eMedicine - Pathology: Squamous Cell Carcinoma : Article by Gerard Domanowski

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Pathology: Squamous Cell Carcinoma

Article Last Updated: Feb 14, 2007

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.

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.

On initial presentation, more than 90% of cancers of the head and neck are SCCs. In the United States, head and neck carcinomas account for approximately 5% of all malignancies in adults. The percentage is slightly lower than this in women and slightly higher in men. Nevertheless, the low percentage belies the fact that SCC is a major public health problem.

The 2004 report by the American Cancer Society illustrates this point dramatically, as shown in Table 1 below.

Table 1. Estimated Number of New Cancer Cases and Deaths in Both Sexes in the United States in 2004

Note.—The US Census Bureau estimated that the US population was approximately 282,000,000.

The etiology of cancer is a difficult, ill-defined, and incomplete concept. Etiology is not synonymous with cause. Cause implies a condition that is necessary and sufficient to produce a certain result, whereas etiology is literally the study of causes. As such, etiology implies a complex interaction of entities, their introduction, and their interaction with a host to produce a malignancy. This is an important point because it underscores the reality that few etiologic agents are necessary or sufficient to produce a particular type of malignancy. Therefore, a number of etiologic agents are associated with various degrees of risk in the development of SCC of the head and neck.

These risk factors include use of tobacco or alcohol; age; familial or genetic predisposition; nutritional status; chronic irritation; and exposure to industrial products or heavy metals, viruses, or ionizing radiation. Some of these risk factors are discussed in more detail below. These etiologic agents, as determined on the basis of demographic and statistical data, are of limited predictive value in any given individual.

The medical and epidemiologic literature contains numerous reports of the association between carcinomas of the head and neck and use of tobacco, including tobacco inhaled as smoke and the smokeless products, such as snuff and chewing tobacco. Although the association is strong and dose related, the issue is more complex than is usually assumed.

Factors that make assessing the role of tobacco in cancer causation difficult are problems with self-reporting, variations in responses to tobacco and tobacco products among individuals, the complex chemical nature of tobacco and its products, and the presence of confounding risk factors or causes.

Self-reporting is notoriously unreliable; therefore, dose dependency is not as reliable as it may seem at first. Moreover, the fact that some individuals have an impressive tobacco exposure history but never develop malignancy highlights the complex relationship of putative etiologic agents. Conversely, some people develop head and neck cancers and have relatively limited tobacco exposure or none at all.

Both smoked and smokeless forms of tobacco contain considerable numbers of putative carcinogens. Therefore, pinpointing the mechanism of tobacco-induced carcinogenesis is exceedingly difficult and largely speculative.

Finally, smokers are likely to have other risk factors or etiologic agents in addition to their tobacco use. Factors such as poor dentition, ethanol use, and poor nutrition are associated with tobacco use. Even more difficult to remove from consideration is the person's age, which is inextricably linked with the years of tobacco use. Age may be one of the most important risk factors for many malignancies.

An association between alcohol use and human cancer has been observed since 1910, when it was noted in Paris that 80% of patients with esophageal carcinomas were heavy drinkers. Even then, confounders were similar to those noted for tobacco. The fact that absinthe, a fermentation product of wormwood (Artemisia absinthium) accounted for much of the alcohol consumed at that time in Paris suggests a possibility that other substances may have contributed to this association.

Nevertheless, the incidence of head and neck carcinoma is undoubtedly associated with the use of ethanol. In 1998, the International Agency for Research on Cancer (IARC) of the World Health Organization (WHO) concluded that evidence was sufficient to show that alcoholic beverages are carcinogenic in humans.

Both case-control and cohort studies have shown an association between alcohol and carcinomas of the oral cavity, oropharynx, and larynx. In some studies, the use of both ethanol and tobacco increased the risk of head and neck cancer 100-fold.

Head and neck cancers have age-related patterns similar to those of many epithelial malignancies, with rising rates of occurrence closely linked to increasing age. In the United States, the medial age at which patients present with oral cancers is 63 years.

Although data show that men and women as young as 25 years can die from oral and/or pharyngeal cancer, the mortality rate steadily increases in subsequent decades.

Genetic profiles are associated with an increased, albeit slight susceptibility for oral carcinoma. Patients with xeroderma pigmentosum, polydysplastic epidermolysis bullosa, or Bloom syndrome certainly are at increased risk for oral cancer. These conditions are fairly uncommon and not major public health issues; however, to the individual and family they are rightfully of paramount concern.

Familial associations of head and neck cancers have been investigated. Studies have demonstrated many cases of head and neck cancers, and a case report describes identical twins with oral carcinoma.

However, the familial cases highlight the problem of assigning a role to genetics versus environmental factors to the development of SCC.

The role of a single factor such as nutritional status is difficult to ascribe with certainty. Diet is often associated with numerous confounders, such as tobacco exposure, lifestyle-related viral exposure, alcohol use, and oral hygiene. However, despite this difficulty, some conclusions are fairly cogent.

Vitamins A, D, and E have all been suggested for the prevention or treatment of carcinomas. In addition, increased fruit consumption has shown an effect in preventing malignancy. The role of fruits in the diet may be related to more than simply their vitamin content.

