8 th edition TNM classification and significance of depth of invasion

8TH EDITION
TNM CLASSIFICATION
AND
SIGNIFICANCE OF
DEPTH OF INVASION
DR. ISHITA SINGHAL
MDS SECOND YEAR

INDEX
• DIAGNOSIS
• CANCER STAGING
• RULES FOR CLASSIFICATION
• ADDITIONAL FACTORS
• TNM STAGING
• REFERENCE ARTICLES
• REFERENCES

Diagnosis of oral cancer is completed for:
1. Initial diagnosis
2. Staging
3. Treatment planning
A complete history, and clinical examination is
first completed, then a wedge of tissue is cut
from the suspicious lesion for tissue diagnosis.
In this procedure, the surgeon cuts all, or a piece
of the tissue, to have it examined under a
microscope by a pathologist.
DIAGNOSIS

• With the first biopsy, the pathologist will provide a tissue diagnosis, and classify the cell
structure. They may add additional information that can be used in staging, and treatment
planning, such as the mitotic rate, the depth of invasion, and the HPV status of the tissue.
• After the tissue is confirmed cancerous, other tests will be completed to:
1. Better assess the size of the lesion
2. Look for other cancers in the upper aerodigestive tract
3. Spread to the lymph nodes
4. Spread to other parts of the body

• When the cancer has spread to lymph nodes, their exact location, size, and spread beyond
the capsule needs to be determined, as each can have a significant impact on treatment
and prognosis.
• From these collective findings, taken in consideration with the health and desires of the
person, the cancer team develops a plan for treatment.
• Since most oral cancers require surgical removal, a second set of histopathologic tests will
be completed on any tumor removed to determine the prognosis, need for additional
surgery, chemotherapy, radiation, immunotherapy, or other interventions.

It is the process of determining the extent to
which a cancer has developed by growing and
spreading.
It is assigned a number from I to IV, with I being
an isolated cancer and IV being a cancer that
has spread to the limit of what the assessment
measures.
The stage generally takes into account the size
of a tumor, whether it has invaded adjacent
organs, how many regional lymph nodes it has
spread to, and whether it has appeared in more
distant locations.
CANCER STAGING

• Correct staging is critical because treatment particularly the need for pre-operative
therapy and/or for adjuvant treatment, the extent of surgery is generally based on this
parameter. Thus, incorrect staging would lead to improper treatment.
• Cancer staging can be divided into:
1. Clinical stage (cTNM) is based on all of the available information obtained before a
surgery to remove the tumor. This stage may include information about the tumor
obtained by physical examination, blood tests, radiologic examination, biopsy, and
endoscopy.
2. Pathologic stage (pTNM) adds additional information gained by examination of the
tumor microscopically by a pathologist after it has been surgically removed.

• Pathologic staging is usually considered to be more accurate because it allows direct
examination of the tumor in its entirety, contrasted with clinical staging which is limited
by the fact that the information is obtained by making indirect observations of a tumor
which is still in the body.
• However, clinical staging and pathologic staging often complement each other.
• Not every tumor is treated surgically, so pathologic staging is not always available.
• Also, sometimes surgery is preceded by other treatments such as chemotherapy and
radiation therapy which shrink the tumor, so the pathologic stage may underestimate the
true stage.

1. CLINICAL CLASSIFICATION
2. CLINICAL OR RADIOGRAPHIC
EXTRANODAL EXTENSION
3. IMAGING
4. PATHOLOGICAL CLASSIFICATION
5. PATHOLOGICAL ASSESSMENT OF
EXTRANODAL EXTENSION
RULES FOR CLASSIFICATION

• Clinical staging for Lip and Oral Cavity cancers is predicated most strongly upon the
history and physical examination.
• Biopsy is necessary to confirm diagnosis and is typically done of the primary.
• Nodal biopsy is done by fine needle aspiration when indicated.
• Results from diagnostic biopsy of the primary tumor, regional nodes, and distant
metastases can be included in clinical classification.
• Inspection of the lip and oral cavity typically reveals the greatest diameter of a cancer,
though palpation is essential to assess DOI and submucosal extension.
• The mucosal extent of the cancer usually reflects its true linear dimension. Induration
surrounding a cancer typically is due to peritumoral inflammation.
Clinical Classification
Gress DM, Edge SB, Greene FL, et al. Principles of cancer staging. In: Amin MB, ed. AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer; 2017.

