27 Histopathologic Evaluation of Neck Dissections

The purpose of the neck dissection is to assess for lymph node metastases and excise regional disease. This chapter will discuss the pathologic processing and evaluation of neck dissections, its limitations, and possible solutions for these limitations. Pathologic nodal staging (pN) is based on the American Joint Committee on Cancer (AJCC) staging guidelines.¹ For head and neck tumors, the principal criteria that determine nodal staging and therefore prognosis are (1) the presence or absence of metastases, (2) the size of the largest metastasis, (3) the presence or absence of extranodal extension, and (4) the laterality of involvement. Interestingly, the number of involved lymph nodes has relatively little impact on the pathologic nodal stage, although it is a reflection of the burden of disease. Of these criteria, the single most significant driver of prognosis for all head and neck sites is the presence or absence of lymph node metastases.^2,3,4 The purpose of histopathologic evaluation is to answer each of these questions regarding nodal involvement.

27.2 Processing and Reporting of Neck Dissections

To understand the histopathologic evaluation of neck dissections, it is important to understand how they are processed. The processing of neck dissections requires cooperation between the surgeon and the pathologist. Radical neck dissections have anatomic landmarks, which allow the pathologist to orient and separate the neck dissection into individual nodal levels at the grossing bench. However, these landmarks are absent in both modified neck dissections and selective neck dissections; thus, it is important for the surgeon to aid in the orientation of these specimens. This may be readily achieved in two ways. The entire neck dissection can be pinned out on a cork board and oriented by the surgeon using a surgical marker, either in the operating room or subsequently in the surgical pathology gross room. Alternatively, the specimen can be divided into individual levels in the operating room and the individual levels can be sent separately. Orientation by the surgeon ensures that the specimen will be properly separated into the correct nodal levels for pathologic evaluation.

Once separated into individual levels, the pathologic processing and evaluation of neck dissections follows a generic protocol applicable to lymph node dissections in general.⁵ Specimens should be received and processed fresh rather than in formalin fixative. Fresh tissue is softer than fixed tissue and the difference in the consistency of the lymph nodes and the surrounding soft tissue is more readily appreciable, making them easier to identify. Once identified, each lymph node should be blunt dissected from the surrounding tissue. Fresh processing is particularly relevant for neck dissections as they often contain significant amounts of fibromuscular tissue which can become quite firm after fixation, making blunt dissection difficult. A thorough search for lymph nodes should be made with the intent to identify all lymph nodes in the dissection. Despite the fact that a minimum lymph node count is not part of pathologic nodal staging, it is important to have an accurate lymph node count because it is a surrogate measure of the quality of the neck dissection and is an independent predictor of the risk of recurrence.^6,7,8 If lymph nodes are not identified by palpation, the tissue should be submitted in toto. While this may compromise the integrity of the lymph node count, lymph nodes that are grossly undetectable are unlikely to harbor tumor and in toto submission increases the sensitivity for detecting lymph nodes, which is paramount. All identified lymph nodes should be submitted for evaluation. For lymph nodes grossly involved by tumor, measurement of largest metastasis and evaluation for extranodal extension for each lymph node with one or more gross sections are generally sufficient.

Grossly uninvolved lymph nodes should be serially sectioned at 2-mm intervals and submitted in toto ( Fig. 27.1). Smaller lymph nodes (< 2 cm) should be sectioned perpendicular to the shortest axis (longitudinal), whereas larger lymph nodes should be sectioned perpendicular to the longest axis (transverse). Care should be taken to place the sections in the cassette sequentially such that different surfaces are presented for cutting to ensure that the lymph node is consistently being evaluated at 2-mm intervals. While the Association of Directors of Anatomic and Surgical Pathology (ADASP) recommendations accept a thicker section (3–4 mm),⁵ this risks missing small macrometastases (> 2 mm) and current guidance from the College of American Pathologists favors the 2-mm gross section thickness.⁹ If multiple lymph nodes are submitted in a cassette, the surface of the lymph node should be differentially inked prior to sectioning to identify which sections belong to which lymph node so that positive lymph nodes are only counted once.

Fig. 27.1 Protocol for histologic processing of nonsentinel lymph nodes.

