Changes in the 8^th Edition of the American Joint Committee on Cancer (AJCC) Staging of Head and Neck Cancer: Rationale and Implications

Abstract

Purpose of review

The objectives of this article are to review the major changes in the staging of head and neck cancers and the rationale for the modifications.

Recent findings

Information gathered from various institutional reports lead to a better understanding of the clinical and biological behavior of head and neck tumors, resulting in distinct outcomes, which were used to update the staging system.

Summary

This article reviews the changes in the staging of head and neck cancers published in the 8^th edition of the AJCC/UICC TNM staging system.

Introduction

The American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) staging system is a tool which provides clinicians across the world with the ability to stage cancer prior to any treatment (cTNM), after surgical resection (pTNM), and at recurrence (rTNM). Staging stratifies patients into various prognostic groups and, based on the stage of the disease, it is possible to select best treatment option, plan the treatment, and estimate prognosis.

In 1944, Pierre Denoix proposed a staging system for solid tumors based on tumor characteristics (T), nodal spread (N) and distant metastasis (M)[1]. The UICC adopted this system in 1954. The AJCC was established in 1958. The UICC and AJCC worked independently for nearly 25 years and had separate staging systems for classification of cancer. The first edition of the AJCC/UICC TNM classification was published in 1987. Since then, the TNM classification has been widely used not only to plan treatment and to reliably estimate the prognosis of patients but also to evaluate treatment results and to compare outcomes between institutions in different parts of the world [1, 2].

The simplicity of TNM staging makes it the most accepted and used system in clinical practice. In order to increase acceptance and compliance, by design the TNM staging system has to be kept simple and user-friendly. A highly complex staging system may be most accurate, but may not be easy to accept in clinical practice, and thus will have poor compliance. Therefore, some important prognostic information (tumor and host factors) are often not included in the staging system to keep it simple and increase compliance. Each new edition of the AJCC / UICC staging manual incorporates changes and improves the prognostic accuracy and predictability. The major modifications in the 8^th edition were changes in the T category for oral cavity cancer by incorporating depth of invasion of the primary tumor; inclusion of extranodal extension in N staging except in p16+ oropharynx cancer and nasopharynx cancer; the division of the pharynx chapter into one chapter for oropharynx (p16-) and hypopharynx, a separate chapter describing the staging system for human papilloma virus-related (p16+) oropharyngeal cancer, and a third separate chapter for nasopharynx; new head-and-neck-specific cutaneous malignancy and soft tissue sarcoma chapters; and changes in the age cutoff and N categories for staging of thyroid cancer. These modifications were based on information gathered from various institutional reports leading to a better understanding of the clinical and biological behavior of these tumors, resulting in distinct outcomes [3].

Twenty-eight specialists from various disciplines with expertise and knowledge in head and neck cancer biology and staging formed the AJCC Head and Neck Task Force. The group analyzed in detail chapters from the 7^th edition and proposed changes to incorporate new information. When the task force recommended changes, additional analyses were performed to confirm if there is available data to support the modifications [4]. The aim of this article is to review some of the major changes in the staging of head and neck cancers and the rationale for the modifications that were published in the 8^th edition of the AJCC/UICC TNM staging system.

Oral Cavity Cancer

Traditionally, the greatest dimension of the tumor was the most important characteristic for the T stage categories in oral cancer. Since depth of invasion (DOI) has been shown to have prognostic implications, with deeper tumors showing an increased risk of nodal metastases and decreased disease-specific survival, this parameter was included in the categorization of T stages in the AJCC 8^th edition (Table 1) [5]. Clinical assessment of accurate DOI can be challenging but differentiation among thin (≤ 5 mm), intermediate (> 5 mm and ≤ 10 mm) and thick (> 10 mm) lesions is usually possible in the hands of experienced head and neck surgeons.

Table 1.

Primary tumor (T) definition for oral cavity cancers.

