Histologic and Etiologic Variants of Squamous Cell Carcinoma
Most squamous cell carcinomas (SCCs) of the upper aerodigestive tract are histologically conventional type and as such show, to some degree, a recapitulation of stratified squamous epithelium and are secondary to the use of tobacco products. Certain SCCs, however, of the upper aerodigestive tract have different growth patterns and histologic features. Not only can these tumors sometimes behave differently from conventional-type SCCs, but they can also present the pathologist with differential diagnoses that range from benign to malignant (Table 5.1). For example, verrucous carcinoma, a locally aggressive, nonmetastasizing variant of SCC, can be very difficult, if not impossible, to differentiate from benign disease on biopsy. In addition, variant histologies are sometimes associated with variant etiologies (e.g., high-risk human papillomavirus [HR-HPV] infection), which can affect the prognosis and treatment of the tumors (Table 5.2).
This chapter discusses the clinicopathologic features of the most common variants of SCC found in the upper aerodigestive tract. Verrucous carcinoma, papillary SCC, nonkeratinizing/basaloid SCC, spindle cell carcinoma, adenosquamous carcinoma, adenoid SCC, and undifferentiated carcinoma are all discussed along with their histologic mimics and methods for arriving at their correct diagnoses. It especially focuses on difficulties that are faced with small biopsy specimens. SCCs secondary to HR-HPV, Epstein-Barr virus (EBV), nuclear protein of the testis (NUT) translocations, and with SWI/SNF abnormalities (SMARCB1 and SMARCA4 deficiency) are also discussed (Table 5.3).
A short discussion of the molecular aspects of these neoplasms is also presented. As was discussed in the chapter describing precursor lesions, SCCs of the upper aerodigestive tract arise after a series of genetic events, although these currently appear complex and somewhat variable. It is unclear whether the lack of or acquisition of certain molecular abnormalities leads to the specific phenotypic and behavioral differences between these tumors. Data are currently mixed as to whether most histologic variants have specific abnormalities that would allow for their distinction from one another and conventional-type SCC.1
TABLE 5.1 Squamous Cell Carcinoma (SCC) Histologic Variants and Differential Diagnoses | ||||||||||||||||
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HISTOLOGIC VARIANTS
Verrucous Carcinoma
Verrucous carcinoma was first described and characterized as a distinct entity in 1948 by Lauren Ackerman and is sometimes referred to as “Ackerman tumor.”2 It may develop at different anatomic sites throughout the upper aerodigestive tract and body. When it involves the upper aerodigestive tract, it most commonly is located in the mouth, specifically at the buccal mucosa or gingiva, or the larynx.3,4,5,6,7,8,9,10,11,12,13 These tumors occur in older individuals, usually in the seventh or eighth decade of life and, for oral lesions, are often related to the use of oral tobacco. Other etiologic
factors include smoked tobacco, alcohol, and poor oral hygiene. What role, if any, HPV plays in the development of these lesions remains controversial despite extensive studies.14,15 It does appear that if HPV has a role, it is limited, even in female, nonsmoking patients who develop oral tumors in association with proliferative verrucous leukoplakia. Most studies show that men are much more likely than women to be afflicted with these neoplasms.
factors include smoked tobacco, alcohol, and poor oral hygiene. What role, if any, HPV plays in the development of these lesions remains controversial despite extensive studies.14,15 It does appear that if HPV has a role, it is limited, even in female, nonsmoking patients who develop oral tumors in association with proliferative verrucous leukoplakia. Most studies show that men are much more likely than women to be afflicted with these neoplasms.
