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  In this article
 »  Abstract
 » Introduction
 »  Pulmonary Metast...
 »  Differentiating ...
 »  Types of Surgery...
 »  Changing Landsca...
 » Discussion
 » Conclusion
 »  References
 »  Article Tables

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  Table of Contents  
Year : 2017  |  Volume : 54  |  Issue : 1  |  Page : 2-5

Is pulmonary metastasectomy beneficial in head and neck squamous cell carcinoma? A review of literature

1 Department of Head and Neck Oncology, Amrita Institute of Medical Sciences, Amrita University, Kochi, Kerala, India
2 Department of Surgery, University of Sydney, Sydney, Australia

Date of Web Publication1-Dec-2017

Correspondence Address:
Dr. D Balasubramanian
Department of Head and Neck Oncology, Amrita Institute of Medical Sciences, Amrita University, Kochi, Kerala
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_170_17

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 » Abstract 

Metastatic head and neck squamous cell carcinoma (HNSCC) has traditionally carried a dismal prognosis; however with advances in care, it has been shown that pulmonary metastasectomy is a viable therapeutic option in selected patients, palliating symptoms and improving survival. With the increasing incidence of human papilloma virus-related HNSCC and better availability of minimal access surgery, there is a need to better understand the role of pulmonary metastasectomy in the treatment of HNSCC. This article summarizes the literature on indications, results, surgical options and approaches, clinical dilemmas, and controversies associated with pulmonary metastasectomy in HNSCC, to identify suitable candidates and optimize outcomes.

Keywords: Head and neck squamous cell carcinoma, metastasectomy, pulmonary metastases

How to cite this article:
Subramaniam N R, Reddy R, Balasubramanian D, Thankappan K, Iyer S. Is pulmonary metastasectomy beneficial in head and neck squamous cell carcinoma? A review of literature. Indian J Cancer 2017;54:2-5

How to cite this URL:
Subramaniam N R, Reddy R, Balasubramanian D, Thankappan K, Iyer S. Is pulmonary metastasectomy beneficial in head and neck squamous cell carcinoma? A review of literature. Indian J Cancer [serial online] 2017 [cited 2020 Apr 5];54:2-5. Available from:

 » Introduction Top

Metastatic disease in head and neck squamous cell carcinoma (HNSCC) has carried a dismal prognosis, with a median survival period between 3 and 6 months after diagnosis.[1],[2] Standard therapy is a combination of platinum-based chemotherapy with cetuximab. Immunotherapy has emerged as a strong therapeutic modality in tumors resistant to standard therapy,[3],[4] however improvements in survival have been marginal.

In 1997, Pastorino et al.[5] published long-term results on a series of 5206 patients who underwent pulmonary metastasectomy for a variety of tumors. This study included epithelial tumors, sarcomas, germ-cell tumors, and melanomas, of which head and neck cancers were 247 in number. The overall 5-year survival of the cohort was 33% with a disease-free interval of 0–11 months and 45% for those with a disease-free interval of more than 36 months. Although their results were not specific to HNSCC, they were encouraging.

This study served as proof that pulmonary metastasectomy was a viable therapeutic option, with improvement in survival. Several groups began to perform pulmonary metastasectomy, however there was a lack of objective, universally applicable selection criteria to predict which patients are most likely to benefit.[6],[7] As surgeons began to refine their criteria, outcomes improved. In head and neck cancers, till recently, metastasis has been considered only for palliative chemotherapy, however emerging data have shown that, in carefully selected patients, metastasectomy can improve survival and relieve symptoms; this article reviews the literature on pulmonary metastatectomies in HNSCC, including the indications, contraindications, goals, surgical techniques, and newer considerations in the treatment of these patients.

