Basaloid Squamous Cell Carcinoma of the Oral Cavity: An Analysis of 92 Cases

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1 The Laryngoscope VC 2013 The American Laryngological, Rhinological and Otological Society, Inc. Basaloid Squamous Cell Carcinoma of the Oral Cavity: An Analysis of 92 Cases Valerie A. Fritsch, MD; Daniel R. Gerry, BS; Eric J. Lentsch, MD Objectives/Hypothesis: Basaloid squamous cell carcinoma (BSCC) is considered a rare and possibly more aggressive squamous cell carcinoma (SCC) variant. Until now, a series of exclusively oral cavity BSCC patients has not been previously reported. We endeavored to compare BSCC and SCC of the oral cavity, focusing on epidemiologic factors and survival outcomes. Study Design: Retrospective analysis of population-based data. Methods: We compared epidemiologic factors, clinicopathologic data, and disease-specific survivals (DSS) between 92 patients with oral cavity BSCC and 15,181 patients with SCC. Results: High-grade tumors and distant metastases were more common in the BSCC group (P 0.001). On multivariable analysis controlling for disease stage, BSCC patients had similar DSS to those with typical SCC (P ). Although there was a trend favoring definitive radiotherapy for BSCC, there were no significant differences in treatment approach between BSCC and SCC. The choice of treatment modality (radiation, surgery 6 radiation) did not reveal a difference in DSS between the two tumor subtypes. Conclusion: Analysis of the largest oral cavity BSCC series to date demonstrates that BSCC of the oral cavity carries a comparable prognosis to conventional-type oral SCC. Key Words: Basaloid squamous cell carcinoma, squamous cell carcinoma, oral cavity, SEER database. Level of Evidence: 2b. Laryngoscope, 124: , 2014 INTRODUCTION Basaloid squamous cell carcinoma (BSCC) is a rare variant that is distinct from conventional squamous cell carcinoma (SCC), possessing a pattern of behavior that is regarded as potentially more aggressive than conventional SCC. BSCC is one of at least seven SCC variants that collectively represent approximately 15% of all SCCs encountered in the head and neck. 1 Originally described in a series of 10 cases by Wain et al. 2 in 1986, BSCC was officially recognized as a distinct clinicopathologic entity in the World Health Organization (WHO) 2005 classification, where it was described as an aggressive, high-grade variant of SCC composed of both basaloid and squamous components. 3 The histopathologic appearance is distinct from well- or moderatelydifferentiated SCC, with varying degrees of typical squamous component interspersed with nests of basaloid cells arranged in lobules with prominent peripheral palisading and central foci of comedonecrosis. 3 Immunohistochemical staining for specific cytokeratins and From the Department of Otolaryngology Head and Neck Surgery (V.A.F., E.J.L.), Medical University of South Carolina, Charleston, South Carolina; and the Mercer University School of Medicine (D.R.G.), Savannah, Georgia, U.S.A Editor s Note: This Manuscript was accepted for publication August 5, The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Eric J. Lentsch, MD, 135 Rutledge Avenue MSC 550, Charleston, SC Elentsch@musc.edu DOI: /lary neuroendocrine markers help distinguish BSCC from other nonsquamous carcinomas. 4 BSCC has traditionally been regarded as an aggressive variant, based primarily on higher overall mortality rates and an increased tendency toward distant metastases. Recent case-control studies have demonstrated considerably higher rates of metastases in BSCC compared with SCC, yet with similar rates of locoregional control. 5,6 Whether BSCC is actually a more aggressive neoplasm than typical SCC is still a matter of debate. Although a number of studies have suggested a worse prognosis for BSCC, others have indicated behavior similar to typical SCC. 1 It has been suggested that this disagreement may actually represent the dual behaviors of two separate BSCC subtypes, one associated with heavy, long-term alcohol and tobacco exposure, and a second emerging tumor subtype associated with high-risk human papillomavirus (HPV) infection. 1,4,7,8 Regardless of the suggested underlying mechanisms, evidence indicates that BSCC of the upper aerodigestive tract may in some cases behave in a manner similar to conventional SCC. We hypothesize that BSCCs arising in the oral cavity may similarly behave in a manner more characteristic of conventional SCC. In our study we analyzed a series of 92 cases of oral cavity BSCC, utilizing the Surveillance, Epidemiology, and End Results (SEER) database. Our objective was to describe the clinical presentation and prognosis of BSCC in a large series of patients with BSCC of the oral cavity, and to compare these to a series of patients with conventional-type oral SCC. 1573

