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Original Investigation |

Prognostic Significance of Basaloid Squamous Cell Carcinoma in Head and Neck Cancer FREE

Okechukwu R. Linton, MD, MBA1; Michael G. Moore, MD2; Joseph S. Brigance, MD2; Chris A. Gordon, MD1; Don-John Summerlin, DMD, MS3; Mark W. McDonald, MD1,4
[+] Author Affiliations
1Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis
2Department of Otolaryngology/Head & Neck Surgery, Indiana University School of Medicine, Indianapolis
3Department of Pathology, Indiana University School of Medicine, Indianapolis
4Indiana University Health Proton Therapy Center, Bloomington
JAMA Otolaryngol Head Neck Surg. 2013;139(12):1306-1311. doi:10.1001/jamaoto.2013.5308.
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Published online

Importance  Head and neck basaloid squamous cell carcinoma (BSCC) has been considered a more aggressive variant of squamous cell carcinoma (SCC) with a poorer prognosis, although case-control studies have reached conflicting conclusions.

Objective  To examine the prognostic significance of head and neck BSCC on overall survival in a large population-based registry.

Design and Setting  Retrospective data review of a population-based registry from the Surveillance, Epidemiology, and End Results database.

Participants  Individual case data for 34 196 patients treated between January 2004 and December 2009 with head and neck primary SCC (n = 33 554) and BSCC (n = 642) of the oral cavity, oropharyx, larynx, or hypopharynx. Patients with metastatic disease, incomplete staging information, and those who did not receive surgery or radiation were excluded.

Interventions  Patients had been treated with surgery, radiation, or both.

Main Outcomes and Measures  Distribution of patient characteristics between patients of each histology. Hazard ratios, 3-year overall survival, subgroup, and multivariate analysis of patient and treatment characteristics were investigated.

Results  Across each cohort, patients with BSCC more often had high-grade tumors and treatment with lymph node dissection. Multivariate analysis found that group stage, T stage, N stage, size, lymph node dissection, and age statistically significantly influenced overall survival. In multivariate analysis, the hazard ratio for death for patients with BSCC in the oral cavity and larynx and hypopharynx was not statistically significantly different from that for SCC. In the oropharynx, the hazard ratio for death for BSCC histology compared with SCC histology was 0.73 (P = .03).

Conclusions and Relevance  Compared with SCC, BSCC is not an independent adverse prognostic factor for patients with head and neck cancer. The Surveillance, Epidemiology, and End Results analysis has limits, including lack of information regarding chemotherapy, but after controlling for disease and treatment variables, including neck dissection and radiotherapy, BSCC histology did not have an independent adverse prognostic effect on overall survival. The reported association between human papillomavirus and BSCC histology may explain the lower hazard ratio for death in patients with oropharynx BSCC.

Basaloid squamous cell carcinoma (BSCC) is a rare variant of squamous cell carcinoma (SCC) that may arise in a variety of head and neck locations, including the oropharynx, hypopharynx, and larynx.1 It is estimated that 2% of all head and neck SCCs and 5% of all node-positive SCCs are classified as BSCC.2,3 Compared with those with SCC, patients with head and neck BSCC more often have cervical lymph node involvement and distant metastasis.4,5 Basaloid squamous cell carcinoma has an ulcerating infiltrative growth pattern, peripheral nuclear palisading, increased mitotic activity, and poor differentiation and may be mistaken for adenoid cystic carcinoma.6,7 Like SCC, BSCC is associated with alcohol and tobacco use and is often seen in men in their sixth and seventh decades of life.8,9

Since first being described by Wain et al10 in 1986, BSCC has often been considered to exhibit more aggressive behavior and to have a poorer prognosis than SCC. However, conflicting data exist regarding the prognostic significance of BSCC. Two small case-control studies of BSCC vs SCC of the head and neck reached different conclusions, one suggesting a detriment in survival11 and the other no statistical difference from moderate or poorly differentiated SCC.3

Recent investigations have shown an association between human papillomavirus (HPV) and BSCC, particularly HPV type 16.12 It has also been suggested that BSCC may be a heterogeneous entity, with the subset of BSCC associated with HPV having a more favorable prognosis than those that are not.13

Although several reports suggest that patients with BSCC more often have advanced-stage disease, it is not yet clear if BSCC is an independent prognostic factor after accounting for multiple other variables that influence clinical outcomes in head and neck cancer. Given the conflicting results of small institutional case-control studies and the relative rarity of BSCC, we sought to use a large population-based registry to explore the effect of BSCC on overall survival in head and neck cancer.

The Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute was used. Analyses from SEER are exempt from review at our institutional review board, given the patient deidentified nature of the data. The SEER 18 Registrar Research Database was queried from January 2004 through December 2009 to obtain individual case data on all patients diagnosed with SCC (microinvasive, large cell nonkeratinizing, SCC grade 3, SCC with horn formation, keratinizing SCC not otherwise specified, and SCC not otherwise specified) or BSCC of the oral cavity, oropharynx, larynx, or hypopharynx. Patient data available for abstraction included age at diagnosis, race, sex, primary site, American Joint Committee on Cancer stage, TNM stage, primary tumor size, use of surgery to the primary tumor site, use of radiation and sequencing with surgery, lymph node dissection, and history of prior malignant neoplasms.

Statistical analysis of data was performed with SPSS, version 20 (SPSS, Inc). Patients were divided into 3 cohorts: those with disease in the oral cavity, oropharynx, and larynx or hypopharynx. Patients who had missing staging information (Tx, Nx, and Mx were included), had distant metastasis at presentation, or did not receive curative treatment (no surgery or radiation) were excluded from this study. The distribution of patient and disease characteristics was compared within each histology in every cohort using the Fisher exact test and the χ2 test for categorical variables, and the mean value of continuous variables was compared using an independent samples t test. A 2-sided signifance level set at P < .05 was considered statistically significant. Kaplan-Meier survival analysis was performed to estimate the overall and median survival outcomes. Using the log-rank test, univariate analysis of categorical variables was performed, including histology, tumor grade, race, sex, primary tumor site, group stage, TNM stage, use of radiation, surgery, and lymph node dissection. A univariate Cox proportional hazards regression analysis was performed for the continuous variables of patient age and tumor size. Multivariate analysis was performed using a Cox proportional hazards regression model with block entry of variables, including all variables from univariate analysis with P < .20.

Individual case data were abstracted on 56 138 patients. Of these, the following were excluded: 1712 patients with metastatic disease at presentation, 17 650 who did not have complete staging information, 493 denoted as T0, and 2087 who received neither surgery nor radiation. Of the remaining 34 196 patients, 12 493 had disease in the oral cavity, 13 908 had disease in the oropharynx, and 7795 had disease in either the larynx or the hypopharynx. Patient characteristics for each disease site are listed in Tables 1, 2, and 3.

Table Graphic Jump LocationTable 1.  Oral Cavity Patient Characteristics
Table Graphic Jump LocationTable 2.  Oropharynx Patient Characteristics
Table Graphic Jump LocationTable 3.  Larynx and Hypopharynx Patient Characteristics
Oral Cavity Analysis

Of the 12 493 patients with disease in the oral cavity, 12 417 had SCC and 76 had BSCC. Compared with those with SCC, a higher proportion of patients with BSCC were black (14.7% vs 6.0%, P = .002), were male (73.7% vs 61.7%, P = .03), had high-grade tumors (75.0% vs 17.2%, P < .001), had stage IV tumors (36.8% vs 23.8%, P = .047), and had a lymph node dissection (59.2% vs 44.4%, P = .01).

Univariate analysis identified patient age, race, tumor grade, group stage, TNM stage, size, therapeutic treatment type, lymph node dissection, and prior cancer diagnosis as significant variables influencing overall survival. The 3-year overall survival for those with SCC was 62.3% vs 53.9% for BSCC (P = .28). A Cox proportional hazards regression model was developed including all variables from the univariate analysis with P < .20. All variables from the univariate analysis except histology met this threshold for inclusion in the multivariate analysis. In the multivariate analysis, all variables retained a statistically significant association with overall survival except M status (M0 vs Mx) and prior cancer diagnosis (Table 4).

Table Graphic Jump LocationTable 4.  Multivariate Analysis for the Oral Cavity
Oropharynx Analysis

Of the 13 908 patients with disease in the oropharynx, 13 422 had SCC and 486 had BSCC. Compared with those with SCC, a higher proportion of patients with BSCC had high-grade tumors (90.9% vs 47.0%, P < .001) and a lymph node dissection (39.3% vs 33.1%, P = .01). A lower proportion of patients with BSCC had T3 or T4 disease (24.7% vs 30.9%, P = .04), and the mean tumor size for BSCC was slightly smaller than for SCC (2.7 vs 3.0 cm, P = .045).

