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Sentinel lymph node biopsy for the diagnosis of lymph node involvement in oral/oropharyngeal squamous cell carcinoma

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Abstract

This is a protocol for a Cochrane Review (Diagnostic test accuracy). The objectives are as follows:

The primary objective of this review is to assess the diagnostic accuracy of SLNB in the identification of lymph node involvement in patients with early‐stage (defined as cT1‐T2, cN0) oral and/or oropharyngeal squamous cell carcinoma.

Background

Target condition being diagnosed

Oral and oropharyngeal squamous cell carcinoma (OOSCC) is a common cancer annually affecting more than 350,000 people globally (GLOBOCAN 2008). While the incidence of oral cancer (particularly alveolo‐buccal) is low in the western world, it is the third most common cancer in developing countries. The epidemiology of head and neck cancer in the west appears to be changing due to a rapid increase in the incidence of human papilloma virus (HPV)‐associated oropharyngeal cancer (Chaturvedi 2011). OOSCC is currently staged using the American Joint Commission on Cancer (AJCC) staging system (Edge 2010), which is based on the tumour (T), node (N) and metastasis (M) classification (Table 1). Based on the TNM classification, OOSCC is staged into four main groups (Table 2).

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Table 1. American Joint Committee on Cancer (AJCC) TNM staging classification for OOSCC

T‐status

Characteristics 

TX

Primary tumour cannot be assessed

T0

No evidence of primary tumour 

Tis

Carcinoma in situ 

T1

Tumour 2 cm or less in greatest dimension 

T2

Tumour more than 2 cm but not more than 4 cm in greatest dimension 

T3 (oral cavity)

T3 (oropharynx)

Tumour more than 4 cm in greatest dimension

Tumour more than 4 cm in greatest dimension or involving lingual surface of epiglottis 

T4a 

Oral cavity

Oropharynx

Moderately advanced local disease

Tumour invades through cortical bone, into deep/extrinsic muscle of tongue (genioglossus, hyoglossus, palatoglossus and styloglossus), maxillary sinus or skin of face

Tumour invades any of the following: larynx deep/extrinsic muscle of tongue (genioglossus, hyoglossus, palatoglossus and styloglossus), medial pterygoid, hard palate and mandible 

T4b 

 

Oral cavity

 

Oropharynx

Very advanced local disease

Tumour invades masticator space, pterygoid plates or skull base, or encases internal carotid artery

Tumour invades any of the following: lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, skull base, or encases the carotid artery 

Note: superficial erosion alone of bone/tooth socket by gingival primary is not sufficient to classify a tumour as T4

 

N‐status

Characteristics

NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension

N2

 

 

 

 

Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension; or in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension; or in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension

N2a. Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension

N2b. Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension

N2c

Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension

N3

Metastasis in a lymph node more than 6 cm in greatest dimension

Note: midline nodes are considered ipsilateral nodes

M‐Status

M0

No distant metastasis

M1

Distant metastasis

OOSCC: oral and oropharyngeal squamous cell carcinoma
TNM: tumour (T), node (N) and metastasis (M) classification