2 MATERIALS AND METHODS Data Source The Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute is a coordinated system of population-based cancer registries that is widely used to study a large variety of malignancies. Strategically located across the United States, the SEER registries routinely collect data on patient demographics, primary tumor site, tumor morphology, stage at diagnosis, first course of treatment, and follow-up vital status. The SEER program performs continuous quality control activities to ensure the collection of high quality data; and the 17 registries included in our analysis represent an estimated 26% of the United States population from several geographic regions. 9 This study was exempt from review by the Medical University of South Carolina Institutional Review Board. Patient Selection The SEER database was queried for patients diagnosed with squamous cell carcinoma (SCC) and basaloid squamous cell carcinoma (BSCC) of the oral cavity based on International Classification of Diseases for Oncology (ICD-O-3) anatomic site and histology codes, between the years 2000 and Only cases with conventional and basaloid SCC were included in the cohort (ICD-O-3 codes 8070/3: Squamous cell carcinoma, NOS, 8071/3; Squamous cell carcinoma, keratinizing; 8083/3: Basaloid squamous cell carcinoma). Patients with nonkeratinizing SCC were not included in the analyses. Patients diagnosed at autopsy, and those without a histologically confirmed diagnosis were excluded as well. Patient demographics including age at diagnosis, gender, and race as well as tumor factors were obtained. Race was categorized as White, Black, Asian/Pacific Islander, and American Indian/Alaska native, according to SEER s Race recode variable. Tumor factors queried included tumor size, histologic grade, local extent, lymph node status, and distant metastasis. Histologic grade was classified as low (well to moderately differentiated) or high (poorly differentiated or undifferentiated). AJCC tumor, node, distant metastasis (T, N, and M) stage is recorded (according to the 6th edition of the AJCC Staging Manual 10 ) for patients diagnosed after Patients diagnosed in 2003 and earlier were manually classified based on SEER extent of disease variables. Data were obtained from all 17 U.S. cancer registries participating in the SEER program using SEER*Stat version ( Statistical Analysis Differences in clinicopathologic characteristics between patients with BSCC and conventional-type SCC were compared using the Chi-square test (categorical variables), and the Student s t test or nonparametric rank sum test (continuous variables). Kaplan Meier survival analyses were used to compare 5- year disease-specific survival (DSS) between patients with BSCC and SCC. The log-rank test assessed statistical differences between survival curves. Survival time was provided as the number of months between date of diagnosis and date of death, date last known to be alive, or December 31, 2008 whichever occurred first. Because the endpoint for our analysis was 5-year DSS, patients surviving more than 60 months were coded as censored at 60 months. Patients lost to follow-up before 60 months were censored at time of last contact. In order to explore the independent effect of tumor histology on DSS, univariable and multivariable Cox regression analysis were used to calculate hazard ratios (HRs) with 95% confidence intervals 1574 (CIs). Statistical significance was set at P <0.05. All tests were two-sided. Stata version 10.0 (StataCorp; College Station, TX) statistical software was used for all statistical analysis. RESULTS Study Population Out of 15,273 patients who were identified, 92 patients had BSCC and 15,181 had