|Ahead of print publication
Incidence of bone metastasis in head and neck malignancy: A retrospective study
Sumit Gupta, Vividha Dubey, Shalu Verma, Tauseef Ali, Sahaj Palod, Anand Lodhi, Virendra Bhandari
Department of Radiation Oncology, Sri Aurobindo Medical College and PG Institute, Indore, Madhya Pradesh, India
|Date of Submission||18-Feb-2020|
|Date of Decision||29-Aug-2020|
|Date of Acceptance||04-Sep-2020|
|Date of Web Publication||15-Oct-2021|
Department of Radiation Oncology, Sri Aurobindo Medical College and PG Institute, Indore, Madhya Pradesh
Source of Support: None, Conflict of Interest: None
Aim: The retrospective analysis was done to describe the characteristics and frequency of bone metastases and prognosis of head and neck cancer patients with bone metastases.
Materials and Methods: We investigated total 16209 patients of which 3620 were head and neck cancer patients entering our oncology outpatient department from January 2010 to December 2019. Of 3620 patients, 29 of them developed solitary or multiple bone metastases during the progression of the disease.
Results: The overall incidence of bone metastases was found to be 0.8% (29 cases) in head and neck cancers. Bone metastasis was observed in solitary or multiple bones which includes vertebrae 12 (41.37%), hip 9 (31.03%), femur 3 (10.34%), and involve sternum, ribs, clavicle and orbits in few cases. All the patients had few months of survival after developing bone metastasis.
Conclusions: With the recent advancement in technology, the survival rate and quality of life of patient suffering from head and neck carcinoma had increased. Distant metastasis to bones was rarely observed in these cancers. Bone dissemination is associated with poor outcome; thus it must always be taken into consideration when contemplating intervention in these patients. So, for early diagnose of this metastasis in complete responders' appropriate measures should be taken during follow-up.
Keywords: Bone metastasis, head and neck, squamous cell cancer
|How to cite this URL:|
Gupta S, Dubey V, Verma S, Ali T, Palod S, Lodhi A, Bhandari V. Incidence of bone metastasis in head and neck malignancy: A retrospective study. J Can Res Ther [Epub ahead of print] [cited 2021 Dec 5]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=328260
| > Introduction|| |
Carcinoma of head and neck region is one of the most common cancers worldwide. It consists of approximately 2% of all incident cancers. Worldwide incidence in 2018 was approximately 246,420 in males and 108,444 in females. Among them, 60% are locally advanced, but non metastatic cases. As per the Indian Council of Medical Research, 0.2–0.25 million new head and neck malignancy are diagnosed in India every year. In 2018, globocon reported 119,992 new cases of head and neck cancer in India with two-thirds male and showed 72,616 deaths.,, More than 90% of head and neck cancers are squamous cell carcinomas, while remaining are adenocarcinoma, sarcomas, and lymphoma. They usually metastasize to lymph nodes or spread locally. Tongue and buccal mucosa are the more common site involved in Indian subcontinent region.
The high incidence in our country is mainly attributable to the consumption of oral tobacco, betel leaves, and nuts with lime. Most of the cases present with advanced stage probably due to lack of awareness. The advanced stage presentation is mainly responsible for locoregional failure and distant metastasis. Few studies have reported distant metastasis rates varying between 4% and 26% in patients with most common histology of squamous cell carcinoma. The most common site for distant metastasis is lung followed by liver, mediastinum, and rarely involve bone and brain.
Bone metastasis mainly results from carcinoma of breast, lung, and prostate while head and neck malignancy uncommonly presented with bone metastases. It has been observed that patients with advanced nodal disease shows a higher incidence of distant metastasis, especially when there is extensive involvement of soft tissue or invasion of jugular vein in the neck. In this study, retrospective analysis is done to describe the characteristics and frequency of bone metastases and prognosis of head and neck cancer patients with bone metastases.
| > Materials and Methods|| |
This was retrospective observational study in head and neck patients presenting in oncology outpatient department.
Duration of study
January 2010 to December 2019.
The patient selected with bone metastasis had minimum one distant bone metastasis which was not contiguous with the primary tumor.
Cases with bone metastasis site contiguous with primary tumor were excluded.
Retrospective data showed that out of 16,209 cancer patients registered in the hospital head and neck cancer were 3620. The cases were mostly of known primary in buccal mucosa, tongue, oropharynx, nasopharynx, with nodal metastasis, and squamous cell carcinoma histology. Patients presenting with bone pain on follow-up were investigated by imaging and in some cases FNAC or true cut biopsy was also done from involved bone.
