• Ajcc Cancer Staging Manual 8th Edition Pdf Free Download Pc
• Ajcc Cancer Staging Manual 8th Edition Pdf Free Download Torrent

No thanks Try it free. Ajcc Cancer Staging Manual 8th Edition Etyi Wati. Unsubscribe from Etyi Wati? Cancel Unsubscribe. Subscribe Subscribed Unsubscribe 15. AJCC Cancer Staging Manual 8th Edition PDF.pdf (55.90 MB) Abuse report. Like Our Facebook Page For Free Medical Books. FREE DOWNLOAD FAST INSTANT DOWNLOAD; Notice! DON'T WAIT, BUY A PREMIUM ACCESS AND DOWNLOAD AT HIGH SPEED! We recommend! To purchase a premium, which is usable without waiting or other limitations. 7 Days Premium.

Ajcc Cancer Staging Manual 8th Edition Pdf Free Download Pc

Abstract

BACKGROUND

An accurate staging system is crucial for cancer management. Evaluations for continual suitability and improvement are needed as staging and treatment methods evolve.

METHODS

This was a retrospective study of 1609 patients with nasopharyngeal carcinoma investigated by magnetic resonance imaging, staged with the 7th edition of the American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) staging system, and irradiated by intensity-modulated radiotherapy at 2 centers in Hong Kong and mainland China.

RESULTS

Among the patients without other T3/T4 involvement, there were no significant differences in overall survival (OS) between medial pterygoid muscle (MP)±lateral pterygoid muscle (LP), prevertebral muscle, and parapharyngeal space involvement. Patients with extensive soft tissue involvement beyond the aforementioned structures had poor OS similar to that of patients with intracranial extension and/or cranial nerve palsy. Only 2% of the patients had lymph nodes>6cm above the supraclavicular fossa (SCF), and their outcomes resembled the outcomes of those with low extension. Replacing SCF with the lower neck (extension below the caudal border of the cricoid cartilage) did not affect the hazard distinction between different N categories. With the proposed T and N categories, there were no significant differences in outcome between T4N0-2 and T1-4N3 disease.

CONCLUSIONS

After a review by AJCC/UICC preparatory committees, the changes recommended for the 8th edition include changing MP/LP involvement from T4 to T2, adding prevertebral muscle involvement as T2, replacing SCF with the lower neck and merging this with a maximum nodal diameter>6 cm as N3, and merging T4 and N3 as stage IVA criteria. These changes will lead not only to a better distinction of hazards between adjacent stages/categories but also to optimal balance in clinical practicability and global applicability.

INTRODUCTION

An accurate staging system is crucial in cancer management for predicting the prognosis, guiding clinicians in treatment decisions for different risk groups, and evaluating the results of treatment between centers. The prognostic significance of a staging system changes with advances in investigation and treatment methods. Evaluations of staging systems to ensure continual suitability and exploration for further improvement are essential.

It is well recognized that the natural behavior of and therapeutic considerations for nasopharyngeal carcinoma (NPC) are different from those for other head and neck cancers. A major improvement in the TNM staging system by the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC) was the adoption of a customized system for NPC in the 5th edition.^1,2 With data from large retrospective series from Asia, where NPC is most prevalent, the staging criteria were developed through the merging of the strengths of the 4th edition of the AJCC/UICC system and Ho’s system.^3, This was a milestone development that has gained global acceptance as studies from different countries (endemic and nonendemic) unanimously confirmed substantial improvements in comparison with prior systems.

No change was recommended in the 6th edition^5,6 except for the addition of the term masticator space as a synonym for infratemporal fossa (one of the T4 criteria) because, although the intended extent was described in the staging handbook, the latter was not a clearly defined space with universal acceptance. In the current 7th edition,^7,8 both terms are retained as T4 criteria; however the term masticator space now uses the boundaries described in a classic anatomy textbook instead of the demarcation used for infratemporal fossa. Additional changes included downstaging of tumors with extension to the nasal fossa/oropharynx without parapharyngeal extension (previously T2a) to T1^, and a clear definition of retropharyngeal lymph node involvement (unilateral or bilateral) as N1.

The management of NPC has undergone substantial evolution in the past 2 decades. More accurate imaging methods have allowed better delineation of the tumor extent and early detection of occult metastases. The transition from 2-dimensional conventional radiotherapy to 3-dimensional conformal and intensity-modulated radiotherapy (IMRT) has led to increasing conformity of tumor coverage and sparing of noninvolved structures. The use of combination chemotherapy has further improved tumor control and cure rates, especially for advanced locoregional disease. It is, therefore, important that the new staging system be based on data from patients managed with contemporary methods.

