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Prognostic significance of microscopic and macroscopic extracapsular spread from metastatic tumor in the cervical lymph nodes
Oral Oncology 38 (2002) 747–751 www.elsevier.com/locate/oraloncology
Review
Prognostic significance of microscopic and macroscopic extracapsular spread from metastatic tumor in the cervical lymph nodes Alfio Ferlitoa,*, Alessandra Rinaldoa, Kenneth O. Devaneyb, Ken MacLennanc, Jeffrey N. Myersd, Guy J. Petruzzellie, Ashok R. Shahaf, Eric M. Gendeng, Jonas T. Johnsonh, Marcos B. de Carvalhoi, Eugene N. Myersh a
Department of Otolaryngology-Head and Neck Surgery, University of Udine, Policlinico Universitario, Piazzale S. Maria della Misericordia, I-33100 Udine, Italy b Department of Pathology, Foote Hospital, Jackson, MI, USA c Cancer Research UK, Clinical Cancer Center, St James’s University Hospital, Leeds, UK d Department of Otolaryngology, UT M.D. Anderson Cancer Center, Houston, TX, USA e Department of Otolaryngology-Head and Neck Surgery, Loyola University Medical Center, Maywood, IL, USA f Head and Neck Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA g Department of Otolaryngology-Head and Neck Surgery, Mount Sinai School of Medicine, New York, NY, USA h Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA i Head and Neck Service, Helio´polis Hospital, Sa˜o Paulo, Brazil Received 14 June 2002; accepted 26 June 2002
Abstract It has been established that the presence or absence of cervical node metastases in patients with head and neck squamous cell carcinoma (HNSCC) is a powerful prognostic indicator. This report reviews the evolution of thinking over the past 70 years with regard to the import and detection of cervical nodal metastases which exhibit spread of tumor beyond the confines of the original encompassing nodal capsule. In the process, this discussion touches upon clinical examination, gross and microscopic pathologic examination, and radiographic imaging studies. In particular, the distinction between gross nodal extracapsular spread of tumor and microscopic nodal extracapsular spread of tumor has been drawn in recent reports; this raises the possibility that identification of microscopic breaching of the node capsule by tumor might provide clinically significant information which is not provided by the gross observation of an intact lymph node capsule. While it remains to be seen whether microscopic extracapsular spread alone will prove to be an important prognostic factor, it is recommended that selective neck dissection continue to be offered even in those patients with clinically negative necks; further studies should aid in defining the import of microscopic extracapsular tumor spread in patients with positive cervical nodes. # 2002 Elsevier Science Ltd. All rights reserved. Keywords: Extracapsular spread; Carcinoma of the head and neck; Squamous cell carcinoma; Lymph node metastasis
1. Introduction Despite improvements in surgical and radiation therapy techniques, and the increased use of combined modality chemoradiation, the survival of patients with cancer of the head and neck has not significantly
* Corresponding author. Tel.: +39-0432-559302; fax: +39-0432559339. E-mail address: [email protected] (A. Ferlito).
improved over the past three decades. Most frequently, treatment failures take the form of distant metastases [1] and/or second primary cancers [2]. The presence of metastatic cancer identified in neck dissection specimens is the single most adverse independent prognostic factor in head and neck squamous cell carcinoma (HNSCC) [3], therefore the pathologic examination of neck dissection specimen provides basic information for diagnosis, staging and prognosis to the team treating cancer of the head and neck [4,5]. Historically, pathologic techniques for assessing neck dissections often only
1368-8375/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved. PII: S1368-8375(02)00052-0
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A. Ferlito et al. / Oral Oncology 38 (2002) 747–751
comment on lymph nodes 3 mm or more in diameter [6]. Standard techniques for examination of neck dissection specimens may have difficulty in correctly recognizing node levels and may also miss micrometastases, microscopic extracapsular spread and soft tissue deposits [7]. More recently described pathological techniques are able to identify lymph nodes as small as 0.5 mm [8]. The first description of the pathology of extracapsular spread of cervical lymph node metastasis was published in 1930 by Willis [9]; he based his observations on a series of autopsies of patients with advanced cancer of the head and neck. ‘‘In most cases’’, Willis wrote, ‘‘the tumors had extended far beyond the glandular confines to involve many adjacent structures’’. In 1971, Bennett et al. [10] elaborated upon these earliest observations, describing extranodal spread as a distinct adverse prognostic factor in patients with cancer of the larynx and hypopharynx.