Univariate analysis identified patient race, age, tumor histology, tumor grade, group stage, TNM stage, tumor size, therapeutic treatment type, lymph node dissection, and prior cancer diagnosis as significant variables for overall survival. In the univariate analysis, the 3-year overall survival was 79.8% (95% CI, 75.5%-84.1%) for patients with BSCC and 65.1% (64.1%-66.1%) for those with SCC (P < .001). A Cox proportional hazards regression model was developed including all variables from the univariate analysis with P < .20. All variables from the univariate analysis met this threshold for inclusion in the multivariate analysis. In the multivariate analysis, all variables retained a statistically significant association with overall survival except sex, type of therapy, and prior cancer diagnosis (Table 5). The hazard ratio for death for patients with BSCC compared with patients with SCC was 0.73 (P = .03).

Table Graphic Jump LocationTable 5.  Multivariate Analysis for the Oropharynx
Larynx and Hypopharynx Analysis

Of the 7795 patients with disease in either the larynx or the hypopharynx, 7715 had SCC and 80 had BSCC. Compared with those with SCC, a higher proportion of patients with BSCC had disease in the hypopharynx (70.0% vs 27.0%, P < .001), a high-grade tumor (82.0% vs 21.3%, P < .001), stage IV disease (50.0% vs 25.6%, P < .001), T3 or T4 disease (36.3% vs 28.4%, P < .001), a lymph node dissection (31.3% vs 12.0%, P < .001), and a prior cancer diagnosis (35.0% vs 16.9%, P < .001). A greater proportion of patients with BSCC had nodal disease (51.3% vs 25.6%, P < .001) and fewer received postoperative radiation therapy (22.8% vs 31.3%, P = .03).

Univariate analysis identified patient sex, age, tumor histology, tumor grade, group stage, T stage, N stage, tumor size, therapeutic treatment, lymph node dissection, and prior cancer diagnosis as significant variables for overall survival. In the univariate analysis, the 3-year overall survival was 58.1% (95% CI, 44.6%-71.6%) for patients with BSCC and 67.0% (65.8%-68.2%) for those with SCC (P = .03). A Cox proportional hazards regression model was developed including all variables from the univariate analysis with P < .20. All variables from the univariate analysis except race and M stage met this threshold for inclusion in the multivariate analysis. In the multivariate analysis, group stage, T stage, N stage, tumor size, lymph node dissection, and age statistically significantly influenced overall survival (Table 6).

Table Graphic Jump LocationTable 6.  Multivariate Analysis for the Larynx and Hypopharynx

Our analysis suggests that BSCC is not an independent adverse prognostic factor compared with SCC. In this large population-based registry across all cohorts, patients with BSCC had a higher-grade tumor and were more often treated with lymph node dissection, confirming findings of several institutional experiences. In the oral cavity and the larynx and hypopharynx, patients with BSCC did not have a statistically significantly higher hazard ratio for death compared with those with SCC. Indeed, in the oropharynx, patients with BSCC had a statistically significantly lower hazard ratio for death than did those with SCC. The association between HPV and BSCC in the oropharynx likely explains the relatively favorable outcomes for these patients.

The incidence of HPV-associated tumors appears to be increasing,14 potentially due to increased recognition of the entity or to changing demographics and sexual practices. Since HPV seems to be associated with at least a subset of BSCC, it may be that the prognostic significance of BSCC is changing. Older series of patients with BSCC may represent a more unfavorable population of tumors less commonly driven by HPV compared with our patient population from January 2004 through December 2009, an era of increasing HPV prevalence.

While some have advocated for more aggressive clinical treatment of patients with BSCC, including the suggestion of mandatory neck dissections and postoperative chemoradiation in all patients,11 our data do not support altering current standards of care for treating patients with head and neck cancer based purely on the BSCC. After controlling for disease and treatment variables, including neck dissection and radiotherapy, BSCC did not have an independent adverse prognostic effect on overall survival.

To our knowledge, this is the largest study to date of the outcomes of patients with BSCC compared with those of patients with SCC. Of note, the SEER database has limitations, including lack of information regarding the administration of chemotherapy, no central pathologic review, underreporting of radiation therapy, lack of radiotherapy details, and, inherent in all nonrandomized data, the possibility of unaccounted selection biases that may drive clinical practice and treatment selection, potentially obscuring or enhancing apparent differences in therapeutic effect.15 Despite these limitations, our data suggest no indication of a poorer prognosis for patients who have BSCC compared with those who have SCC.

In conclusion, compared with those with SCC, patients with head and neck BSCC more often had a high-grade tumor and underwent lymph node dissection. After controlling for multiple patient, disease, and treatment characteristics, patients with BSCC had no statistically significant difference in the hazard ratio for death compared with patients with SCC in the oral cavity and the larynx and hypopharynx and had a statistically significantly lower hazard ratio for death in the oropharynx. These findings suggest that BSCC histology is not an independent adverse prognostic factor in head and neck cancer.

