Pediatric head and neck squamous cell carcinoma: Report of 12 cases and illustrated review of literature

Pediatric head and neck squamous cell carcinoma: Report of 12 cases and illustrated review of literature

International Journal of Pediatric Otorhinolaryngology 79 (2015) 1279–1282 Contents lists available at ScienceDirect International Journal of Pediat...

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International Journal of Pediatric Otorhinolaryngology 79 (2015) 1279–1282

Contents lists available at ScienceDirect

International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl

Pediatric head and neck squamous cell carcinoma: Report of 12 cases and illustrated review of literature V. Bhanuprasad, Supriya Mallick *, Suman Bhasker, Bidhu Kalyan Mohanti Department of Radiation Oncology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India

A R T I C L E I N F O

A B S T R A C T

Article history: Received 26 March 2015 Received in revised form 20 May 2015 Accepted 20 May 2015 Available online 30 May 2015

Introduction: Head and neck carcinoma is a very rare entity in pediatric age group. We here present the demography, treatment and outcome of 12 pediatric patients. Methodology: We retrieved the treatment charts of pediatric patients with a diagnosis of head and neck squamous cell carcinoma (PHNSCC). We also retrieved the published literature of pediatric HNSCC to present the treatment modalities being delivered across institutes. Results: We found 12 patients registered with a diagnosis of squamous cell carcinoma. Median age of the entire cohort was 17 years (Range: 8–20). Gender predilection was skewed in favor of male (male:female ratio—11:1). Oral tongue 3(25%) was the commonest sub site followed by soft palate 2(17%) gingiva 2 (17%), supra glottis larynx 2(17%) and one each of hard palate, buccal mucosa, floor of mouth (8.25% each). The most commonly employed modality of treatment was surgery in 6(50%). Radiation was used in seven cases: 7(Adjuvant-4, Radical-3). Two patients received radical chemo-radiation. Neo-adjuvant chemotherapy was used in two cases. Median follow up duration was 2 years (Range: 6 months to 8 years). One patient recurred 6 months post completion of radical chemo-radiation. The patient with recurrent disease had soft palate primary and had isolated local recurrence. The patient was salvaged with surgery and was disease free at the last follow up. At the last follow up all patients were surviving without disease. Conclusion: The treatment and survival are not much different in pediatric patients compared to adult counterpart. However, in the absence of molecular profiling it is difficult to assess the cause of development of SCC in pediatric patients. A detailed study of underlying molecular pathway will further guide the future treatment. ß 2015 Elsevier Ireland Ltd. All rights reserved.

Keywords: Pediatric Squamous cell carcinoma Radiotherapy

1. Introduction Pediatric head and neck squamous cell carcinoma (PHNSCC) (defined as 20 Years) is a rare entity accounting for <2% of all pediatric malignancies put together [1]. In adults these tumors are mostly associated with tobacco abuse or Human papilloma virus [HPV] infection. However, the etiology remains largely unknown for pediatric patients. In comparison to adults, disease biology, management approaches and tolerance to treatment may profoundly vary necessitating a better understanding of this less known subset. Treatment approaches have been extrapolated from the adult HNSCC and surgery remains the standard of care followed by adjuvant radiotherapy or radio-chemotherapy as indicated.

* Corresponding author. Tel.: +91 9899448450; fax: +91 11 26589243. E-mail address: [email protected] (S. Mallick). http://dx.doi.org/10.1016/j.ijporl.2015.05.031 0165-5876/ß 2015 Elsevier Ireland Ltd. All rights reserved.

Radiation with or without chemotherapy have been used in oropharyngeal primaries. We herein present our experience in treating 12 patients of pediatric head and neck squamous cell carcinoma and reviewed the published literature to consolidate treatment schema of such cases. 2. Materials and methods We retrospectively analyzed the treatment charts of patients of HNSCC treated at our institute from 2006 to 2014. A total of 5000 cases were registered during this period. Patients of biopsy proven head and neck squamous cell carcinoma were targeted for the analysis. Patients of either gender, with age limit up to 20 years, disease amenable for curative treatment (non-metastatic), with adequate end organ function and consented to receive treatment in our institute were included. Out of 5000 cases registered only 12 patients were found to meet the study criteria.