2. Definition A lymph node may be defined as an encapsulated collection of lymphoid tissue, of any size, which possesses a peripheral sinus. Approximately 30% of lymph nodes containing metastatic squamous cell carcinoma were 3 mm or less in maximum diameter [7,8,11]. Macroscopic extracapsular spread is visible to the naked eye at the time of nodal dissection. Microscopic extracapsular spread is the extension of tumor through the lymph node capsule with an associated desmoplastic stromal reaction. Soft tissue disease is the presence of metastatic carcinoma in soft tissue with no evidence of a lymph node architecture [7,11,12]; this may represent a lymph node which has been completely replaced by metastatic carcinoma or a true extranodal metastasis.
3. Radiologic imaging of extracapsular spread Some studies have examined the role of preoperative imaging for the detection of extracapsular neoplastic spread. Early work by Yousem et al. [13] demonstrated a sensitivity as high as 100% using computed tomography (CT) for the prediction of extracapsular spread and found that gadolinium enhanced, fat-suppressed magnetic resonance imaging (MRI) did not improve sensitivity. More recently Steinkamp et al. [14] evaluated the efficacy of MRI in the determination of extracapsular neoplastic spread and soft tissue infiltration of metastatic HNSCC within cervical lymph nodes. MRI achieved a specificity of 72.2% in the detection of extracapsular neoplastic spread. The sensitivity of the method proved to be 74.4%. Small (less than 1 cm) areas of extracapsular growth of metastatic tumor were not detected by MRI, and as a consequence represented
false-negative findings in the MRI examinations. Thus the specificity (72.2%) and sensitivity (74.4%) of MRI examination alone in the detection of extracapsular spread of carcinoma in cervical lymph nodes suggests that this technique may be inadequate, in isolation, for detection of all such instances of extracapsular spread of metastatic tumor within cervical lymph nodes.
4. Risk of distant metastasis and prognostic significance of extracapsular spread HNSCC patients who develop regional metastatic disease are more likely to develop distant metastases, and hence more likely to experience a poor survival outcome. Prior work in this area has been focused on identifying and stratifying those factors that place patients at high risk for distant metastasis [15]. Vikram et al. [16] found that the incidence of distant metastases was higher in those patients who presented with palpable cervical lymph nodes than in those who did not (35% vs. 4%, P < 0.05). In particular, this increase in the incidence of distant metastasis was most marked in those patients who had pathologically proven metastases located at multiple levels in the neck, as opposed with those patients who had metastases in a single level or who had negative nodes (35% vs. 5%, P < 0.05). Leemans et al. [17] found that patients who developed pathologically positive lymph nodes in the neck were at double the risk (13.6%) for distant metastatic disease as compared to patients free of lymph node metastases (6.9%). Similarly, patients with more than 3 lymph nodes histologically positive for metastasis faced the highest risk of distant metastases (46.8%). Similar studies have reinforced the correlation between the presence of neck metastases and the increased risk of the development of distant metastatic disease [18,19]. In a retrospective review of 727 HNSCC patients, Calhoun et al. [19] found that not only the presence of nodal metastasis, but also the initial size of the tumor was correlated with distant metastasis. Carter et al. [20] found that macroscopic extracapsular spread was seen most frequently in association with large nodal masses more than 3 cm in diameter, but also occurred in some specimens with smaller lymph nodes less than 3 cm in diameter. Anatomical structures most commonly invaded in areas of neck dissection with macroscopic spread from nodal metastases were skeletal muscle and the adventitia of the internal jugular vein. Macroscopic extracapsular infiltration was associated with a high incidence of recurrent tumor in the ipsilateral neck, particularly within 12 months of surgery. Microscopic extracapsular growth was associated with a lower incidence of recurrent tumor in the ipsilateral neck but the difference did not reach statistical significance. Myers and Alvi [21] reviewed a series of 110 patients treated for
A. Ferlito et al. / Oral Oncology 38 (2002) 747–751