To date no significant, prospective, and comprehensive study has been conducted to evaluate the combined and perhaps synergistic effects of diet, tobacco use, and ethanol consumption.

Recent concern over the use of alcohol-containing mouthwash should be addressed. This is a fascinating issue, and some reports suggest that the frequency and duration of the use of such mouthwash may be associated with an increased risk of oral SCC. This finding certainly deserves further study.

Numerous studies have been undertaken to ascertain the risks of head and neck cancer associated with various occupations and exposures. Studies have demonstrated that individuals working in the heavy-metal, textile, or electronic industry or those exposed to asbestos or wood dusts have increased cancer risks. However, these studies were often small surveys, and, in some cases, subsequent studies did not show increased risks.

Precisely defining the role of poor oral hygiene in SCC of the oral cavity is difficult; however, they are associated. Poor dentition increases the risk of oral carcinoma, with the use of tobacco and ethanol. Some studies have demonstrated an association with ill-fitting dentures with oral cancer. However, other investigations have not revealed a similar association.

Overall, the consensus among oral-cancer investigators is that poor dentition and poor oral hygiene appear to increase the risk of oral SCC.

One of the most exciting developments in oncology within the last 20 years is the investigation of viral oncogenesis. The explosion of research into this topic was the result of 3 major events occurring in a short span: (1) the invention of the polymerase chain reaction (PCR) in 1983 followed by tens of thousands of reports of this technology used in its first 20 years, (2) the observation of unusual tumor types in association with newly identified and unusual viruses (eg, Kaposi sarcoma and HIV, nasopharyngeal carcinoma (NPC) and Epstein-Barr virus (EBV), and hepatitis virus and hepatocellular carcinoma), and (3) improved better understanding of the molecular biology of cancer.

In the arena of head and neck cancer, EBV and human papilloma virus (HPV) are both prominent. High antibody titers to EBV capsid antigen are observed in more than 80% of patients with nasopharyngeal carcinoma.

The geographic distribution of EBV and nasopharyngeal carcinoma in those regions impressively overlap with a high prevalence of EBV infection that corresponds to high incidence of nasopharyngeal carcinoma.

HPV has been demonstrated to be a cause of uterine cervical SCC. Increasing evidence suggests a similar role for HPV in the development of head and neck SCC. Studies of patients without the commonly assumed risk factors for lung SCC (ie, tobacco use, radiation or asbestos exposure) have revealed a previous history of laryngeal papillomatosis and the same type of HPV present in both the laryngeal papillomata and the lung malignancy. Mounting numbers of publications are revealing a role of HPV in the genesis of SCC of the head and neck.

PCR and in situ hybridization have been used to ascertain the role of the various types of HPV in development of SCC of the head and neck. Nearly 100 types of HPV have been identified, and these have been classified as high or low risk with respect to their potential to cause malignancy. Original investigations of this DNA virus and cancer focused on uterine cervical cancer and, to a lesser degree, cutaneous and genital carcinomas.

Evidence now suggests that high- or low-risk HPV in 1 anatomic location may not neatly fit the same category in other anatomic locations. As an example, verrucous carcinomas are associated with HPVs in 30-60% of cases examined, depending on the study. When these are found in the larynx, HPV6 and HPV11 are frequently identified, whereas in the uterine cervix, these viruses are infrequently found and classified as low risk.

External-beam radiation has been used to treat a variety of diseases, such as tonsillar hypertrophy, acne, thyroid disease, and laryngeal papillomatosis.

Laryngeal cancers have been statistically associated with previous radiation. Patients treated with radiation for laryngeal carcinoma are well known to develop metachronous carcinomas years later.

Location of SCCs

SCC of the head and neck possesses unusual features not universally found in carcinomas in other anatomic sites.

SCC is a field-defect phenomenon. Although this is also true of transitional-cell carcinoma of the urinary bladder, it is not the rule for malignant degeneration in all body sites. Simply defined, field defect means that, if dysplastic changes occur in 1 location of an organ or body site, other locations in the same organ are likely to have dysplastic changes. The implications of this phenomenon can be profound. For instance, mild dysplasia in 1 region of the buccal mucosa may be associated with frankly invasive carcinoma only millimeters away.

An invasive carcinoma of the soft palate may be completely excised, in that the margins are free of morphologically recognizable neoplasm. However, the patient may present a year later with a carcinoma of the hard palate. This occurrence does not indicate that the margins were misread but that field-defect lesions are associated with skip lesions.

In this context, the clinician must realize that the pathologist's evaluation of the margins, eg, "free of malignancy or significant dysplasia" or "malignancy completely excised," means that the surgeon did not cut across dysplastic tissue. A premalignant lesion may be still in the patient only 2 mm away from the excisional margin. This knowledge becomes important given the complex nature of the anatomic structures in the head and neck. Wide margins are not always an option. Although a skin lesion of the shoulder may justify 2-cm margins, a "generous" margin of the maxillary sinus may lead to an orbital exenteration.

A parotid tumor may require a decision between close margins or loss of the facial nerve. Dr Charles Vaughan in Boston inculcates his otolaryngology and pathology residents with the knowledge that "SCC of the head and neck is a disease of millimeters." This statement is undeniably true, and a field-defect phenomenon that occurs where a structure must be conscientiously preserved makes oncologic therapy in this area notoriously hazardous.