The preparatory processes for the 8th edition of the AJCC/UICC staging system included an extensive literature review and validation of recommendations by contemporary series before consensus was attained by international multidisciplinary experts. Among the suggestions reported in the literature, 4 issues demand serious consideration: 1) the controversy about the significance of the masticator space,^- 2) the uncertainty about the significance of prevertebral muscle invasion,^- 3) the possibility of replacing the supraclavicular fossa (SCF)³ with anatomic nodal levels,^- and 4) the simplification of unnecessary subgroups by elimination.^,

In this study, we evaluated patients who were staged with magnetic resonance imaging (MRI) and irradiated with IMRT at 2 hospitals (one in Hong Kong and the other in Fujian in mainland China) to address these issues and to develop consensus recommendations by AJCC and UICC for the coming 8th edition.

MATERIALS AND METHODS

Patients

A total of 1609 consecutive patients with nondisseminated NPC who were treated at Fujian Provincial Cancer Hospital and Pamela Youde Nethersole Eastern Hospital from June 2005 to December 2010 were analyzed (Table 1). All patients had histological confirmation: 99.2% had nonkeratinizing (differentiated/undifferentiated) carcinoma and 0.8% had keratinizing squamous cell carcinoma according to the World Health Organization classification. The median age was 47 years (range, 11-84 years); 75% were male, and 25% were female. The median follow-up for the whole cohort was 5 years (range, 0.2-9.3 years).

TABLE 1

This retrospective study was approved by the respective local hospitals.

Clinical Staging and Treatment

All patients underwent a complete physical examination, fiber-optic nasopharyngoscopy, and MRI of the nasopharyngeal and cervical region. An additional metastatic evaluation was performed according to institutional polices. The 7th edition of the AJCC/UICC staging system^7,8 was used for clinical staging at presentation.

Ajcc Cancer Staging Manual 8th Edition Pdf Free Download Torrent

All patients were treated with the IMRT technique with a median total dose of 69.8 Gy (range, 61.6-86.7 Gy). Details of IMRT planning and dose prescription have been described previously.^, Additional treatment with cisplatin-based chemotherapy (various schedules) was administered to 92% of patients with stage III disease and to 73% of patients with stage II disease (Table 1).

Statistical Analysis

The eligibility criteria set for this retrospective study included histologically confirmed NPC, no gross evidence of distant metastases, staging with MRI, and irradiation with radical intent with IMRT. The exclusion criteria were a history of previous treatment or prior malignancy. All consecutive eligible patients treated in the 2 participating centers from June 2005 to December 2010 were analyzed. The study period was chosen to ensure the most consistent staging and radiotherapy methods with a median follow-up of 5 years.

All events were measured from the date of histological diagnosis. The primary endpoint for this analysis was overall survival (OS; time to death due to any cause). Additional endpoints included distant failure-free survival (D-FFS; time to distant metastasis), local failure-free survival according to the T category (L-FFS; time to local persistence/recurrence), and nodal failure-free survival according to the N category (N-FFS; time to nodal persistence/recurrence). The unadjusted actuarial rates were calculated with the Kaplan-Meier method,³¹ and the differences were compared with a log-rank test.³² A Cox proportional hazards model³³ was used to assess the hazard ratio with a 95% confidence level. Two-sided tests were used, and those with P values<.05 were considered statistically significant.

With the current sample size of 1609, the power was 88.5% for detecting a hazard ratio at 1.27 between adjacent stages with a 95% confidence level. The proportional hazard assumption was also tested. All the Cox models satisfied the proportional hazard assumption with P values>.05 for the proportional hazard test.

The performances of the 7th edition of the AJCC/UICC staging system and the proposed 8th edition were also compared with the Akaike information criterion (AIC)³⁶ and Harrell’s concordance index (c-index). Both the AIC and the c-index were calculated for the Cox proportional hazards regression model and were adjusted for age and sex. The AIC refers to the information loss of the selected model; a smaller AIC value suggests a better goodness of fit of the model. The c-index measures the ability to predict the outcomes; a higher c-index suggests a greater ability to discriminate the outcomes with the model (ie, better discriminatory power of the model). Internal validation for the AIC and the c-index was performed via bootstrapping with 1000 replications. All statistical analyses were conducted with SPSS 22 and R 3.1.3.

RESULTS

T Category

Among the patients categorized as T4 on the basis of the current definition of masticator space, those with medial pterygoid muscle (MP)±lateral pterygoid muscle (LP) involvement (n=590) had a significantly higher rate of association with other T3/T4 staging criteria in comparison with those without MP/LP involvement (n=1019; 91% vs 44%, P<.001). However, among the patients without other T3/T4 criteria, the subgroup of patients with MP/LP involvement (n=53) had much better OS than the patients with other T4 criteria (93% vs 71% at 5 years, P=.003); there were no significant differences in OS between those with MP/LP involvement, those with prevertebral muscle involvement, and those with parapharyngeal extension alone (Fig. 1A). On the other hand, the subgroup of patients with extensive soft tissue involvement (infiltration beyond the lateral surface of the LP, hypopharynx, orbital structures, and parotid gland) but no other T4 criteria had poor OS similar to that of the subgroup with intracranial extension and/or cranial nerve palsy (68% vs 73%, P=.816; Fig. 1C).