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Table 2. Stage grouping

Stage 0

Tis

N0

M0

Stage I

T1

N0

M0

Stage II

T2

N0

M0

Stage III

T1, T2

N1

M0

T3

N0, N1

M0

Stage IVA

T1, T2, T3

N2

M0

T4a

N0, N1, N2

M0

Stage IVB

T4b

Any N

M0

Any T

N3

M0

Stage IVC

Any T

Any N

M1

While the long‐term disease outcomes (loco‐regional control and survival) are excellent for early‐stage disease (five‐year survival for stage I is 90% and for stage II is 80%), advanced‐stage disease (stages III to IV) has poor outcomes, with a five‐year survival of less than 40% (Carvalho 2005). Lymph node status remains one of the most important prognostic factors in head and neck cancers, including OOSCC (Gourin 2008). For patients who present with clinically palpable or radiologically demonstrable cervical nodes (cN+), neck dissection with surgical resection of the primary tumour, with or without reconstruction as appropriate, could be considered the current standard surgical management in OOSCC (Byers 1988). The optimal modality for staging the apparently node‐negative neck (cN0) remains controversial. The incidence of occult lymph node metastases in clinico‐radiologically node‐negative OOSCC is variable but is reported to be as high as 30% in some series (El‐Naaj 2011; Shah 1990). Clinical examination of the neck alone is grossly inadequate and highly inaccurate for neck nodal staging (van den Brekel 1993). A staging technique must be sensitive enough to reduce the risk of occult metastases to less than 20%. Unfortunately, all contemporary imaging modalities, although superior to clinical examination alone for detection of neck nodal metastases, still have limited sensitivity and negative predictive value in early‐stage node‐negative OOSCC (de Bondt 2007; Kyzas 2008; Liao 2012).

Index test(s)

The detection of sentinel node(s) in oral/oropharyngeal cancer usually involves sub‐epithelial application of a radioactive tracer substance (e.g. 99mTc (technetium) labelled colloid) at four quadrants around the primary tumour before surgery (Ross 2002). The drainage of radioactive material through the lymphatics to the neck nodes mimics the spread of cancer cells. The first echelon of lymph node receiving the radioactive material will be the same node(s) which would have received the metastatic cancer cells. Usually two or three nodes will be detected during such procedures (Civantos 2010; Sloan 2009). The total radioactive dose varies between 30 and 50 MBq, depending on the time interval between injection and surgery. A lymphoscintigraphy may be performed after injection of a radioactive tracer to map these lymph nodes. This gives the surgeons an idea of the possible location of the sentinel lymph node(s). A blue dye (e.g. methylene blue) may also be used with the radioactive tracers to facilitate detection of the nodes. A hand‐held gamma probe, if available, is most useful and can help in deciding the proper incision site as well as in detecting the radioactive tracer laden nodes lying underneath. Once dissected out, these nodes are again checked for radioactivity outside the body by using the hand‐held probe. Finally they are sent for frozen section and routine histopathological diagnosis using haematoxylin and eosin (H&E) staining. The frozen section allows a quick assessment of the node for the presence of any metastatic malignant cells that can be confirmed by histopathology. If malignant cells are present, these nodes are considered positive. Sometimes additional tests using immunohistochemistry for cytokeratin, molecular tools such as polymerase chain reaction (PCR), or both, may be carried out to detect occult nodal metastasis.

Despite years of experience, sentinel lymph node(s) biopsy for detection of occult metastasis in the neck in early stage OOSCC is still considered investigational and has not become an accepted standard clinical practice. In clinical trials, regardless of the status of the sentinel node(s), a systematic lymphadenectomy is still carried out in order to avoid possible management error in the case of a false negative result. Ideally, if sentinel node(s) assessment is very accurate, it can replace the need for a systematic lymphadenectomy (neck dissection) and its associated risks. However, in case of a false negative result, avoidance of a neck dissection will result in patients receiving suboptimal treatment, leading to a higher chance of regional failure and reduced overall survival.

Alternative test(s)

There are no alternative test(s) that will be considered in this review.