 » Pulmonary Metastatectomies in Head and Neck Squamous Cell Carcinoma Top

One of the first publications on pulmonary metastasectomy in HNSCC was by Liu et al.,[8] who showed a 5-year survival of 34% in 41 patients. They showed a worse prognosis in those with an incomplete resection, patients over 50 years of age, and those with a disease-free survival of under-2 years. Yamazaki et al.[9] showed impressive outcomes in their series of 11 patients, with 1-year survival rate of 79.4% and a 2–5-year rate of 63.2%. Shiono et al.[10] reported the findings of the Metastatic Lung Tumour Study Group of Japan in 114 patients, showing that the overall 5-year survival rate after pulmonary metastasectomy was 26.5% and median survival time was 26 months. Patients with oral cancer did not have significant improvements in survival; subset analysis showed that, at 5 years, no male patients with oral cancer were alive, but 31.6% of the other patients were alive.

Mochizuki et al.[11] also showed oral cancer as being a predictor of poor outcomes; in 23 patients of oral tongue carcinoma with up to three pulmonary metastases who underwent pulmonary metastasectomy, 22 patients went on to develop systemic metastases within 17 months. The median survival was 9.5 months, and overall survival at 3 years was 7%. Their recommendation was against pulmonary metastasectomy for the treatment of oral tongue carcinoma. Haro et al.[12] reiterated these findings in their series of 25 head and neck cancer patients, which revealed that oral and oropharyngeal HNSCC had the worst survival compared to those from different subsites or nonsquamous cell carcinoma (SCC) histology.

The age of the patient, surgical metastasectomy complications, and the completeness of resection have also been showed to impact survival. Winter et al.[13] included 55 patients with HNSCC in their study of 67 patients with pulmonary metastasectomy and found that surgical complications were associated with poorer survival. The 5-year survival rate for patients with a complete resection was 27.7% compared to 6.7% for those who had an incomplete resection. Yotsukura et al.[14] followed 19 patients with HNSCC who underwent metastasectomy and reported that patients had a favorable outcome with an overall 5-year survival rate of 57.9% and a median survival rate of 77 months, with better survival in patients aged below 60 years.

Young et al.[15] performed a meta-analysis of HNSCC who underwent pulmonary metastasectomy. This included 403 patients who had a 5-year survival rate for metachronous metastases of 29.1%. Oral cavity primary was shown to be a poor prognostic factor by Shiono et al. and Mochizuki et al. Primary cervical lymph node metastasis was shown as a poor prognostic factor by Shiono et al. and Mazer et al.[16] Disease-free interval (DFI) of <24 months was shown to be a poor prognostic factor by Shiono et al., and <12 months was shown by Finley, Mazer et al., and Nibu et al.[17],[18],[19] An incomplete resection was shown to be a poor prognostic factor by Shiono et al. and Yamazaki et al.[9],[10] Having two or more pulmonary metastases was shown to be a poor prognostic factor compared to those having one by Finley et al.;[18] however, Shiono et al.[10] showed no survival advantage in a similar analysis. Older patients were shown to have poorer prognosis by Haro et al., Yotsukura et al., and Nibu et al.

It is clear from the retrospective studies that a patient with a nonoral cavity primary, longer DFI, and single metastatic lesion could be considered for pulmonary metastasectomy [Table 1].
Table 1: Median overall survival and predictors of poor survival in pulmonary metastasectomy for head and neck squamous cell carcinoma

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 » Differentiating between Pulmonary Metastases and Second Primary Tumors of the Lung Top

An important consideration in management is differentiating pulmonary metastases from a second primary lung tumor. The risk of developing a second primary lung tumor is high as patients with HNSCC often have a history of chronic tobacco and alcohol exposure, with “field-cancerization” of the upper aero-digestive tract. Traditionally, the two were distinguished through criteria such as comparing histology of the primary and the pulmonary deposit, stage of the primary, site and number of pulmonary lesions, radiological appearance of the pulmonary lesions, presence of hilar lymphadenopathy, and others.

In 2005, Geurts et al.[20] proposed the use of the loss of heterozygosity test to distinguish between metastatic deposits and a second primary lung tumor, determining that 18 of 44 tumors initially diagnosed as metastases were second primary lung tumors. Interestingly, it has been shown that, despite this distinction of the resected tumor, there is a similar survival advantage suggesting that resectability was a more important prognostic factor than the distinction between metastases and second primary lung tumor.[21] Nevertheless, evaluation is important as a second primary tumor may have a different histology, necessitating differences in management strategy.

