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Comprehensive review of small bowel metastasis from head and neck squamous cell carcinoma
Oral Oncology 46 (2010) 330–335
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Review
Comprehensive review of small bowel metastasis from head and neck squamous cell carcinoma Raghav C. Dwivedi a,*, Rehan Kazi a, Nishant Agrawal b, Edward Chisholm a, Suzanne St. Rose c, Behrad Elmiyeh a, Catherine Rennie a, Christopher Pepper a, Peter M. Clarke a, Cyrus J. Kerawala a, Peter H. Rhys-Evans a, Kevin J. Harrington a, Christopher M. Nutting a a
Head and Neck Unit, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK Department of Otolaryngology – Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA c Research, Data and Statistical Unit, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK b
a r t i c l e
i n f o
Article history: Received 15 December 2009 Received in revised form 18 January 2010 Accepted 19 January 2010 Available online 26 February 2010 Keywords: Head and neck cancer Metastasis Small bowel Small intestine Squamous cell carcinoma Distant metastasis
s u m m a r y Secondary tumours of small intestine account for 10% of all small bowel cancers. The most common sites of primary tumour metastasizing to small bowel are uterus, cervix, colon, lung, breast and melanoma. The majority of these metastatic tumours come from adenocarcinoma primaries; squamous cell carcinoma constitutes a very small proportion of all metastatic small intestinal lesions. Metastasis to small bowel by head and neck squamous cell carcinoma is extremely rare and carries an unfavourable prognosis. Owing to the limited number of published studies, its characteristic features, clinical presentation and outcomes are poorly described. This work aims at specifying these characteristics by reviewing, compiling, analysing and reporting all published cases in the published literature on small bowel metastasis secondary to head and neck squamous cell carcinoma. To the best of our knowledge, this is the first comprehensive review article on the small intestinal metastasis from head and neck squamous cell carcinoma. Ó 2010 Elsevier Ltd. All rights reserved.
Introduction The presence of distant metastasis after the initial treatment of head and neck cancers is rare in occurrence and is associated with poor prognosis.1,2 The most frequent site for distant metastasis of head and neck squamous cell carcinoma (SCC) is lung, followed by bone and liver.3–9 Only a few cases of metastases have been reported in other sites10–14, small bowel being one of them.15 Metastasis to small bowel by head and neck SCC is very rare and usually represents widely disseminated disease.16 The first description of a small bowel metastasis from a head neck cancer dates back to 1961, when Boquine et al.16 reported a pyriform fossa primary SCC metastasizing to small bowel. Since then, ten more cases of small intestinal metastasis have been reported in the literature, the majority originating from laryngeal SCC (Table 1). Being a rare disease entity with only a handful of published reports, the characteristic features, clinical presentations, treatment and their outcomes are not clearly understood. This article aims to augment the available literature on small bowel metastasis from head and neck squamous cell carcinoma (HNSCC) by reviewing all published
* Corresponding author. Tel.: +44 2078082202; fax: +44 2078082235. E-mail address: [email protected] (R.C. Dwivedi). 1368-8375/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.oraloncology.2010.01.013
cases in regards to clinical presentation, diagnosis, treatment and survival outcomes.
Material and methods Search strategy and inclusion criteria A comprehensive literature search on PUBMED/MEDLINE, EMBASE, CINAHL and Science Citation Index for small bowel metastasis in head and neck squamous cell carcinoma was performed. Key words used were small bowel metastasis; small intestine metastasis; duodenal metastasis; jejunal metastasis and ileal metastasis in head and neck cancers. The search was further extended by using other related MeSH words like metastatic duodenal; metastatic jejunal and metastatic ileal carcinoma and head and neck cancers. Publications on small bowel metastasis arising from head and neck squamous cell carcinoma were included. Publications mentioning small bowel metastasis from other head and neck cancers were excluded from the review. Reference lists from the relevant articles were then inspected and cross-referenced and any other pertinent publications were added to the review. Relevant details of articles in languages other than English were extracted and tabulated by one of the co-authors separately. A total of 11 articles (with 11 cases) that satisfied the inclusion criteria,
Table 1 Showing details of all published cases of small bowel metastasis originating from primary head and neck squamous cell carcinoma. Age/ sex
Site of primary tumour
Stage at initial presentation
Treatment for primary
Duration between primary and intestinal metastasis
Presentation of intestinal metastasis
Site of intestinal metastasis
Number of metastatic sites
Treatment for intestinal metastasis
Results
Boquien et al.16 Bresler et al.17
Pyriform sinus Supraglottic larynx Tonsil
NR (N2)
RT
10 months
Obstruction
NR
1
T3N1M1
NR
2 days
Obstruction
Ileum
Multiple
NR
RT
3 months
Obstruction
Ileum
1
Supraglottic larynx Supraglottic larynx Larynx
T2N2Mx
SX + PORT
29 months
Ileum
1
T1NxMx
RT
12 months
Intestinal bleeding/ melaena Perforation
Jejunum
1a
NR
RT and SX
36 months
Perforation
Ileum
Multiple
Supraglottic larynx Vocal fold
T3N1M0
SX
18 months
Ileum
1
T3N2M0
RT and SX
NR
Intestinal bleeding/ melaena Perforation
Jejunum
Multiple
T4N0
SX + CT
24 months
Obstruction
Ileum
1
NR
SX + PORT
56 months
Biliary obstruction
1
Guillem et al.15 Our observation
63/ M 65/ M
Base of tongue Base of tongue
T4N1M1
CT
Since initial presentation
Obstruction
Ampulla of Vater (duodenum) Ileum
T4N2cM0
CT + IMRT
10 months
Melaena/intestinal bleeding
Jejunum
Multiple
Resection anastomosis Resection anastomosis Resection anastomosis Resection anastomosis Resection anastomosis Resection and jejunostomy Resection anastomosis Resection anastomosis Resection anastomosis Endobiliary stenting and palliative CT Resection anastomosis Palliative CT
Died 15 days post operatively due to collapse Died 7 day postoperatively due to respiratory distress Died 1 month postoperatively due to pulmonary embolism NR
Gonzales et al.23 Yoshihara et al.24 Büyükçelik et al.25
84/ M 70/ M 90/ M 59/ M 78/ M 68/ M 54/ M 72/ M 71/ M 71/ M
Lesur et al.18 François et al.19 Petiot et al.20 Hamdan et al.21 Airoldi et al.22
Supraglottic larynx Vocal fold
1
Survived for 3 months Died 3 days postoperatively due to septic shock Died 10 months later due to local disease progression in Head Neck Died 14th day postoperatively due to respiratory distress Died 6 months due to abdominal recurrence Died in 12 months due to progressive disease Died 8 months due to abdominal recurrence Died 1 month due to chest infection
R.C. Dwivedi et al. / Oral Oncology 46 (2010) 330–335
Author
NR – not reported; RT – radiotherapy; SX – surgery; PORT – post operative radiotherapy; CT – chemotherapy; IMRT – intensity modulated radiotherapy. a With second metastasis at duodenal bulb.