Another consideration with regard to SCC of the head and neck is that this relatively small region has numerous subdivisions, which authors define in different ways. Some divide them by gross anatomic features, some by histologic barriers, and some by embryologic origins. These divisions are valid for empirical reasons.

Each area has its own peculiarities with regard to etiology, likelihood of malignancy, surgical approach, other therapeutic options, and prognosis. To consider each one individually would be exhaustive, and the literature in the general domain covers these in sufficient detail. In this article, subdivisions are considered only when the nuances of that region illustrate an important teaching point.

Definitions

For purposes of discussing the head and neck, mucosa, a widely used term, refers to the membranous lining protecting the oral cavity, oropharynx, nasopharynx, larynx, and laryngopharynx. The lining is composed of the epithelium covering the surface and the underlying stroma, and (where appropriate), the muscularis mucosae.

The critical anatomic barrier is the basement membrane. This is the layer of collagen and glycoproteins directly beneath the inferior layer of the epithelium and the connective tissue stroma. A breach in this structure by dysplastic epithelial cells is the sine qua non for invasive carcinoma.

Epithelial cells line the surfaces of the body. Categorization is based on the number of layers and on the morphology of the most superficial cells.

Squamous epithelium usually consists of 5-7 cell layers. The basal cell layers are elongated cells arranged so that the long axis of the cell is perpendicular to the basement membrane. In normal epithelium, the basal cell layer, and perhaps the one directly above it, are the only layers engaged in active division and proliferation. For this reason, mitotic figures are the norm in the basal and parabasal layers. Mitotic figures above this level are of increasing concern given their proximity to the surface layers.

As one proceeds upward toward the surface layer, the cells take on an increasingly ovoid to round shape. By midway, the cells are approximately round. Ascending above the midway portion, one sees that the cells begin to assume an elongated shape. This time, however, the long axis of the cell is parallel to the basement membrane, which means it is also parallel to the surface. Finally, at the surface, the epithelium is completely flattened and therefore the ideal shape for complete coverage of the body.

One must understand that epithelium is avascular. Therefore, nonirritated, nontraumatized epithelium should not bleed. This is true for SCC in situ as well. By definition, CIS does not break through the basement membrane; therefore, blood vessels are not exposed. This being the case, a previously dysplastic lesion that begins to bleed is a cause for concern.

The stroma underlying the squamous or respiratory epithelium of the head and neck varies by anatomic site. In some areas, voluntary (striated) muscle (eg, tongue, true vocal cord) is present. In others, no striated muscle but abundant mucous glands (eg, false cord) is present.

With some exception of the cartilaginous tissues, all locations have lymphatic channels, blood vessels, proteoglycans, and neural elements in common. The vascular channels, lymphatic and blood vessels, and nerves allow for rapid and widespread dissemination as soon as these structures are invaded. Furthermore, the stromal matrix offers little resistance to the spread of the tumor into these structures.

The stroma of the Waldeyer ring is markedly different from that of any other in the body, including stroma in other head-and-neck sites. The Waldeyer ring can be envisaged as including the base of tongue, palatine tonsils, soft palate, and pharyngeal tonsils (adenoids). Here, the epithelium does not have a clear basement membrane, and the epithelial cells intermingle with the dense lymphoid tissue in these areas. The stroma does have blood vessels, nerves, or lymphatic, but the abundance of lymphoid tissue largely obscures these structures on routine histologic examination. Invasion of these structures happens early, as no natural barrier exists between the epithelium and stroma. That is, no basement membrane is present.

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.

Dorland's Illustrated Medical Dictionary, 28th edition, defines atypia as the condition of being irregular or not conforming to type, and it defines dysplasia as abnormality of development; 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 almost always is 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 half way 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 this is virtually always associated with full-thickness atypia nearby.

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, ie, 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 SCCs and really indicate a reaction to the tumor or therapy by the stromal cells. Desmoplasia is especially prominent after irradiation.

Clinical terms related to SCC

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.

Both of these terms 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. Dorland's Illustrated Medical Dictionary, 28th edition, defines these terms as follows: 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 latter term 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 pre neoplastic change, the threshold to perform biopsy should be lowered in this context.

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 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.

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 Medical Dictionary defines it: (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 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 metastasize only rarely. 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.

SCC in situ

The topic of SCC in situ was mentioned in Atypia and dysplasia above. SCC in situ is the correct nomenclature for full-thickness atypia of the squamous cells without invasion by any tumor cells beyond the basement membrane. This collective atypia of the cells, being full thickness by definition, results in architectural distortions. Architectural distortion of a normal biologic structure is, again, by definition, dysplasia.

From a consideration of the anatomy and this definition, 2 corollaries follow: (1) Without invasion, the nerves, lymphatics, and blood vessels are not in contact with the tumor and therefore, CIS does not metastasize. (2) Full-thickness atypia must demonstrate atypia that includes the surface.

The second point is of clinical importance. The surface atypia of SCC in situ often has clinically identifiable anomalies. It may appear as leukoplakia because of excessive keratin. It may result in irregular surface contours that may be more or less optically reflective than the surrounding mucosa. This change results in pale, dull, shiny and/or irregular surface features. The cells also may not absorb certain vital stains in the same manner as the normal mucosa. This is why various mouth rinses containing toluidine blue or iodine solutions have been used, with varying degree of success, to target areas for biopsy.