 » Types of Surgery Performed for Pulmonary Metastasectomy and the Era of Video-Assisted Thoracoscopic Surgery Top

The type of surgery performed for pulmonary metastasectomy varies with the number and distribution of metastatic nodules in the lungs. Larger studies have described the different procedures performed, including wedge resection, lobectomy, bilobectomy, and pneumonectomy.[5],[7],[8],[9],[10],[11],[12],[13],[14],[15],[20],[21] None of the studies show any difference in outcome based on the extent of the surgery performed, and only one study by Finley et al.[17] showed that patients with one metastatic nodule had a better outcome than those with more than one.

As time progressed, surgery for pulmonary metastasectomy became less radical with minimally invasive approaches bearing comparable oncological results.[22] Early reports were mixed, with some studies in favor, while others disapproved.[22],[23],[24] The features of video-assisted thoracoscopic surgery (VATS) that made it ideal were the low morbidity associated with surgery, the possibility of performing multiple resections, the use of diagnostic thoracoscopy to determine resectability without a thoracotomy, higher probability of identifying nodules not detected by computed tomography, and a significantly quicker recovery. However, larger reports appeared, one which had over 300 patients of malignancy who successfully underwent pulmonary nodule resection through VATS,[25] which helped to establish its role as the standard of care wherever feasible.[26]

 » Changing Landscape in the Era of Human Papillomavirus Top

In their study, Ang et al.[26] demonstrated that Stage III/IV oropharyngeal SCC displayed significantly improved survival if patients had human papillomavirus (HPV)-positive tumors. HPV-positive tumors were found to have lower rates of locoregional recurrence, but the rate of distant metastases was comparable to those with HPV-negative tumors.[28] This created a new treatment paradox – in stark contrast to their HPV-negative counterparts, HPV-positive tumors had low locoregional recurrence but had a higher chance of distant failure. This led to a renewed interest in the treatment of HPV-positive metastatic recurrences since these patients were likely to have prolonged improved survival.[27]

Spreafico et al.[28] performed a combined analysis of several large trials, which showed that, with chemotherapy alone, HPV-positive patients had a better overall survival, with a 30%–40% reduction in the risk of death over time. However, this combined analysis was limited by a lack of data on smoking status and ambiguity on labeling patients as HPV positive or negative based on the p16 expression on immunohistochemistry where subsequent clinical trials have substratified patients based on HPV status. Extrapolating from studies on locoregionally recurrent HNSCC that showed improved survival with surgical salvage irrespective of HPV status,[30] there is significant interest as to whether this survival advantage is similar in the surgical management of metastatic recurrences as well; however, there is no available data on pulmonary metastasectomy outcomes stratified by HPV status. Studies showing combined data on surgical and nonsurgical salvage of locoregional and distant recurrences stratified by HPV status suggest that patients who are HPV positive are more likely to benefit from aggressive therapy.[31],[32] Despite these encouraging findings, further study is required to determine whether HPV-positive patients are more likely to benefit from surgical therapy.

 » Discussion Top

Pulmonary metastasectomy has developed over the past few decades as a viable therapeutic option for a selected group of patients with HNSCC. The literature has been encouraging with an improvement in survival seen in carefully selected patient groups. These results must be interpreted with caution, as there is an inherent selection bias, wherein poor surgical candidates were excluded from the studies. In addition, almost all these studies have been published from specialized thoracic centers with considerable expertise in handling pulmonary metastatectomies; it is recommended that all patients eligible for pulmonary metastatectomies should be referred to specialized centers for surgical management.

The decision to operate needs to be individualized on a case-by-case basis. Patients of advanced age and poor general condition, those with oral cavity tumors, high nodal burden, multiple pulmonary nodules, and short DFI are unlikely to benefit from this treatment. Another important consideration in a metastatic setting is whether the patient is symptomatic; if not, the decision to operate needs to be based on the likelihood of improving survival through surgical management, balanced against surgical risk and quality of life.