331
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as stated above, were tabulated. We added to this series of 11 cases a personal observation of jejunal metastasis originating from the base of tongue primary SCC. Therefore a total of 12 cases were finally reviewed in this first-of-its-kind study. Data analysis Data on the year of publication, age and sex of the patients, site of primary tumour, stage at initial presentation and treatment for primary tumour were recorded. Duration between primary cancer and appearance of intestinal metastasis, mode of presentation of intestinal metastasis, location of the metastatic lesion in the small intestine and number of metastasic lesions were also noted (Table 1). Treatment given for bowel metastasis and its outcome were also recorded. Descriptive analysis was performed for the above mentioned parameters and median survival time (with 95% confidence intervals) was calculated (Table 2). Results Since the number of studies published on small bowel metastasis from HNSCC is minimal, a proper meta-analysis was not possible. Therefore, simple, descriptive statistics have been presented as follows. All 12 patients were male. The mean age of the patient population was 70.4 (range: 54–90) years. In a majority (67%) of cases primary tumour was found in the larynx with predominance of supraglottic carcinoma (63%); however, vocal folds were the sites of primary tumour in two cases. The base of the tongue was the site of primary lesion in 17% of cases while pyriform sinus and tonsil were sites of primary lesion in 8% case each. The time duration between diagnosis of primary tumour and appearance of intestinal metastasis was between two days and 56 months with a median of 12 (range: 0–56) months. In one study intestinal metastasis was present at the time of initial diagnosis of cancer.15 Fifty percent of patients had a higher T stage (T3 and T4) lesion at the time of initial presentation, two patients19,20 presented with early T lesion (T1 and T2) while no T staging was described in four cases.16,18,21,25 One third of patients presented with high N stage (N2 and above) while early N lesion (N1) was seen in three cases.15,17,22 Nodal status was not specified in three cases18,21,25 and could not be assessed in one case.20 One patient had proven metastasis at the time of initial presentation, one with intestinal metastasis15 and another with intestinal and lung metastasis.17 Metastasis status of two patients was not reported.19,20 According to overall TNM staging, nearly 75% of patients had advanced stage disease (stages 3 and 4) since the initial presentation, while in three cases no staging was provided.18,21,25 One patient had a T1 lesion but his N and M status could not be ascertained.20 Five patients received radiotherapy for their primary tumour and two of these patients later had surgery for the residual disease.21,23 In four patients primary tumour was resected. Two patients19,25 had post operative radiotherapy while one patient24
had chemotherapy after the resection. Two patients received chemotherapy with/without radiotherapy for their primary lesion.15, our observation The median duration of occurrence of intestinal metastasis from the occurrence of primary tumour was 12 months. The patients who underwent surgery for their primary tumour had a longer period of remission compared to those treated by radiotherapy or chemotherapy. The median duration of appearance of intestinal metastasis from surgical treatment of primary cancer was 26.5 (range: 22.5–56) months. Patients treated with primary radiotherapy had a median remission period of 12 (range: 11–36) months, while those treated with chemotherapy had a median remission period of 5.5 (range: 3.3–10) months. Seventy-five percent patients were considered to be in remission, while two patients had metastatic lesions.15,17 Disease status of one patient was not mentioned.23 Nearly half of the patients had multiple metastatic lesions at the time of intestinal metastasis. Ileum was the most common site of occurrence of small bowel metastasis as seen in 58% cases while jejunal and duodenal metastasis were seen in 25% and 17% of the cases, respectively. The site of small bowel metastasis was not specified in one case.16 Intestinal obstructive symptoms were the presenting complaints in 46% patients while perforation and gastrointestinal bleeding were the main presenting features of intestinal metastasis in 27% patients each. One patient presented with obstructive jaundice as the site of small bowel metastasis was at the ampulla of Vater.25 Out of all ileal metastasis 57% presented with obstructive symptoms while 29% had GI haemorrhage/melaena as the presenting symptom of intestinal metastasis. Intestinal perforation as an initial presentation of small bowel metastasis was seen in 14% of the cases. In cases presenting with jejunal metastasis, two-thirds had perforation as initial presentation while one third had GI haemorrhage/ melaena as primary symptom of intestinal metastasis. Seventy-five percent of metastatic lesions were treated by resection and anastomosis, while one patient required a diversion procedure (end-jejunostomy).21 Two patients were treated with palliative chemotherapy; the patient presenting with biliary obstruction was additionally endoscopically stented.25 The observed overall mean and median survival times of patients were 17.3 (range: 5.5–29) weeks and 4 (IQR: 0–15.9) weeks, respectively. Patients with metastasis at one site had mean and median survival times of 26 (range: 10.9–41.1) weeks and 27 (IQR: 0– 62.9) weeks, respectively. Patients with multiple metastatic sites had a mean survival of 2 (range: 0.6–3.4) weeks; the median survival was one week. Discussion Distant metastasis adversely affects patient survival. It has been reported that the incidence of distant metastasis in HNSCC ranges between 7% and 23%.3,4,6–9,26,27 Over half to three fourth of these cases have lung metastasis making it the most common site of distant metastasis, while bone, liver, brain and skin and soft tissue metastasis account for 10–44%, 4–34%, 3–13%, 3–31% and 2–9%,
Table 2 Showing means and medians for survival time (in weeks). Number of metastatic sites
Meana Estimate
Single Multiple Overall survival a
26.000 2.000 17.273
Median Std. error
7.709 .707 6.006
95% Confidence interval Lower bound
Upper bound
10.890 .614 5.501
41.110 3.386 29.045
Estimation is limited to the largest survival time if it is censored.