Overall survival: (A) T2 subgroups (different adjacent soft tissue involvement), (B) T3 subgroups (pterygoid structures vs skull base erosion), and (C) T4 subgroups (extensive soft tissue involvement vs intracranial/cranial nerve involvement).

Among the patients with current T3 criteria, there was no statistically significant difference in OS between those with involvement of pterygoid structures alone (medial/lateral pterygoid plate, pterygoid body/process, pterygomaxillary fissure, and pterygopalatine fossa) and those with erosion of the skull base and/or cervical vertebra (86% vs 79%, P=.186; Fig. 1B).

Hence, the changes recommended for the 8th edition include changing the criterion of MP/LP involvement without other T3/T4 criteria from T4 to T2 and adding prevertebral muscle involvement as a T2 criterion (Fig. 2A and Table 2). With the proposed changes, the differences in L-FFS between T1 and T2 (P=.048), in D-FFS between T2 and T4 (P=.002), and in OS between T2 and T3 (P=.043) now reached statistical significance (Fig. 3). In comparison with the 7th edition,^7,8 the proposed 8th edition led to a lower AIC and a higher c-index for all endpoints (Table 3).

Differences in defining criteria between the current 7th edition and the proposed 8th edition: (A) changing the extent of soft tissue involvement as T2 and T4 criteria and (B) replacing the supraclavicular fossa (blue) with the lower neck (ie, below the caudal border of cricoid cartilage; red) as N3 criteria. CS indicates carotid space; LP, lateral pterygoid muscle; M, masseter muscle; MP, medial pterygoid muscle; PG, parotid gland; PPS, parapharyngeal space; PV, prevertebral muscle; T, temporalis muscle.

Prognostication by T category with (Left) the current 7th edition and (Right) the proposed 8th edition: (A) local failure-free rate, (B) distant failure-free rate, and (C) overall survival.

TABLE 2

Classification Criteria and Stage Grouping According to the 7th Edition and Proposed 8th Edition of the American Joint Committee on Cancer/International Union Against Cancer Staging System

The nodal size was based on the maximum dimension in any direction.

TABLE 3

Distribution and Prognostication (Failure-Free/Survival Rates at 5 Years) According to the 7th Edition and Proposed 8th Edition of the American Joint Committee on Cancer/International Union Against Cancer Staging System

Abbreviations: AIC, Akaike information criterion; c-index, Harrell’s concordance index; FFS, failure-free survival.

N Category

Only 37 patients (2%) had a lymph node larger than 6 cm without extension into the SCF; the differences between N3a and N2 and between N3a and N3b were statistically insignificant for all endpoints. The overall trends were closer to N3b, particularly in terms of D-FFS and long-term OS (Fig. 4). Grouping with N3b without further subclassification is hence suggested.

Prognostication by N category with (Left) the current 7th edition and (Right) the proposed 8th edition: (A) nodal failure-free rate, (B) distant failure-free rate, and (C) overall survival.

Replacing the N3b criterion of the SCF with the lower neck (defined as an extension below the caudal border of the cricoid cartilage with the criteria of levels IV and Vb of Som et al did not affect the N category in 1505 patients but led to upstaging from N2 to N3 in 100 patients and downstaging from N3 to N2 in 4 patients. The 5-year OS for those with extension to the lower neck (70%) was similar to the 5-year OS for those with extension to the SCF (69%). Only 11 patients had a lymph node larger than 6 cm without extension to the lower neck.

Hence, the changes recommended for the 8th edition include changing the criterion of the SCF to the lower neck (defined as extension below the caudal border of the cricoid cartilage) and merging this with asize>6 cm as N3 criteria (Fig. 2B and Table 2). With the proposed changes, the differences between N2 and N3 in terms of D-FFS (P=.010) and OS (P=.007) and the difference in D-FFS between N1 and N2 (P=.042) now reached statistical significance (Fig. 4). In comparison with the 7th edition,^7,8 although the proposed 8th edition did not lead to an improvement in the AIC or the c-index for N-FFS and D-FFS, it did lead to a lower AIC and maintained the same c-index for OS (Table 3).

Stage Group

Only 63 patients (4%) presented with T1N0 disease. There was no statistically significant difference between stages I and II in terms of locoregional failure-free survival (FFS; P=.15) and only a trend toward significance in OS (98% vs 92%, P=.098). However, the survival curves were clearly separated, and there was a significant difference in D-FFS (98% vs 91%, P=.045; Fig. 5). With adjustments for age and sex, the hazard of deaths (from all causes) increased from 1 for stage I to 3.5 for stage II, to 6.1 for stage III, and to 11.0 for stage IVA (Table 4).

Prognostication by stage group with (Left) the current 7th edition and (Right) the proposed 8th edition: (A) locoregional failure-free rate, (B) distant failure-free rate, and (C) overall survival.

