—  SYMPOSIUM #24  —

Oral Pathology
Moderators: Dr. Antonio Cardesa and Dr. Bruce Wenig

Section 5 - Variants of Squamous Cell Carcinoma with the Upper Aerodigestive Tract (UADT)

Mary S. Richardson
Medical University of South Carolina


In the head and neck, the most common malignancy is squamous cell carcinoma (SCC). The vast majority of SCCs emulate the stratified squamous epithelium of the mucosal surfaces. The malignant cells infiltrate the subjacent connective tissue as epithelial nests which exhibit subtle or profound disorder in maturation, intercellular bridges, atypical mitotic figures, and premature or abundant cytoplasmic keratin formation.These findings are easily appreciated as conventional-type SCC.

Subsets of SCC in the UADT however demonstrate unusual histological features and architectural growth patterns. The squamous cell carcinoma variants sometimes have a different clinical behavior as compared to conventional-type SCC. The unusual histological features of the variants can cause the differential diagnoses to include a wide range of possibilities (benign to malignant). Resolving the differential diagnosis can be problematic, if not impossible, with a limited biopsy. The most common variants of SCC can be found in Table 1.

Verrucous carcinoma (VC) was characterized as a distinct entity by Ackerman in 1948. Within the head and neck it most often involves the larynx or oral cavity, particularly the buccal mucosa and gingiva. This variant is estimated to represent less than 5% of laryngeal and oral tumors. VC is considered to lack metastatic potential. The neoplasm is usually found in the elderly and is thought to be related to use of oral tobacco as well as smoked tobacco, alcohol and poor oral hygiene. The involvement of human papillomavirus (HPV) is controversial.

Clinically, this variant has a fungating warty surface which is recapitulated in the histological features. The tumor is composed of undulating acanthotic squamous epithelium which possesses at the base, well circumscribed downward pushing borders, extending deeply into the stroma beyond the boundary of the adjacent normal epithelium. While at the surface of VC, emanate "church spires" of abundant orthokeratin or parakeratin. The acanthotic epithelium shows minimal atypia, focal sporadic dyskeratotic cells and mitotic figures that are confined to the basal region of the epithelium.

Verrucous hyperplasia and papillary SCC may enter the differential diagnosis, however the lack of downward growth and the presence of fibrovascular cores, respectively, can aid in distinguishing these lesions from verrucous carcinoma. The application of the strict histological criteria for VC eliminates verrucoid conventional type SCCs from the differential diagnosis. No specific genetic finding been has been consistently attributed to verrucous carcinoma.

Papillary squamous cell carcinoma (PSCC) is an uncommon variant that is seen most frequently in older men, within the larynx or sinonasal tract. Because of the most common sites of occurrence and a few reported cases in patients with previous squamous papillomas, human papillomavirus association has been reported but not yet substantiated as causal.

The clinical appearance is a usually solitary exophytic lesion, somewhat wart-like or papillary. A complex of papillary fibrovascular fonds covered by malignant epithelium characterizes this variant. Surface keratinization is usually only focally identified, as is koilocytic change. Assessment of definitive invasion is difficult due to the complex architecture however; most often the invasive component will have the features of conventional type SCC.

Sinonasal or laryngeal papilloma, VC and conventional type SCC with an exophytic pattern, all enter the differential diagnosis for this variant. PSCC is a destructive lesion, with complex fond like growth and marked cytologic atypia of the covering epithelium, which aid in separating it from sinonasal papilloma. VC has a similar exophytic gross appearance but the epithelium lacks the carcinoma in situ/severe dysplasia of papillary SCC and VC has abundant surface keratinization. Exophytic conventional type SCC may be more problematic to distinguish but usually is characterized by a more nodular growth with numerous foci of invasion. Limited studies of genetic abnormalities are available. LOH studies have not been convincing in separating this variant from VC or conventional type SCC.

Basaloid SCC (BSCC) is considered an aggressive variant with a propensity to occur in the hypopharynx, base of tongue, supraglottis and tonsillar region. This variant most often presents in a high stage with metastatic disease, is found in older men, and associated with use of tobacco and consumption of alcohol.