cancer of the supraglottis and noted that extracapsular spread was associated with an incidence of distant metastasis of 71%; moreover, they observed that radiation therapy did not prevent the development of distant metastases. They recommended adjuvant chemotherapy in patients with extracapsular spread to reduce the risk of developing distant metastases. In a retrospective study of 130 patients with surgically treated stage III and IV squamous cell carcinoma of the hypopharynx, tongue, and supraglottis, Alvi and Johnson [22] evaluated risk factors for the development of distant metastases. Patients with palpable neck metastases, histological evidence of nodal metastases, involvement of multiple nodes, and evidence of extracapsular spread proved to be at greater risk of treatment failure (via development of spread of tumor to distant sites) than patients who lacked those risk factors. Vaidya et al. [23] examined the pattern of spread and site of recurrent disease in 128 patients with primary HNSSC. In their series the rate of local recurrence was unrelated to the presence of nodal metastasis and extracapsular extension. Extracapsular extension significantly (P=0.002) predicted the development of distant metastasis and the most common site of distant metastasis was the lung. Recently, Myers et al. [24] retrospectively studied 266 patients with squamous cell carcinoma of the oral tongue treated with surgical resection of the primary tumor and neck dissection. They found that extracapsular spread was the most significant predictor of both regional recurrence and development of distant metastasis resulting in a decreased survival. These findings suggest that, intensive regional and systemic adjuvant therapy may be indicated for HNSCC patients with extracapsular spread of tumor. Further evaluation of this cohort of patients by Greenberg et al. [25] found that the extent of extracapsular spread outside the lymph node capsule (either42 mm or > 2 mm beyond the capsule) did not further predict patient outcomes. Rather, the number of lymph nodes involved with extracapsular spread was a highly significant predictor of disease-specific and overall survival. Those patients with two or more nodes with extracapsular spread, had a median survival of less than 1 year. In addition those with two or more nodes with extracapsular spread, had a regional recurrence rate of 58.3% and a rate of distant metastases of 33.3%. These authors also found that of 186 who were clinically N0 in their series, 34% were pathologically node positive and 19% of these patients were found to have extracapsular spread. In clinically N1 patients, 40% of those were pathologically N2b and 50% were positive for the presence of extracapsular spread. This work clearly argues for accurate pathologic nodal staging at the time of surgical management of the primary tumor [26]. In an attempt to stratify different risk groups within the larger group of patients with extracapsular exten-
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sion of tumor from a primary HNSCC, de Carvalho [27] has prospectively analyzed 170 consecutive cases of previously untreated patients with laryngeal or hypopharyngeal squamous cell carcinoma. Of the 170 patients, 101 (59.4%) had pathological confirmation of metastatic nodal disease. These patients were divided into those who were node-positive with no capsular invasion, those with capsular invasion without extracapsular extension, those with capsular invasion with microscopic extracapsular extension, and those with macroscopic extracapsular extension. When the tumor was confined to the lymph node or showed only microscopic invasion beyond the capsule, there were no statistically significant differences in risk rates for treatment failure. The presence of macroscopic penetration of the lymph node capsule by tumor, however, increased the risk of recurrence by 3.5 times when compared with those patients who either lacked metastasis at initial diagnosis, or those patients in whom the tumor was confined within the lymph node. Therefore, macroscopic extracapsular spread of cervical lymph node disease appears to be the most significant independent adverse prognostic factor in patients with extracapsular spread of tumor; patients with macroscopic extracapsular nodal spread in their neck dissection specimens had the highest incidence both of regional recurrence and of distant metastasis. This has led de Carvalho [27] to suggest that microscopic extracapsular spread is not of prognostic significance in patients with cancer of the larynx or hypopharynx. Macroscopic extracapsular spread as the major prognostic factor for recurrent disease in the neck has also been reported by Carter et al. [28]. These authors also stress the importance of differentiating macroscopic from microscopic extracapsular spread. In contrast, Alvi and Johnson [29] documented that even lymph nodes with