Tumor Site
Tonsil
35,339 (53.5%)
11,119 (66.0%)
Base of Tongue
30,767 (46.5%)
5726 (34.0%)
HPV Status
Positive
27,663 (41.9%)
8,780 (52.1%)
Negative
10,566 (16.0%)
2,528 (15.0%)
27,877 (42.2%)
5,537 (32.9%)
Demographics

32. Treatment All surgery 48% primary chemoradiation
HPV+
HPV-
Unknown
Total
Surgery only
1,958 (7.1%)
1,187 (11.2%)
2,790 (1.0%)
5,935 (9.0%)
Surgery+XRT
9,399 (34.0%)
2,482 (23.5%)
5,924 (21.3%)
17,805 (26.9%)
Surgery+ChemoXRT
180 (0.7%)
96 (1.0%)
235 (0.8%)
511 ( 0.7%)
XRT only
1,793 (6.5%)
835 (7.9%)
2,201 (7.9%)
4,829 (7.3%)
Chemoradiation
13,310 (48.1%)
5,112 (48.4%)
13,880 (49.9%)
32,302 (48.9%)
Not received treatment
636 (2.2%)
633 (6.0%)
2176 (7.8%)
3,445 (5.2%)
387 (1.4%)
221 (2.1%)
671 (2.4%)
1,279 (1.9%)
27,663
10,566
27,877
66,106
All surgery
Primary, neck, or both
48% primary chemoradiation
Surgery more common in HPV+ patients
Mostly tonsil (77%)

33. Survival
Two-year 86%
Five-year 74%

34. Survival by HPV Status
HPV+
89%/78%
HPV-
70%/56%

35. Results: Surgery
16,845 patients with primary surgery± adjuvant therapy
8,780 HPV+
11,119 tonsil (66%)
5,726 BOT (34%)
12,256 received adjuvant XRT
6,302 received adjuvant chemotherapy

36. Results: Surgery 13,960 Node (+) disease
55% HPV+ (7761)
Roughly half were ENE negative
More node (-) disease in HPV-

37. Survival by tumor site/ENE

38. ENE by HPV

39. HPV+ vs. SEER

40. HPV- vs. SEER

41. Cox Proportional Hazards
Age
Gender
Race
Tumor site
HPV status
Radiotherapy
CHemotherapy

42. Cox Proportional Hazards
No significant differences between clinical and pathologic ENE
Compared to ENE (-), both had increased risk of mortality (HR 1.83, p<0.001)
HPV- patients had 2.5x risk of mortality
XRT 33% improved survival
Chemotherapy 10% reduction in mortality

43. Discussion
Observational study of the impact of ENE in oropharyngeal cancer
Goal was to determine if the longstanding tenets regarding ENE still held true given the different epidemiology of this disease
Seems to

44. Discussion
It is known that ENE is a significant prognostic indicator in oropharyngeal carcinoma
Increased incidence of regional and distant metastatic disease
Survival rates of 29-45%, improving to 58% with systemic chemotherapy
Some evidence to suggest that chemotherapy is of little benefit in HPV+ disease
Association with advanced T stage

45. Discussion
An, et al
NCDB data through 2012
ENE associated with poorer survival
Chemotherapy (vs. XRT alone) was not associated with improved survival
Stage I or II disease treated with XRT alone did more poorly than chemoradiation or surgery with adjuvant therapy
Stage III disease: trimodality therapy improved survival compared with chemoradiation
Best options for eliminating chemotherapy appear to involve incorporation of surgery into the treatment algorithm

46. Discussion
In this study, ENE was associated with an 83% decreased survival
Extent of ENE not significant
Impact of ENE does not seem to be offset by the use of chemotherapy
Appears to behave similarly to HPV- counterparts

47. Discussion Chemotherapy 6302 patients
4553 observed to have ENE of any type
1749 received chemotherapy without ENE
High volume nodal disease
Positive margins
Other unfavorable features
10% reduction in mortality
Unclear if this is a function of the beneficial effects of chemotherapy given an otherwise high- risk profile

48. Shortcomings
Low number of surgically treated patients (275) with clinical ENE
Surgical selection of more favorable disease
Select out patients with more aggressive ENE
ENE, when present AND surgically resectable, is neither a contraindication for surgery nor does it carry a less favorable profile than more indolent disease
Thus conclusion is there is no difference between pathologic ENE and surgically resectable clinical ENE

49. Shortcomings
Hard to make true treatment recommendations on retrospective data
Difficult to determine if similarities in survival profiles are due to the behavior of the disease or simply a manifestation of appropriately treated disease.
Prospective trials
Evidence for treatment de-escalation applies to adjuvant therapy in the postoperative setting
No evidence for de-escalation in the non-surgical setting

50. Conclusion
ENE remains a significant prognostic indicator in oropharyngeal carcinoma
Clinical and pathologic ENE are both associated with decreased survival
No significant difference between the two
Surgically resectable clinical ENE
Clinical impact of these observations in HPV+ and HPV- disease requires further study

51. Thank you