1. Perineural invasion (PNI) and perineural spread (PNS) in head and neck cancers can involve invasion of tumor cells along cranial nerves from the primary site. 2. PNI is classified based on extent from microscopic to gross involvement visible on imaging. Macroscopic PNI involving large nerves is considered a poor prognostic factor. 3. Magnetic resonance imaging is the preferred method to evaluate PNI and PNS with features including nerve enhancement, enlargement, and loss of perineural fat. 4. The trigeminal, facial, and vestibulocochlear nerves are most commonly involved. Treatment volumes in radiation therapy aim to cover the primary site, involved nerve,

1. PNI and PNS in Head Neck Cancers Zonal Classification

2. • Perineural Spread of HNC described in literature for decades-understanding
is still evolving and has many grey areas
• Neurotropism- spread of tm along loose connective tissue of perineurium
• Carter et all-pathological studies found that cancer cells invade the
perineural space and use it as conduit for spread
• PNI is tumour cell invasion in, around and through nerves
PNI= Histologic- Microscopic entity
PNS= Gross PNI-Clinical, radiological or histological entity

3. • Overall frequency of PNI in HNC – 2.5-5%-- PNS much lower
• Common tms with PNI
1. Cutaneous malignancies- BCC, Melanoma
2. Adenoid Cystic Ca
3. Mucosal SCC- Nasopharynx, Sino nasal, Palate, Oral Cavity and
Tonsils
4. Salivary Gland Malignancies- High grade muco epidermoid ca,
Salivary duct ca
• Only 30-40% with PNI are symptomatic at presentation

4. Delay/Miss in diagnosis of PNI– Vigilant MDT
• C/F- paresthesia, pain, numbness and/or sensory motor deficits
• Symptoms attributed to multiple cranial Ns- suggest more central
involvement such as cavernous sinus, spread from one cranial N to
another
• Must pay attention for these s/s especially in tumours more commonly
a/w PNI

5. Trigeminal N

6. Growth pattern and pathophysiology
• Contiguous retrograde – from primary tumour towards –intra
cranially
• Antegrade spread -- towards skin is also a known pattern
• Rarely Skip lesions are also known
• PNS in HNC MC involves Trigeminal and Facial N– MC sensory motor
nerves of face

7. Classification System of PNI
• No well accepted classification systems– specially there is no system
which is combining all radiological and pathological information
• MRI Classification-
• Minimal- Abnormal enhancement without gross enlargement
• Moderate- Nerve enlargement- 2-3 times greater then normal mean
diameter, with or without abnormal enhancement
• Gross- Nerve enlargement >3 times the normal with or without
abnormal enhancement
William SL RSNA meeting 1998

8. Pathological Classification
• Small N <1 mm (WPOI Grade 1)
• Large N >1 mm (WPOI Grade 3)
• Focal (1 focus)
• Moderate (2-5 foci)
• Extensive (>5 foci)
• Location of PNI –
• Intratumoral
• Extratumoral
Ref
Brandwein Gensler ;Oral SCC HRAS- Am J
Pathology 2005 Feb 29 (2): 167-78
Miller ME; Novel classification system of PNI –
Am J Otolaryngol 2012 Mar Apr 33 (2); 212-5
Aivazian K et all ; PNI in Oral SCC – J Surg
Oncology 2015 Mar ; 111 (3) ; 352-8
Tarsitano et all Oral Surg Med Oral Pathology
Oral Radiol 2015 Feb 119(2)

9. Practical Approach to PNI in HNC
1. PNI present or absent
2 If PNI is present – is it overall “”bad” or “ugly” category
• Focal/ Small N/Microscopic/ Intratumoral- “Bad”
• Extensive/Large N/Gross/Radiological/Clinical – “Ugly”
3.”Bad” PNI in isolation—Alone not a well accepted indication for PORT
• ”Ugly”PNI– Red flag alert- Detailed clinical examination, discussion with
pathologist, review of imaging, intraop findings, MDT
• Named Nerve
• Un named N