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2.1. Pre-treatment evaluation

3. Results

The patients were evaluated in the multi-disciplinary Head and Neck cancer clinic comprising a head and neck surgeon, a Radiation oncologist and a Medical oncologist. The evaluation schema included: complete physical evaluation with indirect laryngoscopy; laboratory investigations with complete blood count; liver function tests (LFT) and renal function tests (KFT); computed tomography (CT) and/or magnetic resonance imaging of the head and neck area in locally advanced cases; direct laryngoscopy or pan-endoscopy(where clinically indicated); and X-ray of chest. Patients treated with primary surgery were offered post-operative radiotherapy if primary tumor size >4 cm, involved margins, close margins as defined as <5 mm, nodal involvement (1 or more than 1), multiple nodal stations involvement and in tongue primary if depth of tumor extension was >4 mm. Patients with oropharyngeal and laryngeal primary were treated with radical chemoradiation with or without neoadjuvant chemotherapy.

3.1. Demographic profile

2.2. Surgery Surgery was contemplated in all cases with oral cavity primary. A wide local excision with Neck dissection was performed. Patients with a N0 neck underwent a supra-omohyoid neck dissection whereas a modified radical neck dissection was performed for node positive neck. Adjuvant radiation was delivered for T3/T4 primary, more than 4 mm depth of invasion for T1/T2 oral tongue primary, Node positive neck, close margin (<5 mm). In the presence of extra capsular extension or margin positive disease adjuvant chemoradiation was delivered. 2.3. Radiation Radiation planning was done using two dimensional flourosimulations with help of bony landmarks. Patients were immobilized in a customized thermoplastic immobilization device in supine position with arms by the side. Opposed lateral fields or two lateral opposed fields with a low anterior neck field were used for conventional radiation. Patients were treated using a Cobalt-60 tele-therapy machine (Theratron1780C). A dose of 70 Gray in 35 fractions over 7 weeks was prescribed for radical radiotherapy. In adjuvant setting the dose varied from 60 to 64 Gray, 2 Gray per fractions with or without concurrent chemotherapy. 2.4. Chemotherapy In patients with adequate organ function with a Karnofsky performance score of more than 70 were given concurrent chemotherapy at the discretion of the treating physician. Weekly cisplatin (40 mg/m2 weekly) was administered intravenously with adequate hydration and diuresis. One patient received induction chemotherapy consisted of Paclitaxel 175 mg/m2 day1 and Carboplatin Area under the curve 5 (AUC5) day 2 for 2 cycles. 2.5. Toxicity and follow up All patients were assessed weekly during the course of RT. Those receiving concurrent chemotherapy also had weekly complete blood count, LFT and KFT. After the completion of treatment, patients were evaluated atone month and then every three months for the first two years, and every six months in the subsequent years. Clinical examination was performed at each follow up, and imaging (CT or magnetic resonance imaging) was conducted every six months, or earlier in cases where there was clinical suspicion of recurrence.

Median age of the entire cohort was 17 years (Range: 8–20). Gender predilection was skewed in favor of male (male:female ratio—11:1).Oral tongue 3 (25%) was the commonest sub site followed by soft palate 2 (17%) gingiva 2 (17%), supra glottis larynx 2 (17%) and one each of hard palate, buccal mucosa, floor of mouth (8.25% each). The presentation of symptoms was varied depending upon the subsite. The median time for onset of symptoms and presentation to cancer Centre was 5.5 months (range: 3 months–1 year). The most commonly used imaging modality was Contrast enhanced computerized tomography (CECT) in 42% (5), followed by MRI16% (2). As a part of policy of the institute 5 patients with very early disease the treatment was based on clinical examination in the multidisciplinary clinic. 5 (42%) patients had stage IV disease at presentation, 3 (25%) stage III, 3 (25%) had stage II, 1 (8%) had stage 1 disease. Three patients had documented history of tobacco chewing (betel quid/Gutkha) for 3–5 years. Only one patient had history of smoking. Only one patient had known predisposing factor in the form of xerodermapigmentosa. Details of patient characteristics are tabulated in Table 1. 3.2. Treatment received The most commonly employed modality of treatment was surgery in 6 (50%). Four patients underwent a supraomohyoid neck dissection and two patients underwent modified radical neck dissection. Radiation was used in seven cases: 7(Adjuvant-4, Radical-3). Two patients received radical chemo-radiation. Neoadjuvant chemotherapy was used in two cases. Of them one received chemo-radiation after Neoadjuvant chemotherapy (NACT) and one underwent surgery and adjuvant radiation. Two patients did not receive any active treatment at our Centre. Of them one succumbed to disease within 2 months of diagnosis without any active treatment. 3.3. Survival Eight patients were evaluated for survival since two patients were lost to follow up and two did not receive active treatment at our Centre. Median follow up duration was 2 years (Range: 6 months to 8 years). One patient recurred 6 months post completion of radical chemo-radiation. The patient with recurrent disease had soft palate primary and had isolated local recurrence. The patient was salvaged with surgery and was disease free at the last follow up. At the last follow up all patients were surviving without disease. 4. Discussion Head and neck squamous cell carcinoma (HNSCC) is common in adults and an extremely rare entity in 20 year’s age group. According to SEER (Surveillance Epidemiology End Results Database), age adjusted incidence for this subgroup was 0.24 per 100,000 [2,3]. Smoking, alcoholism, tobacco chewing, human papilloma virus infection are known risk factors for adult HNSCC. In contrast the high risk features in pediatric populations include Fanconi’s anemia, Blooms syndrome, connexinmutations, xerodermapigmentosa, dyskeratosiscongenita, epidermolysisbullosa, human papilloma virus infection and transplant recipient’s with chronic graft versus host reaction [4–6]. In our cohort, 4 patients had risk factor of tobacco abuse and 1 patient had risk factor of xeroderma pigmentosa. In recent years significant shift has been noticed in lifestyle habits including early exposure to smoking,