Given that all the data available are retrospective and nonrandomized, with little differentiation between metastases and second primary lung tumor or HPV status, further trials with more objective criteria for inclusion/exclusion would further elucidate which patients are most likely to benefit from this therapeutic modality.

 » Conclusion Top

In summary, current evidence shows an improvement in survival in those undergoing pulmonary metastasectomy compared to those who are undergoing nonsurgical therapies, but it is insufficient to accurately predict which patients are most likely to benefit from this therapy. Careful patient selection is the key to ensure good outcomes.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

 » References Top

Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008;359:1116-27.  Back to cited text no. 1
Liao CT, Wang HM, Chang JT, Ng SH, Hsueh C, Lee LY, et al. Analysis of risk factors for distant metastases in squamous cell carcinoma of the oral cavity. Cancer 2007;110:1501-8.  Back to cited text no. 2
Ferris RL, Blumenschein G Jr., Fayette J, Guigay J, Colevas AD, Licitra L, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 2016;375:1856-67.  Back to cited text no. 3
Fuereder T. Immunotherapy for head and neck squamous cell carcinoma. Memo 2016;9:66-9.  Back to cited text no. 4
Pastorino U, Buyse M, Friedel G, Ginsberg RJ, Girard P, Goldstraw P, et al. Long-term results of lung metastasectomy: Prognostic analyses based on 5206 cases. J Thorac Cardiovasc Surg 1997;113:37-49.  Back to cited text no. 5
Yano T, Shoji F, Maehara Y. Current status of pulmonary metastasectomy from primary epithelial tumors. Surg Today 2009;39:91-7.  Back to cited text no. 6
Wedman J, Balm AJ, Hart AA, Loftus BM, Hilgers FJ, Gregor RT, et al. Value of resection of pulmonary metastases in head and neck cancer patients. Head Neck 1996;18:311-6.  Back to cited text no. 7
Liu D, Labow DM, Dang N, Martini N, Bains M, Burt M, et al. Pulmonary metastasectomy for head and neck cancers. Ann Surg Oncol 1999;6:572-8.  Back to cited text no. 8
Yamazaki K, Shodo R, Ueki Y, Matsuyama H, Takahashi S. Therapeutic outcome after resection of pulmonary metastasis from head and neck carcinomas. Indian J Otolaryngol Head Neck Surg 2015;67 Suppl 1:124-8.  Back to cited text no. 9
Shiono S, Kawamura M, Sato T, Okumura S, Nakajima J, Yoshino I, et al. Pulmonary metastasectomy for pulmonary metastases of head and neck squamous cell carcinomas. Ann Thorac Surg 2009;88:856-60.  Back to cited text no. 10
Mochizuki T, Okumura S, Ishii G, Ishikawa Y, Hayashi R, Kawabata K, et al. Surgical resection for oral tongue cancer pulmonary metastases. Interact Cardiovasc Thorac Surg 2010;11:56-9.  Back to cited text no. 11
Haro A, Yano T, Yoshida T, Ito K, Morodomi Y, Shoji F, et al. Results of a surgical resection of pulmonary metastasis from malignant head and neck tumor. Interact Cardiovasc Thorac Surg 2010;10:700-3.  Back to cited text no. 12
Winter H, Meimarakis G, Hoffmann G, Hummel M, Ruttinger D, Zilbauer A, et al. Does surgical resection of pulmonary metastases of head and neck cancer improve survival? Ann Surg Oncol 2008;15:2915-26.  Back to cited text no. 13
Yotsukura M, Kinoshita T, Kohno M, Asakura K, Kamiyama I, Emoto K, et al. Survival predictors after resection of lung metastases of head or neck cancers. Thorac Cancer 2015;6:579-83.  Back to cited text no. 14
Young ER, Diakos E, Khalid-Raja M, Mehanna H. Resection of subsequent pulmonary metastases from treated head and neck squamous cell carcinoma: Systematic review and meta-analysis. Clin Otolaryngol 2015;40:208-18.  Back to cited text no. 15