conventional SCC. Table I describes patient demographics and the distribution of tumor location in each group. The median age at presentation was similar in the BSCC and SCC groups (66 vs. 65, P ). The majority of both BSCC and SCC patients were White males; however, the predominance of White patients was significantly greater in the SCC group (85.8% vs. 77.8% White, P <0.001), and the predominance of male patients was significantly greater in the BSCC group (73.9% vs. 59.7% male, P <0.001). Primary site distribution differed significantly between the two groups (P <0.001). BSCC tumors were most commonly located on the floor of mouth (47%), tongue (13%), and retromolar trigone (13%). In contrast, most conventional-type SCC tumors were located on the tongue (38%), floor of mouth (25%), and gums (14%). Tumor Characteristics Most BSCC tumors were considered high grade (70%), while the majority of SCC tumors were considered low grade (82%, P < 0.001). Data describing tumor staging are summarized in Table II. The majority of patients in our cohort presented with lesions <4 cm (i.e., T1/T2), and the distribution of tumors by T stage was similar in both groups (P ).There was a trend toward a higher incidence of nodal metastasis in the BSCC group (40% vs. 30%, P ). Among nodepositive patients, N-stage distribution was mostly similar, with N1 disease being most prevalent in both BSCC and SCC. Patients with BSCC were significantly more likely to present with distant metastasis (7% vs. 2%, P ). Accordingly, more patients with BSCC presented with stage IV disease (48% vs. 36%, P ). However, the overall distribution of early and late stage disease in BSCC and SCC was similar (26% vs. 31% stage I/II, and 74 vs. 69% stage III/IV, respectively, P ). Treatment Complete treatment data was available for 77 (84%) and 13,627 (90%) patients with BSCC and SCC, respectively (Table II). The majority of patients in both groups underwent surgical resection. Primary radiotherapy was slightly more common in the BSCC group (23% vs. 24%, P ). Survival Analysis The mean follow-up of surviving patients was 37 and 39 months, respectively, in the BSCC and SCC groups (P ). Figure 1 illustrates the effect of tumor histology on DSS. Analysis of the cohort as a whole, as

3 TABLE I. Clinicopathologic Characteristics of Patients With Basaloid and Conventional-Type Squamous Cell Carcinoma of the Oral Cavity. SCC N % BSCC N % P Value 15, Age at Diagnosis: mean (SD) 64.7 (14.1) 66.7 (12.3) Age at Diagnosis: median (range) 65 (6-103) 65.5 (40 98) Male 9, Ethnicity <0.001 White 12, Black 1, Asian/Pacific Islander American Indian/Alaska Native Total 15, Not recorded Primary Site <0.001 Oral tongue 5, Gums 2, Hard palate Buccal mucosa 1, Retromolar trigone 1, Floor of mouth 3, Overlapping lesion of mouth/mouth, NOS GRADE <0.001 Low (well to moderately differentiated) 11, High (poorly differentiated or undifferentiated) 2, Total 13, Not recorded 1, BSCC 5 basaloid squamous cell carcinoma; SCC 5 (Conventional-type) squamous cell carcinoma; SD 5 standard deviation; N 5 number; NOS 5 not otherwise specified. well as stage-stratified analysis, revealed similar rates of DSS for patients in both groups (P ). The results of univariable and multivariable Cox proportional hazards regression analyses of clinicopathological factors with respect to DSS are shown in Table III. Multivariable analysis revealed a significant association between patient age, race, tumor grade, and AJCC stage classification on DSS. Basaloid histology was not associated with DSS on univariable or multivariable analysis. DISCUSSION We and others believe that BSCC may act differently depending on the site of disease. Our study was intended to provide a site-specific comparative analysis of a large series of oral cavity BSCCs against typical SCCs of the oral cavity. We evaluated DSS to determine whether basaloid-variant subtype could serve as a prognostic indicator in cases of oral cavity SCC. Contrary to the traditional characterization of BSCC as an aggressive variant, our study indicates that oral cavity basaloid tumors carry a course and prognosis similar to that of typical SCCs. While previous studies have demonstrated similar survival rates between BSCC and conventional SCC of the head and neck, 6 8 few