microscopic extracapsular spread markedly decreased the outcome. Recently, Coatesworth and MacLennan [11] have prospectively analyzed 96 elective neck dissections in 63 patients with upper aerodigestive tract squamous cell carcinoma and clinically N0 necks to assess the prevalence of microscopic extracapsular spread and soft tissue deposits. The dissections were separated peroperatively into nodal levels; these were cut into 2 mm thick slices, embedded in their entirety and sectioned at six micrometer thickness and stained with hematoxylin and eosin. Using this technique microscopic as well as macroscopic extracapsular spread can be detected. They found that microscopic extracapsular spread and soft tissue deposits occur frequently in patients with a clinically N0 neck, but they may well be missed by routine histopathologic techniques. This study has shown a prevalence of 19.0% for microscopic extracapsular spread and 7.9% for soft tissue deposits. Further studies by this group [30] have shown that extracapsular spread
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has a significant adverse prognostic effect, even microscopic extracapsular spread, when defined by a perinodal desmoplastic stromal response. Indeed there was no significant difference in overall or recurrence free survival between microscopic and macroscopic extracapsular spread. Jose et al. [30] concluded that microscopic and macroscopic extracapsular spread and soft tissue deposits are of prognostic significance for survival and recurrence free survival in patients with upper aerodigestive tract squamous cell carcinoma. The presence of extracapsular spread in one or more metastatic nodes is believed by some to be the most important prognostic parameter [10,24,31–43]. However, other investigators have been unable to make a direct correlation in patients with HNSCC between extracapsular spread and prognosis [44,45]. This discrepancy may well depend on the type of extracapsular spread present—macroscopic versus microscopic—or some combination of the two. Since MRI cannot detect all instances of extracapsular spread of metastatic HNSCC within lymph nodes [14] (and, indeed, the problem of false positive cervical nodes even on physical examination persists [46,47]), it seems likely for the foreseeable future that pathologic examination of cervical nodes will continue to serve as the gold standard for detecting the presence or absence of regional nodal metastases. It is necessary however to use an accurate and comprehensive method of pathological assessment of neck dissections [7,8,11,30]. At this time, the evidence of increased risk of recurrence and metastasis with extracapsular spread in HNSCC patients suggests that observations regarding the relationship of tumor to lymph node capsule should be an essential part of every pathology report. As the reports reviewed above indicate, it is not always clear whether a given group of authors studying the phenomenon of extracapsular extension of metastatic HNSCC are attempting to correlate macroscopic spread of tumor, or microscopic spread, or both. A clear direction for future investigation would be to attempt to distinguish between these two situations, and so determine conclusively whether or not microscopic penetration alone of a lymph node capsule by metastatic carcinoma should warrant a form of therapy different than that offered to patients whose nodal metastases remain confined macroscopically and microscopically within that nodal capsule. Investigators conducting therapeutic trials should stratify treatment groups according to the presence or absence of macroscopic extracapsular spread of metastatic tumor within lymph nodes, the presence or absence of microscopic extracapsular spread, or both; in this way, the relative import of these two potential prognostic factors (alone or in combination) can finally be determined with some sense of certainty. Considering the high incidence (25%) of microscopic neoplastic extracapsular spread and soft tissue
deposits in patients with HNSCC and clinically negative necks [7], selective neck dissection is indicated [48]. In conclusion, the prognosis in individuals with extranodal spread of the tumor in cervical lymph nodes is quite poor. This appears to be the most important prognostic factor in patients with cervical metastasis both in relation to the local recurrence and distant metastasis. It is extremely important for the clinicians to appreciate the implications of this prognostic factor and the pathologists to make every effort to define this in their final pathology reports. Whether the addition of chemotherapy will make any meaningful difference in the long-term outcome needs to be studied further.