Rationale

The appropriate management of the clinico‐radiological node‐negative neck in early stage OOSCC has been a matter of considerable debate within the head‐neck oncologic community (D'Cruz 2011). The two major strategies, elective neck dissection (END) and watchful waiting, continue to be used based on personal and institutional biases rather than solid scientific evidence. A recent meta‐analysis showed that END reduced the risk of disease‐specific deaths but did not comment on all‐cause mortality (Fasunla 2011). Proponents of watchful waiting argue that most patients who fail in the neck at a later date are picked up early due to the close observation policy and hence can be salvaged successfully with a therapeutic neck dissection at relapse (Yuen 2009), thereby avoiding the unnecessary morbidity of neck dissection in the large majority of node‐negative patients who actually do not need it. Smaller oral cavity and/or oropharyngeal tumours (T1/T2) are amenable to resection per orally and a neck dissection, if avoided, could greatly reduce morbidity and associated cosmetic impairments. Proponents of END consider it to be the current gold‐standard staging procedure for the cN0 neck (Ferlito 2003; Mehta 2012) as it not only provides valuable prognostic information regarding nodal status but is also therapeutic for patients found to harbour occult nodal metastases. In an earlier era, END generally entailed a comprehensive neck dissection, such a modified radical neck dissection. However, over the years there has been a gradual but definite shift towards more conservative neck dissection and currently selective neck dissection is considered to be as efficacious as comprehensive neck dissection for the node‐negative neck. Deeper insights and improved understanding of the patterns of lymphatic drainage have allowed the extent of neck dissections to be progressively limited to those nodal levels at highest risk, and sentinel lymph node biopsy (SLNB) represents an extension of this concept (Alkureishi 2009). SLNB is a minimally invasive technique for accurate nodal staging which is well established in melanoma (de Rosa 2011; Valsecchi 2011) and breast cancer (Mansel 2006; Wang 2011). More recently the concept has been extended to other solid tumours (Chan 2009) including head and neck cancers (Coughlin 2010). In an ideal situation, patients with early‐stage OOSCC should need to undergo neck dissection only if the sentinel node(s) is found to be positive. Several studies have shown the accuracy and utility of such an approach in OOSCC (Broglie 2011; Civantos 2010; Kuriakose 2009). However, most of these studies have small numbers of patients, precluding statistical robustness. In addition, the methodology of SLNB was variable and non‐standardised until the publication of joint practice guidelines (Alkureishi 2009).

The improved accuracy of a standardised SLNB approach can potentially dictate the need for neck dissection in the clinically and radiologically negative neck. Hence a systematic review and meta‐analysis is needed to rigorously evaluate the diagnostic accuracy of SLNB in early‐stage node‐negative oral/oropharyngeal cancers.

Objectives

The primary objective of this review is to assess the diagnostic accuracy of SLNB in the identification of lymph node involvement in patients with early‐stage (defined as cT1‐T2, cN0) oral and/or oropharyngeal squamous cell carcinoma.

Secondary objectives

No secondary objectives will be considered for this review.

Methods

Criteria for considering studies for this review

Types of studies

We will include prospective or retrospective consecutive series studies reporting on the diagnostic accuracy of SLNB. We will exclude diagnostic case‐control studies. We will also exclude studies reporting insufficient data for accurate identification of the target population or for the construction of a 2 x 2 table.

Participants

Patients meeting the following criteria will be considered for this review:

  1. squamous cell carcinoma of the oral cavity and/or oropharynx;

  2. size of primary tumour < 4 cm;

  3. no palpable neck nodes (clinically node‐negative);

  4. radiologically node‐negative (if any pre‐surgical imaging has been done).

Index tests

SLNB will be the index test for this study. A sentinel node(s) is defined as a lymph node(s) sending a radioactive signal with an activity more than 10‐fold above background radiation level or a node(s) that appears blue intra‐operatively. The sentinel node(s) identified will be removed and submitted for standard histological examination with H&E staining. If the sentinel node(s) is found to be malignant by histological examination, it is defined as a positive sentinel node. If a sentinel node(s) is detected but histologically does not show any malignancy, it is defined as a negative node(s). If the sentinel node(s) is negative on H&E staining but positive on immunohistochemistry or PCR, it is considered positive. If the sentinel node(s) cannot be identified by tracer substance or blue dye, then it is defined as 'failure to detect sentinel node(s)'.

Comparator tests

No comparator test will be considered in this review.

Target conditions

Lymph node involvement in early‐stage (cT1‐T2), clinically and/or radiologically node‐negative (cN0) oral and/or oropharyngeal cancer.