All the patients whose FNAC or biopsy was done had metastatic squamous cell carcinoma on histology and others had osteolytic bone lesion. These patients were treated with local Radiotherapy 30 Gy in 10 fractions to the involved bone on Varian Linear accelerator with 6 MV or 15 MV photons as per the institutions protocol. Other fractionation schedules were not used in any patient. Post radiotherapy patients were given chemotherapy with cisplatin and paclitaxel or cisplatin and 5Fu combination once every 3 weeks. Bisphosphonates were also given every 28 days. None of the patients received any targeted therapy such as cetuximab or immunotherapy.
Frequency graphs were drawn, and associations between various variables were calculated using the Chi-square test.
| > Results|| |
16,209 patients were registered between January 2010 to December 2019 in the department and 3620 patients (22.33%) were head and neck cancer. A total of 29 patients (0.8%) developed bone metastasis. All had primary squamous cell carcinoma. Bone metastasis was seen in 8 (27.58%) patients of buccal mucosa, 8 (27.58%) of larynx, 8 (27.58%) of tongue, 1 patient of (3.44%) nasopharynx, 1 patient of (3.44%) maxillary antrum, 1 patient of (3.44%) oropharynx, 1 patient of (3.44%) sphenoid sinus, and 1 patient of (3.44%) cricopharynx. The most common site of skeletal metastasis was vertebra found in 12 (41.37%) patients [Figure 1] and second-most common site was pelvis seen in 9 (31.03%) patients [Figure 2]. Other sites of metastasis were femur 3 (10.34%), sternum 3 (10.34%), and ribs 2 (6.89%) patients [Figure 3] and [Graph 1].
|Figure 1: Osteolytic lesion seen along 7th and 8th dorsal vertebra and sacrum|
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|Figure 3: Osteolytic lesion seen on posterior aspect of 9th rib along with soft tissue extension|
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The median period of the development of metastasis from first presentation till appearance of bone metastasis was 7.8 months (range 3–36 months) and the mean survival post metastasis was 5.5 months (range 3–11 months).
Another 26 patients who presented to us for the treatment of bone metastasis with head and neck primary were treated for their primary lesion at other centers so these were not included in the statistics. Among these most common site of metastasis was vertebra in 21 patients (80.76%) followed by pelvis 2 cases (7.69%), sternum 1 (3.84%), femur 1 (3.84%), and clavicle 1 (3.84%) [Graph 2]. The mean duration for the development of bone metastasis after presentation of primary symptoms was 6.5 months (range 3–18 months). The mean survival post treatment for bone metastasis was 5.46 months (range 2–9 months).
| > Discussion|| |
Head and neck carcinoma generally spread through the lymphatics, but 15%–20%, have nonlymphatic spread. Distant metastasis is most commonly seen in lung, bone, liver, and some less commonly seen in the brain and skin., The studies had shown that the incidence of distant metastases depends on the primary tumor site, size, grade, and regional lymph node (RLN) involvement as well as locoregional control of the disease.
Patients associated with the advanced nodal disease have higher chances of distant metastases, which include extensive soft-tissue disease in the neck and jugular vein involvement. As per site of primary tumor, the highest incidence of distant metastases was found in the hypopharynx, followed by the oropharynx and oral cavity. Our study concluded that most of the cases have a higher initial tumor bulk and positive nodes at the time of presentation and all patients had primary tumor either in the nasopharynx, base of the tongue, and buccal mucosa.
Some patients had undergone surgery while others were treated with radiotherapy and chemotherapy as were inoperable. The patients with locally advanced disease or with nodal involvement or extra nodal extension of disease showed bone metastasis in single or multiple bones.
Bone metastasis was recognized based on biopsy/fine-needle aspiration biopsy or by the imaging modalities such as bone scintigraphy, plain X-rays, magnetic resonance imaging/computed tomography (CT), and positron emission tomography/CT (PET/CT).,,,,
Some study like León et al. and Wenzel et al. have shown that the involvement of RLN clinically with N1-N3 disease with histological confirmation, lymph vascular invasion, extracapsular spread, and three or more positive lymph nodes have increased chances for the development of distant metastases.,,
Eighty-five percent of patients of breast, prostate, or lung cancer are associated with bone metastases. Some lesser extent of primary sites with a predisposition for bone metastases include thyroid, melanoma, and kidney.
The most common site of bone metastasis is an axial skeleton than an appendicular skeleton, axial skeleton is most frequently involved in metastasis mainly involving lumber spine, pelvis, and ribs and in the appendicular skeleton most common site involved are proximal femurs, humerus. Bones of feet and hands are rarely involved.,,,
In our study also, lumbar vertebra was most commonly involved followed by pelvic bones and ribs. Bone metastases are slowly progressive and most common symptom is insidious pain that is well localized and worsens during night. Pain was most frequently seen with in the lower back region, pelvis, or hips that may radiate down to legs. For unbearable pain, local radiotherapy 30 Gy in 10 fractions in 2 weeks was given.