TABLE 5.2 Squamous Cell Carcinoma Histologic Variants and Their Etiologies | ||||||||||||||||||
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TABLE 5.3 Squamous Cell Carcinoma Etiologic Variants and Typical Histologies | ||||||||||
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The tumors grossly appear warty and fungating with ulcerations. Histologically, verrucous carcinomas are defined narrowly. They have a wartlike appearance with abundant keratosis and parakeratosis arising from a folded, thickened squamous epithelium (Fig. 5.1, eFigs. 5.1 and 5.2). This leads to the noted appearance of “church spires.” The squamous cells mature toward the surface and only minimal cytologic atypia should be present (Fig. 5.2, eFigs. 5.3 and 5.4). That said, some of the squamous cells may undergo individual keratinization (dyskeratosis), and occasional squamous pearls may be seen within the squamous epithelium. Mitotic figures should be located within or near the basal epithelium. Nuclei have vesicular chromatin with small nucleoli. The bases of the tumors show downgrowth of broad tongues of mature, well-differentiated squamous epithelium that invade the underlying tissues with a circumscribed, pushing border (Fig. 5.3, eFigs. 5.5 and 5.6). Infiltrating irregular nests, typical of conventional-type SCC, should not be present. At the base of the tumors, a dense lymphoplasmacytic infiltrate may be present, as may occasional foreign body-type granulomas.
 FIGURE 5.1 Verrucous carcinoma, surface. |
 FIGURE 5.2 Verrucous carcinoma, maturing epithelium without atypia. |
Although many SCCs will have verrucoid features, it has been noted that the diagnosis of verrucous carcinoma should only be made when tumors meet the strict histologic criteria listed above if the diagnosis is to have meaning. Tumors that are verrucoid, yet do not meet the strict criteria for the diagnosis of verrucous carcinoma, will generally behave in a
manner similar to more conventional-type SCCs. True verrucous carcinomas, however, have no metastatic potential. It is estimated that when strict criteria are applied, verrucous carcinomas represent less than 5% of oral and laryngeal tumors.
manner similar to more conventional-type SCCs. True verrucous carcinomas, however, have no metastatic potential. It is estimated that when strict criteria are applied, verrucous carcinomas represent less than 5% of oral and laryngeal tumors.
 FIGURE 5.3 Verrucous carcinoma, base. |
To diagnose verrucous carcinoma, ample sectioning of an excisional specimen and good sampling of the base of the lesion are needed. For this reason, an unequivocal diagnosis based upon a small biopsy is not warranted. Instead, qualified diagnoses such as SCC with verrucoid features or even verrucoid lesion should be considered, especially as benign diagnoses may sometimes feature in the differential diagnosis. Indeed, even today, most verrucous carcinomas are originally diagnosed as benign lesions on biopsy. The surgeon should be made aware of the diagnostic difficulty with these cases as clinical information often provides the information needed to guide subsequent therapy. Communication between the pathologist and surgeon is thus paramount. With final resection specimens we are loath to use the term “hybrid carcinoma” that others use for lesions that have features of verrucous carcinoma with focal infiltrating areas. It has been well known since the description of this tumor that some cases of upper aerodigestive tract conventional-type SCCs are deceptively bland and have some but not all of the required histologic features of verrucous carcinomas.
More aggressive yet benign forms of leukoplakia can have histologic features resembling verrucous carcinoma and are discussed in Chapter 3.16,17 These lesions have been clinically termed “proliferative verrucous leukoplakia” and often histologically show verrucous hyperplasia. They may be differentiated from verrucous carcinoma both clinically and histologically. Clinically, these lesions tend to recur and often develop into invasive SCCs, both verrucous carcinoma and conventional-type SCC; however, they should not form destructive, mass lesions. Histologically, verrucous carcinoma will show features of invasion with much more acanthosis and larger tongues of squamous epithelium extending deeply into the stromal tissue. The epithelium of verrucous hyperplasia should not extend more deeply than adjacent uninvolved epithelium.18
Verrucous vulgaris has been reported in the larynx and may also enter into the differential diagnosis.19 Like verrucous hyperplasia, these lesions should not invade the stroma. It has also been noted that the rete pegs tend to be thinner with verruca and that verruca have more prominent keratohyalin granules. Finally, papillary SCC is also occasionally mentioned as a differential consideration. The lesions are not very similar histologically and generally should not be confused (see below). Still, there appears to be some histologic overlap in phenotype, and some cases can show mixed features.