• DOI should be distinguished from tumor thickness, and its determination is predicated on
invasion beneath the plane defined by surrounding normal mucosa.
• Any exophytic character should be noted, but assignment of stage is determined by what
transpires at or beneath the surface.
• Clinical evidence of bone destruction should be noted and its depth estimated.
• Thick lesions often are defined by CT or MRI, but the difference between thickness and
DOI must be observed.
• Lesions located near the midline more often involve the contralateral side of the neck
than well-lateralized cancers.
• Complaints of numbness of the lip and/or teeth are commonly associated with nerve
invasion.

• The distinction between 4 mm DOI and 6 mm DOI (for example) may not be possible on
clinical grounds. The stage should only be raised on the basis of DOI if the differences are
clear.
• Evidence of cranial nerve dysfunction should be sought and skin should be examined for
evidence of invasion by underlying nodes.
• Palpable neck nodes should be considered in terms of their location, size, number,
character, attachment to other nodes, and mobility.
• Nodes that do not move in all directions may be invading nearby structures.

• ENE worsens the adverse outcome associated with nodal metastasis.
• The presence of ENE can be diagnosed clinically by the presence of a “matted” mass of
nodes, involvement of overlying skin, adjacent soft tissue, or clinical signs of cranial nerve
or brachial plexus, sympathetic chain or phrenic nerve invasion.
• The most reliable imaging signs are an indistinct nodal margin, irregular nodal capsular
enhancement or infiltration into the adjacent fat or muscle, with the latter finding on CT
and MRI as the most specific sign of ENE.
• Ultrasound appears to be less accurate than CT and MRI, but ENE is suggested by
interrupted or undefined nodal contours with high-resolution ultrasound imaging.
• The absence or presence of clinical/ radiologic ENE is designated ENE (-) or ENE(+),
respectively.
Clinical Or Radiographic Extranodal Extension

• Cross-sectional imaging of the oral cavity may be performed with either CT or MRI,
depending on availability, patient imaging tolerance, contrast allergies, and cost.
• The radiologist's more important role during tumor staging is to determine deep tissue
involvement and assess for nodal and/or distant metastases.
• Imaging studies showing amorphous speculated margins of involved nodes or
involvement of internodal fat resulting in loss of normal oval to round nodal shape
strongly suggest extranodal extension; however, pathological examination is necessary to
prove its presence.
Imaging

• With either modality, the coronal plane view—either as direct MRI or from reformats
obtained from axially acquired thin-slice CT—allows excellent evaluation of the floor of
the mouth.
• CT offers some advantage over MRI in the evaluation of cortical bone erosion.
• MRI offers the additional advantage of evaluation of perineural tumor spread, which for
oral cavity tumors is primarily along the inferior alveolar nerve of the mandible and the
greater and lesser palatine nerves of the maxilla.
• PET/CT is primarily done for nodal staging of disease or when distant metastases are
suspected.
• Ultrasound does not allow adequate evaluation of the oral cavity primary tumor site, but
it may be supplementary for nodal evaluation with otherwise equivocal nodal imaging
findings.

• Weimar EAM et al (2018) stated that inclusion of DOI is applicable to both clinical and
pathologic T-classifications, though its prognostic value is primarily derived from surgical
specimens.
• Although mainly managed via an operation, some patients with OSCC do not undergo an
operation due to the high risk, functional considerations, and personal choice.
• In these cases, radiologic measurement combined with clinical assessment is the only way
to assess TT and DOI to stage a tumor when an operation is not undertaken.
• Therefore, addressing the performance of an imaging-based parameter compared with a
criterion standard pathologic measurement is essential to achieve an accurate T-
classification.
Weimar EAM et al. Radiologic-Pathologic Correlation of Tumor Thickness and Its Prognostic Importance in Squamous Cell Carcinoma of the Oral Cavity: Implications for the Eighth
Edition Tumor, Node, Metastasis Classification. AJNR Am J Neuroradiol. 2018; 1-7.