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Review
Prognostic significance of microscopic and macroscopic extracapsular spread from metastatic tumor in the cervical lymph nodes Alfio Ferlitoa,*, Alessandra Rinaldoa, Kenneth O. Devaneyb, Ken MacLennanc, Jeffrey N. Myersd, Guy J. Petruzzellie, Ashok R. Shahaf, Eric M. Gendeng, Jonas T. Johnsonh, Marcos B. de Carvalhoi, Eugene N. Myersh a
Department of Otolaryngology-Head and Neck Surgery, University of Udine, Policlinico Universitario, Piazzale S. Maria della Misericordia, I-33100 Udine, Italy b Department of Pathology, Foote Hospital, Jackson, MI, USA c Cancer Research UK, Clinical Cancer Center, St James’s University Hospital, Leeds, UK d Department of Otolaryngology, UT M.D. Anderson Cancer Center, Houston, TX, USA e Department of Otolaryngology-Head and Neck Surgery, Loyola University Medical Center, Maywood, IL, USA f Head and Neck Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA g Department of Otolaryngology-Head and Neck Surgery, Mount Sinai School of Medicine, New York, NY, USA h Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA i Head and Neck Service, Helio´polis Hospital, Sa˜o Paulo, Brazil Received 14 June 2002; accepted 26 June 2002
Abstract It has been established that the presence or absence of cervical node metastases in patients with head and neck squamous cell carcinoma (HNSCC) is a powerful prognostic indicator. This report reviews the evolution of thinking over the past 70 years with regard to the import and detection of cervical nodal metastases which exhibit spread of tumor beyond the confines of the original encompassing nodal capsule. In the process, this discussion touches upon clinical examination, gross and microscopic pathologic examination, and radiographic imaging studies. In particular, the distinction between gross nodal extracapsular spread of tumor and microscopic nodal extracapsular spread of tumor has been drawn in recent reports; this raises the possibility that identification of microscopic breaching of the node capsule by tumor might provide clinically significant information which is not provided by the gross observation of an intact lymph node capsule. While it remains to be seen whether microscopic extracapsular spread alone will prove to be an important prognostic factor, it is recommended that selective neck dissection continue to be offered even in those patients with clinically negative necks; further studies should aid in defining the import of microscopic extracapsular tumor spread in patients with positive cervical nodes. # 2002 Elsevier Science Ltd. All rights reserved. Keywords: Extracapsular spread; Carcinoma of the head and neck; Squamous cell carcinoma; Lymph node metastasis
1. Introduction Despite improvements in surgical and radiation therapy techniques, and the increased use of combined modality chemoradiation, the survival of patients with cancer of the head and neck has not significantly
* Corresponding author. Tel.: +39-0432-559302; fax: +39-0432559339. E-mail address: [email protected] (A. Ferlito).
improved over the past three decades. Most frequently, treatment failures take the form of distant metastases [1] and/or second primary cancers [2]. The presence of metastatic cancer identified in neck dissection specimens is the single most adverse independent prognostic factor in head and neck squamous cell carcinoma (HNSCC) [3], therefore the pathologic examination of neck dissection specimen provides basic information for diagnosis, staging and prognosis to the team treating cancer of the head and neck [4,5]. Historically, pathologic techniques for assessing neck dissections often only
1368-8375/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved. PII: S1368-8375(02)00052-0
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A. Ferlito et al. / Oral Oncology 38 (2002) 747–751
comment on lymph nodes 3 mm or more in diameter [6]. Standard techniques for examination of neck dissection specimens may have difficulty in correctly recognizing node levels and may also miss micrometastases, microscopic extracapsular spread and soft tissue deposits [7]. More recently described pathological techniques are able to identify lymph nodes as small as 0.5 mm [8]. The first description of the pathology of extracapsular spread of cervical lymph node metastasis was published in 1930 by Willis [9]; he based his observations on a series of autopsies of patients with advanced cancer of the head and neck. ‘‘In most cases’’, Willis wrote, ‘‘the tumors had extended far beyond the glandular confines to involve many adjacent structures’’. In 1971, Bennett et al. [10] elaborated upon these earliest observations, describing extranodal spread as a distinct adverse prognostic factor in patients with cancer of the larynx and hypopharynx.
