General rules for clinical and pathological studies on oral cancer (2nd edition): a synopsis

For doctors and other medical staff treating oral cancer, it is necessary to standardize the basic concepts and rules for oral cancer to achieve progress in its treatment, research, and diagnosis. Oral cancer is an integral part of head and neck cancer and is treated in accordance with the general rules for head and neck cancer. However, detailed rules based on the specific characteristics of oral cancer are essential. The objective of this article was to contribute to the development of the diagnosis, treatment, and research of oral cancer, based on the correct and useful medical information of clinical, surgical, pathological, and imaging findings accumulated from individual patients at various institutions. Our general rules were revised as the UICC was revised for the 8th edition and were published as the Japanese second edition in 2019. In this paper, the English edition of the “Rules” section is primarily presented.


Introduction
Oral cancer is an integral part of head and neck cancer and is treated in accordance with the general rules for head and neck cancer. A part of the rules for managing oral cancer overlaps with the "General Rules for Clinical and Pathological Studies on head and neck cancer" published in 2018 (6th edition, Tokyo, Kanehara & Co. Ltd.), which can be said to differ from the general rules for cancers of other organs. However, the oral cavity is unique, since it contains the tongue, mandible, and teeth, with corresponding multiple and diverse functions such as swallowing, articulation, occlusion, and mastication. Moreover, the placement of various importance structures, such as nerves, blood vessels, and major salivary gland ducts is responsible for the anatomical complexity of the oral cavity. Therefore, we authored the "General Rules for Clinical and Pathological Studies on Oral Cancer" [1].
These rules were formulated, in principle, on the basis of the UICC and WHO classifications, but were partially revised when revision was considered necessary, and were proposed as a draft by the Japanese Society of Oral Oncology. We have devised detailed and highly accurate rules for the management of oral cancer, in order to overcome these problems. We referred to the contents of the general rules for head and neck cancer to ensure consistency for both rules.
Our general rules were revised as the UICC was revised for the 8th edition and were published as the second edition in Japanese in 2019 [2]. The revision consisted of 3 parts, i.e., the rules, explanations, and references, totaling 169 pages. In this paper, the English edition of the "Rules" section is primarily presented because of a limitation of space.

Objectives
In order to enable people handling oral cancer in various positions to be able to conduct diagnosis, treatment, and research uniformly, the standardization of basic concepts and specific methods for their handling is necessary. The objectives of the rules listed in this article were to collect clinical, surgical, and pathological findings, including image information, by employing common standards; to clarify detailed pathological features; to accumulate useful medical information from individual patients at various facilities; and to contribute to the development of diagnosis, treatment, and research of oral cancer.

Target diseases
In the present rules, oral cancer means carcinoma originating in the covering mucosa of the lip and six sites in the oral cavity, according to the UICC classification. The sites include cancer of the lip, buccal mucosa, upper gingiva, lower gingiva, hard palate, tongue, and floor of the mouth, in order of incidence. Secondary cancer is excluded. Cancer of the minor salivary gland and oral mucosal melanoma are included, while cancer of the major salivary gland is excluded.

Anatomical sites and subsites
Lip (C00) (Fig. 1   as leukoplakia, that continue to the lesion are described separately. Submucosal induration is measured, including the area diagnosed with cancer.

Depth of invasion (DOI)
The depth of invasion (DOI) has been added as a modification to T factors. The DOI concept applies only to carcinomas arising in the lip and oral cavity. DOI is measured from the level of the basement membrane of the closest adjacent normal mucosa. A "plumb line" is dropped from this place to the deepest portion of cancer invasion. Thus, it is important to recognize the distinction between tumor thickness and true DOI. Clinically, DOI is categorized as being less than or equal to 5 mm, greater than 5 mm but not greater than 10 mm, and greater than 10 mm.
• Different from the DOI used in the digestive tract. Tumor 2 cm or less in greatest dimension and 5 mm or less depth of invasion. T2