Submitted for Publication: May 23, 2013; final revision received July 25, 2013; accepted August 7, 2013.

Corresponding Author: Mark W. McDonald, MD, Indiana University Health Proton Therapy Center, 2425 N. Milo B Sampson Ln, Bloomington, IN 47408-1398 (mmcdona2@iuhealth.org).

Published Online: October 24, 2013. doi:10.1001/jamaoto.2013.5308.

Author Contributions: Drs Linton and McDonald had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Moore, Gordon, McDonald.

Acquisition of data: Linton, Gordon, Summerlin, McDonald.

Analysis and interpretation of data: All authors.

Drafting of the manuscript: Linton, Gordon, McDonald.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Linton, Gordon, McDonald.

Administrative, technical, and material support: Gordon, McDonald.

Study supervision: McDonald.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported in part by the Jesse N. Jones III Memorial Fund for Head and Neck Cancer Research at the Indiana University Melvin and Bren Simon Cancer Center.

Role of the Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Previous Presentation: This study was presented in part at the 52nd annual meeting of the American Society for Radiation Oncology; November 2, 2010; San Diego, California.

Bahar  G, Feinmesser  R, Popovtzer  A,  et al.  Basaloid squamous carcinoma of the larynx. Am J Otolaryngol. 2003;24(3):204-208.
PubMed   |  Link to Article
Erisen  LM, Coskun  H, Ozuysal  S,  et al.  Basaloid squamous cell carcinoma of the larynx: a report of four new cases. Laryngoscope. 2004;114:1179-1183.
PubMed   |  Link to Article
Thariat  J, Ahamad  A, El-Naggar  AK,  et al.  Outcomes after radiotherapy for basaloid squamous cell carcinoma of the head and neck: a case-control study. Cancer. 2008;112:2698-2709.
PubMed   |  Link to Article
Banks  ER, Frierson  HF  Jr, Mills  SE, George  E, Zarbo  RJ, Swanson  PE.  Basaloid squamous cell carcinoma of the head and neck: a clinicopathologic and immunohistochemical study of 40 cases. Am J Surg Pathol. 1992;16:939-946.
PubMed   |  Link to Article
Paulino  AF, Singh  B, Shah  JP, Huvos  AG.  Basaloid squamous cell carcinoma of the head and neck. Laryngoscope. 2000;110:1479-1482.
PubMed   |  Link to Article
Daroca  PJ  Jr, Dhurandhar  HN.  Basaloid carcinoma of uterine cervix. Am J Surg Pathol. 1980;4(3):235-239.
PubMed   |  Link to Article
Sarbia  M, Verreet  P, Bittinger  F,  et al.  Basaloid squamous cell carcinoma of the esophagus: diagnosis and prognosis. Cancer. 1997;79:1871-1878.
PubMed   |  Link to Article
Bracero  F, Gámiz  MJ, Soldado  L,  et al.  Hypopharynx and larynx basaloid squamous carcinoma: our experience with 6 cases [in Spanish]. Acta Otorrinolaringol Esp. 2001;52(3):229-236.
PubMed   |  Link to Article
Eryilmaz  A, Gocer  C, Acar  A, Dagli  M, Albayrak  L.  Basaloid squamous cell carcinoma of the larynx. J Laryngol Otol. 2002;116:52-53.
PubMed
Wain  SL, Kier  R, Vollmer  RT, Bossen  EH.  Basaloid-squamous carcinoma of the tongue, hypopharynx, and larynx: report of 10 cases. Hum Pathol. 1986;17(11):1158-1166.
PubMed   |  Link to Article
Soriano  E, Faure  C, Lantuejoul  S,  et al.  Course and prognosis of basaloid squamous cell carcinoma of the head and neck: a case-control study of 62 patients. Eur J Cancer. 2008;44(2):244-250.
PubMed   |  Link to Article
Thariat  J, Badoual  C, Faure  C, Butori  C, Marcy  PY, Righini  CA.  Basaloid squamous cell carcinoma of the head and neck: role of HPV and implication in treatment and prognosis. J Clin Pathol. 2010;63:857-866.
PubMed   |  Link to Article
Chernock  RD, Lewis  JS, Zhang  Q, El-Mofty  SK.  Human papillomavirus–positive basaloid squamous cell carcinomas of the upper aerodigestive tract: a distinct clinicopathologic and molecular subtype of basaloid squamous cell carcinoma. Hum Pathol. 2010;41(7):1016-1023.
PubMed   |  Link to Article
Joseph  AW, D’Souza  G.  Epidemiology of human papillomavirus–related head and neck cancer. Otolaryngol Clin North Am. 2012;45(4):739-764.
PubMed   |  Link to Article
Yu  JB, Gross  CP, Wilson  LD, Smith  BD.  NCI SEER public-use data: applications and limitations in oncology research. Oncology (Williston Park). 2009;23(3):288-295.
PubMed