10. Imaging Findings

11. • Majority MRI finding are subtle and require targeted imaging
• MRI has high rate of detection of PNS with sensitivity of 95- 100%
• Recommended imaging technique- High resolution, small FoV, thin
collimation; preferably 3 T
• T1 Axial and Coronal plain and fat suppressed PC- Most Important
• T2 Coronal fat suppressed- Denervation changes, CSF cleft around
ganglions
• ?CISS/Hypercube
• Multi planar reformations important in evaluation of base skull
foramina
• Foramen ovale and Meckels cave are best seen in coronal images

12. Imaging Features
• T1 weighted MRI- Fat is usually present around nerves & is
hyperintense
• Obliteration of fat pads is the key sign for PNI
• Enlargement and enhancement along course of N
• Asymmetrical thickening of a nerve/ganglion
• Convexity of cavernous sinus wall and soft tissue enhancement within
Meckel cave –s/o macroscopic PNI
• CT scan is good for bony anatomy-routinely check and compare all
important foramina

13. Zonal Classification of PNS
• Zone 1- Peripheral
• Zone 2 Central/Skull base
• Zone 3- Cisternal
Medenhall WM IJROBP Vol 49,No 49;1061-69, 2001.

16. Asymmetrical enhancement of a nerve/ganglion
Secondary denervation changes in muscles
T1 PC coronal- Enhancement and
thickening of V3 along foramen ovale
Zone 2 disease of V3- Mandibular N
Denervation changes in pterygoid ms

17. Loss of perineural fat pad within a foramina
containing cranial N branch
Normal fat on the right side
Loss of normal fat around N
on left side
Zone 1
Disease of V3(inferior
alveolar Nerve)

18. Enlargement of the foramina
Enlargement or enhancement of cavernous sinus or Meckel’s cave
Zone 3 disease of Trigeminal N
Axial fat suppressed T1 PC
Enhancement and enlargement of
Gasserian ganglion extending into
nerve root entry zone in pre
pontine cistern

19. CISS Sequence
b and c- Sensory and motor nucleus of V N in Brain
Stem
D- Root Zone entry
F- Cisternal segment of V N
E- Porus trigeminalis
G- Meckel’s Cave
Meckel’s cave lies just lateral to cavernous
sinus and is continuous with pre pontine
cistern
CSF containing pouch lined with dura

21. Important Landmarks
• PPF- Pyramidal shaped space-
located b/w posterior wall of
maxillary sinus and pterygoid
process
• Important “crossroads” for PNS
as it connects Masticator space
with orbit and NPX
• Contents- Maxillary N V2, PP
ganglion, Internal maxillary A
HUB OF PNI

22. PPF
• On reaching PPF, tumours may extend to Meckel’s cave and cavernous
sinus via F rotundum
• Normally it’s a fat filled space
• Replacement of fat
• Enhancement
• Abnormal widening are imp features

24. Cavernous Sinus CN III, IV, VI , V1 and V2
Superior orbital fissure CN III, IV, V1 and VI
F Rotundum V2; Connects cavernous sinus and PPF
Vidian Canal Vidian N ( Formed by GSPN/V3 and Deep
petrosal N VIIN)
F Spinosum Middle meningeal A
F Ovale V3
PPF V2
Stylomastoid Foramina VII
Infra Orbital F V2
Greater Palatine F V2
Mandibular and Mental Foramen Inferior Alveolar N- Branch of V3
Hypoglossal Canal Hypoglossal N

25. V3

29. Nerve supply of tongue
Nerves involved in tongue and buccoalveolar complex
V
VII

30. Buccal mucosa – buccal nerve – V3

32. COMMUNICATIONS BETWEEN NERVES
• BETWEEN BRANCHES OF TRIGEMINAL N
• 1. Communication b/w branches of V1 and V2 at orbital apex (where
they lie close to each other after passing through superior orbital
fissure)
• 2.Communication b/w branches of V1 and V2 in PPF via inferior
orbital fissure
• 3. Communication b/w branches of V2 and V3 in PPF via pterygo
palatine fissure

