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10.1245/ASO.2004.03.057
Annals of Surgical Oncology 11:213-218 (2004)
© 2004 Society of Surgical Oncology
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ORIGINAL ARTICLES

Improved Staging of Cervical Metastases in Clinically Node-Negative Patients With Head and Neck Squamous Cell Carcinoma

G.L. Ross, MRCSEd, D.S. Soutar, ChM, D.G. MacDonald, FRCPath, T. Shoaib, FRCSEd, I.G. Camilleri, FRCS (Plast) and A.G. Robertson, PhD

From the Plastic Surgery Unit (GLR, DSS, TS, IGC), Canniesburn Hospital, Bearsden, Glasgow; Oral Pathology Unit (DGM), Glasgow Dental Hospital and School, Glasgow; and Beatson Oncology Centre (AGR), Western Infirmary, Glasgow, United Kingdom.

Correspondence: Address correspondence and reprint requests to: Gary Ross, MRCSEd, Plastic Surgery Unit, Canniesburn Hospital, Switchback Road, Bearsden, Glasgow, G61 1QL, UK; Fax: 00-44-141-211-5652; E-mail: gary.ross{at}canniesburn.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: The management of the N0 neck in oral and oropharyngeal cancer is often determined by the risk of metastases related to features of the primary tumor. Where the risk of metastases is >20%, elective neck dissection (END) has been advocated. This study reviewed clinical staging, surgical staging, pathologic staging, and histopathologic parameters to determine the prediction of nodal metastases and micrometastases in patients with head and neck squamous cell carcinoma.

Methods: A prospective series of 61 clinically neck node–negative patients undergoing surgical resection of a T1/2 intraoral or oropharyngeal invasive squamous cell carcinoma and surgical staging of the neck, with sentinel node biopsy (SNB) alone or SNB-assisted END, between June 1998 and March 2002 were included in this study.

Results: Pathologic upstaging of the clinically N0 neck occurred in 27 (44%) of 61 patients. Routine pathology with hematoxylin and eosin upstaged disease in 22 of 27 patients (sensitivity of 81%). Five patients with micrometastasis were staged pN1mi after stepped serial sectioning and immunohistochemistry. Tumor thickness, a noncohesive invasive front, and perineural and bone invasion were all histological predictors for cervical metastases. Five patients with micrometastases were staged pN1mi.

Conclusions: Both clinical staging and routine pathologic staging underestimate the presence of nodal metastases. Staging with either SNB alone or SNB-assisted END shows promise in the management of the N0 neck by identifying patients with micrometastases (pN1mi).

Key Words: Head and neck • Neoplasms • Sentinel node biopsy • Elective neck dissection • Cervical metastases


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Numerous retrospective studies indicate that patients with head and neck squamous cell carcinoma (HNSCC) whose lymph nodes are treated on an elective basis have much better regional control and survival outcome than patients whose necks are salvaged after failure of treatment of the primary site alone.1–4 Because the prognosis of delayed cervical metastasis is poor, most authors cautiously favor elective neck dissection (END) and believe that the elective dissections are predominantly staging procedures and that the information obtained by pathologic examination should be used to direct adjuvant treatments.5,6 Where micrometastasis has been found in elective lymph node dissections, surgery has often been considered curative.

Assessment of the status of the neck is imperative for staging/treatment planning. However, 70% of HNSCC patients with N0 necks will have no detectable metastatic deposits within the neck specimen and may therefore not benefit from an END. Assessment with clinical palpation alone has proven unreliable for the detection of lymph node disease and is hence unreliable for staging purposes.7,8 Since the advent of sophisticated imaging technology, clinicians have focused on diagnostic refinement in an attempt to define and hence stage the N0 neck. Compared with routine pathologic evaluation of nodal disease, diagnostic imaging such as computed tomography,9–12 magnetic resonance imaging,10,12 and ultrasound scan12,13 have shown a specificity of 75% to 92%. Ultrasound fine-needle aspiration cytology12,14,15 has been reported as showing 100% specificity, although the sensitivity is between 42% and 73%, which is similar to the sensitivities of the other imaging techniques already mentioned (40% to 80%).9–13 Recent reports of the use of positron emission tomography show a sensitivity of 87%,16 a specificity of 90%,17 and a low false-positive rate. The $1 to $2 million cost of a dedicated positron emission tomography scanner and the small number of false positives prevent this imaging option as a standard of care, and its use as an indicator for surgery is still controversial.17

Because uniform criteria to identify the presence of metastatic disease have not been established diagnostically, the gold standard to stage the neck remains the identification of metastatic deposits by careful examination of the surgical specimen obtained at the time of END. END, however, carries with it associated morbidity and an effect on quality of life18–21 and does not benefit most patients. In HNSCC, a technique of superselecting lymph nodes that reflect the status of the lymph node basin is now available in the form of sentinel node biopsy (SNB). This less-invasive staging technique has been mainly used in other cancers, such as melanoma and breast cancer.22,23 SNB was used initially in HNSCC to assist END24–26 and more recently has been described alone as a staging tool in HNSCC.26–28