TX	Primary tumor cannot be assessed
Tis	Carcinoma in situ
T1	Tumor ≤ 2 cm and DOI ≤ 5 mm
T2	Tumor ≤ 2 cm, DOI > 5 mm and ≤ 10 mm or tumor > 2 cm and ≤ 4 cm and DOI ≤ 10 mm
T3	Tumor > 4 cm or any tumor with DOI > 10 mm
T4  T4a  T4b	Tumor invades adjacent structures only (e.g., through cortical bone of mandible or maxilla, or involves the maxillary sinus or skin of the face) Tumor invades masticator space, pterygoid plates, or skull base and/or encases the internal carotid artery

^*DOI: depth of invasion. AJCC is currently discussing further refinement of T-stage stratification for small tumors (< 2 cm) with DOI > 10 mm.

From: Amin MB, E.S., Greene FL, et al, eds, AJCC Cancer Staging Manual. 8th ed. Springer International Publishing: American Joint Commission on Cancer; 2017, New York.

In the past, lip was included in oral cavity primary sites. Lip is now divided into mucosal and cutaneous lip. Mucosal lip is included in oral cavity.

The N category was also modified in the 8^th edition. Extranodal extension (ENE) has been shown to have a profound effect on prognosis of most head and neck cancers, except for tumors associated with HPV, and therefore, it was incorporated in the N category [6]. In order to clinically classify the disease as ENE+, unambiguous evidence of ENE in clinical examination supported by strong radiological evidence ENE must be present. Note that once clinical ENE is detected, the disease is cN3b. In case of doubt, the lower category should be assigned (ENE-) [3]. Clinical and pathological N stage categories for squamous cell carcinomas of the oral cavity and all other head and neck sites (except for HPV-related oropharynx, nasopharynx, melanoma, thyroid, and sarcoma) are described in Tables 2 and 3, respectively.

Table 2.

Clinical assessment of regional lymph nodes (cN).

NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Metastasis in a single ipsilateral lymph node, ≤ 3 cm and ENE-
N2  N2a  N2b  N2c	Metastasis in a single ipsilateral lymph node > 3 cm and ≤ 6 cm and ENE-; or metastases in multiple ipsilateral lymph nodes, ≤ 6 cm and ENE-; or in bilateral or contralateral lymph nodes, ≤ 6 cm and ENE- Metastasis in a single ipsilateral lymph node > 3 cm and ≤ 6 cm and ENE- Metastases in multiple ipsilateral lymph nodes, ≤ 6 cm and ENE- Metastases in bilateral or contralateral lymph nodes, ≤ 6 cm and ENE-
N3  N3a  N3b	Metastasis in a lymph node > 6 cm and ENE-; or metastasis in any lymph node(s) with ENE+ clinically Metastasis in a lymph node > 6 cm and ENE- Metastasis in any lymph node(s) with ENE+ clinically

From: Amin MB, E.S., Greene FL, et al, eds, AJCC Cancer Staging Manual. 8th ed. Springer International Publishing: American Joint Commission on Cancer; 2017, New York.

Table 3.

Pathological assessment of regional lymph nodes (pN).

NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Metastasis in a single ipsilateral lymph node, ≤ 3 cm and ENE-
N2  N2a  N2b  N2c	Metastasis in a single ipsilateral lymph node, ≤ 3 cm and ENE+; or metastasis in a single ipsilateral lymph node > 3 cm and ≤ 6 cm and ENE-; or metastases in multiple ipsilateral lymph nodes, ≤ 6 cm and ENE-; or in bilateral or contralateral lymph nodes, ≤ 6 cm and ENE- Metastasis in a single ipsilateral lymph node, ≤ 3 cm and ENE+; or metastasis in a single ipsilateral lymph node > 3 cm and ≤ 6 cm and ENE- Metastases in multiple ipsilateral lymph nodes, ≤ 6 cm and ENE- Metastases in bilateral or contralateral lymph nodes, ≤ 6 cm and ENE-
N3  N3a  N3b	Metastasis in a lymph node > 6 cm and ENE-; or 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+; or a single contralateral node of any size and ENE+ Metastasis in a lymph node > 6 cm and ENE- 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+; or a single contralateral node of any size and ENE+

From: Amin MB, E.S., Greene FL, et al, eds, AJCC Cancer Staging Manual. 8th ed. Springer International Publishing: American Joint Commission on Cancer; 2017, New York.