• Robust data confirming the reliability of measuring radiologic depth of invasion (rDOI) versus
pathologic depth of invasion (pDOI) do not exist, likely due to the unavailability of the latter
because institutions traditionally only reported pathologic TT (pTT) not pDOI.
• Several studies have reported that TT measured on MRI or CT correlates well with pTT.
• He found that pTT is generally thinner than rTT, potentially attributable to tumor shrinkage
after formaldehyde fixation.
• Most interesting, the shrinkage factor was smaller for oral tongue compared with other subsite
tumors.
• He hypothesized that the tongue, an organ with more free margins, has less propensity to
shrink than tumors that are more deeply embedded in surrounding tissues.

• Because the eighth edition TNM includes DOI for the clinical T-classification, confirming its
reliability and prognostication clinically and radiologically is important because not all patients
undergo an operation.
• Clinicians need to use both clinical assessment and imaging to best determine the clinical T-
classification for this population.
• A practical challenge in assessing rDOI is the starting point of the “plumb line.”
• Pathologic assessment used the adjacent mucosal basement membrane, which is invisible on
imaging because the thickness of the oral mucosal epithelium is < 0.5 mm, representing a
negligible difference between the potential originating points of measurement.
• Correspondingly, for practical reasons, he proposed that imaging could use an interpreted
mucosal plane across the “surface” of the adjacent normal mucosa for rDOI measurement.

• Complete resection of the primary site and/or regional lymph node dissections, followed by
pathological examination of the resection specimen allows for the use of this designation for pT
and/or pN, respectively.
• Resections after radiation or chemotherapy should be identified and considered in context.
• pT is derived from the actual measurement of the unfixed tumor in the surgical specimen.
• It should be noted that, up to 30% shrinkage of soft tissues may occur in resected specimen after
formalin fixation.
• Pathological staging represents additional and important information and should be included as
such in staging, but it does not supplant clinical staging as the primary staging scheme.
• Metastasis found on imaging is considered cM1. Biopsy proven metastasis is considered pM1.
Pathological Classification

• Verma A et al (2019) stated that out of all imaging modalities, MRI delineates soft-tissue
involvement better and is considered the most accurate imaging for assessing tumor
extent in tongue carcinoma.
• As tumor has 3D anatomy, the definition of TT should be considered not only in terms of
the lengths but also in the anterior-posterior, superior-inferior, and medial-lateral
directions.
• This better represents the extent of invasion of oral tongue (OT) SCC and will be an
important factor in deciding the surgery and predicting prognosis.
• Different studies focused on the proper definitions of TT and DOI.
• TT refers to the thickness of the entire tumor mass.
• DOI refers to the extent of tumor beneath an epithelial surface.
Verma A, Singhal A, Hadi R, Singh P, Raj G. Evaluation of tumor thickness in three dimensions on magnetic resonance imaging and its comparison with final histopathology in
squamous cell carcinoma of the tongue. Clin Cancer Investig J 2019;8:161-6

Measurement of tumor thickness on magnetic resonance imaging.
Tumor thickness was obtained from the summation of the distance of the perpendicular line from the reference line to the deepest infiltration
point (a) and to the most projecting point of tumor (b)
(A) The Longest Tumor Diameter Antero-
posteriorly On The Axial View (B) Mediolaterally On The Coronal View (C) Supero-inferiorly On The Sagittal View

• Comparing the two parameters, DOI predicts the risk of lymphatic and hematogenous
spread more accurately.
• Therefore, proper assessment of tumor extent on imaging is important for appropriate
treatment planning.
• He found out that on comparing the TT on MRI in antero-posterior plane and
craniocaudal plane with the pathology reports, TT measured on MRI was greater than that
of pathological TT due to shrinkage.
• He also found out that TT measured in MRI in axial plane was nearly equal that of
pathological TT, because there is minimum shrinkage in the axial plane. The minimum
shrinkage may be due to varying amount of edema and fibrotic tissue in vicinity of tumor,
as a larger amount of lesions were located on the lateral border and are probably
exophytic.

• And when DOI reported on MRI was correlated with the pathology reports, TT measured
in MRI was greater than that of pathological TT, because of maximum shrinkage factor
seen in this category which in fact may be due shrinkage of muscle mass by
electrocautery and formalin.
• It is generally considered that DOI and prediction of risk of nodal metastases are based on
pathologic assessment and not on clinical or radiographic assessment as they may under
or overestimate DOI and did not have the same ability to predict nodal metastases.
• While MRI was shown to correlate well with pathological depth and is more sensitive and
specific for depth measurements than clinical assessment; nevertheless, the palpation of
tumor for assessment of depth is complementary and may be useful in situations where
either MRI is unavailable or difficult to interpret due to artifacts.