Immunohistochemistry has shown the accumulation of p53 protein in many of these tumors, and proliferation markers are often noted to be overexpressed when compared to benign epithelium (although not to the degree of more cytologically abnormal cases).15,20 Retinoblastoma protein expression remains intact, and some growth factors, such as c-erb-3, have
been shown to be overexpressed.21 Loss of heterozygosity (LOH) studies investigating multiple microsatellite markers have shown that these tumors have fewer abnormalities than more poorly differentiated SCC variants such as basaloid SCC or spindle cell carcinoma and have an LOH incidence similar to that of well-differentiated conventional-type SCC.1 The tumors frequently contain deletions at 9p, a region believed to be involved early in the development of upper aerodigestive tract SCC. Whether these tumors lack any specific genetic abnormalities that would explain their lack of metastatic potential has not conclusively been shown. While some have shown differences of LOH at 4q and 17p between verrucous SCC and conventional-type SCC, these differences were not confirmed with a study that compared verrucous carcinoma with only well-differentiated, conventional-type SCC. In our experience, verrucous carcinomas are not immunoreactive with antibodies to p16, nor do they contain HR-HPV by in situ hybridization.
been shown to be overexpressed.21 Loss of heterozygosity (LOH) studies investigating multiple microsatellite markers have shown that these tumors have fewer abnormalities than more poorly differentiated SCC variants such as basaloid SCC or spindle cell carcinoma and have an LOH incidence similar to that of well-differentiated conventional-type SCC.1 The tumors frequently contain deletions at 9p, a region believed to be involved early in the development of upper aerodigestive tract SCC. Whether these tumors lack any specific genetic abnormalities that would explain their lack of metastatic potential has not conclusively been shown. While some have shown differences of LOH at 4q and 17p between verrucous SCC and conventional-type SCC, these differences were not confirmed with a study that compared verrucous carcinoma with only well-differentiated, conventional-type SCC. In our experience, verrucous carcinomas are not immunoreactive with antibodies to p16, nor do they contain HR-HPV by in situ hybridization.
Papillary Squamous Cell Carcinoma
Papillary SCC is an uncommon variant of SCC that may involve the upper aerodigestive tract.22,23,24,25,26,27,28,29 The lesions occur most frequently in older male patients, like nearly all variants of SCC in this region. The lesions occur throughout the upper aerodigestive tract, but most often involve the larynx, oropharynx, and sinonasal tract. Because of their rarity, their pathogenesis remains unclear. Approximately half of the cases in a recent study were secondary to HR-HPV infection; these tumors most frequently involved the oropharynx or sinonasal tract.29 Occasional cases have been reported in patients with previously diagnosed benign squamous papillomas.
Grossly, these lesions are largely exophytic and appear papillary or even warty, akin to verrucous carcinomas. These lesions are defined histologically and have a low-power appearance similar to sinonasal papillomas (Fig. 5.4, eFigs. 5.7 and 5.8). Numerous complex papillary and filiform structures extend in all planes, often rendering the assessment of true tissue invasion extremely difficult. The papillary fronds are covered with a stratified squamous epithelium, which has overt features of malignancy, replete with lack of maturation, increased nuclear to cytoplasmic ratios, nuclear irregularities, and numerous mitotic figures located throughout the entire thickness of the epithelium (Fig. 5.5, eFigs. 5.9 and 5.10). Koilocytic change is often noted (eFig. 5.11). The epithelial component thus appears similar to high-grade squamous intraepithelial lesions of the cervix. Intracellular keratinization or dyskeratosis may be present; however, surface keratosis is often not seen or may be only focal (Fig. 5.6, eFig. 5.12). The papillary fronds have fibrovascular cores that usually contain some degree of lymphoplasmacellular infiltrate, which then extends to the base of these lesions where it becomes denser.