have done so in a site-specific fashion. In prior series that have included the oral cavity, either a direct comparison was never made between BSCC and conventional SCC, or cohorts have been too small to perform meaningful statistical analysis, or outcomes did not include survival Our study represents the largest series to date comparing DSS for oral cavity basaloid-variant tumors with conventional SCCs. Due to our cohort s uniformity and large size, we were able to perform multivariable analysis comparing DSS according to subgroups defined by patient demographics, tumor grade, and AJCC stage classification. The results have revealed that while BSCC of the oral cavity was more often high-grade and carried a greater incidence of distant metastases, DSS was not significantly different from that of typical SCC (Fig. 1, Table III). Similarly, rates of response to surgery or radiation therapy did not show any significant divergence between the two tumor types (Fig. 2, Table II). Interestingly, our findings in this study are in contrast to other site-specific BSCC SEER database analyses. 14,15 Although BSCC and conventional SCC appear to carry similar prognoses in the oral cavity, BSCC patients have significantly better DSS when tumors are located in the oropharynx 14 and worse DSS when tumors are located in the larynx. 15 In the oropharynx, BSCC s more favorable prognosis is most likely due to its higher 1575

4 TABLE II. Staging and Treatment of Patients with Basaloid and Conventional-type Squamous Cell Carcinoma of the Oral Cavity. SCC N % BSCC N % P Value 15, T1 5, T2 2, T T4 3, Total 11, Not recorded 3, N0 9, N1 1, N2a N2b 1, N2c N Total 13, N positive, NOS Not recorded 1, M0 13, M Total 14, Not recorded AJCC Stage (6th ed.) I 4, II 1, III 1, IV 4, Total 11, Not recorded 4, Treatment Surgery 7, Radiation 1, Surgery 1 Radiation 4, Total 13, Complete treatment data not available 1, Survival (months): mean (SD) 17 (16.0) 18.7 (18.2) Survival (months): median (range) 12 (0-104) 17 (0-79) Follow-up (months): mean (SD) 43.6 (30.8) 35.4 (24.0) Follow-up (months): median (range) 39 (1-107) 37 (1-93) AJCC 5 American Joint Committee on Cancer; BSCC 5 basaloid squamous cell carcinoma; NOS 5 not otherwise specified; SCC 5 (conventional-type) squamous cell carcinoma; SD 5 standard deviation; TNM 5 tumor, node, distant metastasis. rate of HPV positivity (vs. conventional SCC of the Oropharynx (OP)). However, the prevalence of HPVrelated cancer is much lower in the oral cavity and larynx; and HPV s prognostic relevance in non-oropharynx upper aerodigestive tract sites remains unclear Current evidence leads us to believe that HPV is not an important factor for recurrence and survival in patients with oral cavity primaries 16,17 ; but this is a topic that should be investigated in future studies. It is worth emphasizing that the HPV status of the tumors in our series could not be obtained through the SEER database. Only recently has the implementation of HPV testing become commonplace, owing to the emerging recognition of HPV as an important etiologic and prognostic factor in SCC of the head and neck. With the increasing utilization of screening tests for HPV antigens or infection-associated oncoproteins 4 such as p16, a growing national database should allow for future large-scale studies evaluating the link between this virus and the behavior of BSCC. Another unfortunate drawback of the SEER database is its lack of data regarding disease recurrence rates or disease-free survival. Ultimately, the breadth and depth of the data contained in the SEER registry set the constraints for our 1576

5 Fig. 1. Disease-specific survival by AJCC stage. AJCC 5 American Joint Committee on Cancer; BSCC 5 basaloid squamous cell carcinoma; SCC 5 conventional squamous cell carcinoma. TABLE III. Univariable and Multivariable Analysis of Factors Related to Disease-Specific Survival in Oral Cavity Carcinoma. Multivariable Univariable HR CI (LL) CI (UL) P HR CI (LL) CI (UL) P Age at diagnosis (per year) < <0.001 Male sex White Referent Referent Black < <0.001 Asian/Pacific Islander <0.001 American Indian/Alaska Native Not recorded Low grade Referent Referent High grade < <0.001 Grade not recorded Stage I Referent Referent Stage II < <0.001 Stage III < <0.001 Stage IV < <0.001 Stage not recorded < <0.001 Basaloid Squamous Cell Carcinoma CI 5 95% confidence interval; HR 5 hazard ratio; LL 5 lower limit; UL 5 upper limit. 1577