Macroscopic types
Tumor 2 cm or less in greatest dimension and more than 5 mm depth of invasion or tumor more than 2 cm but not more than 4 cm in greatest dimension and depth of invasion no more than 10 mm. T3 Tumor more than 2 cm but not more than 4 cm in greatest dimension and depth of invasion more than 10 mm or tumor more than 4 cm in greatest dimension and not more than 10 mm depth of invasion. T4a (Lip) Tumor invades through cortical bone, inferior alveolar nerve, floor of mouth, skin (of the chin or the nose) * T4a (Oral cavity) Tumor more than 4 cm in greatest dimension and more than 10 mm depth of invasion, or tumor invades through the cortical bone of the mandible or maxilla or involves the maxillary sinus, or invades the skin of the face* T4b (Lip and oral cavity) Tumor invades masticator space, pterygoid plates or skull base, or encases internal carotid artery.
Note: *Superficial erosion alone of bone/tooth socket by gingival primary is not sufficient to classify a tumor as T4a.
• Evaluation is based on the physical and imaging findings. • For minor salivary gland tumors, this rule is applied, but the concept of DOI is excluded in T factor.
(2) Regional Lymph Node Metastasis The classification and range of cervical lymph nodes are the same as described in the Rules Regarding Lymph Nodes by the Japan Society of Clinical Oncology (JSCO). Lymph node metastasis was evaluated according to the UICC classification (8th Edition). Internationally, the level classification system by ACHNSO based on the area of neck dissection is widely used, and the AAO-HNS classification, a fragmented version of the ACHNSO classification, has also been proposed.
(2) Number of metastasis Number of metastatic lymph nodes. Clinical N (cN).
NX Regional lymph nodes cannot be assessed. N0 No regional lymph node metastasis. N1 Metastasis in a single ipsilateral lymph node, ≤ 3 cm in greatest dimension and cENE (−). N2a Metastasis in a single ipsilateral lymph node > 3 cm but ≤ 6 cm in greatest dimension and cENE (−). N2b Metastasis in multiple ipsilateral lymph nodes, none > 6 cm in greatest dimension and cENE (−).
N2c Metastasis in bilateral or contralateral lymph nodes, none > 6 cm in greatest dimension and cENE (−). N3a Metastasis in a lymph node, > 6 cm in greatest dimension and cENE (−). N3b Metastasis in any node(s) and cENE ( +)* Note: *The presence of skin involvement or soft tissue invasion with deep fixation/tethering to underlying muscle or adjacent structures or clinical signs of nerve involvement is classified as clinical extranodal extension (cENE).
(4) Stage (Table 1) The clinical stage is determined according to the UICC classification (8th edition). The T, N, M factors and stages are recorded (Stage 0, I, II, III, IVA, IVB, and IVC).
• In the 1st edition of general rules for clinical and pathological studies on oral cancer, lower gingival cancer with invasion through the cortical bone is insufficient for T4a classification, but the tumor with invasion reaching the mandibular canal (MC) is classified as T4a [1,2]. This classification has been supported by a study of 345 patients with lower gingival cancer [3]. The status of bone invasion in oral cancer should, therefore, be clarified. Bone invasion in oral cancer is categorized into three types: no bone invasion [BI (−)], bone invasion is absent or limited to cortical bone; medullary invasion [BI ( +)], invasion into cancellous bone is present, but does not extend into the MC; and MC invasion [MC ( +)], invasion extends into the MC.

(5) Oral mucosal melanoma
Oral mucosal malignant melanoma is described separately because the classification is different. This classification applies only to oral malignant melanoma. Classification rules are based on the malignant melanoma of the head and neck and gastrointestinal tract. There should be histological confirmation of the disease and division of cases by site. The evaluation methods in the TNM category are physical examination and diagnostic imaging. The description is based on the description of oral cancer.   Tis  0  T1  I  III  IVA  IVB  IVC  T2  II  III  IVA  IVB  IVC  T3  III  III  IVA  IVB  IVC  T4a  IVA  IVA  IVA  IVB  IVC  T4b  IVB  IVB  IVB  IVB  IVC pN0: Histological examination of regional lymphadenectomy specimens will ordinary include 6 or more lymph nodes. If the lymph nodes are negative, but the number ordinarily examined is not met, classify as pN0.
T-Primary Tumor. TX Primary tumor cannot be assessed. T0 No evidence of primary tumor. T3 Tumor limited to epithelium and/or submucosa (mucosal disease). T4a Tumor invades deep soft tissues, cartilage, bone, or overlying skin. T4b Tumor invades any of the following: brain, dura, skull base, lower cranial nerves (IX, X, XI, XII), masticator space, carotid artery, prevertebral space, mediastinal structures.

Note:
Mucosal melanoma is an aggressive tumor, therefore, T1 and T2 are omitted, as are stages I and II. N-Regional Lymph Nodes. NX Regional lymph nodes cannot be assessed. N0 No regional lymph node metastasis. N1 Regional lymph node metastasis.