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Table 1 Summarizes demography, treatment details of individual cases of the present series.. Authors

Year

N

Sex

Age in years

Site

Histology

Our cohort

2014

10

M-9 F-1

Range:10–20

Smith et al. [8] Moubayed et al. [9] Sidell et al. [10] Stolk-Liefferink et al. [11] Bill et al. [12] Thompson et al. [13]

2014 2011 2009 2007 2001 1999

1 1 1 1 1 20

6 Neonate 6 11 14 2–20

Well-4 Moderate-5 Poor-1 NA Moderate Well Well Well NA

Atula et al. [14] Sarkaria et al. [15] Tsukuda et al. [16]

1996 1994 1993

1 1 4

Lund and Howard [17] Keukens et al. [18] Earle et al. [19] Sacks et al. [20] Son and Kapp [21]

1990 1989 1988 1985 1985

1 1 1 1 4

1983 1983 1981 1981 1981

4 1 1 1 19

Tongue Tongue Gingiva Gingiva Tongue-2,gingiva-1 Cheek-1, Tongue-4 Tongue Tongue Tongue NA

NA Well Moderate Well Well

Newman et al. [22] Mcgregor et al. [23] Yagi et al. [24] Harper and Copeman [25] Krolls and Hoffman [26]

M F M M M M-10 F-10 M M M-2 F-2 – M M M M-3 F-1 NA F F M –

Tongue-3, Palate-3 Manbile, gingiva, floor of mouth, buccal mucosa-1 each Gingiva Lip Gingiva Gingiva Gingiva Tongue-9 Lip-6, unknown-5 Tongue Tongue NA

Byers [27]

1975

4

Tongue(4)

Well-1 Modeate-1 Poor-1 Unknomn-1

19 17 14–19 20 9 7 13 10, 17, 18, 19 14, 16, 18, 18 18 10 18 14–3 15–19(16) 17(1) 19(3)



alcoholism and oro-genital sexual intercourse. Hence, in near future physicians may end up seeing more of oral cavity and oropharyngeal and laryngeal cancers in population less than 20 years of age. In older patients with history of tobacco chewing and alcoholism P53 mutations and activation of epidermal growth factor receptor (EGFR) pathway have been implicated in head and neck squamous cell carcinogenesis. In young patients HPV early proteins induced molecular aberrations have been implicated. In population less than 20 years there is no data on possible molecular pathways for tumorogenesis. In future if these are elucidated; prognostication and better therapeutic target can be explored in this subset of patients. In a matched pair analysis of squamous cell carcinoma of oral cavity by Morris et al. outcomes of overall survival, disease free survival and relapse free survival were similar in 10:40 pediatric: adult matched patients [7]. Most studies found outcomes and prognosis in PHNSCC similar to adult populations. In our cohort median disease free survival was 2 years with range of 6 months to