2. Definition A lymph node may be defined as an encapsulated collection of lymphoid tissue, of any size, which possesses a peripheral sinus. Approximately 30% of lymph nodes containing metastatic squamous cell carcinoma were 3 mm or less in maximum diameter [7,8,11]. Macroscopic extracapsular spread is visible to the naked eye at the time of nodal dissection. Microscopic extracapsular spread is the extension of tumor through the lymph node capsule with an associated desmoplastic stromal reaction. Soft tissue disease is the presence of metastatic carcinoma in soft tissue with no evidence of a lymph node architecture [7,11,12]; this may represent a lymph node which has been completely replaced by metastatic carcinoma or a true extranodal metastasis.
3. Radiologic imaging of extracapsular spread Some studies have examined the role of preoperative imaging for the detection of extracapsular neoplastic spread. Early work by Yousem et al. [13] demonstrated a sensitivity as high as 100% using computed tomography (CT) for the prediction of extracapsular spread and found that gadolinium enhanced, fat-suppressed magnetic resonance imaging (MRI) did not improve sensitivity. More recently Steinkamp et al. [14] evaluated the efficacy of MRI in the determination of extracapsular neoplastic spread and soft tissue infiltration of metastatic HNSCC within cervical lymph nodes. MRI achieved a specificity of 72.2% in the detection of extracapsular neoplastic spread. The sensitivity of the method proved to be 74.4%. Small (less than 1 cm) areas of extracapsular growth of metastatic tumor were not detected by MRI, and as a consequence represented
false-negative findings in the MRI examinations. Thus the specificity (72.2%) and sensitivity (74.4%) of MRI examination alone in the detection of extracapsular spread of carcinoma in cervical lymph nodes suggests that this technique may be inadequate, in isolation, for detection of all such instances of extracapsular spread of metastatic tumor within cervical lymph nodes.
4. Risk of distant metastasis and prognostic significance of extracapsular spread HNSCC patients who develop regional metastatic disease are more likely to develop distant metastases, and hence more likely to experience a poor survival outcome. Prior work in this area has been focused on identifying and stratifying those factors that place patients at high risk for distant metastasis [15]. Vikram et al. [16] found that the incidence of distant metastases was higher in those patients who presented with palpable cervical lymph nodes than in those who did not (35% vs. 4%, P < 0.05). In particular, this increase in the incidence of distant metastasis was most marked in those patients who had pathologically proven metastases located at multiple levels in the neck, as opposed with those patients who had metastases in a single level or who had negative nodes (35% vs. 5%, P < 0.05). Leemans et al. [17] found that patients who developed pathologically positive lymph nodes in the neck were at double the risk (13.6%) for distant metastatic disease as compared to patients free of lymph node metastases (6.9%). Similarly, patients with more than 3 lymph nodes histologically positive for metastasis faced the highest risk of distant metastases (46.8%). Similar studies have reinforced the correlation between the presence of neck metastases and the increased risk of the development of distant metastatic disease [18,19]. In a retrospective review of 727 HNSCC patients, Calhoun et al. [19] found that not only the presence of nodal metastasis, but also the initial size of the tumor was correlated with distant metastasis. Carter et al. [20] found that macroscopic extracapsular spread was seen most frequently in association with large nodal masses more than 3 cm in diameter, but also occurred in some specimens with smaller lymph nodes less than 3 cm in diameter. Anatomical structures most commonly invaded in areas of neck dissection with macroscopic spread from nodal metastases were skeletal muscle and the adventitia of the internal jugular vein. Macroscopic extracapsular infiltration was associated with a high incidence of recurrent tumor in the ipsilateral neck, particularly within 12 months of surgery. Microscopic extracapsular growth was associated with a lower incidence of recurrent tumor in the ipsilateral neck but the difference did not reach statistical significance. Myers and Alvi [21] reviewed a series of 110 patients treated for