• Maximum shrinkage factor of approximately 1 cm was obtained in axial dimension; this
may be due inflammatory, post biopsy changes and exophytic nature of tumor mass as
maximum tumors were located on lateral border of the tongue.
• Recently, DOI has been included in AJCC 8th staging for oral cavity cancers.
• However, depth is accurately determined on the postoperative histopathology reports.
• If determined preoperatively, it can determine the prognosis and appropriate planning of
the treatment.
• MRI is the best imaging modality for TT and DOI, there are no standard guidelines
regarding it and studies with larger number of patients will be required in future to set up
MRI protocols regarding accurate assessment of TT and DOI.

• Resected positive lymph nodes require examination for the presence and extent of ENE.
• ENEmi is defined as microscopic ENE < 2 mm.
• ENEma is defined as macroscopic ENE which is either extranodal extension apparent to the
the naked eye at the time of dissection or extension > 2 mm beyond the lymph node
capsule microscopically. This is used to define pathological ENE(+) nodal status.
• For assessment of pN, a selective neck dissection will ordinarily include 10 or more lymph
nodes, and a comprehensive neck dissection will ordinarily include 15 or more lymph
nodes.
• Examination of fewer tumor-free nodes still mandates a pNO designation.
Pathological Assessment Of Extranodal Extension

1. EXTRANODAL EXTENSION
2. DEPTH OF INVASION
3. RESECTION MARGINS
4. WORST PATTERN OF INVASION
5. PERINEURAL INVASION
6. LYMPHOVASCULAR INVASION
7. OVERALL HEALTH
8. COMORBIDITY
9. LIFESTYLE FACTORS
10. TOBACCO USE
ADDITIONAL FACTORS

• ENE is defined as extension of metastatic carcinoma within lymph node, through the
capsule, and into the surrounding connective tissue, regardless of associated stromal
reaction.
• Histopathologic designations for ENE are as follows:
1. ENE0 (none)
2. ENEmi (microscopic ENE < 2 mm)
3. ENEma (ENE>2 mm or gross ENE)
• Only ENEma is used to define pathological ENE nodal status.
• ENEmi versus ENE0 will not affect current nodal staging, but data collection is
recommended to allow standardization of data collection and future analysis.
Extranodal Extension

• In order for pathologists to properly identify these nodes, they must be familiar with the
terminology of the regional lymph node groups and with the relationships of those
groups to the regional anatomy.
• Which lymph node groups surgeons submit for histopathologic evaluation depends on
the type of neck dissection they perform.
• Therefore, surgeons must supply information on the types of neck dissections that they
perform and on the details of the local anatomy in the specimens they submit for
examination or, in other manners, orient those specimens for pathologists.
Seethala RR et al. Protocol for the Examination of Specimens from Patients with Cancers of the Lip and Oral Cavity. LipOralCavity 4.0.0.1. 2017.

• If it is not possible to assess the levels of lymph nodes, then the lymph node levels may
be estimated as follows:
1. Level II, upper third of internal jugular (IJ) vein or neck specimen
2. Level III, middle third of IJ vein or neck specimen
3. Level IV, lower third of IJ vein or neck specimen
all anterior to the sternocleidomastoid muscle.

(a) Extranodal extension of
metastatic carcinoma, low-
power. The large vessels
(black arrows) are
extranodal in location.
(b) The direction of the
collagen and the location
of vessels guide the
estimation of the natural
lymph node boundary
(yellow line).
(c) This carcinoma extends > 2
mm from the estimated
lymph node boundary
(green line) and should be
classified as ENEma.

• DOI assesses the invasiveness of a carcinoma, regardless of any exophytic component.
• It is measured by first finding the “horizon” of the basement membrane of the adjacent
squamous mucosa.
• A perpendicular “plumb line” is established from this horizon to the deepest point of
tumor invasion, which represents DOI.
• The DOI is recorded in millimetres.
• Measurements in millimetres can easily be accomplished by printing rulers on acetate
sheets, which can be overlaid onto glass slides.
Depth Of Invasion

• Proper gross techniques (avoidance of tangential cuts and serial sectioning of the lesion
at 2-3 mm intervals) will facilitate subsequent microscopic assessment.
• While thickness and DOI are often regarded as synonymous, they have slight differences.
• Thickness is usually measured from the mucosal surface of the tumor to the deepest
point of tissue invasion in a perpendicular fashion with an optical micrometre or
transparent ruler overlaid on the slide, while DOI is measured from the basement
membrane of adjacent normal to the deepest point of invasion of the tumor.