Nasopharyngeal Cancer

Nasopharyngeal cancers (NPC) have a unique biology and was given a separate chapter in the AJCC 8^th edition. The major changes are the inclusion of a T0 category for patients with Epstein-Barr virus (EBV) positive metastatic cervical lymph nodes with unknown primary, clarification to avoid ambiguity for the other T categories, and changes in the regional lymph node definition. Unlike the other head and neck cancer sites for which surgery plays an important role in primary treatment, NPC is treated primarily with radiotherapy with or without chemotherapy. For this reason, pathological classification is not relevant in this disease. Tables 4, 5 and 6 describe the tumor, node and overall stage classification of NPC, respectively [3].

Table 4.

Primary tumor (T) definition for nasopharyngeal cancers.

TX	Primary tumor cannot be assessed
T0	No tumor identified, but EBV+ cervical node(s) involvement
Tis	Carcinoma in situ
T1	Tumor confined to nasopharynx, or extension to oropharynx and/or nasal cavity without parapharyngeal involvement
T2	Tumor with extension to parapharyngeal space, and/or adjacent soft tissue involvement (medial pterygoid, lateral pterygoid, prevertebral muscles)
T3	Tumor with infiltration of bony structures at skull base, cervical vertebra, pterygoid structures, and/or paranasal sinuses
T4	Tumor with intracranial extension, involvement of cranial nerves, hypopharynx, orbit, parotid gland, and/or extensive soft tissue infiltration beyond the lateral surface of the lateral pterygoid muscle

From: Amin MB, E.S., Greene FL, et al, eds, AJCC Cancer Staging Manual. 8th ed. Springer International Publishing: American Joint Commission on Cancer; 2017, New York.

Table 5.

Assessment of regional lymph nodes (N) in nasopharyngeal cancers.

NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Unilateral metastasis in cervical lymph node(s) and/or unilateral or bilateral metastasis in retropharyngeal lymph node(s), ≤ 6 cm, above the caudal border of cricoid cartilage
N2	Bilateral metastasis in cervical lymph node(s), ≤ 6 cm, above the caudal border of cricoid cartilage
N3	Unilateral or bilateral metastasis in cervical lymph node(s), > 6 cm, and/or extension below the caudal border of cricoid cartilage

From: Amin MB, E.S., Greene FL, et al, eds, AJCC Cancer Staging Manual. 8th ed. Springer International Publishing: American Joint Commission on Cancer; 2017, New York.

Table 6.

AJCC prognostic stage groups for nasopharyngeal cancers.

0	TisN0M0
I	T1N0M0
II	T0N1M0, T1N1M0, T2N0M0, or T2N1M0
III	T0N2M0, T1N2M0, T2N2M0, T3N0M0, T3N1M0, or T3N2M0
IVA	T4N0M0, T4N1M0, T4N2M0, T0N3M0, T1N3M0, T2N3M0, T3N3M0, or T4N3M0
IVB	Any T, any N, and M1

From: Amin MB, E.S., Greene FL, et al, eds, AJCC Cancer Staging Manual. 8th ed. Springer International Publishing: American Joint Commission on Cancer; 2017, New York.