The tumors are usually noted as an infiltrative submucosal mass with a less impressive ulcerative surface lesion. A small biopsy, devoid of the overlying dysplasia surface epithelium can be very challenging in distinguishing this variant of SCC. The characteristic histological features of BSCC include a predominance of nests of basaloid cells with areas of peripheral palisading, notable comedo necrosis, hyalinized or myxoid stroma, cribriform or gland-like structures and foci of abrupt keratinization.

The differential diagnosis includes adenoid cystic carcinoma (ACC), small cell neuroendocrine carcinoma (SCNC) and basal cell adenocarcinoma (BCA) of salivary gland. ACC may be distinguished by: 1) lack of cytologic pleomorphism; 2) lack of squamous differentiation; 3) is not associated with surface squamous dysplasia; and 4) may show p63 nuclear staining of the peripheral cells. The distinction between ACC and BSCC is important for the appropriate prognosis and clinical management. BCA and SCNC may share histological features with BSCC. However, in contrast, BCA is not associated with surface dysplasia and may diffusely stain with cytokeratin 7. On the other hand, SCNC is found to stain with neuroendoncrine markers: CD56, chromogranin, synaptophysin. The reported genetic abnormalities for BSCC are variable.

Spindle cell carcinoma (SpCC) is considered a poorly differentiated SCC composed of neoplastic cells that have a mesenchymal or sarcomatoid phenotype. This variant can present as a polypoid mass anywhere in the upper areodigestive tract although it has a propensity for the larynx. SpCC may arise de novo within a less aggressive conventional type SCC or after irradiation of a SCC.

The microscopic features defining SpCC require the identification of a malignant undifferentiated malignant spindle cell component with the presence of a squamous component (surface dysplasia, carcinoma in situ, conventional type SCC). If surface epithelium is present, then sometimes (about 40%) a pancytokertin can demonstrate the surface cytokeratin positive cells blending into subjacent cytokeratin positive spindle cells. Necrosis is not prominent feature. The mesenchymal component may show a range of appearances from notable cytologic atypia to whirling bland spindle cells with mitotic activity.

Adenosquamous carcinoma (ASCC) is an extremely rare variant of SCC. This variant occurs in older men, usually located in the larynx or oral cavity and is associated with tobacco and alcohol use. It is composed of a superficial squamous carcinoma that blends into subjacent cords or nests of a tubular or glandular component. The glandular differentiation can be confirmed with histochemical stains for mucin. The chief differential diagnosis is mucoepidermoid carcinoma (MEC), which usually has a better prognosis than ASCC. Glandular differentiation in MEC is present throughout the tumor lobules and not predominately at the base of lesion in the advancing margin, as is seen in ASCC. Molecular and genetic information about ASCC is limited.

Adenoid squamous cell carcinoma (AdSCC) is distinguished by marked acatholysis. This variant is most often seen on sun exposed areas such as the lip but occurs in other UADT sites. The histologic features include discohesive, markedly atypical, glassy squamous cells that fill pseudolumina. This variant of SCC is negative for histochemical evidence of mucin. If conventional type SCC is adjacent there is no diagnostic dilemma however lack of adjacent SCC coupled with attenuation of the rimming cells may suggest a vascular process. Pancytokeratin stain should be positive in AdSCC and resolve the dilemma.

Undifferentiated carcinoma (UC) is an aggressive, nonkeratinizing SCC commonly originating in Waldeyer's ring or the nasopharynx. There is a unique bimodal age distribution (second and sixth decades) and the patients are usually male. This variant is most common in eastern Asia . Etiologic factors include genetic, environmental and a probable role of Epstein-Barr virus in the oncogenesis of this variant. UC is characterized by sheets of cells with, large vesicular nuclei containing prominent nucleoli, scant cytoplasm, indistinct cell borders, an associated dense lymphoplasmacytic infiltrate. The differential diagnosis for this lesion on histological features alone is lymphoma. Immunohistochemical staining for various cytokeratins easily identifies UC. The tumor cells should not stain for CD15, leukocyte common antigen or CD30.

The diagnosis of the variants of SCC is challenging on limited biopsy material. Familiarity with key features of these subsets of SCC can facilitate an accurate diagnosis. The accurate diagnosis in turn will greatly influence surgical considerations and provide valuable prognostic information.
Table 1: Variants of Squamous Cell Carcinoma

Verrucous carcinoma
Papillary SCC
Basaloid SCC
Spindle cell carcinoma
Adenosquamous carcinoma
Adenoid SCC
Undifferentiated carcinoma

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