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cancer of the supraglottis and noted that extracapsular spread was associated with an incidence of distant metastasis of 71%; moreover, they observed that radiation therapy did not prevent the development of distant metastases. They recommended adjuvant chemotherapy in patients with extracapsular spread to reduce the risk of developing distant metastases. In a retrospective study of 130 patients with surgically treated stage III and IV squamous cell carcinoma of the hypopharynx, tongue, and supraglottis, Alvi and Johnson [22] evaluated risk factors for the development of distant metastases. Patients with palpable neck metastases, histological evidence of nodal metastases, involvement of multiple nodes, and evidence of extracapsular spread proved to be at greater risk of treatment failure (via development of spread of tumor to distant sites) than patients who lacked those risk factors. Vaidya et al. [23] examined the pattern of spread and site of recurrent disease in 128 patients with primary HNSSC. In their series the rate of local recurrence was unrelated to the presence of nodal metastasis and extracapsular extension. Extracapsular extension significantly (P=0.002) predicted the development of distant metastasis and the most common site of distant metastasis was the lung. Recently, Myers et al. [24] retrospectively studied 266 patients with squamous cell carcinoma of the oral tongue treated with surgical resection of the primary tumor and neck dissection. They found that extracapsular spread was the most significant predictor of both regional recurrence and development of distant metastasis resulting in a decreased survival. These findings suggest that, intensive regional and systemic adjuvant therapy may be indicated for HNSCC patients with extracapsular spread of tumor. Further evaluation of this cohort of patients by Greenberg et al. [25] found that the extent of extracapsular spread outside the lymph node capsule (either42 mm or > 2 mm beyond the capsule) did not further predict patient outcomes. Rather, the number of lymph nodes involved with extracapsular spread was a highly significant predictor of disease-specific and overall survival. Those patients with two or more nodes with extracapsular spread, had a median survival of less than 1 year. In addition those with two or more nodes with extracapsular spread, had a regional recurrence rate of 58.3% and a rate of distant metastases of 33.3%. These authors also found that of 186 who were clinically N0 in their series, 34% were pathologically node positive and 19% of these patients were found to have extracapsular spread. In clinically N1 patients, 40% of those were pathologically N2b and 50% were positive for the presence of extracapsular spread. This work clearly argues for accurate pathologic nodal staging at the time of surgical management of the primary tumor [26]. In an attempt to stratify different risk groups within the larger group of patients with extracapsular exten-
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sion of tumor from a primary HNSCC, de Carvalho [27] has prospectively analyzed 170 consecutive cases of previously untreated patients with laryngeal or hypopharyngeal squamous cell carcinoma. Of the 170 patients, 101 (59.4%) had pathological confirmation of metastatic nodal disease. These patients were divided into those who were node-positive with no capsular invasion, those with capsular invasion without extracapsular extension, those with capsular invasion with microscopic extracapsular extension, and those with macroscopic extracapsular extension. When the tumor was confined to the lymph node or showed only microscopic invasion beyond the capsule, there were no statistically significant differences in risk rates for treatment failure. The presence of macroscopic penetration of the lymph node capsule by tumor, however, increased the risk of recurrence by 3.5 times when compared with those patients who either lacked metastasis at initial diagnosis, or those patients in whom the tumor was confined within the lymph node. Therefore, macroscopic extracapsular spread of cervical lymph node disease appears to be the most significant independent adverse prognostic factor in patients with extracapsular spread of tumor; patients with macroscopic extracapsular nodal spread in their neck dissection specimens had the highest incidence both of regional recurrence and of distant metastasis. This has led de Carvalho [27] to suggest that microscopic extracapsular spread is not of prognostic significance in patients with cancer of the larynx or hypopharynx. Macroscopic extracapsular spread as the major prognostic factor for recurrent disease in the neck has also been reported by Carter et al. [28]. These authors also stress the importance of differentiating macroscopic from microscopic extracapsular spread. In contrast, Alvi and Johnson [29] documented that even lymph nodes with microscopic extracapsular spread markedly