Pathologic reports should include the following information: the total number of lymph nodes identified in each nodal level and the number involved by tumor, the presence of extranodal extension, the size of the largest metastasis (not the size of the involved lymph node), the presence of any soft-tissue deposits without evidence of lymph node architecture, and the presence of submandibular glands and associated pathology.⁵

27.3 Limitations of Histopathologic Evaluation

The greatest limitation of histologic evaluation of neck dissection specimens is that it only evaluates a minute fraction of the tissue received. When tissue is received from the operating room, based on gross evaluation, only representative gross sections are usually taken to evaluate critical information such as margin status, histologic type and grade, lymphovascular invasion, and mitotic activity. Because of this, the taking of representative gross sections requires both judgment and experience to maximize yield. It is a testament to the importance of nodal status that grossly uninvolved lymph nodes are generally submitted in toto. Even then, only a tiny fraction of the submitted tissue is ever histologically evaluated. Given 2-mm gross sections, the fact that a histologic section is 2 μm means that only 0.1% of the tissue is evaluated in each histologic section. The standard protocol essentially takes a representative “snapshot” of the tissue at 2-mm intervals, and can therefore identify all lesions larger than 2 mm in smallest dimension if the gross section thickness is 2 mm and the sections are properly oriented and embedded. Smaller lesions may never enter the plane of sectioning and can therefore be missed altogether.

So why do we accept this limitation? Essentially, complete histologic evaluation is impractical. True complete histologic evaluation of even a single 1 cm × 0.6 cm × 0.6 cm lymph node would require 3,000 histologic sections, more than the entire daily workload of the average academic surgical pathology laboratory and would thus be both prohibitively expensive and technically infeasible. Even with representative histologic evaluation, each incremental improvement in sensitivity increases the histopathologic workload geometrically. This is a big deal because the typical neck dissection contains approximately 20 lymph nodes which currently require 20 to 40 H&E slides to evaluate so workloads can quickly spiral out of control. The current processing protocol is a tradeoff between yield and resource utilization and can identify all macrometastases (> 2 mm) but have a significant risk of missing micrometastasis (2 to 0.2 mm) and largely miss isolated tumor cells (ITCs; < 0.2 mm).

Another limitation of standard processing is the difficulty of identifying small tumor deposits on routine H&E stain. Small groups and single tumor cells may resemble histiocytes or endothelial cells, which are normal components of the lymph node. Similarly, basaloid and small round blue cell tumors can blend into the background lymphoid tissue at scanning power. This limitation can usually be overcome by careful examination and judicious use of immunohistochemical (IHC) stains. However, routine use of IHC stains to evaluate lymph nodes is cost prohibitive and can generate false-positive results.

Despite these limitations, standard processing and reporting works well for neck dissections in which gross disease is evident. Once gross tumor is identified in a lymph node, the main additional pieces of information needed are the size of the largest metastasis and whether there is contralateral involvement. Since the standard grossing protocol can find all macrometastases, high N stage disease can be readily assessed in this manner.

27.4 The Dilemma of the cN0 Neck

Clinical N0 necks (cN0) present a problem. It is well documented that a significant portion of cN0 necks contain tumor on pathologic evaluation.^3,10 The risk of involvement is dependent on tumor site, tumor (T) stage, and tumor thickness. In high T stage cancers (T3 and T4), a substantial fraction of cN0 necks contain tumor and elective neck dissection is generally considered to be prudent regardless of the clinical nodal status.^4,10 The real challenge lies with low T stage (T1 and T2) lesions, which are estimated to have an approximately 20 to 50% risk of nodal metastases despite being cN0, depending on primary site.⁴ That these clinically unapparent nodal metastases affect survival has been amply demonstrated both by comparison of watchful waiting versus elective prophylactic neck dissection^11,12 and by comparison of pN0 and pN1 patients given elective neck dissection despite cN0 status.¹³ In these low T stage patients, routine elective neck dissection risks overtreatment with its associated morbidity and expense but watchful waiting risks undertreatment and worse disease-free and overall survival. This has led to significant research into strategies to predict the risk factors for nodal metastases in low T stage tumors, clinically, radiologically, and pathologically.

27.5 Sentinel Node Biopsy

The premise of sentinel lymph node biopsy is that the lymphatic drainage of a tumor can be identified using tracers (radioactive, colorimetric, fluorescent, etc.), which, if injected into the tumor site, will enter the lymphatics around the tumor and accumulate in the first lymph node (s)—the sentinel lymph node (s)—that drain the tumor site. Tumor cells travelling through the lymphatics either take residence in the first lymph node (s) they encounter or “skip” metastasizes, i.e. bypass the first encountered lymph nodes. Skip metastases are rare. If the “sentinel lymph nodes” are negative, the likelihood of nodal involvement in the entire nodal basin is low. This strategy has been used successfully in other cancers and has in fact become the standard of care in breast cancer and melanoma. While not widely used for squamous cell carcinoma of the head and neck in the United States, many studies, mostly in the European and Asian literature, suggest that this strategy has the potential to solve the dilemma of the cN0 neck in low T stage head and neck tumors.^14,15,16,17