Bone metastases develop in the red marrow of the axial skeleton due to greater vascularity as compared to yellow marrow in the appendicular bones. Most often metastasizes through hematogeneous route then direct extension. Bone metastases are either osteolytic or osteoblastic. The mechanism of pain from bone metastases can be mechanical instability, irritation of periosteal stretch receptors, tumor cells itself, tumor-directed osteoclast-mediated osteolysis, tumor-induced nerve injury, production of nerve growth factor or stimulation of cytokine receptors.
Other important causes of pain are fractures and impending fractures, especially in weight-bearing bones. In our study, buccal mucosa and tongue are main primaries that showed metastasis to bones and also the most common sites of HNSCC registered in our hospital. Overall, 0.3% of HNSCC patients had skeletal metastases in this study. A study of Bhandari and Jain shows, out of 624 patients of head and neck cancers, 6 (0.96%) cases developed metastasis to single or multiple bones during the disease.
Snow et al. demonstrated that lesions arising in the larynx and hypopharynx have a higher tendency to metastasize than oral lesions, although true vocal cord lesions uncommonly metastasize.
The rate of distant metastases increased with the stage (2% for Stage I to 19.5% for Stage IV), chances were also high with the T and N classification, N stage had greater effect on the rate of metastases than the T stage and incidence of distant metastases was significantly higher when there was a recurrence above the clavicles (16.7%) as shown by Merino et al. 90% of such cases, the time interval between the diagnosis of distant metastasis and death is <2 years.
Distant metastasis has a greater impact on survival, so early detection of this can regulate therapeutic strategy. For high-risk patients, routine metastatic work-up for lung, liver, and bone should be performed and any type of mild bone pain should not be left un-investigated. León et al. demonstrated 37%–57% prevalence of bone metastases at autopsy which is much higher than in clinical studies (4%–26%).
A retrospective study of Pietropaoli et al., was conducted using radiographs and nuclear medicine studies on 363 cases of head and neck squamous cell carcinoma had been performed. To identify the bone involvement in those patients and it shows approximately 1% of these patients had bone metastases. Bone involvement was identified in eight sites, three pelvic, two femoral and one each humeral, rib, and thoracic spine. Few lesions were lytic and few were blastic. Time from initial primary tumor diagnosis to the recognition of metastatic lesions ranged from being present at diagnosis to a maximum 3.5 years. Time from the identification of metastatic lesions to patient death was no more than 8 months. All bones lesion has appeared 3–12 months after the completion of primary treatment. In other studies, the observation remained the same regarding the site and duration as in this study. In our study also, the bone metastasis occurred 9 months to 3 years after completing the primary treatment and patients survived from 3 to 11 months with solitary or multiple bone metastases.
So with the information regarding the natural history of various tumors and the factors that associated to develop distant metastases as well as good judgment are essential for the cost-effective approach of treatment planning and decision making for both pre- and post-operative assessment of distant metastases in head and neck cancer.
| > Conclusions|| |
In our study, higher chance of bone metastasis is due to use of newer radiotherapy techniques along with chemotherapy and good operative skills to achieve the negative margins. Moreover, more patients being treated and operated outside are received with bone metastasis for treatment.
Even though the increasing overall survival of advanced head and neck carcinomas patients, distant bone metastases are uncommon, but should be considered a possibility in any patient with a concurrent or past diagnosis of head and neck carcinoma. There is a little time interval from the identification of bone metastasis to death in these patients. Hence, it should be taken into consideration during follow-up. Those patients who have shown the complete response should get a regular bone scan or a PET/CT scan to detect this metastasis such that they can be treated early.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global Cancer Statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424.
Trivedi NP, Kekatpure VD, Trivedi NN, Kuriakose MA. Head and neck cancer in India: Need to formulate uniform national treatment guideline? Indian J Cancer 2012;49:6-10.
] [Full text]
Takiar R, Nadayil D, Nandakumar A. Projections of number of cancer cases in India (2010-2020) by cancer groups. Asian Pac J Cancer Prev 2010;11:1045-9.
Sankaranarayanan R, Masuyer E, Swaminathan R, Ferlay J, Whelan S. Head and neck cancer: A global perspective on epidemiology and prognosis. Anticancer Res 1998;18:4779-86.
Troell RJ, Terris DJ. Detection of metastases from head and neck cancers. Laryngoscope 1995;105:247-50.