Reference standards

Completion neck dissection (either selective or comprehensive neck dissection) followed by standard histological assessment of the surgical specimen will be the only reference standard. Selective neck dissection means the removal of selected neck node levels (e.g. supraomohyoid neck dissection wherein level I‐III lymph nodes are dissected) whereas comprehensive neck dissection refers to the removal of neck nodes at all levels (e.g. modified neck dissection wherein levels I‐V are dissected). The removed surgical pathology specimen is submitted for standard histological examination (H&E staining). If any of the removed nodes (either at SLNB or completion neck dissection) show metastasis, the reference standard will be considered positive.

Search methods for identification of studies

We will conduct systematic searches for diagnostic test accuracy studies. There will be no language, publication year or publication status restrictions. We may contact original authors for clarification and further data if study reports are unclear and we will arrange translations of papers where necessary. We may also contact experts in the field to ask for additional studies if any, both published and unpublished

Electronic searches

We will identify published, unpublished and ongoing studies by searching the following databases from their inception: the Cochrane Register of Diagnostic Accuracy Studies; MEDION; ARIF (1996 onwards); PubMed (1940 onwards); EMBASE, via Ovid (1947 onwards); CINAHL, via EBSCO; LILACS; KoreaMed (1997 onwards); IndMed (1985 onwards); PakMediNet; CAB Abstracts; Web of Science; BIOSIS Previews; Google Scholar and Google. We will model subject strategies for databases on the search strategy designed for PubMed (see Appendix 1).

Searching other resources

We will examine the reference lists of the retrieved articles. We will search The Cochrane Library, TRIP database and the National Guidelines Clearing House to retrieve evidence‐based resources relevant to this systematic review, so that we can scan their reference lists for additional studies.

Data collection and analysis

Selection of studies

We will download all titles and abstracts retrieved by electronic searching to the reference management database Endnote. We will remove duplicates and two review authors (SK, TG) will examine the remaining references independently. We will exclude those studies which clearly do not meet the inclusion criteria, and obtain copies of the full text of potentially relevant references. Two review authors (SN, TG) will assess the eligibility of retrieved papers independently. We will resolve disagreements if possible between SN and TG and, if necessary, involve a third review author (PC or SK). We will document the reasons for exclusion.

Data extraction and management

We will extract data on the following items.

  • Author, year of publication and journal (including language)

  • Country

  • Settings

  • Inclusion and exclusion criteria

  • Study design

  • Study population

  • Number of patients

  • Imaging prior to the index test, if any

  • Staging details of oral/oropharyngeal cancer

  • Biopsy/histopathology from primary site

  • Reference standard and performance of the reference standard

    • Type of neck dissection

    • Lymph node(s) yield (number and levels)

    • Histological assessment methods

  • Performance of the index test (SLNB)

    • Radioactive tracer or blue dye, or both

    • Technique of injection of radioactive substance and blue dye

    • Timing of injection

    • Amount of tracer used and location of injection

    • Exact technique of detection of tracer substance

    • Histological assessment methods

    • Failed test if any

  • Reporting of results

  • QUADAS items

  • Data for 2 x 2 table (true positive, true negative, false positive, false negative)

Two review authors (TG, SN) will abstract data independently onto a data abstraction spreadsheet specially designed for the review. We will resolve differences between review authors by discussion or by appeal to a third review author (SK or PC) if necessary. We will use two primary diagnostic studies to pilot the data abstraction spreadsheet (including the quality assessment).

Assessment of methodological quality

We will use the QUADAS‐2 quality assessment tool (Whiting 2011) to assess quality. Two authors (TG and SK) will independently assess the quality of each study. Any disagreement will be resolved by discussion and consensus with all review authors. We will report the results in a tabular and graphical form. We will carry out quality assessment of the studies according to the phases/domains outlined in Appendix 2.

Statistical analysis and data synthesis

We will input data from 2 x 2 tables and calculate sensitivity, specificity, positive predictive value and negative predictive value with 95% confidence intervals (CI) for all studies. We will use RevMan 5.1 to create coupled forest plots to evaluate the variation in the estimates of sensitivity and specificity between studies (RevMan 2011). We will plot the results of individual studies of diagnostic test accuracy in a summary receiver operator characteristic (SROC) space. As there is no threshold, we will use the bivariate method to provide summary estimates of sensitivity and specificity (Reitsma 2005). We will carry out analysis using the Metandi module of STATA v11.

