Head and Neck Carcinoma in the Young Patient: [Print] eMedicine Otolaryngology and Facial Plastic Surgery
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- Bu səhifədəki naviqasiya:
- Treatment Chemotherapy and radiation therapy
- Outcome and Prognosis Prognosis
- Authors Year Site(s) [a] Age Young Control
- Future Directions and Controversies
- Multimedia Media file 1: Reddening of the soft palate, perhaps with scattered areas of white and velvet red
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Human immunodeficiency virus Infection with the human immunodeficiency virus (HIV) and progression to AIDS is positively correlated with malignancies of the upper aerodigestive tract, particularly Kaposi sarcoma and non-Hodgkin lymphoma and, to a lesser extent, squamous cell carcinoma (SCC). [39 ]
Funk and colleagues reported a very high incidence of Kaposi sarcoma in young African American males between 1985 and 1996, a time when the AIDS epidemic heavily affected that demographic. [14 ]
Other series have not addressed (even indirectly) immunodeficiency due to HIV or other causes in young patients. Genetics Some genetic component to cancer development in young patients is likely, particularly in those patients with no recognized risk factors. These patients have been shown to have increased DNA fragility, which may make them more likely to develop genetic abnormalities. [40 ]
However, studies examining specific genetic alterations in HNSCC as a function of patient age, including mutations in p53, p21, Rb, and MDM2, [23,41 ]
[42 ] have failed to find an increase in these abnormalities among young patients. Likewise, Koch and colleagues found tumors of nonsmokers with HNSCC to have fewer genetic abnormalities than those of their smoking counterparts, leading them to conclude that the genetic alterations in tumors from nonsmoking patients remain undiscovered. [36 ] Llewellyn and colleagues’ larger series reported a positive family history of cancer in 75% of female and 59% of male subjects younger than age 45 with HNSCC, suggesting genetics, immunology, or some common environmental exposure may play a role in the development of HNSCC in the young. [15 ]
A rare inherited cancer syndrome associated with HNSCC is Fanconi anemia (FA), an autosomal recessive syndrome caused by defects in DNA repair. FA carries a high risk of development of malignancy at a young age, with a median age of presentation of 31, and a cumulative incidence of HNSCC of 14% by age 40. [43,44 ]
Patients with FA and HNSCC are more likely to be female (2:1), with very few reporting tobacco use. Oral cavity is the most common site and the outcome is poor, with a 63% rate of second primaries and a 2-year overall survival of 49%. [44 ]
Workup No specific additional workup is required for young patients with head and neck squamous cell carcinoma (HNSCC) compared with their older counterparts. However, a young patient presenting with no traditional risk factors may warrant at least a careful history to examine for other possible etiologies, including a familial syndrome or evidence of immunodeficiency. If these etiologies are uncovered, appropriate additional workup should be carried out. In centers with active protocols examining the role of human papillomavirus (HPV) or other genetic abnormalities, eligibility for these studies should be assessed and participation offered. As of yet, no role for HPV serotyping or genetic testing in young patients has been standardized.
Please see sections on specific head and neck subsites for workup of malignancies in these areas. Treatment Chemotherapy and radiation therapy 11/12/10 7:23 AM Head and Neck Carcinoma in the Young Patient: [Print] - eMedicine Otolaryngology and Facial Plastic Surgery Page 7 of 17 http://emedicine.medscape.com/article/855871-print No studies have specifically examined different types or doses of chemotherapy or radiation therapy as a function of age. Most studies using chemotherapy as a modality for head and neck squamous cell carcinoma (HNSCC) fail to stratify age in looking at outcome. Currently, available studies looking at outcomes with regards to patient age give little to no data about specific chemotherapeutic agents or radiation techniques and dosing. Given that less than 2% of HNSCC patients are enrolled in clinical trials nationwide, only future enrollment of all patients into clinical trials can give us knowledge about the role of modality and outcome regarding patient age.