Estimate
Std. error
27.000 1.000 4.000
18.330 – 6.055
95% Confidence interval Lower bound .000 – .000
Upper bound 62.927 – 15.868
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respectively.3,4,6–9,26–28 Location of primary tumour, initial N and T stage of the neoplasm, and presence or absence of regional control above clavicle have a direct relation with distant metastasis.28 Overall clinical stage and treatment modality adopted have also been suggested to have an effect on distant metastasis.3,28 Reported rates of distant metastasis for stage I, II, III and IV HNSCC are 1%, 14%, 15% and 20% respectively.28 Distant metastasis in the absence of nodal metastasis is very rare in head and neck SCC.28 Patients with advanced nodal disease have a high incidence of distant metastasis, particularly in the presence of jugular vein invasion or extensive soft tissue disease in the neck.28 The rate of early distant metastasis increases up to 16.7% for N3 disease as against 9.2% for N2 disease, while anytime metastasis for N3 disease reaches as high as 27.6%.3 There is generalised consensus that primary hypopharyngeal and laryngeal SCC have a higher incidence7,9,29,30 of distant metastasis but the opinion is split for oropharyngeal cancers. Leon et al.7 demonstrated that oropharyngeal tumours had less chances of distant metastasis as compared to tumours of the supraglottic larynx and hypopharynx. This observation was later supported by Garavello et al.1 based on a study of a large series involving 1972 patients. Ferlito et al.28 observed that oropharyngeal primaries have a higher incidence of distant metastases.28 Higher incidence of distant metastasis in laryngeal and hypopharyngeal SCC can probably be explained by advanced stage of disease at initial presentation and early involvement of lymph nodes due to rich bilateral lymphovascular connectivity of the region. Small bowel metastasis represents less than 10% of malignant tumours of the small bowel.15 The most frequent sites of primary lesions are uterus, uterine cervix and colon which are the adjacent organs to the small intestine. Other common sites contributing to intestinal metastasis are lung, breast, kidney, bladder, ovary and melanoma skin cancers.31 Metastasis to the gastrointestinal tract from head and neck SCC is very unusual. Furthermore, small intestine metastasis is extremely rare.24 Small bowel metastasis from HNSCC, as any other SCC distant metastasis results from haematogenous dissemination25 of the disease and represents florid micro-metastasis from the primary tumour. It is seen that there is a predilection for distal small bowel involvement (ileum) as compared to the proximal (jejunum), duodenum being least preferred. In an interesting report, ampulla of Vater has been shown to be infiltrated by metastasis from a recurrent laryngeal cancer.25 The exact reason for proximal small bowel predilection is not known, how ever it can be ascribed to difference in lymphovascular drainage of the two sub-sites. Small bowel metastasis can also occur as a result of transperitoneal spread from colorectal, ovarian, gastric and pancreatic tumours32, but not with HNSCC. Although intestinal metastases are a frequent autopsy finding, they rarely become clinically apparent. The signs and symptoms largely depend on the site of the metastatic tumour. Metastatic disease to small intestine may present with acute or sub-acute intestinal obstruction, ileus, gastrointestinal (GI) haemorrhage or bowel perforation.32,33 Intestinal haemorrhage is always a forerunner of perforation34 which may be complicated by peritonitis in select cases. It is seen that jejunal metastasis are rather complicated by perforation while ileal metastatic lesions are obstructive, the exact reason of this is not known.15 These extreme complications are usually preceded by a period of non-specific symptoms (abdominal pain, nausea, vomiting, weight loss and weakness)33 which camouflage with symptoms classical to advanced stage cancer and therefore are often ignored/overlooked by both patients and clinicians. Moreover small bowel being a rare site for metastasis from HNSCC often contributes in it being ignored. In a rare case of small bowel metastasis a patient presented with hyperbilirubinemia35 as a consequence of biliary obstruction secondary to the involvement of ampulla of Vater.33
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The factors that affect the development of complications from intestinal metastasis are unknown. However, it is hypothesized that histological type, tumour grade, and other biological parameters play a significant role. Contributing factors are immunosuppression, chemotherapy, radiotherapy, use of cortisone and other drugs.33 There are no data from the literature to correlate these factors with the evolution of intestinal metastases. It has been suggested that certain chemotherapeutic agents may also contribute to occurrence of perforation.36,37 We assume that the risk factors for intestinal metastasis are not different from those listed for usual distant metastasis. Risk factors for distant metastases are still a matter of debate; however, locoregional control and N stage of the tumour are shown to be associated with an increased probability of developing distant metastases.1 There is a general consensus on these specific risk factors.7,9,26,30,38–45 Some other factors that may play a role are cancer localization, histologic grade, local extension of tumour (T stage), and, to a lesser extent, younger age.1 Along with clinical examination, histopathology of primary lesion can be of much value in identifying high risk patients. Extracapsular invasion and lymphovascular infiltration are ominous signs. As distant metastases develop, the chances of cure become very low and the survival dramatically decreases.1 Detecting distant metastases even at an early stage and subjecting them to excision or radiation therapy