Figures

Tables

Table Graphic Jump LocationTable 1.  Oral Cavity Patient Characteristics
Table Graphic Jump LocationTable 2.  Oropharynx Patient Characteristics
Table Graphic Jump LocationTable 3.  Larynx and Hypopharynx Patient Characteristics
Table Graphic Jump LocationTable 4.  Multivariate Analysis for the Oral Cavity
Table Graphic Jump LocationTable 5.  Multivariate Analysis for the Oropharynx
Table Graphic Jump LocationTable 6.  Multivariate Analysis for the Larynx and Hypopharynx

References

Bahar  G, Feinmesser  R, Popovtzer  A,  et al.  Basaloid squamous carcinoma of the larynx. Am J Otolaryngol. 2003;24(3):204-208.
PubMed   |  Link to Article
Erisen  LM, Coskun  H, Ozuysal  S,  et al.  Basaloid squamous cell carcinoma of the larynx: a report of four new cases. Laryngoscope. 2004;114:1179-1183.
PubMed   |  Link to Article
Thariat  J, Ahamad  A, El-Naggar  AK,  et al.  Outcomes after radiotherapy for basaloid squamous cell carcinoma of the head and neck: a case-control study. Cancer. 2008;112:2698-2709.
PubMed   |  Link to Article
Banks  ER, Frierson  HF  Jr, Mills  SE, George  E, Zarbo  RJ, Swanson  PE.  Basaloid squamous cell carcinoma of the head and neck: a clinicopathologic and immunohistochemical study of 40 cases. Am J Surg Pathol. 1992;16:939-946.
PubMed   |  Link to Article
Paulino  AF, Singh  B, Shah  JP, Huvos  AG.  Basaloid squamous cell carcinoma of the head and neck. Laryngoscope. 2000;110:1479-1482.
PubMed   |  Link to Article
Daroca  PJ  Jr, Dhurandhar  HN.  Basaloid carcinoma of uterine cervix. Am J Surg Pathol. 1980;4(3):235-239.
PubMed   |  Link to Article
Sarbia  M, Verreet  P, Bittinger  F,  et al.  Basaloid squamous cell carcinoma of the esophagus: diagnosis and prognosis. Cancer. 1997;79:1871-1878.
PubMed   |  Link to Article
Bracero  F, Gámiz  MJ, Soldado  L,  et al.  Hypopharynx and larynx basaloid squamous carcinoma: our experience with 6 cases [in Spanish]. Acta Otorrinolaringol Esp. 2001;52(3):229-236.
PubMed   |  Link to Article
Eryilmaz  A, Gocer  C, Acar  A, Dagli  M, Albayrak  L.  Basaloid squamous cell carcinoma of the larynx. J Laryngol Otol. 2002;116:52-53.
PubMed
Wain  SL, Kier  R, Vollmer  RT, Bossen  EH.  Basaloid-squamous carcinoma of the tongue, hypopharynx, and larynx: report of 10 cases. Hum Pathol. 1986;17(11):1158-1166.
PubMed   |  Link to Article
Soriano  E, Faure  C, Lantuejoul  S,  et al.  Course and prognosis of basaloid squamous cell carcinoma of the head and neck: a case-control study of 62 patients. Eur J Cancer. 2008;44(2):244-250.
PubMed   |  Link to Article
Thariat  J, Badoual  C, Faure  C, Butori  C, Marcy  PY, Righini  CA.  Basaloid squamous cell carcinoma of the head and neck: role of HPV and implication in treatment and prognosis. J Clin Pathol. 2010;63:857-866.
PubMed   |  Link to Article
Chernock  RD, Lewis  JS, Zhang  Q, El-Mofty  SK.  Human papillomavirus–positive basaloid squamous cell carcinomas of the upper aerodigestive tract: a distinct clinicopathologic and molecular subtype of basaloid squamous cell carcinoma. Hum Pathol. 2010;41(7):1016-1023.
PubMed   |  Link to Article
Joseph  AW, D’Souza  G.  Epidemiology of human papillomavirus–related head and neck cancer. Otolaryngol Clin North Am. 2012;45(4):739-764.
PubMed   |  Link to Article
Yu  JB, Gross  CP, Wilson  LD, Smith  BD.  NCI SEER public-use data: applications and limitations in oncology research. Oncology (Williston Park). 2009;23(3):288-295.
PubMed

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