8 th edition TNM classification and significance of depth of invasion

Diagnosis of oral cancer is completed for:
Initial diagnosis
Staging
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.

1. 8 TH EDITION TNM CLASSIFICATION AND SIGNIFICANCE OF DEPTH OF INVASION DR. ISHITA SINGHAL MDS SECOND YEAR

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

3. Diagnosis of oral cancer is completed for: Initial diagnosis Staging 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

4. 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: Better assess the size of the lesion Look for other cancers in the upper aerodigestive tract Spread to the lymph nodes Spread to other parts of the body

5. 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.

6. 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

7. 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: 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 . Pathologic stage ( pTNM ) adds additional information gained by examination of the tumor microscopically by a pathologist after it has been surgically removed .

8. 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.

9. CLINICAL CLASSIFICATION CLINICAL OR RADIOGRAPHIC EXTRANODAL EXTENSION IMAGING PATHOLOGICAL CLASSIFICATION PATHOLOGICAL ASSESSMENT OF EXTRANODAL EXTENSION RULES FOR CLASSIFICATION

10. 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.

11. 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. 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.

12. 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. 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.

13. 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 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.

14. 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 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.

15. 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. 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.

16. 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.

17. 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. 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.

18. 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. 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.

19. 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.

20. 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 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.

21. 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

22. 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 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

23. 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. 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

24. 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. 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

25. 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. 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

26. Resected positive lymph nodes require examination for the presence and extent of ENE. ENE mi is defined as microscopic ENE < 2 mm. ENE ma is defined as macroscopic ENE which is either extranodal extension apparent to 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 pN O designation. Pathological Assessment Of Extranodal Extension 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.

27. EXTRANODAL EXTENSION DEPTH OF INVASION RESECTION MARGINS WORST PATTERN OF INVASION PERINEURAL INVASION LYMPHOVASCULAR INVASION OVERALL HEALTH COMORBIDITY LIFESTYLE FACTORS TOBACCO USE ADDITIONAL FACTORS

28. 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: ENE ( none ) ENE mi ( microscopic ENE < 2 mm ) ENE ma ( ENE>2 mm or gross ENE ) Only ENE ma is used to define pathological ENE nodal status. ENE mi versus ENE will not affect current nodal staging, but data collection is recommended to allow standardization of data collection and future analysis. Extranodal Extension 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.

29. 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.

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

31. LOCATION OF THE LYMPH NODE LEVELS IN THE NECK 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.

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

33. 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 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.

34. 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. 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.

35. 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.

36. 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

37. 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

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

39. 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 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.

40. “ 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. 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. Lower edge. The green line measures dispersion of almost 2 mm. This carcinoma reveals only few dispersed satellites fulfilling this criteria, likely due to extratumoral lymphovascular emboli.

41. 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 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.

42. 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.

43. 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 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.

44. 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.

45. Lymphovascular invasion should be reported as either: Intratumoral Extratumoral Focal Multifocal Lymphovascular Invasion 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.

46. 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 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.

47. 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

48. 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: T describes the size of the original ( primary ) tumor and whether it has invaded nearby tissue N describes nearby ( regional ) lymph nodes that are involved M describes distant metastasis ( spread of cancer from one part of the body to another )

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

50. TIME OF CLASSIFICATION

51. PRIMARY TUMOR [T] 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

52. T1 IS DEFINED AS A TUMOR 2 CM OR SMALLER IN GREATEST DIMENSION

53. T2 IS DEFINED AS A TUMOR LARGER THAN 2 CM BUT NOT LARGER THAN 4 CM IN GREATEST DIMENSION

54. T3 IS DEFINED AS TUMOR LARGER THAN 4 CM IN GREATEST DIMENSION

55. T4A (LIP) IS DEFINED AS MODERATELY ADVANCED LOCAL DISEASE, TUMOR INVADING THROUGH CORTICAL BONE, INFERIOR ALVEOLAR NERVE, FLOOR OF MOUTH, OR SKIN OF FACE, i.e., CHIN OR NOSE

56. T4B IS DEFINED AS VERY ADVANCED LOCAL DISEASE, TUMOR INVOLVES MASTICATOR SPACE, PTERYGOID PLATES, OR SKULL BASE AND/OR ENCASES INTERNAL CAROTID ARTERY

57. REGIONAL LYMPH NODE – CLINICAL [cN] 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(-)

58. REGIONAL LYMPH NODE – CLINICAL [cN] N CATEGORY N CRITERIA 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(+)

59. 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 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(-) REGIONAL LYMPH NODE – PATHOLOGICAL [pN]

60. N CATEGORY N CRITERIA 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(+) REGIONAL LYMPH NODE – PATHOLOGICAL [pN]

61. DISTANT METASTASIS M CATEGORY M CRITERIA M0 No distant metastasis M1 Distant metastasis

62. PROGNOSTIC STAGE GROUPS 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

63. HISTOLOGIC GRADING [G]

64. ICD-O-3 TOPOGRAPHY CODES

65. ANATOMICAL SITES AND SUBSITES OF THE ORAL CAVITY

66. ANATOMICAL SITES AND SUBSITES OF THE ORAL CAVITY

67. ANATOMICAL SITES AND SUBSITES OF THE ORAL CAVITY

68. CHARACTERISTICS OF LIP AND ORAL CAVITY TUMORS A.EXOPHYTIC B.ULCERATED C.ENDOPHYTIC

69. 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

70. 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.

71. Rajendran, Arya, and Shivapatha Sundaram. Shafer's Textbook of Oral Pathology. 2012. 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. 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. 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. 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. REFERENCES

72. Tan WJ, Chia Claramae, Tan HK, Soo KC, Iyer NG. Prognostic Significance of Invasion Depth in Oral Tongue Squamous Cell Carcinoma. ORL. 2012; 74:264–270. Berdugo J, Thompson LDR, Purgina B, et al. Measuring Depth of Invasion in Early Squamous Cell Carcinoma of the Oral Tongue: Positive Deep Margin, Extratumoral Perineural Invasion, and Other Challenges. Head Neck Pathol. 2019;13(2):154–161. Ghazi N, Ghazi A, Shafiee S, Fayyazi M. Importance of depth of invasion in patients with oral squamous cell carcinoma: A review article. J Orofac Sci. 2018; 10:3-6 Moe J, McHugh JB, Udager AM, Braun TM, Helman JI, Ward BB. Intraoperative Depth of Invasion Is Accurate in Early-Stage Oral Cavity Squamous Cell Carcinoma. J Oral Maxillofac Surg. 2019; 77:1704-1712. Chang WC, Chang CF, Li YH, Yang GY, Su RY, Lin CK, Chen YW. A histopathological evaluation and potential prognostic implications of oral squamous cell carcinoma with adverse features. Oral Oncol. 2019 Aug; 95:65-73.