TABLE 4

HRs According to the 7th Edition and Proposed 8th Edition of the American Joint Committee on Cancer/International Union Against Cancer Staging System

Abbreviations: CI, confidence interval; FFS, failure-free survival; HR, hazard ratio.

The data are presented as HRs and 95% CIs (in parentheses); the corresponding P values are shown beneath them. Cox regression models with adjustments for age and sex were used to calculate HRs.

There were no significant differences between the subgroup with T4N0-2 disease and the subgroup with T1-4N3 disease for all endpoints, including D-FFS (78% vs 72%, P=.080) and OS (72% vs 70%, P=.114). Hence, the change recommended for the 8th edition is to merge T4 and N3 as the criteria for advanced locoregional disease (stage IVA) without further subclassification (Table 2). With the proposed system, the difference in D-FFS between stages II and III now reached statistical significance (P=.048; Fig. 5). In comparison with the 7th edition,^7,8 the proposed 8th edition led to a lower AIC and a higher c-index for D-FFS and OS, and it maintained the same c-index for locoregional FFS (Table 3).

DISCUSSION

Since the milestone change in the 5th edition of the AJCC/UICC staging system,^1,2 with the development of a customized staging system for NPC based on a combination of the strengths of Ho’s system^3, and the AJCC/UICC system, substantial support has been attained in both endemic and nonendemic regions. As staging and treatment methods evolve, evaluations for continual suitability and improvement are important. A specific Literature Watch program has been implemented by the UICC to capture the studies on staging systems reported in the literature, and feedback has been obtained from an international expert panel regarding whether changes should be considered for subsequent editions. However, the reported studies on the evaluation of the current 7th edition of the AJCC/UICC staging system^7,8 and suggestions for further improvement are based largely on series managed with past methods. Validation by more contemporary series is needed.

The current study was initiated to address the concerns outlined in the introduction and to explore potential optimal changes for the coming 8th edition of the AJCC/UICC staging system. This series of 1609 patients with a median follow-up of 5 years, all staged with MRI and irradiated with IMRT at 2 major centers in Hong Kong and mainland China, provides useful data for this validation. Furthermore, extensive discussions by the AJCC and UICC preparatory committee were conducted to review the results and attain a consensus among international multidisciplinary experts to ensure not only prognostic accuracy but also optimal balance in clinical practicability and global applicability. The main weakness of the current study is that this is a retrospective study; further validation by prospective data will be useful.

It would be ideal if the current study could be further validated by data from nonendemic regions; however, most centers in nonendemic regions have only small series of patients, and even major centers rarely capture details of tumor extent as in the current study. Nevertheless, we are confident that the current conclusions should be applicable across countries as evidenced by the global support for the 5th edition of the AJCC/UICC staging system, a landmark development when we used data from Hong Kong to combine the strengths of the 4th edition of the AJCC/UICC staging system and Ho’s staging system to design a customized system for NPC.

As for the T categories, the main area for improvement is defining the extent of soft tissue involvement as a T4 criterion. According to the definition stated in the 7th edition of the AJCC cancer staging handbook, the masticator space primarily consists of the muscles of mastication encompassed within the superficial layer of the deep cervical fascia and extends from the medial and lateral pterygoid (MP/LP) muscles to the masseter and temporalis muscles (Fig. 2A). The current study concurs with the study by Sze et al: the involvement of the MP/LP per se did not lead to poor survival similar to that of patients with extensive infiltration beyond the lateral surface of the LP. The claim that patients with MP/LP have a poor prognosis is likely due to the intrinsic association with other sinister criteria. Our data showed that for patients without other T3/T4 criteria, there were no significant differences in OS among those with infiltration of adjacent soft tissue, including the MP/LP, prevertebral muscles, and parapharyngeal space alone (Fig. 1A). Involvement of pterygoid structures should remain as T3 because the prognosis was similar to that with other skull base bony erosions (Fig. 1B). Our data also confirmed that patients with extensive soft tissue infiltration beyond these structures did have a poor prognosis similar to that of patients with intracranial extension/cranial nerve palsy (Fig. 1C). Therefore, tumors involving these structures should continue to be classified as T4.

Hence, the changes recommended for the 8th edition include changing the criterion of MP/LP involvement from T4 to T2, adding prevertebral muscle involvement as a T2 criterion (Fig. 2), and replacing the ambiguous terms masticator space and infratemporal fossa with a specific description of soft tissue involvement (Table 2). This change could help to refine the decision on the addition of chemotherapy. Although aggressive chemotherapy with a concurrent±adjuvant/induction sequence is indicated for patients with stage IV, the benefit for patients with stage II is less certain (especially for patients irradiated with the optimal intensity-modulated technique), and even if chemotherapy is used, the concurrent-alone sequence is the one generally recommended. Hence, with more accurate prognostication by downstaging pterygoid muscle involvement to T2, these patients might be spared unnecessary chemotherapy if there are no other unfavorable prognostic factors.