(6) Multiple, Double, and Multiple Primary Cancers
(1) Multiple oral cancers: The occurrence of two or more primary cancers fulfilling the following conditions: 1. Cancer located at different sites according to the UICC classification 2. Cancer located at the same but contralateral sites. 3. Cancer located at ipsilateral sites, but not continuous, and clinically separated by 2.0 cm or more. 4. Each lesion is histopathologically confirmed to be a carcinoma.

(7) Oral potentially malignant disorders (OPMDs)
Since oral cancers are often accompanied by oral potentially malignant disorders, such as leukoplakia, erythroplakia, and oral lichen planus, details including their site, size, surface properties, and number, as well as whether they are synchronous or metachronous are recorded.

(8) Lifestyle
Individual lifestyle is very significant as a risk factor for oral cancer. Smoking and drinking, in particular, are major risk factors for cancer. Therefore, the lifestyle needs to be recorded.
The presence or absence of preference history regarding smoking and drinking should be described. Furthermore, the amount of smoking is recorded according to the Brinkman index, and the amount of drinking is recorded according to the Sake index.
• Brinkman index = mean number of cigarettes smoked per day × number of smoking years • Sake index = mean amount of drinking per day (in mL of sake) × number of drinking years Scales for conversion into ml of Sake: 180 ml of sake = a large bottle of beer (633 mL) = 2 single glasses of whisky (70 mL) = 90 mL of shochu (distilled spirit) = 2 glasses of wine (220 mL).

II. Recording of intraoperative findings and those on gross examination of the resected specimens
(1) Surgical procedure The details entered into the operation record should be illustrated in detail. Whether or not reconstruction was performed, the construction procedure, intraoperative complications, radicality of the procedure, and the postoperative course should also be recorded.

Location of the lesion. 2. Number and size of the lesions.
Long diameter (mm) × Short diameter (mm) × Thickness (mm).

Depth of invasion (mm). 4. Macroscopic types
Superficial type: Those primarily showing superficial growth.
Endophytic type: Those primarily showing endophytic growth.

Number of metastatic lymph nodes
Number of metastatic lymph nodes/number of resected lymph nodes. 3. Size (< 3 < 6 <) cm 4. Extranodal extension. cENE (−): no finding of clinical ENE. cENE ( +): finding of clinical ENE. • Histological examination of a selective neck dissection specimen ordinarily includes 10 or more lymph nodes. Histological examination of a radical or modified radical neck dissection specimen ordinarily includes 15 or more lymph nodes. If the lymph nodes are negative, but the number ordinarily examined is not met, it is classified as pN0. 2. pN-Regional lymph node pNX Regional lymph node cannot be assessed. pN0

III. Recording of pathological findings
No regional lymph node metastasis. pN1 Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension without extranodal extension. pN2 Metastasis described as: pN2a Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension with extranodal extension or, more than 3 cm but not more than 6 cm in greatest dimension without extranodal extension.
pN2b Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension, without extranodal extension. pN2c Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension, without extranodal extension. pN3a Metastasis in a lymph node more than 6 cm in greatest dimension without extranodal extension. pN3b Metastasis in a lymph node more than 3 cm in greatest dimension with extranodal extension or, multiple ipsilateral, or any contralateral or bilateral node(s) with extranodal extension.
Note: (i) Histological examination of a selective neck dissection specimen ordinarily includes 10 or more lymph nodes. Histological examination of a radical or modified radical neck dissection specimen ordinarily includes 15 or more lymph nodes. If the lymph nodes are negative, but the number ordinarily examined is not met, it is classified as pN0. (ii) Midline nodes are considered ipsilateral nodes. (iii) Direct invasion of the primary tumor to lymph nodes is classified as lymph node metastasis. (iv) When size is a criterion for pN classification, measurement is made of the metastasis, not of the entire lymph node. The measurement should be that of the largest dimension of the tumor. The conglomerate of lymph nodes should be considered as the individual lymph node. 3. pM-Distant metastasis pM1: Distant metastasis microscopically confirmed. Note (1) pM0 and pMX are not valid categories. Note (2) Metastasis in any lymph node other than regional is classified as M1 and metastatic organs are described with the following notation: Lymph node (LYM), Skin (SKI), Pulmonary (PUL), Bone marrow (BAR), Osseous (OSS), Brain (BRA), etc. Note: If immunostaining has been used for the evaluation of perineural invasion, it must be recorded, e.g., Pn1a (S-100).