There are a number of theoretical limitations to sentinel lymph node biopsy in head and neck tumors that may explain its slow adoption in the United States.^10,17 It has been asserted that the proximity of the lymph node basins to the tumor site, and therefore to the site of tracer injection, can obscure the detection of the sentinel lymph node, particularly in floor-of-mouth tumors. Also, mass effect by a tumor might obstruct draining lymphatics and redirect tracers to nonsentinel lymph nodes. Additionally, some studies suggest that there is a high false-negative rate if only a single sentinel lymph node is evaluated and more extended tracer injections identify multiple lymph nodes, typically two to three, the removal of which may not be superior to an ultraselective nodal dissection in terms of morbidity and expense. Furthermore, the small surgical window used to extract the sentinel lymph nodes might risk injury to adjacent structures, which would not occur with a larger operative field. Despite these limitations, several multicenter randomized clinical trials have shown that sentinel lymph node biopsy is safe and highly reproducible, and has high sensitivities and negative predictive values.^{14,15,16,17,18,19}

27.5.1 Intraoperative Evaluation of Sentinel Lymph Nodes

Ideally, once a sentinel lymph node is identified, intraoperative evaluation could allow for immediate triage to neck dissection if tumor is identified. The two primary mechanisms for intraoperative evaluation are frozen section and touch imprint cytology. For frozen section, the sentinel lymph node is bisected perpendicular to the shortest axis and the tissue is embedded in optimum cutting temperature compound and frozen in a cryostat. Two to three frozen sections are cut at 5- to 10- μm thickness and are H&E stained for evaluation. For touch imprint cytology, the sentinel lymph node is bisected or serially sectioned longitudinally, the cut surfaces are touched to a glass slide, and the slide is H&E stained.

Much of the literature regarding the performance of frozen section versus touch imprint cytology is derived from the breast cancer literature,⁹ but the findings are likely applicable to the head and neck. Frozen section benefits from greater general familiarity in the general surgical pathology community but it is both more expensive and time consuming (15–20 minutes per frozen section block processed). This significantly limits the number of sections that can be evaluated within the real-time constraints of a surgery. Additionally, frozen section artifact can both compromise permanent H&E evaluation and interfere with ancillary IHC studies.

Touch imprint cytology is significantly faster (a few minutes) to process, allows rapid evaluation of multiple cut surfaces, and could potentially evaluate a much larger volume of the sentinel lymph node if it is serially sectioned. Unfortunately, it suffers from less familiarity in the surgical pathology community, resulting in a slightly decreased overall sensitivity for touch imprint cytology as compared to frozen section.

Both frozen section and touch imprint cytology techniques have broad range of reported sensitivities, ranging from 50 to 90%, likely as a result of variable sectioning protocols, patient populations, tumor sites, types and sizes, and overall experience of the evaluating pathologists.⁹ It is therefore important to recognize the limitations of intraoperative evaluation and to communicate to the patient that the decision to perform a neck dissection may need to be deferred to permanent processing of the sentinel lymph node (s). Despite these limitations, the fact that intraoperative sentinel lymph node evaluation can triage roughly half of patients requiring nodal dissection to immediate dissection represents a substantial cost saving and justifies its use. Other modalities for intraoperative evaluation have been studied including one-step RT-PCR (reverse transcription polymerase chain reaction) and ultrafast immunohistochemistry, but these methods are both time consuming and expensive and are therefore not currently ready for routine clinical use.⁹

27.5.2 Permanent Evaluation of Sentinel Lymph Nodes

The use of sentinel lymph node biopsy is attractive from a histopathologic standpoint because it provides a smaller target to concentrate more extensive histologic evaluation. As previously discussed, intensive histologic evaluation of a full neck dissection is both technically and financially infeasible. However, if evaluation can be focused on one or a few sentinel lymph nodes, a more aggressive approach may be taken. How extensive this evaluation should be is dependent on the clinical significance of macrometastases, micrometastases, and ITCs. The prognostic significance of macrometastases and the therapeutic value of neck dissection in this setting are well documented and serve as the basis for both the current AJCC pathologic nodal staging system and the standard histopathologic grossing protocol.

A growing body of evidence suggests that micrometastases and even ITCs also have clinical prognostic significance.^20,21,22 Two main strategies have been employed to identify micrometastases and ITCs, step sectioning and IHC. Step sectioning is the process of taking histologic sections at discrete intervals through the paraffin-embedded gross section. Suggested intervals range from 50 to 500 μm. Obviously, smaller intervals increase sensitivity but this must be balanced with practical considerations. To avoid missing any micrometastases, the section interval would have to be 200 μm or less; to find all ITCs is technically infeasible. However, even a small lymph node with a shortest axis of 6 mm would require 30 histologic sections to evaluate at this interval. Given that an average of 3 sentinel lymph nodes are identified, this translates to 90 histologic sections, roughly the current histologic workload equivalent of a full neck dissection, per sentinel lymph node procedure. This would place a significant workload and financial burden on pathology departments given the current reimbursement environment, so its feasibility remains to be seen. IHC can detect smaller lesions than routine H&E but is more time consuming and expensive and thus becomes infeasible at even relatively large sectioning intervals.