The complex nature of these specimens can make the assessment of invasion difficult, especially when the invasive component remains papillary. Often, however, the invasive component will have infiltrating, irregular
nests of squamous epithelium morphologically identical to conventional-type SCC. As with verrucous carcinoma, invasion can almost never be excluded at biopsy, and, because of the complex and highly exophytic nature of the noninvasive component of these tumors, definitive invasion can rarely be diagnosed at biopsy. Resection specimens should be carefully
assessed for invasion as invasive lesions tend to behave in a manner similar to conventional-type SCC of the upper aerodigestive tract. Lesions that lack invasion can be locally aggressive and difficult to fully resect, especially when they involve the sinonasal tract. Such lesions often eventually progress to invasive malignancies.
nests of squamous epithelium morphologically identical to conventional-type SCC. As with verrucous carcinoma, invasion can almost never be excluded at biopsy, and, because of the complex and highly exophytic nature of the noninvasive component of these tumors, definitive invasion can rarely be diagnosed at biopsy. Resection specimens should be carefully
assessed for invasion as invasive lesions tend to behave in a manner similar to conventional-type SCC of the upper aerodigestive tract. Lesions that lack invasion can be locally aggressive and difficult to fully resect, especially when they involve the sinonasal tract. Such lesions often eventually progress to invasive malignancies.
 FIGURE 5.4 Papillary squamous cell carcinoma reminiscent of sinonasal papilloma. |
 FIGURE 5.5 Full-thickness dysplasia in papillary squamous cell carcinoma. |
 FIGURE 5.6 Intracellular keratinization at the base of a papillary squamous cell carcinoma. |
The most common differential to be considered with these lesions includes benign papillary lesions, especially sinonasal or schneiderian papillomas. The degree of epithelial atypia present in these lesions should not generally be seen in other squamous papillary lesions of the upper aerodigestive tract, and the diagnosis is usually not very difficult. Occasional sinonasal papillomas or laryngeal papillomas can show inflammation with cytologic atypia or even dysplasia with numerous mitotic figures, however, and methods for definitively distinguishing such lesions from noninvasive papillary carcinomas are lacking histologically. In general, papillary SCC should be a destruction lesion whereas laryngeal papillomas are not.
Distinguishing these lesions from verrucous carcinomas should not be difficult, although the two may grossly appear similar (Table 5.4). Thompson et al. have also argued that the lesions should be differentiated from a more garden-variety exophytic SCC.25 They point out that true papillary SCC has a better prognosis than exophytic SCC. Histologically, it is more filiform and not as complex. The authors note that papillary SCCs appear more like stalks of celery cut on cross section and should not be complex and resemble a cut section of cauliflower.
Studies investigating genetic abnormalities in these tumors are somewhat limited due to the rarity of these neoplasms.1,26 Overexpression of
p53 protein has been shown by immunohistochemistry. LOH studies have shown a similar incidence of genetic abnormalities between these tumors and verrucous carcinoma and well-differentiated conventional-type SCC. It is interesting to note that these tumors showed an increased LOH for a microsatellite marker on the long-arm of chromosome 11 when compared with other variants of SCC, although the finding was not statistically significant. Tumors secondary to HR-HPV infection are diffusely and strongly immunoreactive with antibodies to p16 (Fig. 5.7, eFig. 5.13).29
p53 protein has been shown by immunohistochemistry. LOH studies have shown a similar incidence of genetic abnormalities between these tumors and verrucous carcinoma and well-differentiated conventional-type SCC. It is interesting to note that these tumors showed an increased LOH for a microsatellite marker on the long-arm of chromosome 11 when compared with other variants of SCC, although the finding was not statistically significant. Tumors secondary to HR-HPV infection are diffusely and strongly immunoreactive with antibodies to p16 (Fig. 5.7, eFig. 5.13).29
TABLE 5.4 Verrucous Carcinoma Versus Papillary Squamous Cell Carcinoma | ||||||
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Nonkeratinizing Squamous Cell Carcinoma and Basaloid Squamous Cell Carcinoma
Some SCCs at various sites throughout the body retain a distinctly epidermoid phenotype while lacking cellular maturation and extracellular keratin formation (i.e., keratinization). The cells remain immature in appearance and resemble those of the basal layer of typical stratified squamous epithelium. For that reason, these tumors are termed “basaloid squamous cell carcinomas,” although a variety of names have been used for these tumors when they occur at different sites in the body (e.g., cloacogenic carcinoma when they arise in the anus).30,31,32,33 There has been and remains some confusion as to whether the terms “nonkeratinizing” and “basaloid” are synonymous. As the years have passed, we have come to use the term “basaloid” for a specific histology of nonkeratinizing SCC while acknowledging that there is a spectrum of histologic features for infiltrating nonkeratinizing SCCs (see below).