Histological evaluation of therapeutic effect
In examining patients after preoperative treatment, specimens of the grossly estimated lesion must be prepared as much as possible, and the state of the remaining tumor must be evaluated histologically.
No therapeutic effect is noted in cancer tissue or cancer cells. Grade 1: Slightly effective.
Some degenerative change is noted in cancer tissue/ cells, but cancer cells considered to be capable of proliferation (those showing eosinophilic cytoplasm with vacuolation and enlargement of the nucleus are also included) occupy 1/3 or more of the cancer in a tissue section. Grade 1a: Very slightly effective.
Cancer cells considered to be "capable of proliferation" occupy 2/3rd or more of the cancer.
Cancer cells considered to be "capable of proliferation" occupy 1/3rd or more but less than 2/3rd of the cancer. Grade 2: Moderately effective.
Cancer cells considered to be "capable of proliferation" occupy less than 1/3rd of the cancer, and those showing a tendency toward nuclear disintegration are dominant. Grade 3: Markedly effective.
No cancer cell considered to be "capable of proliferation" is observed, and all cancer cells show a tendency toward nuclear disintegration, or only a trace of cancer is noted.
If a part clearly judged to be a focus of reproliferation is noted in a treated cancer focus, the entry "evidence of reproliferation ( +)" should be made after the judgment.
Note: (i) If radiation therapy or chemotherapy has been conducted for oral cancer, conditions of treatment including the dose of radiation, irradiation method, kinds, doses, and administration methods of the drugs used, and time from the last treatment to resection of the lesion should be recorded. (ii) This criterion is used for the primary lesion of the surgical material. For lymph node dissection specimens, describe any evidence of cancer cell disappearance, necrosis, or degeneration. For biopsy material, only histological findings should be included.

IV. Other Treatments and Clinical Evaluation of the Therapeutic Effect
(1) Radiation Therapy

Clinical target volume (CTV)
primary lesion, cervical lymph nodes (left or right, levels), distant metastases (sites). 3. Irradiation methods one field irradiation (anterior, posterior, others), twofield irradiation (left-right, anterior-posterior, diagonal, others), three-dimensional conformal radiotherapy (3D-CRT), intensity-modulated radiotherapy (IMRT), stereotactic body radiation therapy (SDRT), others. If 2 or 3 sites are treated, treatment for each site is recorded separately. If the irradiation method has been changed the objective of the change (reduction in the irradiation field, change in the junction line, protection of the spinal cord, others) and the dose at the change are recorded. 4. Planning of radiation therapy radiation therapy planning device, dose-volume histogram (DVH 3. Relationships of reference points or planes for dose evaluation with tumor and radiation source. 4. Dose calculation method radiation therapy planning device. 5. Doses for organs at risk.

Effects of irradiation
The therapeutic effects shortly after, 1 month after, and 3 months after irradiation are recorded.

Acute adverse events
The severest organ or tissue damage, signs and symptoms, and the period of their observation are recorded, according to the latest version of CTCAE.

Late adverse events
Adverse events that occur more than 91 days after the beginning of irradiation and are considered to be related to irradiation are recorded.

(2) Chemotherapy
With regard to the administration of chemotherapy using cytotoxic agents, molecular targeting drug, or immune checkpoint inhibitor, the following items should be included in the medical record: Before treatment: description of the treatment plan 3. Information for concomitant treatment If chemotherapy will be administered combined with local treatment, its details of (dose, timing, and purpose) should also be recorded.

Identification of lesions to be evaluated
Assessment of the change in tumor burden is an important feature of the clinical evaluation of cancer therapeutics. As baseline data, the target and non-target lesions should be identified before starting treatment, according to the latest Response Evaluation Criteria in Solid Tumors (RECIST) [4] guidelines at that time.

Evaluation of adverse events caused by chemotherapy
Assessment of the toxicity caused by chemotherapy is important for the adjustment of treatment plan and patient safety. Adverse events after the administration of chemotherapy should be evaluated according to the latest Common Terminology Criteria for Adverse Events (CTCAE) [5] at that time, including the causal relationship with chemotherapy.

Evaluation of therapeutic effect and decision of treatment continuation
The therapeutic effect is evaluated by changes in the lesions identified at the baseline.
As a note, RECIST [4] is just a criterion for therapeutic effect, not an absolute indicator in clinical practice.
The decision for treatment continuation should be made with comprehensive consideration of the clinical course or patient condition.