Oropharyngeal Cancer

Human papillomavirus (HPV) related or p16-positive oropharyngeal cancer (OPC) is a different entity that occurs more frequently in younger individuals, with little or no tobacco exposure, and that usually shows excellent response to treatment even in patients with advanced stage disease. The incidence of OPC associated with HPV has been rising since 1990 and the observation of the diverse clinical and biological behavior of p16-positive OPC versus p16-negative OPC has been reported by many authors [7, 8]. Because it behaves as a completely different disease when compared to p16-negative OPC, a separate staging system was developed for HPV-related (p16-positive) OPC [9]. However, the T categories for both p16-positive and p16-negative OPC remain similar. The main differences are: Tis is not included in p16-positive OPC, T0 (unknown primary in patients with metastatic nodes tested positive for p16) category is only used in p16-positive metastatic nodes, where the primary is presumed to be OPC, and the T4b category has been removed from p16-positive OPC. Table 7 describes the T categories for p16-positive OPC. The clinical N staging categories for p16-positive disease are shown in Table 8. Ipsilateral nodes (one or multiple), none larger than 6 cm are staged N1. Contralateral or bilateral nodes are classified as N2, as long as none of them is larger than 6 cm. Nodes that are greater than 6 cm are included in N3 category. Pathological staging is only applicable to patients who are treated with surgery. For HPV-related (p16-positive) OPC treated with surgery, an important change in behavior is observed when the number of positive nodes was between 1 and 4 versus 5 or more [3]. This was incorporated in pN staging for p16-positive tumors. The pathological N categories for HPV-related (p16-positive) OPC are shown in Table 9. The clinical and pathological prognostic stage groups are described in Tables 10 and 11.

Table 7.

Primary tumor (T) definition for HPV-related (p16-positive) oropharyngeal cancers.

T0	No tumor identified, but p16+ cervical node(s) involvement
Tis	Carcinoma in situ
T1	Tumor ≤ 2 cm
T2	Tumor > 2 cm and ≤ 4 cm
T3	Tumor > 4 cm or extension to lingual surface of the epiglottis
T4	Moderately advanced local disease; tumor invades larynx, extrinsic muscle of tongue, medial pterygoid, hard palate, or mandible or beyond

From: Amin MB, E.S., Greene FL, et al, eds, AJCC Cancer Staging Manual. 8th ed. Springer International Publishing: American Joint Commission on Cancer; 2017, New York.

Table 8.

Clinical assessment of regional lymph nodes (cN) in HPV-related (p16-positive) oropharyngeal cancers.

NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	One or more ipsilateral lymph nodes ≤ 6 cm
N2	Contralateral or bilateral lymph nodes ≤ 6 cm
N3	Lymph node(s) > 6 cm

From: Amin MB, E.S., Greene FL, et al, eds, AJCC Cancer Staging Manual. 8th ed. Springer International Publishing: American Joint Commission on Cancer; 2017, New York.

Table 9.

Pathological assessment of regional lymph nodes (pN) in HPV-related (p16-positive) oropharyngeal cancers.

pNX	Regional lymph nodes cannot be assessed
pN0	No regional lymph node metastasis
pN1	Metastasis in 4 or fewer lymph nodes
pN2	Metastases in more than 4 lymph nodes

From: Amin MB, E.S., Greene FL, et al, eds, AJCC Cancer Staging Manual. 8th ed. Springer International Publishing: American Joint Commission on Cancer; 2017, New York.

Table 10.

AJCC prognostic clinical stage groups for HPV-related (p16-positive) oropharyngeal cancers.

I	T0N1M0, T1N0M0, T1N1M0, T2N0M0, or T2N1M0
II	T0N2M0, T1N2M0, T2N2M0, T3N0M0, T3N1M0, or T3N2M0
III	T0N3M0, T1N3M0, T2N3M0, T3N3M0, T4N0M0, T4N1M0, T4N2M0, or T4N3M0
IV	Any T, any N, and M1

From: Amin MB, E.S., Greene FL, et al, eds, AJCC Cancer Staging Manual. 8th ed. Springer International Publishing: American Joint Commission on Cancer; 2017, New York.

Table 11.

AJCC prognostic pathological stage groups for HPV-related (p16-positive) oropharyngeal cancers.

I	T0N1M0, T1N0M0, T1N1M0, T2N0M0, or T2N1M0
II	T0N2M0, T1N2M0, T2N2M0, T3N0M0, T3N1M0, T4N0M0, or T4N1M0
III	T3N2M0, or T4N2M0
IV	Any T, any N, and M1

From: Amin MB, E.S., Greene FL, et al, eds, AJCC Cancer Staging Manual. 8th ed. Springer International Publishing: American Joint Commission on Cancer; 2017, New York.