NA NA NA

NA Well Well Poor NA

8 years. This follow up duration partially restricts us from observing the disease biology and may be considered as a limitation of the present article. In the cohort of 69 patients of PHNSCC accumulated by literature review, gender was reported in 51 patients of whom 34 were male and 17 were female [8–27]. The details of the published cases are summarized in Table 2. Most commonly reported sub site was oral tongue in 28 patients, followed by gingiva in 8 patients, age ranged from neonate to 20 years. Similarly, in our cohort also the most common sub-site was tongue. Imaging modality of choice for head and neck malignancies is MRI. In resource limited setting like ours early stage T1, T2 lesions clinical examination alone is employed and in locally advanced lesions CECT is more commonly done. Laryngeal squamous malignancies were reported in 75 patients with varied demographic profile. This has not been separately tabulated in view of incomplete data in most reports. Management protocols are similar to adult population with specific emphasis on radiation induced facial asymmetry, growth defects, secondary malignancies, cosmetic outcomes and quality of

Table 2 Summarizes all published reports of head and neck squamous cell carcinoma. Age

Sex

Site

Symptom duration

Tobacco use

TNM

Stage

Treatment received

HPE

Response to treatment

Status at last follow up

10 12 15

Male Female Male

RMT Soft palate Gingiva

1 year 6 months 4 months

No No N0

T4N1M0 T2N0M0 T4N2bM0

Stage IVA Stage II Stage IVB

MDSCC WDSCC MDSCC

– CR CR

Lost to follow up NED at 8 years Lost to follow up

15 17 17 19 20 20 20

Male Male Male Male Male Male Male

Tongue Soft palate Hard palate Floor of mouth Tongue Tongue Buccal mucosa

4 1 4 4 1 3 6

Yesa No Yesa No No Yesa No

T4aN2cM0 T3N1M0 T2NOMO T2N2aMo T1N0M0 T2N0M0 T3N0M0

Stage Stage Stage Stage Stage Stage Stage

WLE + MND WLE + SOND Neo-adjuvant chemo-radiation – Radical chemoradiation WLE + SOND-adjuvant RT WLE + MND-Adjuvant RT WLE + SOND WLE + SOND-Adjuvant RT –

MDSCC MDSCC PDSCC MDSCC WDSCC WDSCC WDSCC

– CR CR CR CR CR –

Expired without treatment Recurrence at 6 months NED at 1.5 years NED at 2 years NED at 1year NED at 2 years Lost to follow up

months year months months month months months

IVB III II IVA 1 II III

[WDSCC-well differentiated squamous cell carcinoma; MDSCC-moderately differentiated squamous cell carcinoma; PDSCC-poorly differentiated squamous cell carcinoma]. a Patient had history of tobacco use.

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life. Surgery remains the cornerstone of treatment with adjuvant RT and chemotherapy based on indication. In upfront surgically inoperable patients, neo-adjuvant chemotherapy remains a valid option upfront for appropriate down staging as employed by us in 2 of our patients. The shortcomings of this review are the lack of early toxicity data, retrospective nature of review and failure to have molecular profiling for this uncommon subset. 5. Conclusion PHNSCC is a unique challenge. Apart from its hitherto unknown origin, the toxicities of treatment, quality of life, cosmetic outcomes and secondary malignancies are important issues that need to be addressed. Molecular profiling can widen our vision about the aggressiveness of tumors and newer therapeutic targets. Disclosures The authors have nothing to disclose. Meeting presentation Not presented. Financial support No financial support received. Conflicts of interest statement The authors have no conflict of interest. References [1] J.T. Albright, A.K. Topham, J.S. Reilly, Pediatric head and neck malignancies: US incidence and trends over 2 decades, Arch. Otolaryngol. Head Neck Surg. 128 (6) (2002) 655–659. [2] J.L. Young Jr., R.W. Miller, Incidence of malignant tumors in U. S. children, J. Pediatr. 86 (2) (1975) 254–258. [3] L. Berstein, J.G. Gurney, Carcinomas and other malignant epithelial neoplasms, in: L.A. Ries, M.A. Smith, J.G. Gurney, et al. (Eds.), Cancer Incidence and Survival Among Children and Adolescents: United States SEER Program 1975–1995, National Cancer Institute, SEER Program, Bethesda, MD, 1999. [4] H. Reinhard, I. Peters, S. Gottschling, W. Ebell, N. Graf, Squamous cell carcinoma of the tongue in a 13-year-old girl with Fanconi anemia, J. Pediatr. Hematol. Oncol. 29 (7) (2007) 488–491.

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