27.5.3 Proposed Protocol for Evaluation of Sentinel Lymph Nodes of the Head and Neck

Work from the breast literature provides promise for a feasible histologic protocol for sentinel lymph nodes. In breast cancer, micrometastases and ITCs within lymph nodes tend to be multiple. In a classic study, sentinel lymph nodes initially called negative on routine H&E were completely serially sectioned at 150 μm to identify occult micrometastases and ITCs. In 95% of these sentinel lymph nodes, at least one micrometastasis or ITC was identified within the first three levels by immunohistochemistry. Importantly, much of this effect was due to additional sampling rather than the increased sensitivity of IHC because 80% of these micrometastases and ITCs would have been identifiable by H&E.²³ If the same holds true for head and neck tumors, it will provide a feasible strategy for histologic evaluation of sentinel lymph nodes.

The feasibility of representative sampling in head and neck tumors is further supported by a recent evaluation of the distribution of micrometastases in the sentinel lymph nodes of patients with head and neck squamous cell carcinoma.²⁴ This study shows metastatic foci are asymmetrically distributed and tend to aggregate near the afferent pole along the central axes of the lymph node. As a result, representative sampling in this region of the lymph node identifies most occult metastases. In this study, at least 90% of micrometastases and 80% of ITCs were identified by evaluation of the first four slices of a sentinel lymph node sectioned at 150 μm along the shortest axis.

Based on these two studies, the following protocol ( Fig. 27.2) is recommended to evaluate sentinel lymph nodes in head and neck tumors. The sentinel lymph node should be grossly bisected or sectioned at 2-mm intervals (if larger than 5 mm in shortest diameter) perpendicular to the shortest axis with the plane of bisection as the central sectioning plane, and embedded to insure that the central slices are cut starting at the center at the plane of bisection and stepping outward but all other slices present a different surface for cutting. Note that this is different from the embedding protocol for nonsentinel lymph nodes. Two unstained slides at 2 to 4 μm should be cut at each of four levels at 150- μm intervals. One slide from each level should be routinely stained with H&E and evaluated. If all of these H&E slides are negative, one or more of the unstained slides should be subjected to IHC for evaluation. This strategy maximizes sensitivity within the confines of feasible representative sectioning and minimizes the use of more expensive and time-consuming IHC studies without loss of sensitivity. Studies by Broglie et al show 96% long-term neck control in patients with cN0 necks who have negative sentinel lymph nodes as assessed by a similar protocol.^20,21

Once micrometastases and ITCs are identified histopathologically, the question is what to do about them. In the breast literature, there is convincing evidence that while small micrometastases and ITCs in sentinel lymph nodes predict a low but real risk of nonsentinel lymph node axillary involvement (13–26%),²⁵ they do not appear to affect overall survival.²⁶ The presence of micrometastases and ITCs in the sentinel lymph nodes of head and neck tumors also predicts a similar likelihood of involvement (13–20%)²⁷ of nonsentinel lymph nodes. While we know that microscopic disease in cervical lymph nodes affects survival in head and neck tumors, it is unclear if elective neck dissection in these cases would necessarily improve survival. However, the behavior of head and neck micrometastases and ITCs cannot be assumed to be analogous to those of the breast. Numerous systemic adjuvant chemotherapy options are used routinely for breast cancer, while surgical intervention or radiotherapy remains the mainstay of disease control in the head and neck. Therefore, until a reliable nomogram, analogous to those used in breast cancer, can be formulated to estimate the risk of additional nonsentinel lymph node metastases, elective neck dissection or adjuvant radiation to the neck is prudent for all cases with identified metastases to sentinel lymph nodes regardless of size.

27.6 Special Considerations for Thyroid Cervical Metastases

Unlike other head and neck sites, thyroid carcinoma (except anaplastic carcinoma) benefits from effective systemic therapy in the form of radioactive iodine (RAI), which can ablate microscopic metastatic disease. As such, the purpose of neck dissection is to de-bulk gross disease to maximize the effectiveness of RAI. Therefore, clinically positive necks are treated much as they would be for any other head and neck site but cN0 necks are not aggressively pursued. The 2015 American Thyroid Association (ATA) guidelines²⁸ recommend ultrasound evaluation of the central and lateral neck compartments prior to surgery for well-differentiated thyroid carcinoma and biopsy of sonographically suspicious lymph nodes, but does not recommend sentinel lymph node biopsy in clinically and radiographically unremarkable necks. Postsurgical use of a scanning dose of RAI may help identify occult disease and a therapeutic dose of RAI may be used in patients with high-risk features, but prophylactic neck dissection for the cN0 neck is generally not warranted. The primary means of pathologic evaluation for clinically or radiologically suspicious lymph nodes is ultrasound-guided fine needle aspiration ( Fig. 27.4a, b) with or without thyroglobulin assay.

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