Cutaneous Carcinoma of the Head and Neck

Staging of skin cancers was developed by a multidisciplinary team to create a system for nonmelanoma skin cancers of the head and neck. It encompasses 82 different types of skin cancers excluding melanoma and Merkel cell carcinoma. The cutaneous lip consisting of the keratinizing epithelium of the vermilion border is included in this classification. In spite of expected diversity among skin cancers that are included in this group, basal cell carcinomas and squamous cell carcinomas are the most common varieties in the head and neck area. A decision was made for a common staging system because it would not be feasible to have a meaningful system for each of the individual histologic types. This new chapter was created to emphasize the importance of staging these tumors in the head and neck area. T categories are based on independent risk factors for poor prognosis [10]. Table 12 describes the T categories for cutaneous carcinomas of the head and neck.

Table 12.

Primary tumor (T) definition for cutaneous carcinomas of the head and neck.

TX	Primary tumor cannot be assessed
Tis	Carcinoma in situ
T1	Tumor ≤ 2 cm
T2	Tumor > 2 cm and ≤ 4 cm
T3	Tumor > 4 cm or minor bone erosion or perineural invasion or deep invasion*
T4  T4a  T4b	Tumor with gross cortical bone/marrow, skull base invasion and/or skull base foramen invasion Tumor with gross cortical bone/marrow invasion Tumor with skull base invasion and/or skull base foramen involvement

^*Deep invasion is defined as invasion beyond the subcutaneous fat or > 6 mm (as measured from granular layer of adjacent normal epidermis to the base of the tumor); perineural invasion for T3 classification is defined as tumor cells within the nerve sheath of a nerve lying deeper than the dermis or measuring 0.1 mm or larger in caliber, or presenting with clinical or radiographic involvement of named nerves without skull base invasion or transgression.

From: Amin MB, E.S., Greene FL, et al, eds, AJCC Cancer Staging Manual. 8th ed. Springer International Publishing: American Joint Commission on Cancer; 2017, New York.

Head and Neck Soft Tissue Sarcoma

Sarcomas of the head and neck are separately staged from the general soft tissue sarcomas of the trunk and extremities because that staging system did not suit this anatomic region. The size cutoffs for T are changed to 2 and 4 cm (T1 ≤ 2 cm, T2 > 2 cm and ≤ 4 cm, T3 > 4 cm, T4 tumor invades adjoining structures). Nodal disease is uncommon and is staged as N0 (when no regional lymph node metastases are present or if the lymph node status is unknown) or N1 (lymph node metastasis is present) [3].

Thyroid

Significant changes were made in thyroid cancer staging. Modifying the age cutoff from 45 to 55 years of age [11] and excluding microscopic extrathyroidal extension from the definition of T3 resulted in downstaging a significant number of patients. Downstaging these patients correctly fitted them in the right group according to their risk for dying from thyroid cancer [12]. Table 13 describes the definition of the primary tumor (T). The definition of nodal metastases is also revised. Metastatic lymph nodes in the central neck (levels VI and VII) are now staged as N1a. Lymph nodes in the lateral neck are staged N1b (table 14). In the previous editions, all anaplastic thyroid cancers were staged as T4. In this new edition, anaplastic thyroid cancers are classified using the same definitions for T category as differentiated thyroid cancer. Tables 15 and 16 describe the prognostic stage groups for differentiated and anaplastic thyroid cancers, respectively.

Table 13.

Primary tumor (T) definition for papillary, follicular, poorly differentiated, Hurthle cell and anaplastic thyroid carcinoma.

TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
T1  T1a  T1b	Tumor ≤ 2 cm limited to the thyroid Tumor ≤ 1 cm limited to the thyroid Tumor > 1 cm but ≤ 2 cm limited to the thyroid
T2	Tumor > 2 cm and ≤ 4 cm limited to the thyroid
T3  T3a  T3b	Tumor > 4 cm limited to the thyroid or gross extrathyroidal extension invading only strap muscles Tumor > 4 cm limited to the thyroid Gross extrathyroidal extension invading only strap muscles (sternohyoid, sternothyroid, thyrohyoid, or omohyoid muscles) from a tumor of any size
T4  T4a  T4b	Includes gross extrathyroidal extension into major neck structures Gross extrathyroidal extension invading subcutaneous soft tissue, larynx, trachea, esophagus, or recurrent laryngeal nerve from a tumor of any size Gross extrathyroidal extension invading prevertebral fascia or encasing carotid artery or mediastinal vessels from a tumor of any size

^*All categories may be subdivided: (s) solitary tumor and (m) multifocal tumor (the largest tumor determines the classification).