Although the differences in D-FFS and OS between T1 and T2 remained insignificant, the difference in L-FFS now reached statistical significance (P=.048). In addition, although the differences in L-FFS and D-FFS between T2 and T3 remained insignificant, the difference in OS now reached statistical significance (P=.043). Therefore, continuing to classify them as a discrete T category is recommended (Fig. 3).

As for the N categories, the current 7th edition of the AJCC/UICC staging system^7,8 subdivides N3 into N3a and N3b with a nodal diameter>6 cm (maximum dimension) and extension into the SCF³ as respective criteria. The significance of the size criterion was difficult to evaluate because few patients had a large lymph node without reaching the SCF³ (n=35) or the lower neck (n=11). Because the outcome pattern of N3a was similar to that of N3b, particularly for long-term D-FFS and OS (Fig. 4), continuing to use this as an N3 criterion was supported. However, in agreement with the study by Lee et al, further subclassification could be discontinued as the number of patients was too few for meaningful impact.

The feasibility of replacing the SCF³ with the lower neck (defined as extension below the caudal border of the cricoid cartilage; ie, levels IV and Vb; Fig. 2B) without affecting the prognostic significance was first reported by Ng et al in 2007. This was adopted as the criterion for N3 in the Chinese system (2008 version).^- There is little controversy that this leads to easier and more reproducible demarcation by imaging instead of clinical palpation. Although the current data showed that this did not lead to an improvement in the AIC or the c-index for N-FFS and D-FFS, the c-index for OS was maintained (Table 3). Together with merging with nodes>6 cm (maximum dimension), differences in D-FFS and OS were significant between all adjacent N categories in the proposed 8th edition.

As for the stage grouping scheme, the current article concurs with the study by Lee et al: subclassification into IVA and IVB was unnecessary because the OS of patients with T4N0-2 disease was similar to the OS of those with T1-4N3 disease (72% vs 70% at 5 years, P=.114). Hence, all T4 and N3 can be merged into 1 substage (IVA) for advanced locoregional disease. How-ever, further simplification by the merging of stages I and II was not recommended. Even though only 4% of patients presented with T1N0 disease and there was no significant difference between stages I and II in locoregional FFS (P=.15) or OS (98% vs 92%, P=.098), the difference in D-FFS was significant (98% vs 91%, P=.045). Because of the concern that stage II patients might benefit from the addition of chemotherapy, keeping stages I and II separate is recommended.

NPC has a highly skewed global distribution, with 80% of the global burden in Asian countries. According to the statistics from GLOBOCAN in 2012,³⁸ the total number of new cases of NPC in the world was 86,691, and 33,198 of these cases (38%) were registered in China. It is understandable that centers from China take great interest in developing the best possible staging system for this cancer. Although most countries adopt the AJCC/UICC system, China is the only country that still commonly uses a different system. A comparison of the 2 systems by Pan et al showed that the prognostic value of the T category in the 7th edition of the AJCC/UICC staging system^7,8 was superior, whereas the prognostic value of the N category in the 2008 Chinese edition was superior; for the prediction of OS by stage group, the 2 systems were comparable. The study by OuYang et al also supported the superiority of the N category in the Chinese 2008 edition in the IMRT era. Our current analyses support merging the strengths of the 2 systems.

In summary, the proposed 8th edition adopts the easily reproducible definition of the lower neck as an N3 criterion, clarifies the appropriate T2 criteria, avoids ambiguous terms, and discontinues subclassifications that have little impact. These changes will lead to a better distinction of hazards between adjacent stages/categories (Figs. 2–4) and improvements in both the AIC and the c-index by the proposed T category for all endpoints and by the proposed stage group for D-FFS and OS. This represents a concerted effort by endemic centers together with multidisciplinary international experts to develop the optimal staging system and work toward global unity.

After the optimization of the fundamental TNM staging system, further refinement of prognostication by additional independent factors will be useful for guiding treatment and cost-effective use of health care resources. There are increasing data showing that tumor volume is one of the most promising factors, but this is not incorporated into the current TNM system because the measurement of this criterion is not globally available and consensus on the cutoff value has yet to be attained. Further studies to develop a nomogram with the incorporation of additional prognostic factors are now ongoing in an attempt to work toward a personalized treatment strategy tailored to an individual’s risk pattern.

Footnotes

FUNDING SUPPORT

No specific funding was disclosed.

CONFLICT OF INTEREST DISCLOSURES

Quynh Thu Le reports a grant from Amgen to Stanford University to conduct a long-term follow-up study of patients enrolled in past trials.

REFERENCES

Introduction

Staging of cancer of the esophagus and esophagogastric junction (EGJ), presented in chapter 16 of the 8th edition American Joint Committee on Cancer (AJCC) Cancer Staging Manual (1), was derived from a machine-learning analysis of data from six continents from the Worldwide Esophageal Cancer Collaboration (WECC) (2-7). The purpose of this manuscript is to review staging in the 8th edition, which now includes clinical (cTNM), pathologic (pTNM), and postneoadjuvant therapy (ypTNM) stage groupings, and examine its application to clinical practice.