33. • BETWEEN BRANCHES OF V and VII N
• Communication b/w branches of V2 in PPF and VII N in the vidian N
canal
• Auricuotemporal branch of V3 crosses body of parotid at right angle
to VII N- and can have communication
• If macroscopic PNI involving V N is present , carefully examine VII N
clinically and radiologically and vice versa

34. Radiation Therapy Planning
• When designing target volumes in PNI – weigh the risk benefit
• Increasing volumes to cover CN central origin can increase toxicity
• Decision to include elective CN pathways in addition to primary
tumour region depends on extent of PNI, histology, margin status and
clinical presentation

35. • Microscopic PNI of named N-CTV is 0.5 cm AA nerve
• Nerves at max risk are chosen to be covered according to anatomic
location of tumour
• Gross PNI- Clinical/radiological/Intra operative- consider elective
coverage of CNS via inter nerve connections
• ACC- higher predilection for tracking proximally along nerve tissues
towards base skull– cover CNs till base skull and inter nerve
connections

36. Treatment Volumes for “Ugly” PNI
• HR CTV =GTV= Entire post contrast enhancing path of nerve +5 mm AA
• LR CTV = Additional margin of 30 mm along nerve path and potential
margin along skull base
• In case skull base is involved- LR CTV should be prolonged up to brain
stem
• Consider appropriate margins for antegrade PNI spread and cross
commuincation b/w CNs
• Follow Zonal Classification- Involved Zone HR CTV and Subsequent zone
LR CTV
Garden AS IJROBP 1995; 32:619-26
Zukauskaite R RO 2018; 126”48-55

38. Doses
• Microscopic PNI with negative margins on Nerve- 54Gy along course
of nerve
• Gross PNI with negative margin on the nerve- 60Gy along course of N
• Gross PNI with positive margin on N 66Gy to tumour bed – while
remaining N gets 60Gy – while respecting OARs

40. 48 years old gentleman
May 2018 presented with a ulcer on
right lateral border tongue
Biopsy- MD SCCC
Surgery- Partial glossectomy + MND
HPR- 3x 1.5 x1 cm tumour
MD SCC
DoI- 10 mm
LVI +
PNI + in large nerves
All Margins free
3/51 LN positive
Largest LN 2 Cm
Microscopic ECE+
Patient with ca tongue and large
N PNI

41. Post op MRI-
• Contralateral Level IV LN
• Enhancement along ipsilateral V3 N
extending along foramen ovale to
meckel’s cave
• V3 Zone II

42. Patient had numbness along V3 distribution
FNAC- LN positive for malignancy
Left ( Contralateral LND)
HPR- 2/32 LNs with ECE
One LN at level II and second at level IV
High Risk Ds- Large N PNI
Bilateral LNs with ECE
Contralateral Lower neck LN

43. CTV 63Gy/30 fr
CTV 56GY/30 fr

44. Treatment Considerations
• MICROSCOPIC PNI
• SCC- Focal/intratumoral small N PNI- relative indication for PORT –
needs case by case discussion
• Salivary Duct Ca and Adenoid cystic Ca- have higher incidence of local
and base skull recurrences– need PORT

45. Treatment Considerations
• MACROSCOPIC PNI
• All pts with macroscopic PNI merit PORT + Concurrent Chemotherapy
• RT with IMRT
• Prerequisite-
• Good clinical examination to identify specific territory affected
• Detailed study of MRI and pathological and intraop findings

46. Recommended Reading
• Raut AA et al. Imaging of Skull base – Indian Journal of Radiology and
Imaging (Nov 2012) Vol 22. Issue 4
• Baskt RL et al. PNI and PNTS in HNC. PRO (2014);
• Baskt RL et al. Contouring guide for HNC with PNI. IJROBP (2019); Vol
103(5).
• Goraykai P et al. Post Op RT in for large nerve PNS in HNC. J Neuro Surg B
(2016); 77. 173-181.
• Gandhi M et al. Imaging of large nerve PNS. J Neuro Surg B (2016); 77. 113-
123.
• Bourhis J. Practical guidelines for contouring trigeminal nerve.
Radiotherapy and Oncology. (2018).