From: Amin MB, E.S., Greene FL, et al, eds, AJCC Cancer Staging Manual. 8th ed. Springer International Publishing: American Joint Commission on Cancer; 2017, New York.

Table 14.

Assessment of regional lymph node (N).

NX	Regional lymph nodes cannot be assessed
N0  N0a  N0b	No evidence of locoregional lymph node metastasis One or more cytological or histologically confirmed benign lymph node No radiologic or clinical evidence of locoregional metastasis
N1  N1a  N1b	Metastasis to regional nodes Metastases to level VI or VII (pretracheal, paratracheal, or prelaryngeal/Delphian, or upper mediastinal) lymph nodes. This can be unilateral or bilateral disease Metastasis to unilateral, bilateral, or contralateral lateral neck lymph nodes (levels I, II, III, IV or V) or retropharyngeal lymph nodes

From: Amin MB, E.S., Greene FL, et al, eds, AJCC Cancer Staging Manual. 8th ed. Springer International Publishing: American Joint Commission on Cancer; 2017, New York.

Table 15.

AJCC prognostic stage groups for differentiated thyroid cancer.

When age at diagnosis is…	And T is…	And N is…	And M is…	Then the stage group is…
< 55 years	Any T	Any N	M0	I
< 55 years	Any T	Any N	M1	II
≥ 55 years	T1	N0/NX	M0	I
≥ 55 years	T1	N1	M0	II
≥ 55 years	T2	N0/NX	M0	I
≥ 55 years	T2	N1	M0	II
≥ 55 years	T3a/T3b	Any N	M0	II
≥ 55 years	T4a	Any N	M0	III
≥ 55 years	T4b	Any N	M0	IVA
≥ 55 years	Any T	Any N	M1	IVB

From: Amin MB, E.S., Greene FL, et al, eds, AJCC Cancer Staging Manual. 8th ed. Springer International Publishing: American Joint Commission on Cancer; 2017, New York.

Table 16.

AJCC prognostic stage groups for anaplastic thyroid cancer.

When T is…	And N is…	And M is…	Then the stage group is…
T1-T3a	N0/NX	M0	IVA
T1-T3a	N1	M0	IVB
T3b	Any N	M0	IVB
T4	Any N	M0	IVB
Any T	Any N	M1	IVC

From: Amin MB, E.S., Greene FL, et al, eds, AJCC Cancer Staging Manual. 8th ed. Springer International Publishing: American Joint Commission on Cancer; 2017, New York.

Improving the TNM staging system

The goal of updating the staging system is to use new knowledge about the disease to develop a model to predict outcomes better than the previous editions. Advances in understanding the behavior of the disease and risk factors, as well as new imaging technologies and emerging new therapies can improve outcomes. For this reason, periodically revising the outcome prediction capability of the system is needed. Keeping the staging system as simple as possible is important to make it universally used and to standardize the way head and neck oncologists present and discuss their results. A simple system, however, will not allow for an accurate personalized prognostic tool. Nomograms are calculation devices that have been widely tested in a variety of cancers, including in the head and neck [13–19]. This prediction tool is dynamic, personalized, and can predict prognosis individually with a higher accuracy. Therefore, nomograms will likely be widely used in the near future.

Conclusions

Since the 1940s when it was first described, the TNM staging system has been continuously used for cancer prognostication. Its user-friendliness has allowed it to be implemented and used worldwide. With the understanding of many other tumor and host factors that can influence outcomes, it will be challenging to create a tool as simple as the TNM that can incorporate all these factors