Ferlito A, Shaha AR, Silver CE, Rinaldo A, Mondin V Incidence and sites of distant metastases from head and neck cancer. ORL J Otorhinolaryngol Relat Spec 2001;63:202-7.
Marioni G, Blandamura S, Calgaro N, Ferraro SM, Stramare R, Staffieri A, et al.
Distant muscular (gluteus maximus muscle) metastasis from laryngeal squamous cell carcinoma. Acta Otolaryngol 2005;125:678-82.
Gowen GF, Desuto-Nagy G. The incidence and sites of distant metastases in head and neck carcinoma. Surg Gynecol Obstet 1963;116:603-7.
Bhandari V, Jain RK. A retrospective study of incidence of bone metastasis in head and neck cancer. J Cancer Res Ther 2013;9:90-3.
Flickinger FW, Sanal SM. Bone marrow MRI: Techniques and accuracy for detecting breast cancer metastases. Magn Reson Imaging 1994;12:829-35.
Hamaoka T, Madewell JE, Podoloff DA, Hortobagyi GN, Ueno NT. Bone imaging in metastatic breast cancer. J Clin Oncol 2004;22:2942-53.
Evan-Sapr E, Mester U, Mishani E, Lievshitz G, Lerman H, Leibovitch I. The detection of bone metastases in patients with high-risk prostate cancer: 99 mTc-MDP Planar bone scintigraphy, single-and multi-field-of-view SPECT, 18F-fluoride PET, and 18F-fluoride PET/CT. J Nucl Med 2006;47:287-97.
Fujimoto R, Higashi T, Nakamoto Y, Hara T, Lyshchik A, Ishizu K, et al.
Diagnostic accuracy of bone metastases detection in cancer patients: Comparison between bone scintigraphy and whole-body FDG-PET. Ann Nucl Med 2006;20:399-408.
Daldrup-Link HE, Franzius C, Link TM, Laukamp D, Sciuk J, Jürgens H, et al
. Whole-body MR imaging for detection of bone metastases in children and young adults: Comparison with skeletal scintigraphy and FDG PET. AJR Am J Roentgenol 2001;177:229-36.
León X, Quer M, Orús C, del Prado Venegas M, López M. Distant metastases in head and neck cancer patients who achieved loco-regional control. Head Neck 2000;22:680-6.
Wenzel S, Sagowski C, Kehrl W, Metternich FU. The prognostic impact of metastatic pattern of lymph nodes in patients with oral and oropharyngeal squamous cell carcinomas. Eur Arch Otorhinolaryngol 2004;261:270-5.
Kapoor C, Vaidya S, Wadhwan V, Malik S. Lymph node metastasis: A bearing on prognosis in squamous cell carcinoma. Indian J Cancer 2015;52:417-24.
] [Full text]
Asdourian PL, Weidenbaum M, DeWald RL, Hammerberg KW, Ramsey RG. The pattern of vertebral involvement in metastatic vertebral breast cancer. Clin Orthop Relat Res 1990;(250):164-70.
Hitchins RN, Philip PA, Wignall B, Newlands ES, Begent RH, Rustin GJ, et al.
Bone disease in testicular and extragonadal germ cell tumours. Br J Cancer 1988;58:793-6.
Matsuyama T, Tsukamoto N, Imachi M, Nakano H. Bone metastasis from cervix cancer. Gynecol Oncol 1989;32:72-5.
Steinmetz MP, Mekhail A, Benzel EC. Management of metastatic tumors of the spine: Strategies and operative indications. Neurosurg Focus 2001;11:e2.
Kapoor A, Kalwar A, Narayan S, Kumar N, Singhal MK, Kumar HS. Analysis of bone metastasis in head and neck squamous cell carcinoma: Experience of a regional cancer center. Clin Cancer Investig J 2015;4:206-10. [Full text]
Goblirsch MJ, Zwolak PP, Clohisy DR. Biology of bone cancer pain. Clin Cancer Res 2006;12:6231s-5s.
Snow JB Jr, Gelber RD, Kramer S, Davis LW, Marcial VA, Lowry LD. Randomized preoperative and postoperative radiation therapy for patients with carcinoma of the head and neck: Preliminary report. Laryngoscope 1980;90:930-45.
Merino OR, Lindberg RD, Fletcher GH. An analysis of distant metastases from squamous cell carcinoma of the upper respiratory and digestive tracts. Cancer 1977;40:145-51.
Pietropaoli MP, Damron TA, Vermont AI. Bone metastases from squamous cell carcinoma of the head and neck. J Surg Oncol 2000;75:136-41.
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