The most important issues to consider with respect to SCC in situ of the head and neck are the following: (1) SCC in situ may develop into invasive SCC. (2) Given the concept of field defect (see Location of SCCs above), frankly invasive carcinoma in proximity frequently accompanies SCC in situ.

One final fact is absolutely essential for the clinician to appreciate. Not all invasive SCCs go through a progressive cycle of dysplasia to in situ carcinoma to invasive carcinoma! This is of extreme importance because a normal-appearing surface may hide de nova invasive SCC.

Invasive SCC

Invasive SCC is simply a malignancy of squamous epithelium that has invaded beyond the basement membrane. Of note, invasive nests of malignant squamous epithelium often surround themselves with a material similar, if not identical, to basement membrane. This is because the cells can still produce the necessary biomolecules that create the basement membrane, or they can induce the stroma to contribute to the basement membrane. This ability does not indicate lack of invasion. Breaching of the normal infrabasaloid basement membrane defines invasive SCC.

The dangers of invasive SCC are numerous. First, the cells have access to structures that allow them to travel to distant sites. Lymphatics, blood vessels, and nerves are ideal conduits. Second, they can erode into vital structures and cause pain, paresthesias, hemorrhage, vocal changes, or obstructive phenomenon. Third, surgery is complicated because individual cells or small clusters of cells may lie beyond what may appear to be a free margin. Fourth, selecting the ideal therapeutic option is difficult. One is never sure if lymph-node dissection of the tumoral drainage area or if irradiation to this area is prudent. Microscopic metastases cannot be detected by clinical or radiologic means. Fifth, depending on the location of the tumor in the head and neck, the natural barrier to explosive invasion and distant metastases may be limited. As an example, the tongue is rich in nerves, lymphatics, and blood vessels.

Therefore, invasive tongue tumors have many routes to spread widely. In addition, the rich vascularity guarantees an abundant supply of oxygen and nutrients to support rapid growth. Last, the tongue musculature has evolved to produce motion in all directions and thus effectively move the tumor to distant sites.

When dealing with SCC, the pathologist must inform the clinician of several parameters.

Many pathologists accept the subjective nature and use this simple rule: If the lesion is obviously malignant but takes considerable time to determine that it is squamous in origin, it is classified as poorly differentiated. If the lesion demonstrates obvious squamous differentiation but a prolonged search for atypical cells or atypical mitotic figures is necessary, the lesion is classified as well differentiated. All other lesions are moderately differentiated.

One must remember that a well-differentiated tumor may metastasize with moderately or poorly differentiated nests. Likewise, a well-differentiated SCC in a lymph node does not mean that the primary is also well differentiated. In addition, therapy affects the degree of differentiation. A poorly differentiated SCC of the buccal mucosa treated with irradiation or chemotherapy that produces an incomplete response may demonstrate well-differentiated carcinoma in its wake.

The gross appearance of SCC varies by location. Overall, it is usually a firm, elevated, or umbilicated mass that often is ulcerated. With ulceration, supervening infection is common.

The histologic appearance of a usual invasive SCC varies with the degree of differentiation. In common to all are the following:

Spindle-cell carcinoma

This morphologically deceptive and unusual tumor has been referred to as spindle-cell carcinoma, carcinosarcoma, spindle-cell SCC, or sarcomatoid carcinoma. All of these terms have distinct disadvantages. Carcinosarcoma is a different tumor with both malignant epithelial and malignant mesenchymal elements. Use of this term to mean a spindle-cell tumor with exclusively epithelial elements on immunoperoxidase testing is never justified. Spindle-cell SCC is an oxymoron; the word squamous is derived from the Latin for scale and implies a plate and not a needle or spindle shape. Sarcomatoid carcinoma is etymologically a good term, but mistyping, miscommunication, and poor coding have led to patients being informed that they have a sarcoma, which spindle-cell carcinoma certainly is not. Therefore, the preferred term is spindle-cell carcinoma.

The lesion is a polypoid, exophytic, or fungating mass that occurs in head-and-neck sites (in order of decreasing frequency): larynx, oral cavity, hypopharynx and pyriform sinus, sinonasal tract, and oropharynx.

Surface ulceration is common with these tumors. As with any ulcerated lesion, these are likely to be infected and therefore may exude pus or contain abscess formation.

On histology, one may see spindle cells, which are elongated cells with central, elongated nuclei. These are arranged in entangled fascicles and intertwining bundles. The degree of hyperchromasia, enlarged nuclear to cytoplasmic ratio, mitoses and pleomorphism are strongly suggestive of a leiomyosarcoma or a fibrosarcoma.

Not infrequently, foci of a storiform pattern may be seen; these may resemble findings of a malignant fibrous histiocytoma. Vascular structures are occasionally associated with the tumor. However, this is not to be confused with an angiosarcoma, as vessel-lining endothelial cells do not display atypia. The stroma may be heavily collagenized, presenting a hyalinized appearance or, at the other end of the spectrum, the stroma may be loose and myxoid. Multinucleated giant cells occur at times and, in the setting of hyalinized collagen, which resembles osteoid; confusion with an osteogenic sarcoma is a pitfall to be avoided.