Mazer TM, Robbins KT, McMurtrey MJ, Byers RM. Resection of pulmonary metastases from squamous carcinoma of the head and neck. Am J Surg 1988;156:238-42.  Back to cited text no. 16
Finley RK 3rd, Verazin GT, Driscoll DL, Blumenson LE, Takita H, Bakamjian V, et al. Results of surgical resection of pulmonary metastases of squamous cell carcinoma of the head and neck. Am J Surg 1992;164:594-8.  Back to cited text no. 17
Nibu K, Nakagawa K, Kamata S, Kawabata K, Nakamizo M, Nigauri T, et al. Surgical treatment for pulmonary metastases of squamous cell carcinoma of the head and neck. Am J Otolaryngol 1997;18:391-5.  Back to cited text no. 18
Geurts TW, Nederlof PM, van den Brekel MW, van't Veer LJ, de Jong D, Hart AA, et al. Pulmonary squamous cell carcinoma following head and neck squamous cell carcinoma: Metastasis or second primary? Clin Cancer Res 2005;11:6608-14.  Back to cited text no. 19
Geurts TW, Balm AJ, van Velthuysen ML, van Tinteren H, Burgers JA, van Zandwijk N, et al. Survival after surgical resection of pulmonary metastases and second primary squamous cell lung carcinomas in head and neck cancer. Head Neck 2009;31:220-6.  Back to cited text no. 20
Roth JA, Pass HI, Wesley MN, White D, Putnam JB, Seipp C. Comparison of median sternotomy and thoracotomy for resection of pulmonary metastases in patients with adult soft-tissue sarcomas. Ann Thorac Surg 1986;42:134-8.  Back to cited text no. 21
Casson AG, Putnam JB, Natarajan G, Johnston DA, Mountain C, McMurtrey M, et al. Efficacy of pulmonary metastasectomy for recurrent soft tissue sarcoma. J Surg Oncol 1991;47:1-4.  Back to cited text no. 22
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Ginsberg MS, Griff SK, Go BD, Yoo HH, Schwartz LH, Panicek DM. Pulmonary nodules resected at video-assisted thoracoscopic surgery: Etiology in 426 patients. Radiology 1999;213:277-82.  Back to cited text no. 24
Schuchert MJ, Pettiford BL, Pennathur A, Abbas G, Awais O, Close J, et al. Anatomic segmentectomy for stage I non-small-cell lung cancer: Comparison of video-assisted thoracic surgery versus open approach. J Thorac Cardiovasc Surg 2009;138:1318-25.e1.  Back to cited text no. 25
Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tân PF, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010;363:24-35.  Back to cited text no. 26
Huang SH, Perez-Ordonez B, Weinreb I, Hope A, Massey C, Waldron JN, et al. Natural course of distant metastases following radiotherapy or chemoradiotherapy in HPV-related oropharyngeal cancer. Oral Oncol 2013;49:79-85.  Back to cited text no. 27
Spreafico A, Amir E, Siu LL. Demystifying the role of tumor HPV status in recurrent and/or metastatic squamous cell carcinoma of the head and neck. Ann Oncol 2014;25:760-2.  Back to cited text no. 28
Fakhry C, Zhang Q, Nguyen-Tan PF, Rosenthal D, El-Naggar A, Garden AS, et al. Human papillomavirus and overall survival after progression of oropharyngeal squamous cell carcinoma. J Clin Oncol 2014;32:3365-73.  Back to cited text no. 29
Deeken JF, Newkirk K, Harter KW, Marshall MB, Banovac F, Johnson L, et al. Effect of multimodality treatment on overall survival for patients with metastatic or recurrent HPV-positive head and neck squamous cell carcinoma. Head Neck 2015;37:630-5.  Back to cited text no. 30
Chen F, Sonobe M, Sato K, Fujinaga T, Shoji T, Sakai H, et al. Pulmonary resection for metastatic head and neck cancer. World J Surg 2008;32:1657-62.  Back to cited text no. 31
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