Radiation is used as single modality therapy for early stage disease (stage I-II) and in multimodality therapy for advanced disease (stage III-IV). However, radiation of young patients has specific implications given their potential lifespan. As patients survive longer after radiation treatment for head and neck cancer, the long-term consequences of this treatment become more significant. Difficulties with xerostomia, fibrosis, and swallowing are significant quality of life issues in long-term survivors of head and neck irradiation. [45 ]
Radiation-induced malignancies, such as sarcoma or thyroid carcinoma, although uncommon, are also a concern in the long-term follow-up of irradiated patients. Young HNSCC patients successfully treated with radiation have longer posttreatment lives in which to potentially develop these malignancies, and this has prompted some authors to suggest surgery as the primary modality for treatment of the young patient. [46 ]
tumors. [37 ]
This may lead to organ preservation therapy being the preferred modality for both young and old patients who are HPV positive. Surgical therapy No studies specifically address the extent of surgical resection in young patients. As discussed in Histology (in the Introduction section) and Outcome and Prognosis, most young patients with HNSCC do not have an inherently more aggressive disease, and, therefore, do not require a departure from standard treatment for any given stage. However, by the same token, efforts should not be made to perform a more limited or less complete resection simply because of a patient’s young age. Further research may reveal if young women with aggressive disease (Funk’s Group I) warrant more aggressive initial treatment, even when presenting with early disease (stage I-II). [47 ]
The vast majority of publications on young patients with head and neck squamous cell carcinoma (HNSCC) address outcome, and yet debate in the literature continues as to whether age at presentation has any effect on prognosis. Identified papers addressing prognosis in young patients with HNSCC are summarized in Table I below. Many of the studies are smaller, retrospective, matched studies and case series that suffer limitations of this methodology, as well as other methodological issues. [48 ]
Only one study matched patients by treatment and found no difference in survival among 31 patients younger than 40 years and 62 matched controls. [25 ]
Venables and Craft 1967 T
<30 13 none Case Series Worse
Byers 1975 T
<30 11 none Case Series Worse
Amsterdam et al 1982 OC
<35 12 none Case Series Worse
McGregor et al 1983 OC
<40 27 none Case Series Better
11/12/10 7:23 AM Head and Neck Carcinoma in the Young Patient: [Print] - eMedicine Otolaryngology and Facial Plastic Surgery Page 8 of 17 http://emedicine.medscape.com/article/855871-print Newman et al 1983 T
<30 13 none Case Series Similar
Mendez et al 1985 A
<=40 63 none
Case Series Similar
Son and Kapp 1985 OC,
OP <40 27 none Case Series Worse
McGregor and Rennie
1987 OC <40 13 none Case Series Worse
Benninger et al 1988 A
<=40 41 none
Case Series Worse
Cusamano et al 1988 CO,
OP <=40 23 none
Case Series Worse
Tsukuda et al 1993 A
<40 48 none Case Series Better
Sarkaria and Harari
1994 T <40 6 none Case Series Worse
Atula et al 1996 T
<40 34 none Case Series Similar
Martin-Granizo et al
1997 OC <40 24 none Case Series Similar
Pitman et al 2000 T
<40 28 none Case Series Similar
Iype et al 2001 OC
<35 264
none Case Series Similar Vermund et al 1982 T <40 16 384 Institutional Series Better
Von Doersten et al 1995 A <40 23 122 Institutional Series Similar
Siegelmann- Danieli et al 1998 T
57 Institutional Series Similar Veness et al 2003 T
142
Institutional Series Similar
Lipkin et al 1985 OC,
OP, L <=40 39 39 Matched Control (sx, si, st) Similar Schantz et al 1988 A
83 Matched Control (sx, st, si, y) Worse Kuriakose et al 1992 OC
37 37 Matched Control (random sample) Similar
Friedlander et al 1998 T
<40 36 36 Matched Control (sx, st, y) Similar
Verschuur et al 1999 A
<40 185
185 Matched Control (sx, si, y) Better Vargas et al 2000 T <40 17 17 Matched Control (st) Worse
Pytynia et al 2004 A
<40 31 62 Matched Control (sx, r, si, st, tx) Similar
Sasaki et al 2005 OC
<40 35 110 Matched Control (random sample) Similar
11/12/10 7:23 AM Head and Neck Carcinoma in the Young Patient: [Print] - eMedicine Otolaryngology and Facial Plastic Surgery Page 9 of 17 http://emedicine.medscape.com/article/855871-print Garavello et al 2007 T
<=40 46 92 Matched Control (sx, si, st) Worse Lee et al 2007 T
20 20 Matched Control (sx, st) Better
Ho et al 2008 OC
<45 28 56 Matched Control (sx, si, st) Better
Lacy et al 2000 A
<=40 40 990
Database Review (Washington University Cancer Registry) Better Davidson et al 2001 T <40 N/A [d] N/A [d] Database Review (SEER 1988-1993) Better Annertz et al 2002 T
276
4748 Database Review (Scandanavian Cancer Registry) Better
Funk et al 2002 OC
<35 2,148
56776 Database Review (National Cancer Database) Better
Schantz and Yu 2002 A
<40 3339
60070 Database Review (SEER 1973-1997) Better Kolker et al 2007 PC,
OP <50 1343
9401 Database Review (Michigan State Cancer Registry) Worse
Table Legend Table I: Articles addressing prognosis of young patients with head and neck cancer were identified from PubMed searches and from reference lists of primary and review articles.