Simply having knowledge that tumors such as spindle-cell carcinoma exist should eliminate the danger of a missed diagnosis. Two key procedures should be followed to ascertain if one is dealing with a true mesenchymal neoplasm or an epithelial malignancy mimicking a sarcoma. The easiest, quickest, and least expensive method is to examine the surface epithelium overlying the neoplasm. If one sees a conventional SCC with a gradual transition into elongated cells as one looks deep into the stroma, special studies are not necessary. The search for these intermediate cells, ie, ovoid-to-shortened versions of true spindle cells, should be the first step when one sees a spindle-cell malignancy in the head and neck.

If a transitional region is not present or not identified, spindle-cell carcinoma is not ruled out. In this case, immunoperoxidase testing is useful. However, some keratin stains of the spindle cells are not always positive. Therefore, the best method is to perform a battery of keratin stains. AE1/AE3 and CAM 5.2 are particularly useful.

Surgery is the preferred method of treatment where anatomically feasible. Despite its odd appearance, the behavior of this tumor is about the same as that of conventional SCC of the same stage.

Basaloid SCC

Basaloid SCC is less common than conventional SCC of the head and neck. It is considerably more aggressive than unqualified SCC, with a tendency to involve the tongue base, supraglottic larynx, the pyriform sinuses, esophagus, lungs, anal region, and uterine cervix. This reputation for aggressive behavior is well earned in that, aside from widespread local invasion at the time of presentation, many patients have local metastases when the lesion becomes apparent.

Men are 4 times more likely than women to have this cancer, and most patients are aged 40-70 years.

Almost all basaloid SCCs have regions with conventional SCC. In addition, they have a follicular or lobular pattern of invasion, with peripheral, slightly elongated, palisaded cells surrounding each lobule. On serial sections, these follicles are interconnected. The lobules often contain central comedo necrosis with visible necrotic material. At other times the central material completely "drops out," giving a pseudoglandular appearance. Of interest is that a hyaline basement membrane–like material is occasionally present in the center of these islands. Because the islands have an architecture of interlocking masses similar to that seen in adenoid cystic carcinoma, the addition of these eosinophilic regions sometimes makes this tumor hard to distinguish from adenoid cystic carcinoma.

Basaloid SCCs are usually treated with surgical techniques, but the 2-year mortality rate is still 30-40%. Increasing evidence suggests that HPV is involved in the genesis of at least some of these lesions. Furthermore, HPV-positive basaloid SCCs may be less aggressive than HPV-negative basaloid SCCs. In fact, some oncologic pathologists contend that HPV-positive basaloid squamous cell carcinoma is less aggressive than any other type of SCC in the same anatomic location.

Verrucous carcinoma

As the name suggests, verrucous carcinoma is a lesion with a gross appearance of a verruca or wart. Verrucous carcinomas are often immense in size at presentation. Despite their size, however, pure forms of verrucous carcinoma rarely, if ever, metastasize.

The tumors are indeed carcinomas in that they are locally destructive. However, they are extremely well differentiated SCCs. In cytologically terms, they do not possess any of the qualities that one usually associates with malignancy. They have no increased nuclear-to-cytoplasmic ratio, hyperchromasia, increased number of atypical mitotic figures, or pleomorphism. Therefore, a deep, large biopsy sample is required to examine the specimen for the necessary diagnostic criteria of verrucous carcinoma, ie, the architecture. The architecture is that of a broad, pushing, and expansile epithelial lesion that extends into the stroma. Variably intense infiltration of mononuclear inflammatory cells at the interface of the tumor with the stroma is always present.

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, HPV is frequently implicated in its genesis. Findings from sophisticated molecular studies confirm the viral etiology of many of these lesions.

The most important consideration in diagnosing verrucous carcinoma is that an unknown percentage of these lesions contain a focus or foci of standard SCC. When this is found, the neoplasm has the potential of conventional carcinomas to metastasize. Given the large size of verrucous carcinomas on presentation, the entire specimen is not examined histologically every time. This practice leads to occasional underdiagnosis of areas of conventional SCCs. Therefore, the pathologist must adequately sample all putative verrucous carcinomas to rule out SCC of the usual type.

Verrucous carcinoma is effectively treated by means of surgical excision. Interest in chemotherapy and radiotherapy to treat this lesion increases from time to time.

Papillary SCC

Papillary SCC is uncommon but certainly merits discussion because of the confusion it may cause the pathologist and surgeon. Papillary or exophytic lesions with full-thickness atypia, ie, SCC in situ, and/or frankly invasive SCC as a component have been reported in many locations in the body. These include the skin, uterine cervix, and even the eye, as well as the larynx, oropharynx, nasal septum, and nasopharynx.

Papillary SCCs have been reported in both sexes and in patients aged 30-80 years. The mean age of presentation is in the 60s, and women are affected less often than men.

The lesions range from <1 cm to >5.0 cm. The location determines the symptoms. 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.

On histology, in situ or invasive papillary SCCs have similar architectures. They contain benign, fibrovascular cores with overlying squamous epithelium. The epithelial layer may be keratinizing or nonkeratinizing and, with in situ lesions, full-thickness atypia is present.