Basaloid SCCs of the upper aerodigestive tract, as originally described, occur in older individuals, usually in their seventh or eighth decades of life,
and occur predominately in men. First reports of these tumors reported a strong association with tobacco and alcohol use; however, many cases that develop today are secondary to infection by HR-HPV and occur in younger patients than those first presented (many of these tumors we would simply diagnose as nonkeratinizing SCCs).34,35,36,37,38 The tumors show a predilection for involvement of the base of tongue, hypopharynx, and supraglottic larynx but have been noted throughout the entire upper aerodigestive tract. Most patients present at a high stage with nodal metastases. Behavior for these tumors is related to HR-HPV status, with tumors harboring infection (especially those of the oropharynx) behaving better stage for stage than conventional SCCs, whereas those not secondary to HR-HPV infection behave the same or worse than other SCCs.39
and occur predominately in men. First reports of these tumors reported a strong association with tobacco and alcohol use; however, many cases that develop today are secondary to infection by HR-HPV and occur in younger patients than those first presented (many of these tumors we would simply diagnose as nonkeratinizing SCCs).34,35,36,37,38 The tumors show a predilection for involvement of the base of tongue, hypopharynx, and supraglottic larynx but have been noted throughout the entire upper aerodigestive tract. Most patients present at a high stage with nodal metastases. Behavior for these tumors is related to HR-HPV status, with tumors harboring infection (especially those of the oropharynx) behaving better stage for stage than conventional SCCs, whereas those not secondary to HR-HPV infection behave the same or worse than other SCCs.39
 FIGURE 5.7 p16 immunoreactivity is sometimes seen with papillary squamous cell carcinoma and is associated with high-risk human papillomavirus infection. |
The histology of basaloid SCC has been well described. The neoplasms are composed of variably sized nests and cords of basaloid cells (Fig. 5.8, eFigs. 5.14 and 5.15). Larger nests can have central comedoform necrosis (Fig. 5.9, eFig. 5.16). Nuclear palisading can sometimes be seen at the periphery of the nests. Focal cribriforming is often present and glandlike spaces are commonly identified (Fig. 5.10, eFigs. 5.17 and 5.18). The surrounding stroma can appear either hyalinized or somewhat myxoid and can be focally intimately intermixed with the basaloid cells. Adequate sectioning of most cases will reveal at least focal conventional-type SCC (Fig. 5.11, eFigs. 5.19 and 5.20). When overlying epithelium is present, an intimate relationship between it and the tumors can often be identified and high-grade dysplasia is usually seen. Cytologically, the cells have high nuclear to cytoplasmic ratios with dense, hyperchromatic nuclei. A
moderate amount of cellular and nuclear size and shape variability is commonly present. Numerous mitotic figures and apoptotic bodies are often seen (Fig. 5.12, eFigs. 5.21 and 5.22).
moderate amount of cellular and nuclear size and shape variability is commonly present. Numerous mitotic figures and apoptotic bodies are often seen (Fig. 5.12, eFigs. 5.21 and 5.22).