Investigations of heterogeneity

We will investigate heterogeneity by visual examination of forest plots and ROC plots of sensitivities and specificities. We will analyse the sources of heterogeneity as covariates in meta‐regression analysis. The categorical covariates that we will analyse include:

  • year of publication (before or after 31 December 2005);

  • geographical location (North America, Europe, Asia Pacific);

  • sentinel node procedure (use of radioactive tracer, blue dye or a combination of the two);

  • type of neck dissection (selective, comprehensive);

  • histological methods of assessment (H&E, immunohistochemistry, PCR).

Sensitivity analyses

We will carry out sensitivity analysis by including studies with a rating of low risk of bias for patient selection, index test, reference standard, and flow and timing. The studies with high or unclear risk of bias will be omitted.

Assessment of reporting bias

As stated previously we will try to account for withdrawals and drop‐outs from individual studies (if not described) by contacting the corresponding author of the respective study (to minimise reporting bias).

To minimise publication bias, we will try to retrieve unpublished data on the accuracy of SLNB in OOSCC by contacting leading experts in the field.

We will produce an effective sample size funnel plot and associated regression test of asymmetry to ascertain publication bias (Deeks 2005) within the limitations of such assessment.

Table 1. American Joint Committee on Cancer (AJCC) TNM staging classification for OOSCC

T‐status

Characteristics 

TX

Primary tumour cannot be assessed

T0

No evidence of primary tumour 

Tis

Carcinoma in situ 

T1

Tumour 2 cm or less in greatest dimension 

T2

Tumour more than 2 cm but not more than 4 cm in greatest dimension 

T3 (oral cavity)

T3 (oropharynx)

Tumour more than 4 cm in greatest dimension

Tumour more than 4 cm in greatest dimension or involving lingual surface of epiglottis 

T4a 

Oral cavity

Oropharynx

Moderately advanced local disease

Tumour invades through cortical bone, into deep/extrinsic muscle of tongue (genioglossus, hyoglossus, palatoglossus and styloglossus), maxillary sinus or skin of face

Tumour invades any of the following: larynx deep/extrinsic muscle of tongue (genioglossus, hyoglossus, palatoglossus and styloglossus), medial pterygoid, hard palate and mandible 

T4b 

 

Oral cavity

 

Oropharynx

Very advanced local disease

Tumour invades masticator space, pterygoid plates or skull base, or encases internal carotid artery

Tumour invades any of the following: lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, skull base, or encases the carotid artery 

Note: superficial erosion alone of bone/tooth socket by gingival primary is not sufficient to classify a tumour as T4

 

N‐status

Characteristics

NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension

N2

 

 

 

 

Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension; or in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension; or in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension

N2a. Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension

N2b. Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension

N2c

Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension

N3

Metastasis in a lymph node more than 6 cm in greatest dimension

Note: midline nodes are considered ipsilateral nodes

M‐Status

M0

No distant metastasis

M1

Distant metastasis

OOSCC: oral and oropharyngeal squamous cell carcinoma
TNM: tumour (T), node (N) and metastasis (M) classification

Figuras y tablas -
Table 1. American Joint Committee on Cancer (AJCC) TNM staging classification for OOSCC
Table 2. Stage grouping

Stage 0

Tis

N0

M0

Stage I

T1

N0

M0

Stage II

T2

N0

M0

Stage III

T1, T2

N1

M0

T3

N0, N1

M0

Stage IVA

T1, T2, T3

N2

M0

T4a

N0, N1, N2

M0

Stage IVB

T4b

Any N

M0

Any T

N3

M0

Stage IVC

Any T

Any N

M1

Figuras y tablas -
Table 2. Stage grouping