would not be expected to obtain higher cure rates.1 It is therefore suggested that it would be useful to identify groups of patients who are at high risk for the development of distant metastases to target them for adjuvant chemotherapy. There are contradictory findings in adoption of this strategy. Findings from a study by Shingaki et al.46 showed improved survival rates and decreased distant metastases with adjuvant chemotherapy, while other studies showed no survival benefit; however, significant reduction in distant metastasis rates were recorded.47,48 Primary SCC of small bowel is very unusual but have been reported.31,49,50 It can occur as a result malignant transformation of heterotrophic rests of squamous epithelium in the submucosa; aberrant differentiation of stem cells to squamous cells with subsequent malignant change; squamous metaplasis of glandular cells with subsequent malignant change or transformation of an adenoma or adenocarcinoma into an SCC.49 Also distant metastasis to small bowel from primary HNSCC is known to occur though rare. The occurrence of an intestinal second primary tumour subsequent to clonal expansion51,52 from a head and neck primary SCC is yet another possibility53, though they are seen more commonly in esophagus rather than in the small bowel. The differentiation between a metastatic tumour and a second primary can be clinically made as majority of distant metastatic disease presents within first 2–3 years (50% presenting in 1st year) from the treatment of primary while the time period between the primary tumour and second primary is relatively longer (2–4 years).53–56 Presence of intestinal adenoma/adenocarcinoma, inflammatory bowel disease or an anatomical abnormality indicates towards a primary small bowel SCC.49 Though the clinical evaluation can suggest, but final confirmation and differentiation of these entities is debatable. Recently certain genetic based approaches like analysis of p53 mutation and patterns of allelic loss have been used with partial success.3,57–59 Imaging modalities are helpful in diagnosing small bowel metastatic disease. Upper GI endoscopy can be used to diagnose/exclude lesions proximal to the ligament of Treitz and can replace upper GI radiography.32 Portions of small bowel distal to the Ligament of Treitz can be assessed either by enteroscopy, upper GI small bowel follow-through (SBFT) or enteroclysis. Small bowel enteroscopy remains technically challenging and is unavailable in most institutions. Bessette et al.60 in a direct comparison found sensitivity of 61% for SBFT and 95% for enteroclysis, demonstration
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of tumour was achieved in 33% of SBFT studies and 90% of enteroclysis60 in primary small bowel cancers. Contrast-enhanced computerised tomography (CT) remains the mainstay61 of diagnostic battery with 97% sensitivity and 80% of specificity in detecting primary small bowel disease62 However, there is no such data available for metastatic lesions to compare efficacy of any imaging modality in identifying small bowel disease. Role of 18F-2-fluoro2-deoxy-D-glucose-positron emission tomography (FDG PET)/CT and capsule endoscopy in diagnosing metastatic small bowel disease is still being explored with some early success.61,63 In difficult cases of undiagnosed GI bleeding, tc-99 tagged red blood scan may help identify the source in small bowel.32 Treatment of small bowel metastasis from HNSCC remains a matter of debate. There are not sufficient studies to compare the efficacy of different treatment modalities. However, there appears to be a consensus regarding adoption of palliative treatment policy in these patients. These patients should be managed symptomatically and any major surgical procedures should be avoided except in emergency situations. Patient’s general health, life expectancy and associated co-morbidities should be taken into consideration before embarking on any treatment modality. In an otherwise healthy patient presenting with an isolated small bowel lesion, surgical resection with end to end anastomosis appears to offer the best results. Patients presenting with acute intestinal obstructive symptoms on the background of multiple macroscopic metastatic lesions, wherever possible a palliative diversion procedure (end-ileostomy or end-jejunostomy) may be required. Patients presenting with GI haemorrhage/melaena represents a difficult problem. Palliative chemotherapy may be given but platelet counts should be monitored closely in these patients as some of the chemotherapeutic agents (especially carboplatin) are known to cause thrombocytopenia and may exacerbate the haemorrhage. Intestinal perforation involves end stage patients and carries very dismal prognosis. Appropriate judgement and immediate intervention with laparotomy, which is of palliative nature, is the best option of survival with acceptable quality of life for a short period of time. The overall prognosis of HNSCC patients with intestinal metastasis remains very poor with survival running in weeks only. Conclusion Incidence of metastasis to small bowel from HNSCC may be low; the examination of abdomen in patients with advance N/T stage or high risk patients should be kept in mind especially in symptomatic patients with hypopharyngeal, laryngeal and oropharyngeal cancers. Adjuvant chemotherapy using cisplatin and 5FU may be used in these patients in order to decrease the rates of distant metastasis and improve survival, which irrespective of treatment modality remains poor. Financial disclosure Dr. Raghav Dwivedi and Dr. Rehan Kazi are supported by Research Grants from the Head and Neck Cancer Research Trust/ The Oracle Cancer Trust. Conflict of interest statement None declared. References 1. Garavello W, Ciardo A, Spreafico R, Gaini RM. Risk factors for distant metastases in head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 2006;132(7):762–6.