 FIGURE 5.8 Basaloid squamous cell carcinoma. |
When the majority of the features stated above are present, we use the diagnosis of “basaloid SCC.” The is in contrast with the tumors that grow predominately as nests or islands of immature squamous cells but
lack other features of basaloid SCC outlined above. For these tumors, we use the diagnosis of “nonkeratinizing SCC.” In our experience, the vast majority of oropharyngeal and HR-HPV-related SCCs fall into this latter category. Indeed, basaloid SCC is now a diagnosis we use only seldom.
lack other features of basaloid SCC outlined above. For these tumors, we use the diagnosis of “nonkeratinizing SCC.” In our experience, the vast majority of oropharyngeal and HR-HPV-related SCCs fall into this latter category. Indeed, basaloid SCC is now a diagnosis we use only seldom.
 FIGURE 5.9 Basaloid squamous cell carcinoma with comedo necrosis. |
 FIGURE 5.10 Basaloid squamous cell carcinoma with a cribriform architecture. |
Correctly diagnosing basaloid and nonkeratinizing SCC can be challenging with small biopsies. The differential diagnosis may include adenoid
cystic carcinoma (ACC), small cell neuroendocrine carcinoma, and other rare basaloid neoplasms of the minor salivary glands, including basal cell adenocarcinoma. Distinguishing the tumors from salivary gland neoplasms, especially ACC, is sometimes difficult but is very important.
cystic carcinoma (ACC), small cell neuroendocrine carcinoma, and other rare basaloid neoplasms of the minor salivary glands, including basal cell adenocarcinoma. Distinguishing the tumors from salivary gland neoplasms, especially ACC, is sometimes difficult but is very important.
 FIGURE 5.11 Focal keratinizing squamous cell carcinoma. |
 FIGURE 5.12 Basaloid squamous cell carcinoma, high-power image. |
ACC is one of the most common malignancies of the minor salivary glands and will be discussed in the following chapter. While histologically some cases of basaloid SCC can resemble the cribriform or solid variant of ACC, there are both histologic and clinical differences that can help the pathologists distinguish these tumors (Table 5.5). Histologically, ACCs show less cytologic pleomorphism and fewer mitotic figures and should not contain areas of squamous differentiation or dysplasia of the surface epithelium. The presence of nodal metastases virtually excludes the diagnosis of ACC as this tumor rarely metastasizes to lymph nodes. A caveat of this stresses the importance of correct diagnosis at biopsy. A neck dissection is not warranted for patients prospectively diagnosed with ACC.
Basal cell adenocarcinoma is a malignant salivary gland-type neoplasm that arises most commonly in the major salivary glands although some smaller series of these tumors arising in the minor salivary glands have been reported.40,41 The tumors are composed of nests of basaloid cells that may have nuclear and cytologic atypia and may show squamous metaplasia. The nests may be solid or contain multiple tubular profiles. Comedo-type necrosis has also been identified in these cases but is rare. Unlike ACCs, somewhere between 10% and 20% of these neoplasms will metastasize to regional lymph nodes. Basaloid SCCs share many of these features but should show more pleomorphism, overlying squamous dysplasia and conventional-type SCC focally. Cytokeratin 7 immunostaining may
be helpful as the rare cases of basal cell adenocarcinoma that have been stained have shown strong and diffuse reactivity, unlike basaloid SCCs.
be helpful as the rare cases of basal cell adenocarcinoma that have been stained have shown strong and diffuse reactivity, unlike basaloid SCCs.
TABLE 5.5 Basaloid Squamous Cell Carcinomas Versus Adenoid Cystic Carcinomas | ||||||||
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On small biopsy, basaloid SCC can also resemble small cell neuroendocrine carcinoma. This problem is akin to that faced by pathologists when they deal with small, often crushed, bronchial biopsies. Small cell neuroendocrine carcinoma of the upper aerodigestive tract is extremely rare but can occur.42 When it does, it most frequently involves the larynx. The presence of areas of squamous differentiation and surface dysplasia is suggestive of basaloid SCC. Large areas of geographic necrosis and identifiable Azzopardi effect are suggestive of small cell neuroendocrine carcinoma.
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