As usual, this atypia manifests as an increased nuclear-to-cytoplasmic ratio, hyperchromasia of the nuclei, angulated nuclei, various degrees of pleomorphism, increased mitotic figures (especially above the basal layers), and atypical mitoses. In addition, an unusual type of cellular atypia, koilocytotic atypia, is present. Koilocytotic atypia is defined as nuclei with perinuclear halos where the nucleus itself is twisted with bilobed to multilobed outlines and where indentations of nuclear contour are frequent.

This particular form of cellular distortion is well related to HPV infection of the cells. What is interesting about this koilocytotic atypia is that it is not expressed in all cells of papillary SCC. In fact, it is seen in fewer cells than it is in benign laryngeal papillomatosis.

If the lesion is of the in situ variety, full-thickness epithelial atypia is observed without an invasive component. This is the same situation as in conventional SCC in situ. The invasive variety demonstrates frank stromal invasion. This component is indistinguishable from any other form of invasive SCC.

Papillary SCC does present a unique difficulty to the pathologist and surgeon. The very architecture of this neoplasm leads to sampling errors. The base of the lesion is often not represented in the biopsy sample, or the histologic technicians do not cut them thoroughly enough. These situations lead to potential false-negative results for an invasive component. It is absolutely necessary to evaluate the epithelial and/or stromal interface of the entire lesion to rule out invasion. Papillary lesions always present a clinical differential diagnosis rather than a confident single diagnostic entity.

However, the histologic criteria for the main lesions in the clinical differential diagnosis are rigid. This clarity should enable the pathologist to make an unequivocal diagnosis in most cases.

The 3 main entities in the clinical considerations with papillary epithelial lesions are (1) benign squamous papilloma, including those associated with adult and juvenile laryngeal papillomatosis; (2) papillary SCC, in situ or invasive; and (3) verrucous carcinoma. Benign squamous papilloma has a fibrovascular core and may occur in the same age ranges and anatomic locations as those of papillary SCC. However, the epithelium itself should allow for easy distinction by the pathologist. Although epithelial atypia, especially koilocytotic atypia, may be present in benign squamous papilloma, it is not widespread and never of the degree seen in papillary SCC in situ. The invasive variant of papillary SCC is not to be confused with benign lesions. Any unequivocal stromal invasion by malignant epithelium, defines the lesion as a carcinoma.

Verrucous carcinoma is also an exophytic mucosal lesion that affects the same anatomic areas and age groups as does papillary SCC. Verrucous carcinoma may demonstrate epithelial atypicality, including koilocytic atypia; however, the atypia is mild. In fact, the cytologic picture of verrucous carcinoma is that of bland epithelium rather than that seen in conventional or papillary SCC. Papillary SCC may have keratinization on the surface, but it is never as thick or as widespread as that of verrucous carcinoma. Finally, verrucous carcinoma invades with broad pushing fronts, not the thinned, stabbing edges, small nests, or individual cells seen in papillary SCC.

The treatment of papillary SCC is excision with free margins. This is true for both the in situ and the invasive types.

Mucoepidermoid carcinoma

Although mucoepidermoid carcinoma is a neoplasm of the salivary glands, it occurs in most of the locations in the upper aerodigestive tract where SCCs and their variants occur. This is true because the head and neck is an area rich in mucous glands from which this tumor arises.

Mucoepidermoid carcinoma occurs over a wide age range, including the pediatric population. Therefore, although it most commonly is seen in those aged 20-60 years, mucoepidermoid carcinoma should never be ruled out as a possibility clinically on the basis of the patient's age alone.

As the name implies, mucoepidermoid carcinoma is a malignant epithelial neoplasm with both mucus producing cells and epidermoid (ie, squamous) cells. These 2 cell types are present in various tumors in different proportions. The ratio of these cell types is the criterion for grading the malignancy. The higher the percentage of squamous cells, the higher the grade of the tumor. Technically, a third cell type, the intermediate cell, is also present in mucoepidermoid carcinoma. The cytologic description of these cells is inconsistent and somewhat vague. They are of theoretical interest only in terms of therapy and prognostication.

The grade is of particular interest because the correlation between behavior and grade is fairly good. Low-grade tumors are slow growing, and unless they are ulcerated and superinfected, they are uncomfortable but painless. High-grade tumors are rapidly growing masses that do produce pain with or without ulceration. Intermediate-grade tumors are slightly more aggressive than low-grade tumors but have a growth rate closer to that of low-grade tumors than that of high-grade tumors.

At present, therapy for all 3 grades includes surgery. Low- and intermediate-grade lesions are initially treated more conservatively than are high-grade mucoepidermoid tumors, but margins are still made wide enough to ensure reasonable success in complete resection. Neck dissection is not necessary if the lesion is low or intermediate grade unless clinical or pathologic findings are highly suggestive of metastases to the regional nodes. On respective review, this situation includes fixed, firm, and enlarged neck nodes or unequivocal lymphatic invasion by the main tumor. Many advocate postoperative radiation therapy, particularly for intermediate- or high-grade tumors.

High-grade tumors are initially treated with surgery; however, wide resection usually includes margins that are more generous than those obtained with lower-grade lesions because these tumors frequently extend deeper than what their clinical appearance might suggest, even when observed during surgical examination under anesthesia. Therefore, removal of the facial nerve is likely necessary with high-grade parotid-based lesions. In addition, because of the increased rate of metastatic disease with high-grade mucoepidermoid tumors, neck dissections are frequently included in the surgical procedure. Finally, postoperative radiation is usually given to the tumor bed in cases of high-grade mucoepidermoid tumors.