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R.C. Dwivedi et al. / Oral Oncology 46 (2010) 330–335 34. Pang JA, King WK. Bowel haemorrhage and perforation from metastatic lung cancer. Report of three cases and a review of the literature. Aust N Z J Surg 1987;57(10):779–83. 35. Coit DG. Cancer of small intestine. In: DeVita Jr VT, Hellman S, Rosenberg SA, editors. Cancer, principles and practice of oncology. Philadelphia, New York: Lippencott-Raven; 1997. p. 1128–43. 36. Seewaldt V, Cain JM, Greer BE, Tamimi H, Figge DC. Bowel complications with taxol therapy. J Clin Oncol 1993;11(6):1198. 37. Hata K, Kitayama J, Shinozaki M, Komuro Y, Watanabe T, Takano T, et al. Intestinal perforation due to metastasis of breast carcinoma, with special reference to chemotherapy: a case report. Jpn J Clin Oncol 2001;31(4):162–4. 38. Leemans CR, Tiwari R, Nauta JJ, van der Waal I, Snow GB. Regional lymph node involvement and its significance in the development of distant metastases in head and neck carcinoma. Cancer 1993;71(2):452–6. 39. Alvi A, Johnson JT. Development of distant metastasis after treatment of advanced-stage head and neck cancer. Head Neck 1997;19(6):500–5. 40. Shingaki S, Suzuki I, Kobayashi T, Nakajima T. Predicting factors for distant metastases in head and neck carcinomas: an analysis of 103 patients with locoregional control. J Oral Maxillofac Surg 1996;54(7):853–7. 41. Matsuo JM, Patel SG, Singh B, Wong RJ, Boyle JO, Kraus DH, et al. Clinical nodal stage is an independently significant predictor of distant failure in patients with squamous cell carcinoma of the larynx. Ann Surg 2003;238(3):412–22. 42. Calhoun KH, Fulmer P, Weiss R, Hokanson JA. Distant metastases from head and neck squamous cell carcinomas. Laryngoscope 1994;104(10):1199–205. 43. Kotwall C, Sako K, Razack MS, Rao U, Bakamjian V, Shedd DP. Metastatic patterns in squamous cell cancer of the head and neck. Am J Surg 1987;154(4):439–42. 44. Zbären P, Lehmann W. Frequency and sites of distant metastases in head and neck squamous cell carcinoma. An analysis of 101 cases at autopsy. Arch Otolaryngol Head Neck Surg 1987;113(7):762–4. 45. Nishijima W, Takooda S, Tokita N, Takayama S, Sakura M. Analyses of distant metastases in squamous cell carcinoma of the head and neck and lesions above the clavicle at autopsy. Arch Otolaryngol Head Neck Surg 1993;119(1):65–8. 46. Shingaki S, Takada M, Sasai K, Bibi R, Kobayashi T, Nomura T, et al. Impact of lymph node metastasis on the pattern of failure and survival in oral carcinomas. Am J Surg 2003;185(3):278–84. 47. Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB, et al. Radiation Therapy Oncology Group 9501/Intergroup. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350(19):1937–44. 48. Laramore GE, Scott CB, al-Sarraf M, Haselow RE, Ervin TJ, Wheeler R, et al. Adjuvant chemotherapy for resectable squamous cell carcinomas of the head and neck: report on Intergroup Study 0034. Int J Radiat Oncol Biol Phys 1992;23(4):705–13.
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Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Review
Comprehensive review of small bowel metastasis from head and neck squamous cell carcinoma Raghav C. Dwivedi a,*, Rehan Kazi a, Nishant Agrawal b, Edward Chisholm a, Suzanne St. Rose c, Behrad Elmiyeh a, Catherine Rennie a, Christopher Pepper a, Peter M. Clarke a, Cyrus J. Kerawala a, Peter H. Rhys-Evans a, Kevin J. Harrington a, Christopher M. Nutting a a
Head and Neck Unit, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK Department of Otolaryngology – Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA c Research, Data and Statistical Unit, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK b
a r t i c l e
i n f o
Article history: Received 15 December 2009 Received in revised form 18 January 2010 Accepted 19 January 2010 Available online 26 February 2010 Keywords: Head and neck cancer Metastasis Small bowel Small intestine Squamous cell carcinoma Distant metastasis
s u m m a r y Secondary tumours of small intestine account for 10% of all small bowel cancers. The most common sites of primary tumour metastasizing to small bowel are uterus, cervix, colon, lung, breast and melanoma. The majority of these metastatic tumours come from adenocarcinoma primaries; squamous cell carcinoma constitutes a very small proportion of all metastatic small intestinal lesions. Metastasis to small bowel by head and neck squamous cell carcinoma is extremely rare and carries an unfavourable prognosis. Owing to the limited number of published studies, its characteristic features, clinical presentation and outcomes are poorly described. This work aims at specifying these characteristics by reviewing, compiling, analysing and reporting all published cases in the published literature on small bowel metastasis secondary to head and neck squamous cell carcinoma. To the best of our knowledge, this is the first comprehensive review article on the small intestinal metastasis from head and neck squamous cell carcinoma. Ó 2010 Elsevier Ltd. All rights reserved.
Introduction The presence of distant metastasis after the initial treatment of head and neck cancers is rare in occurrence and is associated with poor prognosis.1,2 The most frequent site for distant metastasis of head and neck squamous cell carcinoma (SCC) is lung, followed by bone and liver.3–9 Only a few cases of metastases have been reported in other sites10–14, small bowel being one of them.15 Metastasis to small bowel by head and neck SCC is very rare and usually represents widely disseminated disease.16 The first description of a small bowel metastasis from a head neck cancer dates back to 1961, when Boquine et al.16 reported a pyriform fossa primary SCC metastasizing to small bowel. Since then, ten more cases of small intestinal metastasis have been reported in the literature, the majority originating from laryngeal SCC (Table 1). Being a rare disease entity with only a handful of published reports, the characteristic features, clinical presentations, treatment and their outcomes are not clearly understood. This article aims to augment the available literature on small bowel metastasis from head and neck squamous cell carcinoma (HNSCC) by reviewing all published
* Corresponding author. Tel.: +44 2078082202; fax: +44 2078082235. E-mail address: [email protected] (R.C. Dwivedi). 1368-8375/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.oraloncology.2010.01.013
cases in regards to clinical presentation, diagnosis, treatment and survival outcomes.