8th edition clinical staging

TNM categories—the facts about cancer—are judged clinically (cTNM) based on imaging studies, with minimal histologic information. This distinguishes them from pathologic cancer facts (pTNM) obtained by and large through microscopic examination of resection specimens. These TNM cancer facts (Table 1) are central to treatment decision-making and rely on cTNM being an accurate reflection of pTNM.

Stage groups are coarse prognostic collections based on an amalgamation of cancer facts. That prognostication based on cTNM differs from that based on pTNM reflects inaccuracies of obtaining cancer facts by current clinical staging modalities. These inaccuracies result in dissimilar stage group composition and survival profiles of cTNM vs. pTNM groups (2,5-7).

Histopathologic cell type markedly affects survival of cTNM-staged patients. Survival of early- and intermediate-stage patients is worse for those with squamous cell carcinoma than those with adenocarcinoma, necessitating separate stage grouping by cell type.

Histologic grade (G) markedly affects survival of patients with cT1-2N0M0 adenocarcinomas and cT2N0M0 squamous cell carcinomas. The AJCC Upper Gastrointestinal Expert Panel, concerned about the accuracy of G on biopsy, eliminated G from 8th edition cTNM stage groups, with the expectation that it would be reexamined for the 9th edition. Thus, although cTNM stage groups have been introduced into the 8th edition, they are more for coarse prognostication rather than for decision-making (Table 2).

Applications of 8th edition clinical staging (cTNM) to clinical practice

Clinical staging is limited by resolution of imaging methods. Strengths and limitations of each method should be taken into account when interpreting clinical staging.

Location (cL)

Assessment of cancer location (cL) made during esophagoscopy is crucial (1). The definition of cL has changed from the position of the upper edge of the cancer (7th edition) to its epicenter (8th edition), both referenced to distance from the incisors. Clinically, the epicenter is determined from upper and lower border measurements, which also provide cancer length. For treatment planning, it is critical to know the upper border for cancers of the cervical and upper thoracic esophagus and the lower border for cancers of the lower thoracic esophagus and EGJ. Alternatively, cL may be determined from chest computed tomography (CT) (1).

EGJ staging has been limited by reliance on simple measurements to determine whether an adenocarcinoma is esophageal or gastric. Conflicting statistical analyses necessitated a “place card” consensus decision; thus, the EGJ was redefined in the 8th edition: adenocarcinomas with epicenters no more than 2 cm into the gastric cardia are staged as esophageal adenocarcinomas, and those extending further are staged as stomach cancers (1). The genetic signature of EGJ cancers may be more accurate in identifying the cell of origin for cancer staging rather than its gross location (8,9). Cancer genetics will be a subsequent focus of the 9th edition staging of EGJ cancers.

Histologic cell type

Biopsy is mandatory and is the principal means of determining cell type. Because obliterative neoadjuvant therapy or endoscopic resection may prohibit future assessment of the primary cancer, this biopsy may provide the only facts about the cancer.

In most instances, classifying cancers as squamous cell carcinoma or adenocarcinoma relies on identifying features of squamous differentiation (keratin pearl formation, intercellular bridges, and cells with abundant glassy eosinophilic cytoplasm) versus gland formation for adenocarcinoma. However, this distinction can be challenging in specimens with limited diagnostic material and in higher G cancers. Ancillary markers, such as p63, p40, and cytokeratin 5/6 for squamous differentiation, and Alcian blue-PAS stain to demonstrate subtle intracellular mucin for adenocarcinoma, can be helpful.

cG

cG is important for treatment decisions regarding cT1-2N0M0 adenocarcinomas and cT2N0M0 squamous cell carcinomas and is a predictor of survival. Unfortunately, it is inconsistently reported in biopsy specimens, because superficial biopsy samples may provide limited material to accurately grade cancer differentiation.

Additionally, reporting cG has not been required previously for biopsy specimens (Table 1). Every attempt should be made to grade cancers using criteria outlined by the World Health Organization (10,11). Low-grade (G1) and moderately differentiated cancers (G2) are likely subject to substantial interobserver variability. However, poor differentiation or signet-ring cell morphology (G3) are associated with poor outcome (12) and thus must be documented in the biopsy pathology report as cG.

cT

Esophageal ultrasound (EUS) provides detailed examination of the esophageal wall and currently is the procedure of choice for determining cT. The esophageal wall is viewed as alternating hyperechoic (white) and hypoechoic (black) layers on EUS. The muscularis propria, imaged as the fourth layer (hypoechoic), is vital in differentiating T1, T2, and T3 cancers. Hypoechoic cancers are cT1 if there is no invasion of the fourth layer, cT2 if invasion is into the fourth layer, or cT3 if invasion is beyond the fourth layer. Additionally, EUS is used to evaluate the interface (between 4th and 5th layers) between the primary cancer and adjacent structures. If invasion of the fifth layer is detected, the cancer is cT4.