Estimation of DOI (red line) is achieved by measuring the distance perpendicularly from the level of
adjacent normal epithelial basement membrane (green line) to the point of deepest invasion. TT (blue line)
is a measure of entire dimension of the tumour from the surface to the point of deepest invasion. (a) in
exophytic/superficial OSCC: TT > DOI and (b) in ulcerative OSCC: DOI > TT. Note: In this case, TT is
deceivingly less than the actual DOI which would underestimate the true aggressive potential of the
tumour. DOI: depth of invasion; TT: tumour thickness; OSCC: oral squamous cell carcinoma.

Depth of invasion (DOI).
The horizon is established at
the level of the basement
membrane relative to the
closest intact squamous
mucosa. The greatest DOI is
measured by dropping a
“plumb line” from the
horizon.
PLUMB LINE
HORIZON FROM ADJACENT MUCOSAL BASEMENT MEMBRANE
9 mm

Depth of invasion (DOI) in
an ulcerated carcinoma.
Notice how “tumor
thickness” would be
deceptively thinner than
DOI.
PLUMB LINE
HORIZON FROM ADJACENT MUCOSAL BASEMENT MEMBRANE
6 mm

Tumor thickness to the nearest 0.1
mm is determined with an ocular
micrometre.

• The ideal manner of intraoperative margin assessment is the “specimen driven
approach”.
• Direct discussion between surgeon and pathologist at specimen hand-off allows for
correct anatomic orientation and identification of any intraoperative non-margin tissue
tears or cuts.
• The pathologist maps the specimen, paints the different margin planes with unique
colours, and documents the designations.
• The pathologist makes multiple cuts into the margins at 5 to 10 mm intervals
perpendicular to the resection plane. Initial gross assessment yields important preliminary
information.
• This is followed by targeted microscopic examination of margins of interest.
• The distance between carcinoma and resection margin should be reported in millimetres.
Resection Margin

“WPOI-5” describes a dispersed
tumor pattern of invasion which
is significantly predictive of
worst outcome. Carcinomas are
classifiable as WPOl-5 when
satellite dispersion is > 1 mm
from neighbouring satellites.
a) Low-power overview
demonstrating a context of
generalized tumor
dispersion. Tumor dispersion
is measured at the advancing
tumor edge. Carcinoma
satellites in the green box are
shown in panel.
b) Lower edge. The green line
measures dispersion of
almost 2 mm.
c) This carcinoma reveals only
few dispersed satellites
fulfilling this criteria, likely
due to extratumoral
lymphovascular emboli.

• Worst pattern of invasion (WPOI) is a validated outcome predictor for oral cavity
squamous carcinoma patients in multivariate analysis.
• To simplify prognostication and enhance adaptation, the only cut point recommended for
assessment is whether or not WPOI-5 is present.
• WPOI-5 is defined as tumor dispersion of > 1 mm between tumor satellites.
• With respect to low-stage oral cavity squamous carcinomas > 4 mm DOI, the presence of
WPOI-5 is significantly predictive of locoregional recurrence and disease-specific survival
and the probability of developing locoregional recurrence is almost 42%.
• Tumor dispersion is assessed at the advancing tumor edge. The most common WPOI-5
phenotype is tumor dispersion through soft tissue.
Worst Pattern Of Invasion

Top: A “strandy” pattern with
intervening skeletal muscle
observable at low-power is often
classifiable as WPOI-5.
Bottom: This strand pattern is also
often associated with perineural
invasion.

• Perineural invasion (PNl) should be subclassified as either intratumoral or extratumoral.
• Involvement of named nerves should be specifically reported.
• PNl should be subclassified as focal or multifocal.
• Extensive multifocal PNl is usually extratumoral and frequently associated with a “strand-
like” tumor phenotype.
• The largest nerve diameter should be reported for multifocal, extratumoral PNl.
Perineural Invasion

Carcinoma should
demonstrate a specific
relationship with nerve,
such as wrapping
around nerves, in order
to be classified as
perineural invasion
(PNI).
Merely “bumping” into
a nerve does not
constitute PNI.