[a] Site abbreviations are as follows: T=tongue, OC=oral cavity, OP=Oropharynx, L=larynx, A=all head and neck sites. [b] Matching criteria is as follows: sx=sex, si, site, st=stage, r=race, tx=treatment, y=year at presentation; SEER=Surveillance, Epidemiology, and End Results program.
[c] Relative prognosis of young patients compared with older patients reported here is what was reported by the authors of the identified papers. For all of the case series listed, authors made comparisons to historic "controls" to assign relative prognosis.
[d] Specific numbers are not listed in the paper. Additionally, remember that young patients are not necessarily free of other medical problems. Singh and colleagues found the presence of advanced comorbidity to diminish disease-free interval and tumor specific survival in an analysis of 70 patients with HNSCC younger than age 45. [44 ]
This remains another element that is not typically accounted for in matched studies.
The larger database studies may be more reliable. Funk and colleagues analyzed the 1985-1996 NCDB, finding an increased 5-year survival rate for patients with HNSCC age 35 or younger compared with patients age 36-65, and for patients age 36-65 compared with patients 65 years and older across all stages, but these differences were only significant for stage I disease. [14 ] Shiboski and colleagues’ analysis of the 1973-2001 SEER database revealed an overall increased 5-year survival for patients with HNSCC who were younger than 45 years. [4 ]
An analysis of Scandinavian cancer registries by Annertz and colleagues similarly found increased 5-year survival among patients younger than 40 years. [9 ]
Lacy and colleagues reviewed the cancer database of the Washington University School of Medicine from 1980-1991. [48 ] Forty patients aged 40 years or younger were identified out of 1030 patients with 5-year survival data available. Young patients had a significantly better 5-year 11/12/10 7:23 AM Head and Neck Carcinoma in the Young Patient: [Print] - eMedicine Otolaryngology and Facial Plastic Surgery Page 10 of 17 http://emedicine.medscape.com/article/855871-print survival than the middle-aged (41-64 y) or old (>65 y) age groups (65% vs 52% and 35%, respectively). Young patients also had a lower recurrence rate and a lower incidence of second primaries than their older counterparts.
An astute caveat to these reported 5-year survival rates, as pointed out by Vargas and colleagues, is the difference between 5-year overall survival and 5-year disease-free survival. In their series of 17 female patients younger than age 40 with tongue squamous cell carcinoma (SCC) and 17 controls matched for stage, the 5-year overall survival of the study group was 65%, but the 5-year disease-free survival was only 47%. [47 ]
This distinction between “alive with no evidence of disease” and “alive with disease” was not explicitly addressed in the NCDB, SEER, Scandinavian, or Washington University studies above. [14,4,9,48 ] Young, otherwise healthy patients may be able to survive with incurable disease longer than their older counterparts, and this may confound studies based on cancer databases that do not make this distinction. Patterns of recurrence Several small case series have been published reporting young patients with a high rate of locoregional recurrence. [1,49,50,46 ] These case series may be subject to publication or referral bias but do highlight a subset of young patients that may have more aggressive disease. Another explanation for the higher local recurrence rate could be a lack of appropriate initial surgical treatment. Because of their young age, these patients may not have been as aggressively treated as their older counterparts, although in the absence of details about margin assessment and extent of resection, this would be speculation.
Two small, matched control studies [28,47 ] and one retrospective institutional series [22 ] also found high locoregional recurrence in younger patients compared with older patients, but none demonstrated a corresponding difference in 5-year survival. On the contrary, Von Doersten and colleagues did not find age to affect recurrence at all in a multivariate analysis on 155 patients, of whom 23 were under age 40. [51 ] Thus,
whether young patients, or a subset thereof, have a higher propensity for locoregional recurrence has yet to be definitely determined.
