1

Introduction

Papillary squamous cell carcinoma (PSCC) is a rare malignancy of the upper aerodigestive tract (UADT) . A review of the literature reveals only a few small series and scattered case reports . Although multiple groups have had some success in identifying various strains of human papillomaviruses (HPVs) in the UADT of affected patients , the etiology and risk factors have not been clearly delineated; and a true causal relationship with HPV has never been established . Because there is a high rate of recurrence, it has been suggested that these lesions arise in areas affected by a field-exposure defect . PSCC lesions predominantly arise in subsites most prone to benign squamous papillomas (ie, the larynx and sinonasal tract) of men between the ages of 50 and 70 years, but can also arise in the oropharynx, sinonasal tract, and oral cavity . Despite an established definition of PSCC as “invasive squamous carcinomas which have an exophytic papillary component” , diagnosing these tumors has proven difficult primarily because of the controversial interpretation of this definition . Some authors have contended that such a broad definition is likely to include hybrid verrucous carcinomas (VSCC), which can also demonstrate a papillary configuration . However, the cytologic features of malignancy inherent in PSCC necessarily exclude a diagnosis of VSCC . Features such as absence of keratinization, propensity of the subsite for development of benign squamous papillomas, and morphologic patterns have also been suggested as more stringent criteria, with limited concordance between published studies . An illustrative example is that of keratinization, which was noted as present to varying degrees in 3 initial series . Subsequently, Suarez et al described a lack of surface keratinization; and the recent literature has considered an absence of keratinization as a hallmark of PSCC strictly defined . Mortality has likewise been debated as ranging from dismal to good to excellent . Although treatment modality has not been found to affect prognosis , tumor subsite , microscopic features , and HPV status have been suggested to play some role. The objectives of this study were to review the outcomes of patients treated for PSCC of the head and neck at the Cleveland Clinic Foundation Head and Neck Institute and to describe factors associated with recurrence and survival.

2

Materials and methods

This study was approved by the Cleveland Clinic Foundation institutional review board. A retrospective chart review of the Head and Neck Institute and also the Pathology patient registries was performed to identify all patients previously diagnosed with PSCC of the UADT from the years 1979 to 2008, and 65 patients were identified. Squamous cell carcinomas (SCCs) with various combinations of filiform to broad-based papillae were included. Seven cases did not meet pathologic criteria and were excluded upon histologic review. Six additional cases for which slides were not available were excluded because they had not been diagnosed by a dedicated head and neck pathologist. Thus, there were evaluable data for 52 patients. Medical records were reviewed with the objective to identify patient demographics, risk factors, primary subsite, treatment modalities, failure pattern, and survival statistics. For patients lost to follow-up, a publicly available version of the Social Security Death Index (rootsweb.com) was accessed to determine date of death, if any. Initial treatment given to the patient was considered the primary treatment modality. All lesions were classified using the American Joint Committee on Cancer staging (2002) TNM classification . Lesions have been defined as recurrence if they recur within 2 cm of the initial lesion within 5 years of initial diagnosis.

Statistics were analyzed using SAS (Cary, NC) version 9.2. P values were significant if < .05. Log-rank tests were used for determining P values of overall and disease-free survival by subsite and treatment modality.

2

Materials and methods

This study was approved by the Cleveland Clinic Foundation institutional review board. A retrospective chart review of the Head and Neck Institute and also the Pathology patient registries was performed to identify all patients previously diagnosed with PSCC of the UADT from the years 1979 to 2008, and 65 patients were identified. Squamous cell carcinomas (SCCs) with various combinations of filiform to broad-based papillae were included. Seven cases did not meet pathologic criteria and were excluded upon histologic review. Six additional cases for which slides were not available were excluded because they had not been diagnosed by a dedicated head and neck pathologist. Thus, there were evaluable data for 52 patients. Medical records were reviewed with the objective to identify patient demographics, risk factors, primary subsite, treatment modalities, failure pattern, and survival statistics. For patients lost to follow-up, a publicly available version of the Social Security Death Index (rootsweb.com) was accessed to determine date of death, if any. Initial treatment given to the patient was considered the primary treatment modality. All lesions were classified using the American Joint Committee on Cancer staging (2002) TNM classification . Lesions have been defined as recurrence if they recur within 2 cm of the initial lesion within 5 years of initial diagnosis.

Statistics were analyzed using SAS (Cary, NC) version 9.2. P values were significant if < .05. Log-rank tests were used for determining P values of overall and disease-free survival by subsite and treatment modality.

3

Results

There were 36 men and 16 women, a ratio of 2.3:1. The mean age at diagnosis was 65 years, with a range from 38 to 84 years. The laryngopharynx was the most commonly affected site (n = 19, 36.5%), followed in frequency by the oral cavity (n = 18, 34.6%), sinonasal tract (n = 8, 15.4%), and oropharynx (n = 7, 13.5%) ( Table 1 ). A total of 73.1% (n = 38) of the patients had a history of tobacco use, whereas 21.2% (n = 11) used alcohol at least daily; 19.2% (n = 10) had a history of both tobacco use and daily alcohol use; 23.1% (n = 12) had a history of benign squamous papillomas of the UADT that had been confirmed by pathology. Two patients had a history of lichen planus; and 2 other patients had a history of conventional head and neck SCC 7 and 9 years, respectively, before diagnosis of PSCC. One patient presented with synchronous lesions of varying morphology, only one of which was PSCC, whereas the other was conventional SCC. Presenting symptoms were consistent with well-described symptoms for other head and neck cancers specific to the affected subsite.

Lesions of the laryngopharynx were often found at an early stage, whereas neoplasms of the oral cavity were more commonly of a higher stage ( Table 2 ). Ten patients (19.2%) were noted to have clinically positive cervical lymph nodes at presentation by physical examination or radiologic criteria, whereas 22 underwent neck dissection at some point in treatment. Ultimately, 6 (27.3%) of the 22 patients with a neck dissection were determined to have pathologically positive neck disease, whereas an additional patient was noted to have neck disease by biopsy that was treated nonsurgically.

Grossly, lesions were described as exophytic, friable, and papillomatous, consistent with the clinical image in Fig. 1 A . Primary tumors ranged in size from 0.5 to 6.5 cm at initial presentation. When initially diagnosed, 65.4% (n = 34) of cases had resection specimens beyond a simple biopsy available for microscopic review. Histologic architecture ranged from delicate, finger-like papillae with conspicuous fibrovascular cores to more broad-based projections. Most examples contained combinations of both patterns. All demonstrated cytologic features of malignancy such as nuclear atypia, prominent nucleoli, loss of cellular polarity, and increased mitotic figures. Surface keratinization and cellular keratinization were present to varying degrees. The presence of cytologic atypia precluded classification as VSCC, whereas architectural features were not consistent with those of conventional SCC ( Fig. 1 B- D ). Excluded lesions demonstrated features more consistent with benign papillomatosis, VSCC, or conventional SCC.

(A) This clinical image, from a patient with multiple recurrences of PSCC, demonstrates several exophytic lesions of the oral cavity. (B) This PSCC of the tongue has a complex papillary architecture with invasion of the underlying skeletal muscle (hematoxylin and eosin [H&E], ×20). (C) The slender papillae have central fibrovascular cores with outer layers of atypical squamous epithelial cells that lack surface keratinization (H&E, ×200). (D) Small nests of the carcinoma invade the stroma. An associated lymphoplasmacytic infiltrate is present (H&E, ×200).

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