The reliability of routine histopathologic examination of lymph nodes in neck dissection specimens, thus establishing the number and level of lymph node metastases, is seldom questioned. Guidelines for such identification are available in the United Kingdom from the royal college of pathologists.29 However, the sensitivity of current routine histopathologic methods in assessing regional lymph node involvement is imperfect in that it, like clinical staging, can rarely detect the presence of micrometastasis within those nodes.30 Also, greater sampling of lymph nodes will lead to a greater probability of metastasis detection.31 It is important to realize that the term micrometastasis is not synonymous with occult disease. The term occult describes nodal metastatic disease that has not been detected by clinical staging investigations. The accuracy of staging is influenced by the range of available investigations, as well as by multiple technical and patient factors.32 The pathologic extent of occult disease varies from a single positive node to multiple positive nodes. Hence, outcome with minimal metastatic disease and the wide variation in the pathologic stage of N0 neck dissections account for the diverse outcome of patients with occult nodal disease.32 The definition of micrometastatic disease is a single deposit or multiple deposits of tumor within the lymph node sinuses with minimal replacement of the nodal architecture and measuring in total no more than 2 mm at any level of sectioning.33 The nomenclature of N1mi has been attributed to such patients within this article.

We looked prospectively at a group of patients in whom SNB-assisted END or SNB alone was used to stage the clinically N0 neck for patients with T1/2 tumors of the oral cavity or oropharynx. We assessed clinical staging (cT), surgical staging, pathologic staging (pT), and histopathological parameters to determine the prediction of nodal metastasis (pN) and micrometastasis (pNmi).


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
A prospective series of 61 clinically node-negative patients undergoing surgical resection of a T1/2 intraoral or oropharyngeal invasive SCC and surgical staging of the neck between June 1998 and March 2002 were included in this study. None of the patients had received preoperative radiotherapy, chemotherapy, or previous surgery other than the primary procedure. Only patients in whom tumor thickness was able to be accurately assessed and recorded were included.

Thirty-eight patients underwent SNB to stage the clinically N0 neck. Twenty-three patients underwent an SNB-assisted END in the form of a modified radical neck dissection.34 This comprehensive neck dissection allowed a complete and thorough investigation of the entire nodal basin for accurate comparison with the sentinel node pathology.

The SNB procedure has already been described24,25,27,28 and involved the triple diagnostic technique of preoperative lymphoscintigraphy, intraoperative use of blue dye, and a gamma probe detector. All nodes, including sentinel nodes, were fixed in 10% neutral buffered formalin. After fixation, they were bisected through the hilum (if this was identifiable) or through the long axis of the node. If the thickness of the halves was more than 2.5 mm, the nodes were further trimmed to provide additional 2.5-mm blocks. One routine hematoxylin and eosin (H&E)-stained section was taken from each block.

Twenty-two patients were initially staged positive on H&E. Out of the 39 remaining patients, full pathologic evaluation for micrometastasis was performed in 27 patients. Within the full pathologic protocol, if H&E sections were found to be free from tumor, all blocks were step serial sectioned with a ribbon of six exactly serial sections cut at 150-µm intervals. The numbered sections were individually mounted. Section 3 from each level was stained with H&E and examined. If these sections seemed to be negative, section 2 at each level was reacted with cytokeratin antibody AE1/AE3. Immunocytochemically positive areas were compared with the corresponding area in the H&E-stained serial section to confirm that the positivity represented viable tumor cells. Patients pathologically upstaged with step serial sectioning and immunohistochemistry were staged as pN1mi.33

Histopathologic parameters of disease that were recorded prospectively were evaluated. These included tumor thickness, maximum tumor diameter, invasive front, and presence of perineural, perivascular, and bone invasion. Statistical analysis was performed with SPSS 8.0 software (SPSS Inc., Chicago, IL) by using the t-test to compare primary parameters between groups.


   RESULTS
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 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The tumor staging for 61 patients was cT1, n = 34; cT2, n = 27; pT1, n = 36; pT2, n = 16; 6pT2, n = 1; pT3, n = 1; and pT4, n = 8. Nine patients (15%) were upstaged from early T1/2 to advanced pT3/4 disease.

Pathologic upstaging of the clinically N0 neck occurred in 27 (44%) of 61 patients. Patients’ nodal stages were pN0, n = 34; pN1mi, n = 5; pN1, n = 11; and pN2B, n = 11. Pathologic upstaging with routine H&E evaluation of sentinel nodes was 22 (36%) of 61. The use of immunocytochemistry and step serial sectioning upstaged disease in 5 (19%) of 27 patients.

Cervical metastases were present in 12 (29%) of 34 T1 tumors and 17 (63%) of 27 T2 tumors (P < .05). Clinical and pathologic staging and rates of cervical metastasis are listed in Table 1.


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  		TABLE 1. Cervical metastases detected pathologically (pN) according to clinical (cT) and pathologic (pT) tumor staging
 
Although tumor thickness was a significant predictor of metastasis (P < .05), there were cervical metastases present in 3 (23%) of 13 tumors with a thickness of <=2 mm and 24 (50%) of 48 tumors with a thickness of >2 mm (P = .063; Table 2). For tongue tumors, none of 3 tumors with a thickness of <=2 mm had cervical metastasis, compared with 7 of 18 tumors with a thickness of >2 mm (not significant). Although this was not statistically significant, there were five tongue tumors with a tumor thickness of <=3 mm, none of which developed cervical metastases.


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  		TABLE 2. Nodal staging (pN) in comparison to tumor thickness
 
Cervical metastases were present in 9 (45%) of 20 floor-of-mouth tumors, 7 (33%) of 21 anterior tongue tumors, 3 (75%) of 4 posterior tongue tumors, 5 (71%) of 7 retromolar trigone (RMT) tumors, and 3 (33%) of 9 other sites (not significant; Table 3). The presence of perineural invasion was recorded in 44 patients; 8 of 9 tumors with perineural invasion and 8 of 35 without perineural invasion had cervical metastasis (P < .05). The sensitivity of using perineural invasion as a predictor was 8 (50%) of 16, and specificity was 27 (96%) of 28.


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  		TABLE 3. Nodal staging according to tumor site
 
An invasive front was documented in 36 patients as either cohesive or noncohesive. Seven of 11 tumors with a noncohesive front, compared with 5 of 25 tumors with a cohesive front, had cervical metastasis (P < .05). The sensitivity of using the presence of a noncohesive front as a predictor of metastases was 58% (7 of 12), and the specificity was 83% (20 of 24).

Both an invasive front and the presence of perineural invasion were recorded in 33 cases. All five tumors with both a noncohesive front and the presence of perineural invasion developed cervical metastasis. There was no evidence of cervical metastasis in 86% (18 of 21) of tumors with a cohesive front and no evidence of perineural invasion.

The presence of vascular invasion was recorded in 46 patients: 3 of 4 patients with tumors with vascular invasion and 15 of 42 without vascular invasion developed cervical metastases (P = .214). Documented presence or absence of bone invasion was available in 35 patients. Six of 8 with bone invasion compared with 8 of 27 with no bone invasion developed metastasis (P < .05).

A total of 25 patients staged SNB negative have been followed up for an average of 20 months (range, 9–36 months). Twelve patients staged SNB positive underwent a therapeutic lymph node dissection (TLND). One patient staged SNB positive did not undergo a therapeutic neck dissection because of concomitant medical problems. One patient developed nodal recurrence 26 months after SNB and underwent a TLND. This patient developed further nodal disease 3 months later after TLND. Eleven patients staged negative with SNB-assisted END have been followed up on average for 32 months (range, 9–51 months). None of these patients has developed nodal recurrence.

Three patients have developed local recurrence, three have developed a second primary tumor, and two have developed distant metastases. Two patients are dead because of disease, and three are dead because of unrelated causes during the follow up period. A total of 56 patients continued to be followed up in the clinic.

SNB sensitivity was 25 of 27 (sensitivity 93%); both failures were in tumors in the floor of mouth. A total of 17 (71%) of 24 patients staged SNB positive had no further disease in the TLND.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
A total of 27 (44%) of 61 patients in our series were upstaged from cN0 to pN+. Clinical palpation alone has hence proven unreliable in the detection of lymph node disease and is unreliable for staging purposes.35,36

Tumor thickness, the presence of a noncohesive invasive front, the presence of perineural invasion, and the presence of bone invasion were statistically significant histopathologic predictors of the presence of cervical metastasis. Tumor site and the presence of vascular invasion were not able to predict the presence of cervical metastasis. As with clinical palpation, however, we cannot rely on histopathologic parameters alone to determine the need for an END, with individual sensitivities all <60%. The only way, therefore, currently to stage patients adequately is pathologic dissection of the lymph node basin.

The use of SNB allows a more detailed search for metastasis in relatively few nodes. The use of extensive sampling of nodes in cancers such as melanoma and breast cancer has shown the percentage of patients being upstaged by serial sectioning as 3% to 33% and by immunocytochemistry as 8% to 41%.35

The prognostic significance of micrometastasis in malignant melanoma has been highlighted in a study by Gershenwald et al.,36 in which a large number of recurrences in melanoma could have been prevented had extensive sampling been performed prospectively rather than in retrospect. In breast cancer, reports suggest that there is a worse prognosis associated with even a single micrometastasis.37 The Ludwig trial38 noted that the finding of a single micrometastasis in a single node by more extensive pathologic evaluation was associated with a decreased survival of approximately 50%. Similar prognostic influences have been reported for other tumors.39–43

In HNSCC, relying on serial sectioning and immunocytochemistry with an antibody to pan-cytokeratin, Ambrosch and Brinck44 uncovered eight micrometastases (7.9%) in six specimens from six patients. Woolgar32 found that 8% of patients with oral or oropharyngeal squamous cell carcinoma had micrometastasis by using step serial sectioning at 100-µm intervals.

For breast cancer and melanoma, extensive histopathologic investigation, including step serial H&E sectioning and immunocytochemistry, is now considered mandatory for reliable detection of metastases in sentinel nodes.45–47 As yet, molecular techniques such as reverse transcription-polymerase chain reaction, which may detect a single cancer cell among 106 normal cells, is not part of the recommended protocol to evaluate sentinel nodes.45–47 It remains to be proven whether reverse transcription-polymerase chain reaction may identify those few patients not identified by step serial sectioning and immunohistochemistry.45–47

In breast cancer and melanoma, the resultant upstaging of disease by the presence of micrometastases within current staging criteria remains controversial.45 Although the micrometastases must be <.2 mm in greatest dimensions to be classified as pN1mi33 rather than N1, it is the upstaging of micrometastasis from N0 to N1mi that is debated. The College of American Pathologists has suggested that immunocytochemistry-positive cells should be visualized and confirmed on the H&E-stained section to qualify as a micrometastasis before disease is upstaged from N0 to N1mi. With this classification, difficulties still exist in pathologic interpretation of small clusters of epithelial cells as benign, degenerating malignant, or viable malignant. This has been addressed by the International Union Against Cancer (UICC). For staging as pNmi, a nodal metastasis must extravasate out of lymphatic sinuses, thus demonstrating stromal reaction and tumor cell proliferation.33

Pathologic staging with routine H&E, like clinical palpation, proved unreliable in predicting metastasis in our series; 22 (36%) of 61 patients were upstaged from cN0 to pN+ with routine H&E. The sensitivity of routine pathology was 22 (81%) of 27, and 5 (19%) of 27 patients were upstaged from pN0 to pN1mi with additional pathologic evaluation of sentinel nodes.

It may not be cost-effective to stage a lymph node dissection specimen for the presence of micrometastasis in the absence of metastases on routine H&E.32,43,48 SNB or SNB-assisted END, however, is an effective and reliable means of assessing nodal basins for micrometastasis with additional pathologic techniques being used on the sentinel nodes only.

The identification of micrometastasis by additional pathologic techniques, such as step serial sectioning and immunocytochemistry, provides a dilemma for the current staging classifications of the UICC in HNSCC. Patients who are upstaged by additional pathologic methods but show no further disease in the neck specimen have only micrometastatic disease. These patients may well have a different prognosis than patients with one 2-mm metastasis, which is classified as N1 in the current UICC classification.49 The nomenclature of N1mi has been attributed to such patients within this article, and it remains to be seen whether this will be adopted by the UICC in the future for HNSCC, as it has already done for both breast cancer and melanoma.33,50

There may be a prognostic difference between patients staged as N1mi and N1. Further adjuvant trials may be possible for patients staged as N1mi who currently receive no form of adjuvant therapy in our series.

SNB alone in combination with additional pathologic techniques was successful in upstaging the clinically N0 neck in 25 (93%) of 27 patients. It remains unclear whether SNB will replace END in treatment of the clinically N0 neck, and we require the results of multicenter trials to determine this.26–28 However, it is clear that the best staging option for patients remains a combination of clinical staging, surgical staging, and pathologic staging.


   ACKNOWLEDGMENTS
 
The acknowledgments are available online in the fulltext version at www.annalssurgicaloncology.org. They are not available in the PDF version.


   FOOTNOTES
 
Clinical and routine pathologic staging underestimate the presence of nodal metastasis in patients with head and neck squamous cell carcinoma. Sentinel node biopsy or sentinel node biopsy–assisted elective neck dissection can more accurately stage the clinically N0 neck.

Received for publication January 2, 2003. Accepted for publication October 1, 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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S. J. Stoeckli, M. Pfaltz, G. L. Ross, H. C. Steinert, D. G. MacDonald, C. Wittekind, and D. S. Soutar
The Second International Conference on Sentinel Node Biopsy in Mucosal Head and Neck Cancer
Ann. Surg. Oncol., November 1, 2005; 12(11): 919 - 924.
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