In patients of all ages who have been treated for HNSCC, the risk of development of second primaries increases over time [52 ]
and is linked to tobacco consumption. [3 ] In a matched control study, Verschuur and colleagues found a decreased incidence of second primaries among patients younger than 40 years compared with older patients (8% versus 18%) over 10 years, but this may have been confounded by the higher proportion of smokers in the older age group. [3 ] Similarly, Lacy and colleagues in a retrospective database review in which 40 of the 1030 patients were age 40 or younger, the risk of recurrence or second primary tumors was significantly lower than in the older age groups. [48
]
Young patients may have a lower incidence of second primaries, at least in the short term. However, for those young patients who developed cancer in the absence of known risk factors, the continued presence of an unknown risk factor should be assumed. These as-of-yet unidentified risk factors may have long incubation times and patients may not present with another primary for decades after treatment of the first cancer. Only long term-studies on young patients who have been treated for HNSCC will answer these questions. In the meantime, young patients cured of their first primary deserve long-term adherence to routine follow-up and cancer surveillance, regardless of the etiology. Medicolegal Pitfalls In Byers’s 1975 publication, he wrote, “the failure of physicians to vigorously investigate a persistent ulcer of the tongue in a patient less than thirty years of age resulted in considerable delay in diagnosis of many of these patients.” Enough evidence in the literature confirms that young patients can develop malignancy to warrant a high level of suspicion for cancer in any patient with worrying signs and symptoms, regardless of age.
appropriate workup or referral for patients presenting with sings and symptoms of head and neck cancer. 11/12/10 7:23 AM Head and Neck Carcinoma in the Young Patient: [Print] - eMedicine Otolaryngology and Facial Plastic Surgery Page 11 of 17 http://emedicine.medscape.com/article/855871-print In 2006, the Scottish Intercollegiate Guidelines Network published its national clinical guideline for the diagnosis and management of head and neck cancer. [53 ]
More than 3 decades after the first reports focusing on young patients with head and neck cancer, much remains to be learned about this subset of patients. The low incidence of head and neck squamous cell carcinoma (HNSCC) in the young patient has made development of prospective studies and analysis of single-institution data difficult. With the advent of more sophisticated and cooperative multi-institutional cancer databases, further details regarding the prognosis and treatment response of young patients may become available.
As more is learned about the association of human papillomavirus (HPV) with head and neck cancer, screening and chemopreventive strategies may have a larger role in preventing the development of HNSCC in all patients. The young patient may particularly benefit from population-based programs because they may be intercepted at an age prior to infection with HPV.
Finally, an as-of-yet-unidentified genetic defect, error in immune surveillance, or environmental exposure may be implicated in cancer development in the young patient. Future research should be directed toward identifying these risk factors. Multimedia Media file 1: Reddening of the soft palate, perhaps with scattered areas of white and velvet red patches, tobacco-induced squamous cell carcinoma involving the tongue base and/or supraglottis, and a firm, mobile mass that is palpable at the left carotid bifurcation. References 1. Byers RM. Squamous cell carcinoma of the oral tongue in patients less than thirty years of age. Am J Surg. Oct 1975;130(4):475- 8. [Medline] . 2. McGregor GI, Davis N, Robins RE. Squamous cell carcinoma of the tongue and lower oral cavity in patients under 40 years of age. Am J Surg. Jul 1983;146(1):88-92. [Medline] . 3. Verschuur HP, Irish JC, O'Sullivan B, Goh C, Gullane PJ, Pintilie M. A matched control study of treatment outcome in young patients with squamous cell carcinoma of the head and neck. Laryngoscope. Feb 1999;109(2 Pt 1):249-58. [Medline] . 4. Shiboski CH, Schmidt BL, Jordan RC. Tongue and tonsil carcinoma: increasing trends in the U.S. population ages 20-44 years. Cancer. May 1 2005;103(9):1843-9. [Medline] . 5. Llewellyn CD, Johnson NW, Warnakulasuriya S. Factors associated with delay in presentation among younger patients with oral cancer. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. Jun 2004;97(6):707-13. [Medline] .
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