Material and methods Search strategy and inclusion criteria A comprehensive literature search on PUBMED/MEDLINE, EMBASE, CINAHL and Science Citation Index for small bowel metastasis in head and neck squamous cell carcinoma was performed. Key words used were small bowel metastasis; small intestine metastasis; duodenal metastasis; jejunal metastasis and ileal metastasis in head and neck cancers. The search was further extended by using other related MeSH words like metastatic duodenal; metastatic jejunal and metastatic ileal carcinoma and head and neck cancers. Publications on small bowel metastasis arising from head and neck squamous cell carcinoma were included. Publications mentioning small bowel metastasis from other head and neck cancers were excluded from the review. Reference lists from the relevant articles were then inspected and cross-referenced and any other pertinent publications were added to the review. Relevant details of articles in languages other than English were extracted and tabulated by one of the co-authors separately. A total of 11 articles (with 11 cases) that satisfied the inclusion criteria,
Table 1 Showing details of all published cases of small bowel metastasis originating from primary head and neck squamous cell carcinoma. Age/ sex
Site of primary tumour
Stage at initial presentation
Treatment for primary
Duration between primary and intestinal metastasis
Presentation of intestinal metastasis
Site of intestinal metastasis
Number of metastatic sites
Treatment for intestinal metastasis
Results
Boquien et al.16 Bresler et al.17
Pyriform sinus Supraglottic larynx Tonsil
NR (N2)
RT
10 months
Obstruction
NR
1
T3N1M1
NR
2 days
Obstruction
Ileum
Multiple
NR
RT
3 months
Obstruction
Ileum
1
Supraglottic larynx Supraglottic larynx Larynx
T2N2Mx
SX + PORT
29 months
Ileum
1
T1NxMx
RT
12 months
Intestinal bleeding/ melaena Perforation
Jejunum
1a
NR
RT and SX
36 months
Perforation
Ileum
Multiple
Supraglottic larynx Vocal fold
T3N1M0
SX
18 months
Ileum
1
T3N2M0
RT and SX
NR
Intestinal bleeding/ melaena Perforation
Jejunum
Multiple
T4N0
SX + CT
24 months
Obstruction
Ileum
1
NR
SX + PORT
56 months
Biliary obstruction
1
Guillem et al.15 Our observation
63/ M 65/ M
Base of tongue Base of tongue
T4N1M1
CT
Since initial presentation
Obstruction
Ampulla of Vater (duodenum) Ileum
T4N2cM0
CT + IMRT
10 months
Melaena/intestinal bleeding
Jejunum
Multiple
Resection anastomosis Resection anastomosis Resection anastomosis Resection anastomosis Resection anastomosis Resection and jejunostomy Resection anastomosis Resection anastomosis Resection anastomosis Endobiliary stenting and palliative CT Resection anastomosis Palliative CT
Died 15 days post operatively due to collapse Died 7 day postoperatively due to respiratory distress Died 1 month postoperatively due to pulmonary embolism NR
Gonzales et al.23 Yoshihara et al.24 Büyükçelik et al.25
84/ M 70/ M 90/ M 59/ M 78/ M 68/ M 54/ M 72/ M 71/ M 71/ M
Lesur et al.18 François et al.19 Petiot et al.20 Hamdan et al.21 Airoldi et al.22
Supraglottic larynx Vocal fold
1
Survived for 3 months Died 3 days postoperatively due to septic shock Died 10 months later due to local disease progression in Head Neck Died 14th day postoperatively due to respiratory distress Died 6 months due to abdominal recurrence Died in 12 months due to progressive disease Died 8 months due to abdominal recurrence Died 1 month due to chest infection
R.C. Dwivedi et al. / Oral Oncology 46 (2010) 330–335
Author
NR – not reported; RT – radiotherapy; SX – surgery; PORT – post operative radiotherapy; CT – chemotherapy; IMRT – intensity modulated radiotherapy. a With second metastasis at duodenal bulb.
331
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as stated above, were tabulated. We added to this series of 11 cases a personal observation of jejunal metastasis originating from the base of tongue primary SCC. Therefore a total of 12 cases were finally reviewed in this first-of-its-kind study. Data analysis Data on the year of publication, age and sex of the patients, site of primary tumour, stage at initial presentation and treatment for primary tumour were recorded. Duration between primary cancer and appearance of intestinal metastasis, mode of presentation of intestinal metastasis, location of the metastatic lesion in the small intestine and number of metastasic lesions were also noted (Table 1). Treatment given for bowel metastasis and its outcome were also recorded. Descriptive analysis was performed for the above mentioned parameters and median survival time (with 95% confidence intervals) was calculated (Table 2). Results Since the number of studies published on small bowel metastasis from HNSCC is minimal, a proper meta-analysis was not possible. Therefore, simple, descriptive statistics have been presented as follows. All 12 patients were male. The mean age of the patient population was 70.4 (range: 54–90) years. In a majority (67%) of cases primary tumour was found in the larynx with predominance of supraglottic carcinoma (63%); however, vocal folds were the sites of primary tumour in two cases. The base of the tongue was the site of primary lesion in 17% of cases while pyriform sinus and tonsil were sites of primary lesion in 8% case each. The time duration between diagnosis of primary tumour and appearance of intestinal metastasis was between two days and 56 months with a median of 12 (range: 0–56) months. In one study intestinal metastasis was present at the time of initial diagnosis of cancer.15 Fifty percent of patients had a higher T stage (T3 and T4) lesion at the time of initial presentation, two patients19,20 presented with early T lesion (T1 and T2) while no T staging was described in four cases.16,18,21,25 One third of patients presented with high N stage (N2 and above) while early N lesion (N1) was seen in three cases.15,17,22 Nodal status was not specified in three cases18,21,25 and could not be assessed in one case.20 One patient had proven metastasis at the time of initial presentation, one with intestinal metastasis15 and another with intestinal and lung metastasis.17 Metastasis status of two patients was not reported.19,20 According to overall TNM staging, nearly 75% of patients had advanced stage disease (stages 3 and 4) since the initial presentation, while in three cases no staging was provided.18,21,25 One patient had a T1 lesion but his N and M status could not be ascertained.20 Five patients received radiotherapy for their primary tumour and two of these patients later had surgery for the residual disease.21,23 In four patients primary tumour was resected. Two patients19,25 had post operative radiotherapy while one patient24