Although mucoepidermoid tumors preferentially metastasize to the regional lymph nodes of the neck, they also frequently metastasize to distant sites by the time the disease is diagnosed.

These sites are most frequently the lungs, bones, skin and subcutis and often at distal sites.

Nasopharyngeal carcinoma

The nasopharynx is the part of the pharynx bounded superiorly by the skull base and sphenoid bone, inferiorly by a horizontal plane at the level of the palate, laterally by the superior constrictor muscles, anteriorly by the nasal cavity through the choanae, and posteriorly bounded by the prevertebral fascia.

NPC is one of the most interesting neoplasms of the head and neck for many reasons, as discussed below.

The most frequent site of origin is the fossa of Rosenmüller. This is a structure anterior and superior to the entrance of the eustachian tube. It is basically an outpouching of nasopharyngeal mucosa between the skull base and the muscular layers of the nasopharynx.

In more than 50% of cases studied by means of radiologic investigations, the fossa is deeper than 10 mm, and the opening is less than 5 mm.

These features make the area difficult to examine, and blind biopsy is often preformed because of suspected malignancy during an investigation for an occult primary carcinoma.

NPC arises from an area in the Waldeyer ring, and that characteristic alone places it in an unusual category of carcinomas. The epithelium of this immunologically protective ring is histologically distinct from that of other regions of the head and neck, and tumors from this area differ in etiology, appearance, and behavior from other tumors originating elsewhere.

The epithelium of the Waldeyer ring epithelium is intimately associated with the underlying mononuclear inflammatory cells. This means that, architecturally, no sharp distinctive barrier is observed between the epithelium and the lymphocytes in the vicinity. The lining epithelial surface does not abruptly stop in a palisading basal layer at a stromal interface. Rather, the epithelial cells and lymphocytes intermingle. In addition, the mucosa of the Waldeyer ring is not the planar, flat surface seen throughout much of the head and neck area; instead, the surface dives into deep crypts and involutions. This knowledge is clinically important because it adds to the difficulty of early detection of malignancy in the region with the anatomy of the fossa of Rosenmüller.

Occult 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.

The etiology of this tumor is of special interest as well. Multiple risk factors or causes of this neoplasm have been identified. Geographic location, genetic factors, dietary factors, and viral association are all linked to cases of NPC.

The incidence of NPC is increased in China, especially Southeast China, as well as in Taiwan, Hong Kong, and Singapore. The incidence of NPC in the Southern Chinese population is approximately 30 per 200,000 population.

Northern Canadian and Greenland indigenous peoples also have an incidence of this condition higher than that of the general population. The incidence of NPC among Western people of Caucasian descent is approximately 1 per 200,000 population. The incidence is higher in parts of Central Africa than in areas of Europe, South America, North America, and Australia. These areas in Africa correspond to areas where the prevalence of EBV infection is high. This virus is seriously implicated in the causation of these unusual neoplasms.

However, it is not the only reason because the incidence is also higher in African Americans than in white Americans. This observation implies a genetic component.

The genetics of NPC have been studied in some detail. The histocompatibility locus human leukocyte antigen (HLA)-A2 may be a marker for susceptibility to this tumor. Other loci also being considered include HLA-B17 and HLA-Bw46.

NPC most frequently affects individuals aged 40-60 years. In African Americans, the disease peaks in those aged 10-20 years. In some African populations, NPC is responsible for approximately 15% of childhood malignancies. In fact, in the Sudan, it is the most common malignancy of children.

Dietary factors are also of particular interest. Nitrosamine-rich fish is a large part of the diet in many regions where NPC is prevalent. This diet is by no means universal, it does not seem to explain the sexual distribution of the disease, and it is not as compelling as the association of EBV with this malignancy.

EBV is a DNA-containing herpes virus that has been implicated in at least 5 distinct malignancies: endemic Burkitt lymphoma, NPC, Hodgkin disease, T-cell lymphoma, and immunoblastic lymphoma. In the case of NPC, malignant epithelial cells harboring EBV have been demonstrated on in situ hybridization, PCR tests, immunohistochemical analysis, and ultrastructural studies.

In summary, the etiology of NPC is complex, but the role of EBV does appear to be prominent at this point.

Histopathologic characterization

The histopathologic characterization of this interesting neoplasm also merits recognition as one of the more complicated and controversial in medical history. Although the 1991 classification of the World Health Organization (WHO) is now universally recognized, this lesion has been extensively recategorized and renamed throughout its history. The terms Schmincke tumor, Regaud tumor, keratinizing SCC WHO type I, nonkeratinizing carcinoma WHO type II, undifferentiated carcinoma of nasopharyngeal type III, and lymphoepithelioma have all been applied to its various manifestations.

The current system has been simplified as follows: (1) SCC (keratinizing SCC) or (2) nonkeratinizing carcinoma, which is subdivided as (a) differentiated or (b) undifferentiated (undifferentiated carcinoma of nasopharyngeal type).