The performance index for distinguishing T1 or T2 cancers from T3 or T4 cancers by EUS is 0.89 for esophageal cancers and 0.91 for EGJ cancers (13). This distinction is essential for decision-making: typically, T3–4 cancers have a high probability of N+ and require neoadjuvant therapy, while T1–2 cancers are likely N0, requiring resection alone (14).

The clinical categorization of cT1–2 cancer directs future therapy. At higher EUS frequencies that focus on more superficial layers, subclassification of cT1a from cT1b cancers should be possible. However, most studies have shown poor accuracy in this subclassification (15-18). EUS has been reported as unreliable in staging T2N0M0 cancers (19,20); therefore, for cT1N0M0 and cT2N0M0 cancers, additional information is needed for decision-making. For T1N0M0 cancers, endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) are highly effective in confirming EUS cT1N0M0 and differentiating cT1a from cT1b (18,21-23). Note that pathologically confirmed T1 by EMR remains cT1, not pT1 (24).

For cT2N0M0 cancers, EMR and enhanced imaging are currently unreliable or unavailable. The use of G, particularly the finding of cG3, which is associated with reduced survival, may facilitate decision-making and prognostication (6,21).

cN

EUS, CT, and fluorodeoxyglucose positron emission tomography (FDG-PET) afford regional lymph node imaging and are the principal non-invasive modalities for cN determination. Each examination indirectly assesses the potential of a lymph node harboring metastases and thus has limitations specific to each technique.

EUS is used to evaluate size, shape, border, and internal echocardiographic characteristics of regional lymph nodes. Larger, more rounded, well demarcated hypoechoic lymph nodes are most likely to contain metastasis. However, reliance on EUS imaging assessment of cN is problematic. In patients with a 60% prevalence of pN+, using EUS criteria of >5 mm, round borders, smooth shape, and hypoechoic center for cN+, EUS was only 20% specific for N+, resulting in overstaging in 80% of pN0 cancers (25).

An enlarged lymph node on CT suggests nodal metastasis. The short axis of nodes is easily measured; intrathoracic and abdominal lymph nodes >1 cm are considered enlarged (26). However, probability is small that cN can be determined by lymph node size alone (27). Sources of false-negative examinations are normal-sized nodes that contain metastatic deposits, and metastatic nodes in direct contact with the cancer that may be indistinguishable from it. Similarly, false-positive examinations result from non-malignant nodal enlargement, as seen in inflammation. In a recent review, CT was 50% sensitive (range, 41–60%) and 83% specific (range, 77–89%) in cN assessment (28).

Metabolic evaluation of esophageal cancer by FDG-PET relies not only on metastatic deposit size but also on intensity of FDG uptake and decay. Theoretically, it is possible to identify microscopic metastases if glucose metabolism is sufficient to concentrate large quantities of FDG. FDG-PET cannot differentiate adjacent N+ from the primary cancer (29) and is least sensitive in assessing lymph nodes in the mid- and lower-thoracic esophagus (30). In a meta-analysis of 10 studies, FDG-PET N categorization was 57% sensitive (range, 43–70%) and 85% specific (range, 76–95%) (28). Because of its relatively good specificity, the main role of PET is confirmation of cN0 (31). Adding CT to FDG-PET increases accuracy, sensitivity, specificity, and negative predictive value (NPV) minimally (32); however, its biggest impact is in positive predictive value (PPV), with an increase from 69% to 82%.

These imaging modalities have remarkably similar performance in cN assessment: accuracy is reported to be 66% for EUS, 63% for CT, and 68% for PET, sensitivities 42%, 35%, and 35%, respectively, and specificities 91%, 93%, and 87%, respectively (33).

Therefore, histologic confirmation of cN is critical for accurate clinical staging. Endosonographic-directed fine needle aspiration (EUS-FNA) is strongly recommended by the AJCC (1). In a multicenter study of 171 patients, EUS-FNA of 192 lymph nodes was performed (34). Sensitivity, specificity, PPV, and NPV for determining cN was 92%, 93%, 100%, and 86%, respectively. In a more recent meta-analysis, EUS-FNA was 92% sensitive and 93% specific for cN, with a PPV of 100% and an NPV of 86% (28). Specificity may be lower in FNA samples obtained from lymph nodes located adjacent to the cancer, because passage of the needle through the cancer may cause contamination (35). Inadequate specimens are obtained in 11% to 16% of EUS-FNA specimens, but cytologic examination at the time of harvesting can improve quality (36). More invasive lymph node sampling, such as by thoracoscopy, laparoscopy, or mediastinoscopy and biopsy, may be necessary to ensure optimal clinical staging. Categorization of cytologically or pathologically confirmed regional lymph node metastasis remains cN, not pN (24).