decreased the outcome. Recently, Coatesworth and MacLennan [11] have prospectively analyzed 96 elective neck dissections in 63 patients with upper aerodigestive tract squamous cell carcinoma and clinically N0 necks to assess the prevalence of microscopic extracapsular spread and soft tissue deposits. The dissections were separated peroperatively into nodal levels; these were cut into 2 mm thick slices, embedded in their entirety and sectioned at six micrometer thickness and stained with hematoxylin and eosin. Using this technique microscopic as well as macroscopic extracapsular spread can be detected. They found that microscopic extracapsular spread and soft tissue deposits occur frequently in patients with a clinically N0 neck, but they may well be missed by routine histopathologic techniques. This study has shown a prevalence of 19.0% for microscopic extracapsular spread and 7.9% for soft tissue deposits. Further studies by this group [30] have shown that extracapsular spread
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has a significant adverse prognostic effect, even microscopic extracapsular spread, when defined by a perinodal desmoplastic stromal response. Indeed there was no significant difference in overall or recurrence free survival between microscopic and macroscopic extracapsular spread. Jose et al. [30] concluded that microscopic and macroscopic extracapsular spread and soft tissue deposits are of prognostic significance for survival and recurrence free survival in patients with upper aerodigestive tract squamous cell carcinoma. The presence of extracapsular spread in one or more metastatic nodes is believed by some to be the most important prognostic parameter [10,24,31–43]. However, other investigators have been unable to make a direct correlation in patients with HNSCC between extracapsular spread and prognosis [44,45]. This discrepancy may well depend on the type of extracapsular spread present—macroscopic versus microscopic—or some combination of the two. Since MRI cannot detect all instances of extracapsular spread of metastatic HNSCC within lymph nodes [14] (and, indeed, the problem of false positive cervical nodes even on physical examination persists [46,47]), it seems likely for the foreseeable future that pathologic examination of cervical nodes will continue to serve as the gold standard for detecting the presence or absence of regional nodal metastases. It is necessary however to use an accurate and comprehensive method of pathological assessment of neck dissections [7,8,11,30]. At this time, the evidence of increased risk of recurrence and metastasis with extracapsular spread in HNSCC patients suggests that observations regarding the relationship of tumor to lymph node capsule should be an essential part of every pathology report. As the reports reviewed above indicate, it is not always clear whether a given group of authors studying the phenomenon of extracapsular extension of metastatic HNSCC are attempting to correlate macroscopic spread of tumor, or microscopic spread, or both. A clear direction for future investigation would be to attempt to distinguish between these two situations, and so determine conclusively whether or not microscopic penetration alone of a lymph node capsule by metastatic carcinoma should warrant a form of therapy different than that offered to patients whose nodal metastases remain confined macroscopically and microscopically within that nodal capsule. Investigators conducting therapeutic trials should stratify treatment groups according to the presence or absence of macroscopic extracapsular spread of metastatic tumor within lymph nodes, the presence or absence of microscopic extracapsular spread, or both; in this way, the relative import of these two potential prognostic factors (alone or in combination) can finally be determined with some sense of certainty. Considering the high incidence (25%) of microscopic neoplastic extracapsular spread and soft tissue
deposits in patients with HNSCC and clinically negative necks [7], selective neck dissection is indicated [48]. In conclusion, the prognosis in individuals with extranodal spread of the tumor in cervical lymph nodes is quite poor. This appears to be the most important prognostic factor in patients with cervical metastasis both in relation to the local recurrence and distant metastasis. It is extremely important for the clinicians to appreciate the implications of this prognostic factor and the pathologists to make every effort to define this in their final pathology reports. Whether the addition of chemotherapy will make any meaningful difference in the long-term outcome needs to be studied further.
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