• Lymphovascular invasion should be reported as either:
1. Intratumoral
2. Extratumoral
3. Focal
4. Multifocal
Lymphovascular Invasion

• The protocol tries to remain simple while still incorporating important pathologic features
as proposed by the AJCC cancer staging manual, WHO classification of tumors, the TNM
classification, the American College of Surgeons Commission on Cancer, and the UICC.
• This protocol is to be used as a guide and resource, an adjunct to diagnosing and
managing cancers of the oral cavity in a standardized manner.
• It should not be used as a substitute for dissection or grossing techniques and does not
give histologic parameters to reach the diagnosis. Subjectivity is always a factor, and
elements listed are not meant to be arbitrary but are meant to provide uniformity of
reporting across all the disciplines that use the information.
• It is a foundation of practical information that will help to meet the requirements of daily
practice to benefit both clinicians and patients alike.
Scope Of Guidelines

It is a globally recognised standard for
classifying the extent of spread of cancer.
It is a classification system of the anatomical
extent of tumor cancers.
The TNM staging system for all solid tumors was
devised by Pierre Denoix between 1943 and
1952, using the size and extension of the
primary tumor, its lymphatic involvement, and
the presence of metastases to classify the
progression of cancer.
TNM STAGING SYSTEM

• TNM was developed and is maintained by the Union for International Cancer Control
(UICC) and the American Joint Committee on Cancer (AJCC). In 1987, the UICC and AJCC
staging systems were unified into the single TNM staging system. TNM is a notation
system that describes the stage of a cancer, which originates from a solid tumor, using
alphanumeric codes:
1. T describes the size of the original (primary) tumor and whether it has invaded nearby
tissue
2. N describes nearby (regional) lymph nodes that are involved
3. M describes distant metastasis (spread of cancer from one part of the body to another)

EDITION PUBLICATION
DATES EFFECTIVE FOR CANCER
DIAGNOSED
1ST 1977 1978 – 1983
2ND 1983 1984 – 1988
3RD 1988 1989 – 1992
4TH 1992 1993 - 1997
5TH 1997 1998 - 2002
6TH 2002 2003 – 2009
7TH 2009 2010 - 2016
8TH 2016 2017 – TILL DATE

T CATEGORY T CRITERIA
TX Primary tumor cannot be assessed
Tis Carcinoma in situ
T1
Tumor< 2 cm , < 5 mm depth of invasion (DOI)
DOI is depth of invasion and not tumor thickness.
T2
Tumor < 2 cm, DOI > 5 mm and < 10 mm
or tumor > 2 cm but < 4 cm, and < 10 mm DOI
T3 Tumor > 4 cm or any tumor > 10 mm DOI
T4 Moderately advanced or very advanced local disease
T4a
Moderately advanced local disease
(lip) Tumor invades through cortical bone or involves the inferior alveolar nerve, floor of mouth, or skin of face
(i.e., chin or nose).
(oral cavity) Tumor invades adjacent structures only (e.g., through cortical bone of the mandible or maxilla, or
involves the maxillary sinus or skin of the face)
Note: Superficial erosion of bone/tooth socket.
(alone) by a gingival primary is not sufficient to classify a tumor as T4.
T4b
Very advanced local disease
Tumor invades masticator space, pterygoid plates, or skull base and/or encases the internal carotid artery

N CATEGORY N CRITERIA
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1
Metastasis in a single ipsilateral lymph node,
3 cm or smaller in greatest dimension and ENE(-)
N2
Metastasis in a single ipsilateral node larger than 3 cm but not larger than 6 cm in greatest dimension and ENE(-);
or metastases in multiple ipsilateral lymph nodes, none larger than 6 cm in greatest dimension and ENE(-);
or in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension, and ENE(-)
N2a Metastasis in a single ipsilateral node larger than 3 cm but not larger than 6 cm in greatest dimension, and ENE(-)
N2b Metastasis in multiple ipsilateral nodes, none larger than 6 cm in greatest dimension, and ENE(-)
N2c Metastasis in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension, and ENE(-)

N3
Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE(-);
or metastasis in any node(s) and clinically overt ENE(+)
N3a Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE(-)
N3b Metastasis in any node(s) and clinically overt ENE(+)
NOTE
A designation of “U” or “L” may be used for any N category to indicate metastasis above the lower border of the
cricoid (U) or below the lower border of the cricoid (L).
Similarly, clinical and pathological ENE should be recorded as ENE(-) or ENE(+)

NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1
Metastasis in a single ipsilateral lymph node,
3 cm or smaller in greatest dimension and ENE(-)
N2
Metastasis in a single ipsilateral lymph node- 3 cm or smaller in greatest dimension and ENE(+);
or larger than 3 cm but not larger than 6 cm in greatest dimension and ENE(-);
or metastases in multiple ipsilateral lymph nodes, none larger than 6 cm in greatest dimension and ENE(-);
or in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension, ENE(-)
N2a
Metastasis in single ipsilateral or contralateral node 3 cm or smaller in greatest dimension and ENE(+);
or single ipsilateral node larger than 3 cm but not larger than 6 cm in greatest dimension and ENE(-)
N2b Metastasis in multiple ipsilateral nodes, none larger than 6 cm in greatest dimension and ENE(-)
N2c Metastasis in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension and ENE(-)

N3
Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE(-);
or in a single ipsilateral node larger than 3 cm in greatest dimension and ENE(+);
or multiple ipsilateral, contralateral or bilateral nodes any with ENE(+)
N3a Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE(-)
N3b
Metastasis in a single ipsilateral node larger than 3 cm in greatest dimension and ENE(+);
or multiple ipsilateral, contralateral or bilateral nodes any with ENE(+)
NOTE
A designation o f “U” or “L” may be used for any N category to indicate metastasis above the lower
border o f the cricoid (U) or below the lower border of the cricoid (L) Similarly, clinical and
pathological ENE should be recorded as ENE(-) or ENE(+)

M CATEGORY M CRITERIA
M0 No distant metastasis
M1 Distant metastasis

WHEN T is.. AND N is.. AND M is..
THEN THE STAGE
GROUP is..
T1 N0 M0 I
T2 N0 M0 II
T3 N0 M0 III
T1, T2, T3 N1 M0 III
T4a N0, N1 M0 IV A
T1, T2, T3, T4a N2 M0 IV A
ANY T N3 M0 IV B
T4b ANY N M0 IV B
ANY T ANY N M1 IV C

• Tan WJ et al (2012) that tumors with pathological invasion depth ≥ 4 mm were 3.3 times
more likely to suffer from local recurrence compared with tumors of invasion depth < 4
mm.
• Ghazi N et al (2018) stated that the increasing DOI and the microvascular proliferation
caused by neoplastic growth might determine proximity to blood vessels and lymphatic
channels, thus facilitating the metastatic process. He also said that DOI and TT are strong
and independent predictors of metastatic neck lymph nodes and this finding has also
been confirmed by metanalytic studies.
• Moe J et al (2019) stated that DOI in intraoperative frozen sections has an accuracy of
96.8% and may be reliably used as a clinical tool to determine the need for END in early-
stage OCSCC.
• Chang WC et al (2019) determined that survival prognosis for patients with a pN0 status,
should include all adverse features. In contrast, extra nodal extension was the most
important prognostic factor for patients with a pN+ status.
REFERENCE ARTICLES

• Berdugo et al (2019) stated that a proactive assessment and reporting of DOI on
diagnostic biopsies or documentation of factors limiting DOI measurement (e.g.,
fragmentation, lack of intrinsic tongue musculature, absence of normal mucosa) may
minimize the need to re-review the diagnostic biopsy when glossectomy reveals no or
minimal residual carcinoma.

1. Rajendran, Arya, and Shivapatha Sundaram. Shafer's Textbook of Oral Pathology. 2012.
2. Gress DM, Edge SB, Greene FL, et al. Principles of cancer staging. In: Amin MB, ed. AJCC Cancer Staging
Manual. 8th ed. New York, NY: Springer; 2017.
3. Seethala RR et al. Protocol for the Examination of Specimens from Patients with Cancers of the Lip and Oral
Cavity. LipOralCavity 4.0.0.1. 2017.
4. Weimar EAM et al. Radiologic-Pathologic Correlation of Tumor Thickness and Its Prognostic Importance in
Squamous Cell Carcinoma of the Oral Cavity: Implications for the Eighth Edition Tumor, Node, Metastasis
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8 th edition TNM classification and significance of depth of invasion

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