Subclassification of cN+ requires determining the number of cancer-positive regional lymph nodes. It is possible to determine this number accurately, and this clinical assessment is predictive of survival (37-39).

cM

The value of EUS in screening for distant metastases (cM1) is extremely limited. The distant organ must be in direct contact with the upper gastrointestinal tract for it to be useful. EUS finding of ascites is suspicious for intraperitoneal metastases.

Chest and abdomen CT with intravenous and oral contrast can be used to detect distant metastasis (cM); however, it has been reported to be only 37–66% sensitive (40). FDG-PET imaging is more accurate. In a comparison report on detecting cM1, sensitivity of FDG-PET was 69%, specificity 93%, and overall accuracy 84% compared with 46%, 74%, and 63%, respectively, for CT (41). FDG-PET/CT imaging further increases detection of distant metastases. However, this must be balanced with more false-positive findings, resulting in unnecessary additional investigations. The clinical staging benefit of FDG-PET/CT may be limited if comprehensive conventional staging is performed, which includes chest, abdomen, and pelvis CT, EUS, and ultrasonography of the neck (1).

Cytologic or histopathologic confirmation of cM1 is recommended by the AJCC (1). If there is pathologic confirmation of distant metastatic cancer, categorization is pM1, not cM1, in contrast to cT and cN (1,24).

Clinical staging strategies

In 2017, esophagogastroduodenoscopy (EGD) with biopsy, EMR, ESD, EUS, EUS-FNA, and FDG-PET/CT are mainstays in clinical staging of cancer of the esophagus and EGJ. No single test is sufficient, and thus these investigations are complementary. The order in which they are used is variable and depends on availability, cost, scheduling, and patient and physician preference. There are two common strategies. The first is EGD with biopsy/EMR/ESD, EUS, and EUS-FNA to determine cell type, cG, cT, and cN, followed by FDG-PET/CT for additional cN and cM staging. The endoscopic procedures can be performed at one sitting, ensuring that data for all staging categories are complete. This strategy is efficient, but costly. The second strategy begins with CT or FDG-PET/CT evaluation for cM1 and no further testing if M1 is confirmed. For cM0 cancers, clinical staging addresses the other categories necessary to prescribe therapy. This sequential strategy is cost effective but inefficient and does not ensure that all clinical staging categories are determined (missing cTNM data). The modalities used for clinical staging must therefore be recorded in the patient’s medical record (Box 1).

Clinical staging: decision-making

Clinical staging facilitates decision-making and has the potential to provide precision cancer care. However, as described above, clinical stage may not reflect pathologic stage. Therefore, every effort must be made to add complementary information to increase accuracy of clinical staging categories. Clinically staged cT1N0M0 and cT2N0M0 cancers can be further studied and staging information augmented by adding cG and EMR results. Patients with cN1 and cM1 cancers will benefit from histologic confirmation of advanced cancer. The future of decision-making relies on new clinical staging modalities and cancer-specific therapy.

Clinical staging: prognostication

Survival according to cTNM stage groups is “pinched together” compared with pathologic stage groups (2,3,5,6). This results from multiple factors, including failure to use, or ineffectual use of, clinical staging modalities, understaging of “early” clinical cancers, overstaging of “advanced” clinical cancers, and unpredictability of effectiveness of neoadjuvant treatment (downstaging) of advanced cancers. This results in “regression toward the mean” of survival for cancers, with vastly different survival based on pTNM. Thus, prognostication using clinical stage groups is coarse and may be inaccurate.

8th edition pathologic staging

Cancer staging was initially proposed for “cases not previously treated and that the extent of the disease must be determined and recorded on clinical examination only” (42). However, inaccuracies of clinical staging and pathologic assessment after esophagectomy led to the use of pathologic stage after esophagectomy as the sole basis for all cancer staging. Data analysis in the 8th edition demonstrated that simple sharing of stage groups among classifications was not possible, due to marked survival differences and unique pathologic stage groups after resection (esophagectomy or endoscopic resection) (Table 3) (5-7).

Today, pathologic staging is losing its clinical relevance for advanced-stage cancer as neoadjuvant therapy replaces esophagectomy alone. However, it remains relevant for early-stage cancers, as the most accurate reflection of cancer facts and as a survival reference point.

Applications of 8th edition pathologic staging (pTNM) to clinical practice

Resection

Before resection, the surgeon or endoscopist must confirm the epicenter of the cancer (pL). Complete resection of the primary cancer cannot be overstated. Adequate resection requires obtaining satisfactory margins and preserving all margins, particularly the radial margin. The definition of a positive radial margin depends on the pathologic reporting system used. The Royal College of Pathologists defines an R1 (microscopically positive) margin as cancer within 1 mm of the margin (43); the College of American Pathologists defines R1 as microscopic involvement of the margin (44). A recents early neoplasia: a multicenter study in the United States. Gastrointest Endosc 2016. [Epub ahead of print]. [Crossref] [PubMed]