had chemotherapy after the resection. Two patients received chemotherapy with/without radiotherapy for their primary lesion.15, our observation The median duration of occurrence of intestinal metastasis from the occurrence of primary tumour was 12 months. The patients who underwent surgery for their primary tumour had a longer period of remission compared to those treated by radiotherapy or chemotherapy. The median duration of appearance of intestinal metastasis from surgical treatment of primary cancer was 26.5 (range: 22.5–56) months. Patients treated with primary radiotherapy had a median remission period of 12 (range: 11–36) months, while those treated with chemotherapy had a median remission period of 5.5 (range: 3.3–10) months. Seventy-five percent patients were considered to be in remission, while two patients had metastatic lesions.15,17 Disease status of one patient was not mentioned.23 Nearly half of the patients had multiple metastatic lesions at the time of intestinal metastasis. Ileum was the most common site of occurrence of small bowel metastasis as seen in 58% cases while jejunal and duodenal metastasis were seen in 25% and 17% of the cases, respectively. The site of small bowel metastasis was not specified in one case.16 Intestinal obstructive symptoms were the presenting complaints in 46% patients while perforation and gastrointestinal bleeding were the main presenting features of intestinal metastasis in 27% patients each. One patient presented with obstructive jaundice as the site of small bowel metastasis was at the ampulla of Vater.25 Out of all ileal metastasis 57% presented with obstructive symptoms while 29% had GI haemorrhage/melaena as the presenting symptom of intestinal metastasis. Intestinal perforation as an initial presentation of small bowel metastasis was seen in 14% of the cases. In cases presenting with jejunal metastasis, two-thirds had perforation as initial presentation while one third had GI haemorrhage/ melaena as primary symptom of intestinal metastasis. Seventy-five percent of metastatic lesions were treated by resection and anastomosis, while one patient required a diversion procedure (end-jejunostomy).21 Two patients were treated with palliative chemotherapy; the patient presenting with biliary obstruction was additionally endoscopically stented.25 The observed overall mean and median survival times of patients were 17.3 (range: 5.5–29) weeks and 4 (IQR: 0–15.9) weeks, respectively. Patients with metastasis at one site had mean and median survival times of 26 (range: 10.9–41.1) weeks and 27 (IQR: 0– 62.9) weeks, respectively. Patients with multiple metastatic sites had a mean survival of 2 (range: 0.6–3.4) weeks; the median survival was one week. Discussion Distant metastasis adversely affects patient survival. It has been reported that the incidence of distant metastasis in HNSCC ranges between 7% and 23%.3,4,6–9,26,27 Over half to three fourth of these cases have lung metastasis making it the most common site of distant metastasis, while bone, liver, brain and skin and soft tissue metastasis account for 10–44%, 4–34%, 3–13%, 3–31% and 2–9%,
Table 2 Showing means and medians for survival time (in weeks). Number of metastatic sites
Meana Estimate
Single Multiple Overall survival a
26.000 2.000 17.273
Median Std. error
7.709 .707 6.006
95% Confidence interval Lower bound
Upper bound
10.890 .614 5.501
41.110 3.386 29.045
Estimation is limited to the largest survival time if it is censored.
Estimate
Std. error
27.000 1.000 4.000
18.330 – 6.055
95% Confidence interval Lower bound .000 – .000
Upper bound 62.927 – 15.868
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respectively.3,4,6–9,26–28 Location of primary tumour, initial N and T stage of the neoplasm, and presence or absence of regional control above clavicle have a direct relation with distant metastasis.28 Overall clinical stage and treatment modality adopted have also been suggested to have an effect on distant metastasis.3,28 Reported rates of distant metastasis for stage I, II, III and IV HNSCC are 1%, 14%, 15% and 20% respectively.28 Distant metastasis in the absence of nodal metastasis is very rare in head and neck SCC.28 Patients with advanced nodal disease have a high incidence of distant metastasis, particularly in the presence of jugular vein invasion or extensive soft tissue disease in the neck.28 The rate of early distant metastasis increases up to 16.7% for N3 disease as against 9.2% for N2 disease, while anytime metastasis for N3 disease reaches as high as 27.6%.3 There is generalised consensus that primary hypopharyngeal and laryngeal SCC have a higher incidence7,9,29,30 of distant metastasis but the opinion is split for oropharyngeal cancers. Leon et al.7 demonstrated that oropharyngeal tumours had less chances of distant metastasis as compared to tumours of the supraglottic larynx and hypopharynx. This observation was later supported by Garavello et al.1 based on a study of a large series involving 1972 patients. Ferlito et al.28 observed that oropharyngeal primaries have a higher incidence of distant metastases.28 Higher incidence of distant metastasis in laryngeal and hypopharyngeal SCC can probably be explained by advanced stage of disease at initial presentation and early involvement of lymph nodes due to rich bilateral lymphovascular connectivity of the region. Small bowel metastasis represents less than 10% of malignant tumours of the small bowel.15 The most frequent sites of primary lesions are uterus, uterine cervix and colon which are the adjacent organs to the small intestine. Other common sites contributing to intestinal metastasis are lung, breast, kidney, bladder, ovary and melanoma skin cancers.31 Metastasis to the gastrointestinal tract from head and neck SCC is very unusual. Furthermore, small intestine metastasis is extremely rare.24 Small bowel metastasis from HNSCC, as any other SCC distant metastasis results from haematogenous dissemination25 of the disease and represents florid micro-metastasis from the primary tumour. It is seen that there is a predilection for distal small bowel involvement (ileum) as compared to the proximal (jejunum), duodenum being least preferred. In an interesting report, ampulla of Vater has been shown to be infiltrated by metastasis from a recurrent laryngeal cancer.25 The exact reason for proximal small bowel predilection is not known, how ever it can be ascribed to difference in lymphovascular drainage of the two sub-sites. Small bowel metastasis can also occur as a result of transperitoneal spread from colorectal, ovarian, gastric and pancreatic tumours32, but not with HNSCC. Although intestinal metastases are a frequent autopsy finding, they rarely become clinically apparent. The signs and symptoms largely depend on the site of the metastatic tumour. Metastatic disease to small intestine may present with acute or sub-acute intestinal obstruction, ileus, gastrointestinal (GI) haemorrhage or bowel perforation.32,33 Intestinal haemorrhage is always a forerunner of perforation34 which may be complicated by peritonitis in select cases. It is seen that jejunal metastasis are rather complicated by perforation while ileal metastatic lesions are obstructive, the exact reason of this is not known.15 These extreme complications are usually preceded by a period of non-specific symptoms (abdominal pain, nausea, vomiting, weight loss and weakness)33 which camouflage with symptoms classical to advanced stage cancer and therefore are often ignored/overlooked by both patients and clinicians. Moreover small bowel being a rare site for metastasis from HNSCC often contributes in it being ignored. In a rare case of small bowel metastasis a patient presented with hyperbilirubinemia35 as a consequence of biliary obstruction secondary to the involvement of ampulla of Vater.33