6 rare neoplasms. We feel that the results of retrospective studies generated through this database are particularly useful for their generalizability. The wide scope of the SEER registry provides a broad picture of national trends in standards of care and patient demographics, buffering against regional treatment biases and local/ institutional referral biases. CONCLUSION Our study, which describes the largest series of patients with oral cavity BSCC to date, contradicts the characterization of BSCC as an aggressive SCC variant with a uniformly poor prognosis. Although BSCC of the oral cavity exhibited a higher grade and stage than typical SCC at diagnosis, no statistically significant difference in DSS was found between the two tumor subtypes. In addition, for a variety of treatment protocols, no significant difference in DSS could be identified between BSCC and typical SCC of the oral cavity. Fig. 2. Disease-specific survival by treatment BSCC 5 basaloid squamous cell carcinoma; SCC 5 conventional squamous cell carcinoma. study. However, this registry provides a wealth of important epidemiologic data, including patient demographics, tumor histology, grade and stage, tumor primary site and subsite, and a number of other parameters. Furthermore, as a nationwide population-based tumor registry, the SEER database allows us to analyze a vast number of cases, identifying large cohorts even for extremely BIBLIOGRAPHY 1. 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: 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: Barnes C, Everson J, Reichart P, et al. Pathology and genetics, head and neck tumors. World Health Organization classification of tumors. Lyon, France: IARC Press; Woolgar JA, Lewis JS Jr, Devaney K, et al. Basaloid squamous cell carcinoma of the upper aerodigestive tract: a single squamous cell carcinoma subtype or two distinct entities hiding under one histological pattern? Eur Arch Otorhinolaryngol 2011;268: 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: Thariat J, Ahamad A, El-Naggar AK, et al. Outcomes after radiotherapy for basaloid squamous cell carcinoma of the head and neck: a casecontrol study. Cancer 2008;112: Chernock RD, Lewis JS, Zhang Q, El-Mofty SK. Human papillomaviruspositive basaloid squamous cell carcinomas of the upper aerodigestive tract: a distinct clinicopathologic and molecular subtype of basaloid squamous cell carcinoma. Hum Pathol 2010;41: Begum S, Westra WH. Basaloid squamous cell carcinoma of the head and neck is a mixed variant that can be further resolved by HPV status. Am J Surg Pathol 2008;32: SEER Brochure. National Cancer Institute. NIH Publication No September American Joint Committee on Cancer. AJCC Cancer Staging Manual 6th ed. New York, NY: Springer; Yu GY, Gao Y, Peng X, Chen Y, Zhao FY, Wu MJ. A clinicopathologic study on basaloid squamous cell carcinoma in the oral and maxillofacial region. Int J Oral Maxillofax Surg 2008;37: de Sampaio Goes FC, Oliveira DT, Dorta RG, et al. Prognoses of oral basaloid squamous cell carcinoma and squamous cell carcinoma: a comparison. Arch Otolaryngol Head Neck Surg 2004;130: Ide F, Shimoyama T, Horie N, Kusama K. Basaloid squamous cell carcinoma of the oral mucosa: a new case and review of 45 cases in the literature. Oral Oncol 2002;38: Fritsch VA, Lentsch EJ. Basaloid squamous cell carcinoma of the oropharynx: an analysis of 650 cases. Otolaryngol Head Neck Surg 2013;148: Fritsch VA, Lentsch EJ. Basaloid squamous cell carcinoma of the larynx: analysis of 145 cases with comparison to conventional squamous cell carcinoma. Head Neck doi: /hed [Epub ahead of print]. 16. Reuschenbach M, Kansy K, Garbe K, et al. Lack of evidence of human papillomavirus-induced squamous cell carcinomas of the oral cavity in southern Germany. Oral Oncol pii: S (13) doi: /j.oraloncology [Epub ahead of print]. 17. Lingen MW, Xiao W, Schmitt A, et al. Low etiologic fraction for high-risk human papillomavirus in oral cavity squamous cell carcinomas. Oral Oncol 2013;49: Torrente MC, Rodrigo JP, Haigentz M Jr, et al. Human papillomavirus infections in laryngeal cancer. Head Neck 2011;33: