Head and Neck Cutaneous Squamous Cell Carcinoma Clinical Presentation

A detailed patient history often reveals the presence of one or more risk factors for squamous cell carcinoma (SCC) (see Etiology). The clinician should be obtain at least the following information:

• Existing medical conditions such as xeroderma pigmentosum, or previous history of cutaneous malignancies (basal cell carcinoma [BCC], SCC, sebaceous cell carcinoma, malignant melanoma)
• Immunocompetency of patient (risk factors for human immunodeficiency virus [HIV] infection or acquired immunodeficiency syndrome [AIDS], history of organ transplant, current chemotherapy, immunosuppression, hematologic malignancy [chronic lymphocytic leukemia])
• History of significant sun exposure, occupational exposures (oils, tars, soot)
• Previous history of skin insult or trauma (eg, scars from old burns [Marjolin ulcer]^[72] or vaccinations)
• Family history of skin cancer
• Previous history of benign lesions (eg, actinic keratosis, chalazion); recurrence after treatment of lesion
• Duration for which lesion has been present
• Change in size, contour, or color of lesion - An assessment of the rate of tumor growth is important, as this often reflects the aggressiveness of the lesion.

The initial presentation of cutaneous SCC typically includes a history of a nonhealing ulcer or abnormal growth in a sun-exposed area (see the image below). Similarly, many precancerous lesions (eg, actinic keratosis, Bowen dermatosis) also appear to be related to ultraviolet light exposure. SCC can develop even if the history of sun exposure occurred decades before development of the skin lesion.^[13]

Approximately 70% of all cutaneous SCCs occur on the head and neck, most frequently involving the lower lip, external ear, and periauricular region or the forehead and scalp, with an additional 15% found on the upper extremities (see the following image). Frequently, the presentation is preceded by the presence of actinic keratosis. These precancerous lesions appear as scaly plaques or papules, often with an erythematous base. Actinic keratosis is usually only several millimeters in size and ranges from normal skin color to pink or brown; patients with this condition have an estimated 6-10% lifetime risk of developing skin cancer.

The most common head and neck sites for SCC are the floor of the mouth, the tongue, the soft palate, the anterior tonsillar pillar, and the retromolar trigone. Although most patients with SCC are asymptomatic, symptoms such as bleeding, weeping, pain, or tenderness may be noted, especially with larger tumors. When lesions become palpable masses, symptoms such as a vague persistent sore throat or ear infection occur. Numbness, tingling, or muscle weakness may reflect underlying perineural involvement, and this history finding is important to elicit, because it adversely influences prognosis.^[76] Irritation and/or chronic conjunctivitis may accompany conjunctival SCC, such as in chronic wearers of contact lenses^[77] ; patients may notice a conjunctival mass, which may be enlarging. Ocular symptoms such as decreased vision, diplopia, increasing proptosis, or ocular surface irritation may be associated with eyelid SCC.

Occult nasopharyngeal carcinoma may present long before the tumor is locally detected. In fact, patients rarely present with this mass and usually present with a cervical neck mass due to lymph node metastasis from the tumor. Other signs or symptoms that may call attention to a neoplasm in the nasopharynx are unilateral serous otitis media, nasal obstruction, epistaxis, hearing loss, headache, and involvement of the cranial nerves. Patients with Marjolin ulcer may report a change in the skin (eg, induration, elevation, ulceration, weeping) at the site of a preexisting scar or ulcer. The average latency period is 35 years^[78] ; therefore, the diagnosis requires a high index of clinical suspicion.

Virally induced SCC most commonly manifests as a new or enlarging warty growth on the penis, vulva, perianal area, or periungual region. Patients often present with a history of "warts" that have been refractory to various treatment modalities in the past. A history of previously documented genital human papillomavirus (HPV) infection may be elicited.

The location of papillary SCC determines the symptoms. The size of the lesions ranges from smaller than 1 cm to larger than 5 cm. At any site, this exophytic, fungiform mass usually causes mechanical interference, which brings the lesion to attention of the patient or clinician. For example, a large lesion in the oral cavity may interfere with mastication, it may bleed because of trauma, or it may simply annoy the patient. In the larynx, hoarseness is by far the most common first indication of the neoplasm.

Every patient with suspected squamous cell carcinoma (SCC) should undergo a comprehensive head and neck examination, including the following:

• Location of lesion (eg, eyelid SCC is more common on the lower eyelid)
• Size of lesion
• Character of lesion (smooth/nodular, vascularity, color) – SCC may appear as plaques or nodules with variable degrees of scale, crust, or ulceration
• Presence of ulceration
• Evaluation of subcutaneous tissues (depth of lesion, bony involvement)
• Palpation of preauricular, submandibular, and cervical lymph nodes

In all patients with SCC or suspected SCC, the draining nodal basins should be palpated. If nodes are palpable, a biopsy should be performed using fine-needle aspiration (FNA) or excision. If lymph nodes are clinically negative but the tumor meets high-risk criteria, there are few data available to guide what should be done next. Subsequently, management currently varies with regard to further staging.^[60]

General appearance of lesion

The overall appearance of any skin lesion must be detailed. Of course, the presenting appearance of each cutaneous SCC varies according to the site and extent of disease. In addition to clinical notes, use photography to document the appearance of the lesion(s).

The classic presentation of an SCC is that of a shallow ulcer with heaped-up edges, often covered by a plaque. These lesions are termed erythroplasia (see Definitions and Clinical Terminology) and deserve biopsy. One third of lesions are pure white; they are known as leukoplakia, but only 10% of them are carcinoma in situ or invasive carcinoma.

Surface changes of typical SCC may include scaling, ulceration, crusting, or the presence of a cutaneous horn. Less commonly, the lesion may manifest as a pink cutaneous nodule without overlying surface changes. The absence of surface changes should raise suspicion of a metastatic focus from another skin or nonskin primary site or a different and potentially more lethal tumor such as Merkel cell carcinoma. A background of severely sun-damaged skin, including solar elastosis, mottled dyspigmentation, telangiectasia, and multiple actinic keratoses, is often noted.

Clinically, lesions of SCC in situ (SCCIS) range from a scaly pink patch to a thin keratotic papule or plaque similar to an actinic keratosis. Bowen disease is a subtype of SCCIS characterized by a sharply demarcated pink plaque arising on non–sun-exposed skin (see the first image below). Erythroplasia of Queyrat refers to Bowen disease of the glans penis, which manifests as one or more velvety red plaques (see the second image below).

SCC of the lip usually arises on the vermillion border of the lower lip. It is sometimes predated by a precursor lesion, actinic cheilitis, which manifests as xerosis, fissuring, atrophy, and dyspigmentation. Actinic cheilitis is analogous to actinic keratosis of the skin. SCC on the lip manifests as a new papule, erosion, or focus of erythema/induration. Intraoral SCC typically manifests as a white plaque (leukoplakia) with or without reddish reticulation (erythroplakia). Common locations include the anterior floor of the mouth, the lateral tongue, and the buccal vestibule (see the images below).

Periungual SCC typically mimics a verruca and is frequently misdiagnosed for years as a wart before biopsy. Less commonly, the lesions may resemble chronic paronychia with swelling, erythema, and tenderness of the nail fold; onychodystrophy also may be noted. Periungual SCC is frequently associated with human papillomavirus (HPV).^[79]

Marjolin ulcer appears as a new area of induration, elevation, or ulceration at the site of a preexisting scar or ulcer. The diagnosis of Marjolin ulcer should be considered in any ulcer that fails to heal with standard therapy.

SCC in the anogenital region may manifest as a moist, red plaque on the glans penis; indurated or ulcerated lesions may be seen on the vulva, external anus, or scrotum. Verrucous carcinoma is a subtype of SCC that can be locally destructive but rarely metastasizes. Lesions appear as exophytic, fungating, verrucous nodules or plaques, which may be described as cauliflowerlike. Verrucous carcinoma is further subdivided based on its location in the anogenital region (Buschke-Löwenstein tumor), the oral cavity (oral florid papillomatosis), and the plantar foot (epithelioma cuniculatum).

Invasive SCC involves the epidermis and invades the dermis. The tumors initially appear as skin patches, plaques, and nodules that enlarge and develop central areas of inflammation, induration, and, subsequently, necrosis and oozing.

Size and location of lesion

In addition to the general appearance of the lesion, the size and location of the SCC should be recorded, as both have prognostic and therapeutic importance. For instance, lesions larger than 2 cm and those located on the external ear and lip have been shown to have a higher rate of metastatic spread (see the image below). Additionally, tumor size and location affect the cosmetic and functional outcome of surgical excision. Therefore, reconstructive options should be carefully considered in the assessment of every head and neck cutaneous SCC. Lesions located near critical areas, such as around the eyes, may require additional evaluation by a dedicated reconstructive surgeon before excision.

Up to 14% of cutaneous SCCs exhibit perineural invasion. Evidence of cranial nerve dysfunction on examination should raise concern of significant perineural invasion. The most frequently involved cranial nerves are the facial and trigeminal nerves, underscoring the importance of assessment of facial movement and sensation. Therefore, every patient with head and neck cutaneous SCC should undergo systematic evaluation of cranial nerve function.

Finally, regional lymphatics should be assessed for metastatic spread. Regional metastasis of cutaneous SCC occurs in 2-6% of cases. The risk of metastasis correlates roughly with tumor size and differentiation. The most frequently involved lymphatics include those located within the parotid gland and upper cervical lymph node levels. Investigate regional spread by palpating for enlarged lymph nodes in the head and neck region.

Rarely, cutaneous SCC presents as a parotid or neck mass because of lymphatic spread from an occult cutaneous lesion or remotely treated skin cancer (see image below). The median time from initial treatment to presentation with a parotid or neck mass ranges from 10 to 13 months. Fine-needle aspiration (FNA) biopsy can be of assistance in the evaluation of any mass suspected to represent occult metastasis.

Distinguishing conjunctival SCC from conjunctival intraepithelial neoplasia is difficult on clinical examination alone^[80] ; conjunctival SCC represents a type of conjunctival intraepithelial neoplasia that has either broken through the basement membrane to involve the subepithelial tissue or has metastasized. Epithelial tumors of the conjunctiva are similar to conjunctival intraepithelial neoplasia.^{[81, 82, 83]}

Most SCCs involving the conjunctiva manifest as chronic, unilateral, localized patches of redness or more diffuse conjunctivitis; they can also present as a mass in the interpalpebral fissure at the nasal or temporal limbus with a gelatinous and velvety, papilliform, or leukoplakic appearance. Prominent feeder vessels may be seen. The corneoscleral limbus is the most common location, although the palpebral conjunctiva or cornea may be involved, particularly in the interpalpebral region.

Given its variable appearance, conjunctival SCC may pose a diagnostic challenge as a masquerade syndrome. Patients with an atypical pterygium may have a conjunctival tumor. These patients should be observed much more closely than patients with a classic pterygium. Individuals who are HIV positive and patients with xeroderma pigmentosa are more likely to develop conjunctival SCC, probably because of their diminished immune status. Often, small conjunctival masses are noted on routine eye examinations.

The examination of conjunctival SCC should determine the full extent of the lesion; rose Bengal dye is helpful for this evaluation. In addition, assess any suspicion for intraocular involvement via slit lamp examination, gonioscopy, and echography. Orbital involvement should be investigated with computed tomography (CT) scanning or magnetic resonance imaging (MRI).

Unsuspected ocular surface neoplasia may be present within excised pterygia, and, for this reason, one study recommends the submission of all excised pterygia for histopathological analysis.^[84]

Verrucous carcinoma of the head and neck most commonly occurs anywhere in the oral cavity but most frequently on the buccal mucosa. It is also found in the larynx. Outside of the head and neck region, the anogenital region is a common site. Because of these anatomic locations and because this neoplasm resembles virally induced warts, human papillomavirus (HPV) is frequently implicated in its genesis. Findings from sophisticated molecular studies confirm the viral etiology of many of these lesions.

Identifying high-risk lesions

Advanced-stage cutaneous SCC exhibits an aggressive clinical course with a greater likelihood of recurrence and cervical metastasis (see Prognosis). Therefore, recognition of these higher risk lesions and subsequent treatment by a qualified specialist is critical.

Lesions found on or around the ear have a 5-18% rate of metastatic spread, roughly 3 times the average rate. Those located in the preauricular region are particularly troublesome given their propensity to invade the parotid gland (see the image below). Cutaneous SCC of the lip also shows a high rate of nodal involvement. Therefore, prophylactic neck dissection for select cutaneous SCC located at these sites may be warranted.

As discussed in Prognosis, size is the most important determinant of outcome for patients with cutaneous SCC. Both the depth and width of the lesion influence the potential for recurrence and metastasis. Lesions larger than 2 cm have a higher rate of recurrence (15.2% vs 7.4%) and metastasis (30.3% vs 9.1%) than those smaller than 2 cm. Similarly, lesions that extend to a depth greater than 4 mm have a 45.7% rate of metastatic spread versus 6.7% for those less than 3 mm.

Cutaneous SCC that arises in immunocompromised patients has a high incidence of both initial and recurrent lesions, as well as has the potential for rapid growth and early metastatic spread. Some evidence suggests that these lesions metastasize at a more shallow depth and smaller width than those in nonimmunocompromised patients.

In this section, the following are reviewed briefly in relation to pathology:

• Keratosis
• Atypia and dysplasia
• Pleomorphism, anaplasia, and desmoplasia
• Leukoplakia
• Erythroplasia and erythroplakia
• Metaplasia
• Malignancy
• Carcinoma

Keratosis

Keratinization is the response of the squamous epithelium to physical trauma, which includes not only mechanical trauma but also thermal and chemical trauma. Wherever friction or exposure to other irritating stimuli are present, keratin deposition occurs at the surface. Therefore, skin is keratinized over most of its surface, but mucosal surfaces are selectively keratinized.

The dorsum of the tongue and the hard palate are subjected to masticatory stress, hot foods, noxious industrial vapors, dry air, and other stimuli. Therefore, these areas are always keratinized. Likewise, the linea alba, literally white line, is a horizontal line on both buccal mucosal surfaces. It corresponds to the bite line and is the response to frequent bite trauma of the buccal mucosa in the occlusal plane of teeth. The rest of the head and neck mucosa is not normally keratinized. However, physical trauma produces keratinization, which appears as a white line or patch in the area where the injury took place.

Any area is susceptible to this keratinization. Keratin is frequently seen on the vocal cords, epiglottis, soft palate, and anywhere the mucosa is exposed to physical stimuli.

The white patch is referred to clinically as leukoplakia. Of importance, this patch is not diagnostic of malignancy or even in situ carcinoma. The most abundant keratinization often overlies an entirely benign epithelium. It is reasonable to suppose that this keratinization protects the epithelium from the noxious stimuli and, therefore, no dysplasia has resulted.

Atypia and dysplasia

The 28th edition of Dorland's Illustrated Medical Dictionary, defines atypia as the condition of being irregular or not conforming to type; it defines dysplasia as abnormality of development.^[85] In pathology, alteration is size, shape, and organization of adult cells. Empirically, most pathologists reserve the term atypia for individual cells and dysplasia for the cells and the organization or architecture of a structure.

The term atypia is largely applied with a focus on the nuclear details. Even when the term cytoplasm is invoked, it almost always refers to the size relationship of the cytoplasm to the nucleus, or the nuclear-cytoplasmic ratio. Atypia of an individual cell refers to an enlarged nucleus (ie, an increased nuclear-cytoplasmic ratio), darkening of the nucleus (hyperchromasia), increased lobulation, angulation, or other geometric distortions of the nuclear outline. These phenomena are really just a reflection of increased DNA content (ie, polyploidy). Included in this category of nuclear atypia is the prominence of a nucleolus, intranuclear cytoplasmic inclusions, and abnormal mitotic figures.

Dysplasia is almost always associated with individual cell atypia but not always. In one particular lesion of the salivary glands (eg, low-grade polymorphous adenocarcinoma) the cells are necessarily bland and monotonous, as defined by established criteria for the diagnosis. Only the architecture is polymorphous.

Architectural distortion ranges from hyperplasia, which is simply an increase in the number of cell layers seen at a particular anatomic site, to carcinoma in situ (CIS). This latter term, when used in the context of SCC of the head and neck, is virtually synonymous with severe dysplasia. Squamous CIS can and should be thought of as full-thickness atypia.

For decades, experienced pathologists have used the following trick to determine if CIS or moderate to severe dysplasia is present: The pathologist simply imagines the stroma to be nonexistent and focuses on only the epithelial-cell layers. If they cannot determine the top from the bottom by viewing the epithelium alone, the lesion is CIS, for this is truly full-thickness atypia. If, however elongated basal cells or flattened surface cells are present, these give away the original orientation, and the lesion is downgraded to moderate to severe dysplasia at most.

By convention, head and neck pathologists heavily rely on keratinization and mitotic figures to determine the degree of dysplasia. If a mitotic figure is observed halfway up the epithelial layers to the surface, full-thickness atypia is extremely likely.

Similarly, keratin should not be below the top 2-3 cell layers. Its presence lower than these layers is virtually always associated with full-thickness atypia nearby.

Pleomorphism, anaplasia, and desmoplasia

Pleomorphism is the term used for variance of the size, shape, and staining properties of cells with respect to their neighbors.

Anaplasia is the term applied to the most severe grades of pleomorphism. This term is used when the index cell (eg, the squamous cell) is no longer easily discernible. With anaplasia, the origin, type, and differentiation of the tumor are highly speculative. Simply put, the cells in anaplasia do not resemble their neighbors, and they do not even vaguely resemble any normal differentiated cells.

Desmoplasia is a fascinating phenomenon and an interesting word. Desmo is the Greek prefix for band or ligament, and plasia is the Greek term for molding. What is so intriguing about this term is that desmoplasia has numerous synonyms in medicine, because the ultimate outcome of many pathologic events in the body result in end-stage scarring—that is, a desmoplastic reaction.

The terms, scarring, fibrous deposition, sclerosis, desmoplasia, scirrhous reaction, and collagen deposition are all virtually interchangeable. In addition, other terms are frequently applied, especially with exuberant reactions involving collagen deposition. In essence, both hypertrophic scar and keloid formation are exaggerated desmoplastic reactions. These terms are frequently used to describe squamous cell carcinomas (SCCs) and really indicate a reaction to the tumor or therapy by the stromal cells. Desmoplasia is especially prominent after irradiation.

Leukoplakia

Taken literally, leukoplakia should be restricted to clinical use and not used in pathologic assessments. The term simply refers to a white patch on a mucous membrane that does not rub off. Glycogen and fungi can cause this clinical appearance. However, in most cases, this is the gross correlation to the microscopic finding of keratosis or hyperkeratosis. Keratosis refers to any deposition of keratin on a surface that is not normally keratinized, whereas hyperkeratosis is a somewhat subjective term that refers to excessive keratin deposition on a normally keratinized surface.

Leukoplakia is an indication that something is not right with the underlying epithelium. This something is not necessarily malignancy or even premalignancy. Although leukoplakia may be the first clinical presentation of a neoplastic process, it may also be a simple reaction to trauma, as in callus formation, or part of a mucocutaneous disease, as in some forms of psoriasis. The finding of leukoplakia should alert the clinician to examine the area. After that, the clinician can decide to order biopsy or not on the basis of the clinical setting.

Erythroplasia and erythroplakia

Both erythroplasia and erythroplakia have come into clinical use over the years. Erythroplasia is used far more frequently than erythroplakia; however, strictly speaking, these 2 terms are etymologically different. The 28th edition of Dorland's Illustrated Medical Dictionary defines these terms as follows^[85] : Erythroplasia is a condition of the mucous membrane characterized by erythematous papular lesions, and erythroplakia is a slow-growing, erythematous, velvety red lesion with well-defined margins occurring on a mucous membrane.

As is apparent, the erythroplakia involves observation over time. Practically speaking, the 2 terms refer to red patches. These are more often associated with dysplastic or neoplastic changes than is leukoplakia.

Once again, it is ultimately the clinician's decision to order biopsy or to watch. However, given the association of erythroplasia with neoplastic and preneoplastic change, the threshold to perform biopsy should be lowered in this context.

Metaplasia

Metaplasia is the change of an adult differentiated cell to a different type of an adult differentiated cell that is not normal in that location. In most cases in the head and neck, glandular or respiratory cells are undergoing metamorphosis to squamous cells.

Physical trauma, such as prolonged hot or cold thermal excesses causes metaplasia of the respiratory lining cells to squamous cells. Normal respiratory, ciliated columnar cells of the false vocal cords are not unusually lined by squamous cells instead. The stimulus that precipitates this event is typically known and may be exposure to industrial or natural noxious gases, heated air, or cigarette smoke. These cells are not definitely committed to undergo malignant degeneration. However, this process does suggest that some irritant is causing cellular change; therefore, investigation is merited.

The widely held notion that metaplasia is synonymous with simplification of the epithelium is untrue. Although ciliated, columnar, and mucus-secreting cells that are converting into squamous cells may be simplification, this is not always the case. In fact, chronic reflux with the concomitant exposure of esophageal squamous mucosa to gastric acids and enzymes produces the opposite result. The squamous cells evolve into mucous-secreting cells. Examples of this type of metaplasia occurring in the body are numerous. What the various forms of metaplasia have in common is that the cells change their type to one that is better suited than the former type to deal with the new environment.

Malignancy

Malignancy is surprisingly one of the most loosely defined terms in the field of oncology. Ask any group of medical students, residents, or attending physicians what this term means, and the variety of answers is startling. Given the essential importance of determining what is malignant and what is not simply underscores the need to clarify this term.

The terms metastatic, locally invasive, monoclonal, neoplastic, autonomous, and numerous others have been used to define malignancy. However, tumors can have some but not all of the properties of each type and thus easily refute the usefulness of these terms.

For example, most malignant brain tumors do not metastasize. Conversely, the entity benign metastasizing leiomyoma is an oxymoron if one considers metastases identical to malignancy. Endometriosis is another example in which tissue somehow metastasizes to a site distant from its origin. Therefore, it is best to think of the term malignant as Dorland's Illustrated Medical Dictionary defines it^[85] : (1) tending to become progressively worse and to result in death and (2) having the properties of anaplasia, invasion, and metastasis. The second half of the definition must be tempered with the understanding that not every malignant tumor possesses all of these features.

Therefore, the term malignancy is probably best understood as an empirical or working definition. Malignant tumors are those that continue to produce severe damage.

Carcinoma

Carcinoma is an epithelial malignancy. That is, it is epithelial tissue that causes severe damage. SCC causes local invasion, it becomes ulcerated, and it metastasizes to produce its damage. Basal cell carcinomas are locally invasive, and they become ulcerated, but they only rarely metastasize. Every head and neck surgeon is aware that, despite the lack of metastasis, these lesions can cause death by causing infection or by eroding the brain or other vital structures.

Squamous cell carcinoma (SCC) is an epithelial malignancy with morphologic features of squamous cell differentiation without additional features suggestive of other differentiated tissues. The features of squamous differentiation, observable on routine stained tissues under light microscopy, include one or more of the following: (1) flattened polyhedral, round, or ovoid epithelial cells; (2) intracellular or extracellular keratinization; and (3) intercellular bridges.

If features of spindle cell differentiation, glandular differentiation, or basal-cell differentiation are present with the squamous features just listed, the tumors are named to reflect these distinctive features (see the following image).

The overall architecture is also included in the nomenclature of some select variants of SCC. Papillary carcinomas have cytologic features necessary for the lesions to be referred to as SCCs, but the unusual gross morphologic appearance and the microscopic architecture justifies special subcategorization.

The head and neck possesses more tissue types than any other comparably sized anatomic region. In the head and neck region, salivary glands, squamous epithelium, neural tissue, skeletal muscle, smooth muscle, parathyroid tissue, thyroid tissue, ceruminous glands, sebaceous glands, sweat glands, retinal tissue, corneal tissue, lymphoid tissue and numerous other tissue types are all present in close proximity.

See Histologic Findings.

Squamous cell carcinoma (SCC) is staged according to American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) guidelines, which use the "tumor, node, metastasis" (TNM) classification system.^[58] This clinical staging system used for head and neck cancers is one that allows physicians to compare results across patients, assess prognosis, and design appropriate treatment regimens. The same system is employed for laryngeal tumors. The basic premise of these systems is that smaller cancers with no nodal disease have a better prognosis than a larger lesion with positive neck nodes.

The staging system previously classified tumor stage based solely on tumor diameter and invasion of deep structures (ie, cartilage, muscle, or bone). Along with tumor diameter, the new system incorporates high-risk features and incorporates information about tumor factors that influence prognosis (see Prognosis).Cutaneous SCC of the eyelid is excluded from the updated system.

High-risk tumor features include the following:

• Greater than 2 mm thickness or Clark level IV or higher
• Perineural invasion
• Primary anatomic location on the ear or non–hair-bearing lip
• Poorly differentiated or undifferentiated cellular histology

Primary tumor (T)

The T classification is as follows:

• TX - Primary tumor cannot be assessed (minimum requirements to assess primary tumor cannot be met).
• T0 - No evidence of primary tumor
• Tis - Carcinoma in situ (preinvasive cancer)
• T1 - Tumor 2 cm or smaller in greatest dimension and with 0 or 1 high-risk features
• T2 - Tumor larger than 2 cm but smaller than 4 cm in greatest dimension or with 2 or more high-risk features
• T3 - Tumor larger than 4 cm or involving facial bones (maxilla, mandible, orbit, or temporal
• T4 - Tumor invades deep extradermal structures (ie, extension to other bones, muscle, cartilage) or with perineural invasion involving the skull base

Regional lymph nodes (N)

The new TNM staging system also revised nodal staging. Previously, the system had only had a single N1 level to signify nodal involvement. The new system has 5 levels. The decision to stage patients according to extent of nodal disease was based on significant findings of several studies, both prospective and retrospective, showing that the number and size of lymph node involvement correlated with patient prognosis.^{[86, 87, 88, 89, 90]}

In the new staging system, N1 disease involves a single ipsilateral node 3 cm or smaller in its largest dimension. N2a disease includes cases with a single ipsilateral node greater than 3 cm but less than or equal to 6 cm. N2b refers to those with multiple ipsilateral nodes smaller than or equal to 6 cm. N2c includes cases of bilateral or contralateral involvement less than or equal to 6 cm. N3 disease is reserved for cases with any involved node greater than 6 cm.

The N classification is as follows:

• NX - Regional lymph nodes cannot be assessed (ie, minimum requirements to assess the regional nodes cannot be met
• N0 - No evidence of regional lymph node metastasis
• N1 - Regional lymph node metastases in a single ipsilateral lymph node and 3 cm or smaller in greatest dimension
• N2a - Metastasis in a single ipsilateral lymph node larger than 3 cm but not larger than 6 cm in greatest dimension
• N2b - Metastasis in multiple ipsilateral lymph nodes, none larger than 6 cm in greatest dimension
• N2c - Metastasis in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension
• N3 - Metastasis in a lymph node larger than 6 cm in greatest dimension

In early 2010, Milross et al proposed an alternative nodal staging system (the N1S3), which also stages cutaneous SCC based on the number (single or multiple) and size (< or >3 cm) of lymph nodes involved, as well as incorporates the parotid as one of the regional levels, as follows^[91] :

• Stage I nodal disease refers to those with a single lymph node measuring less than or equal to 3 cm.
• Stage II nodal disease includes cases with a single lymph node greater than 3 cm or multiple lymph nodes less than or equal to 3 cm,
• Stage III nodal disease consists of any patient with multiple lymph nodes greater than 3 cm.

Milross et al’s system was found to have a significant predictive capacity for locoregional control, disease-specific survival, and overall survival in a group of 215 patients and was reproduced on external validation in a cohort of 250 patients.^[91]

Distant metastasis (M)

Distant metastases are staged according to the presence (M1) or absence (M0) of metastases in distant organs or sites outside of regional lymph nodes. This remains unchanged from the previous TNM staging system and is as follows:

• MX - Distant metastasis cannot be assessed (ie, minimum requirements to assess the presence of distant metastases cannot be met).
• M0 - No distant metastasis
• M1 - Distant metastasis

TNM Staging Classification

Stage 0 is equivalent with in situ disease. Disease stages I and II include patients with T1 and T2 tumors, respectively, who have no nodal or distant metastasis (N0, M0). Stage III disease includes T3 cases without nodal involvement (N0) or cases with N1 involvement. Stage IV includes those with T4 disease, or N2 or N3 disease, or distant metastasis (M1). The TNM staging classification is as follows (see also Table 2, below):

• Stage 0 - Tis/N0/M0
• Stage I - T1/N0/M0
• Stage II - T2/N0/M0
• Stage III - T3/N0/M0, T1/N1/M0, T2/N1/M0, or T3/N1/M0
• Stage IV - T4/N0, N1/M0; any T/N2, N3/M0; any T/any N/M1

Table 2. TNM Stage Grouping (Open Table in a new window)