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The factors that affect the development of complications from intestinal metastasis are unknown. However, it is hypothesized that histological type, tumour grade, and other biological parameters play a significant role. Contributing factors are immunosuppression, chemotherapy, radiotherapy, use of cortisone and other drugs.33 There are no data from the literature to correlate these factors with the evolution of intestinal metastases. It has been suggested that certain chemotherapeutic agents may also contribute to occurrence of perforation.36,37 We assume that the risk factors for intestinal metastasis are not different from those listed for usual distant metastasis. Risk factors for distant metastases are still a matter of debate; however, locoregional control and N stage of the tumour are shown to be associated with an increased probability of developing distant metastases.1 There is a general consensus on these specific risk factors.7,9,26,30,38–45 Some other factors that may play a role are cancer localization, histologic grade, local extension of tumour (T stage), and, to a lesser extent, younger age.1 Along with clinical examination, histopathology of primary lesion can be of much value in identifying high risk patients. Extracapsular invasion and lymphovascular infiltration are ominous signs. As distant metastases develop, the chances of cure become very low and the survival dramatically decreases.1 Detecting distant metastases even at an early stage and subjecting them to excision or radiation therapy would not be expected to obtain higher cure rates.1 It is therefore suggested that it would be useful to identify groups of patients who are at high risk for the development of distant metastases to target them for adjuvant chemotherapy. There are contradictory findings in adoption of this strategy. Findings from a study by Shingaki et al.46 showed improved survival rates and decreased distant metastases with adjuvant chemotherapy, while other studies showed no survival benefit; however, significant reduction in distant metastasis rates were recorded.47,48 Primary SCC of small bowel is very unusual but have been reported.31,49,50 It can occur as a result malignant transformation of heterotrophic rests of squamous epithelium in the submucosa; aberrant differentiation of stem cells to squamous cells with subsequent malignant change; squamous metaplasis of glandular cells with subsequent malignant change or transformation of an adenoma or adenocarcinoma into an SCC.49 Also distant metastasis to small bowel from primary HNSCC is known to occur though rare. The occurrence of an intestinal second primary tumour subsequent to clonal expansion51,52 from a head and neck primary SCC is yet another possibility53, though they are seen more commonly in esophagus rather than in the small bowel. The differentiation between a metastatic tumour and a second primary can be clinically made as majority of distant metastatic disease presents within first 2–3 years (50% presenting in 1st year) from the treatment of primary while the time period between the primary tumour and second primary is relatively longer (2–4 years).53–56 Presence of intestinal adenoma/adenocarcinoma, inflammatory bowel disease or an anatomical abnormality indicates towards a primary small bowel SCC.49 Though the clinical evaluation can suggest, but final confirmation and differentiation of these entities is debatable. Recently certain genetic based approaches like analysis of p53 mutation and patterns of allelic loss have been used with partial success.3,57–59 Imaging modalities are helpful in diagnosing small bowel metastatic disease. Upper GI endoscopy can be used to diagnose/exclude lesions proximal to the ligament of Treitz and can replace upper GI radiography.32 Portions of small bowel distal to the Ligament of Treitz can be assessed either by enteroscopy, upper GI small bowel follow-through (SBFT) or enteroclysis. Small bowel enteroscopy remains technically challenging and is unavailable in most institutions. Bessette et al.60 in a direct comparison found sensitivity of 61% for SBFT and 95% for enteroclysis, demonstration
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of tumour was achieved in 33% of SBFT studies and 90% of enteroclysis60 in primary small bowel cancers. Contrast-enhanced computerised tomography (CT) remains the mainstay61 of diagnostic battery with 97% sensitivity and 80% of specificity in detecting primary small bowel disease62 However, there is no such data available for metastatic lesions to compare efficacy of any imaging modality in identifying small bowel disease. Role of 18F-2-fluoro2-deoxy-D-glucose-positron emission tomography (FDG PET)/CT and capsule endoscopy in diagnosing metastatic small bowel disease is still being explored with some early success.61,63 In difficult cases of undiagnosed GI bleeding, tc-99 tagged red blood scan may help identify the source in small bowel.32 Treatment of small bowel metastasis from HNSCC remains a matter of debate. There are not sufficient studies to compare the efficacy of different treatment modalities. However, there appears to be a consensus regarding adoption of palliative treatment policy in these patients. These patients should be managed symptomatically and any major surgical procedures should be avoided except in emergency situations. Patient’s general health, life expectancy and associated co-morbidities should be taken into consideration before embarking on any treatment modality. In an otherwise healthy patient presenting with an isolated small bowel lesion, surgical resection with end to end anastomosis appears to offer the best results. Patients presenting with acute intestinal obstructive symptoms on the background of multiple macroscopic metastatic lesions, wherever possible a palliative diversion procedure (end-ileostomy or end-jejunostomy) may be required. Patients presenting with GI haemorrhage/melaena represents a difficult problem. Palliative chemotherapy may be given but platelet counts should be monitored closely in these patients as some of the chemotherapeutic agents (especially carboplatin) are known to cause thrombocytopenia and may exacerbate the haemorrhage. Intestinal perforation involves end stage patients and carries very dismal prognosis. Appropriate judgement and immediate intervention with laparotomy, which is of palliative nature, is the best option of survival with acceptable quality of life for a short period of time. The overall prognosis of HNSCC patients with intestinal metastasis remains very poor with survival running in weeks only. Conclusion Incidence of metastasis to small bowel from HNSCC may be low; the examination of abdomen in patients with advance N/T stage or high risk patients should be kept in mind especially in symptomatic patients with hypopharyngeal, laryngeal and oropharyngeal cancers. Adjuvant chemotherapy using cisplatin and 5FU may be used in these patients in order to decrease the rates of distant metastasis and improve survival, which irrespective of treatment modality remains poor. Financial disclosure Dr. Raghav Dwivedi and Dr. Rehan Kazi are supported by Research Grants from the Head and Neck Cancer Research Trust/ The Oracle Cancer Trust. Conflict of interest statement None declared. References 1. Garavello W, Ciardo A, Spreafico R, Gaini RM. Risk factors for distant metastases in head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 2006;132(7):762–6.
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