This type of nasopharyngeal tumor is not morphologically distinct from the conventional SCC with keratinization occurring anywhere else in the body. As elsewhere, keratinizing SCC is a dysplastic, invasive epithelial malignancy with increased mitotic figures, atypical mitoses, an increased nuclear-to-cytoplasmic ratio, atypical and enlarged hyperchromatic nuclei with intercellular bridges, and keratin pearls and intracellular keratin. Although this is a common morphologic manifestation of SCCs elsewhere, it is the least common form of NPC.

EBV may well be identified in these tumors but not as frequently as it is in nonkeratinizing carcinoma of the nasopharynx.

The nonkeratinizing squamous carcinoma is most frequently seen where the neoplasm is endemic. It is therefore the most common variety. Virtually all patients have antibodies to EBV antigens, and EBV is extremely frequently identified in tumor cells.

On histology, the differentiated variety has distinctly epithelial cells with polyhedral outlines and distinct cell borders on most cells. These may be individual, but most often they are arranged in elongated strands that intertwine to form an overall reticular pattern. They may be seen streaming from surface stratified squamous epithelium. Extracellular or intracellular keratinization is rare or absent. Epithelial differentiation on light microscopy is so limited that initially the tumor was suspected of having both lymphoid and epithelial origins.

The malignant cells, which are epithelial, do not have the distinct cell borders of the differentiated type of nonkeratinizing carcinoma. The cells may be round, ovoid, polyhedral, or spindled. Nevertheless, immunoperoxidase stains do prove all these variants are epithelial in origin. As stated earlier, the cells may individually percolate throughout the lymphoid tissue, or they may be arranged in a reticular or syncytial pattern vaguely connected to each other. Nearly every tumor has some version of both regions.

Nonkeratinizing NPC undifferentiated type is the type of NPC that has been responsible for much of the early confusion of the origin of NPCs. It has driven much of the controversy regarding classification schemes.

When this tumor type metastasizes to cervical lymph nodes, it often presents a diagnostic dilemma, and tests for epithelial markers and mesenchymal and melanocytic markers are required to rule out other neoplasms. After a cervical metastasis with a poorly differentiated to undifferentiated morphology is proven to be a carcinoma on routine staining, the likelihood that the unknown primary is nasopharyngeal is high.

Until recently, the nasopharynx was regarded as an unapproachable surgical area, and therapy consisted of irradiation alone. In each case, treatment is individualized, and chemotherapy is occasionally used in addition to irradiation. The response to irradiation and, therefore, the prognosis of patients with NPC is strongly related to the category. Keratinizing SCC responds poorly to irradiation, and the overall 5-year survival rate is approximately 15%. The 5-year survival rate for nonkeratinizing carcinoma of the nasopharynx, which responds to irradiation therapy, is approximately 60%. Approaching this tumor by surgical means has been a topic of recent interest.

Summary

Areas of research

Even cursory familiarity with the topics presented above suggests further areas of research, improves prognostication, informs discussions of therapeutic options with patients and their families and therapists, suggests prevention programs, and adds insight into the basic biology of all types of cancers.

Improved communication between the surgeon and the pathologist

On a practical level, certain aspects of SCCs must always be included in the pathology report regardless of the clinician's presumed familiarity with the pathology. Valuable information may be lost because the pathologist and the surgeon miscommunicate. Every experienced surgeon and every experienced pathologist can recall small miscommunications that delayed treatment or reassurance of the patient.

A surgeon is operating on the oral mucosa to treat a tongue carcinoma. During surgery, she sees a 1.2-cm, pigmented lesion on the buccal mucosa that causes concern. She obtains a sample and sends it to the pathologist for frozen sectioning. The requisition accompanying the sample states, "Patient with malignancy, rule out melanoma." The pathologist reviews the slides and sees an amalgam tattoo, ie, a benign, incidental, and clinically unimportant pigmented lesion that forms around dental amalgam. About 15 minutes later, the pathology report to the surgeon states, "No evidence of melanotic neoplasm."

The surgeon was unfamiliar with amalgam tattoos; therefore, she did not even consider this possibility when she sampled the lesion. Confused by the blue-black, irregular, and large lesion, she assumed that the lesion was missed during biopsy. She repeats the biopsy and receives the same report. In disbelief, the surgeon leaves the operating room and walks to the pathology laboratory to review the slide with the pathologist.

Only then, 45 minutes after the start of the procedure, does a 20-second discussion with the pathologist resolve the situation. The surgeon can now return to the original operation.

The breakdown in communication is clearly the cause of this totally preventable delay. The surgeon was really asking, "What is this dark, ugly lesion, and should I be concerned?" However, the pathologist thought, "The surgeon knows a malignancy is present. Does this sample represent the melanoma, or does she have to keep taking biopsy samples to define the borders of the malignancy until she finds its center?"

The examples below are real events or based on real events that occur with alarming frequency. The best way to avoid these and other communications errors is clear and complete communication and not just imparting news.

A surgeon sees a 3.0-cm, ulcerated lesion on the buccal mucosa of a 50-year-old man. It is in an area, the linea alba, that does frequently have dental trauma. The surgeon obtains a biopsy sample from the area and sends the specimen with a requisition stating, "Ulcerated lesion along bite line; rule out malignancy."

On the slides, the pathologist sees an ulcer, marked acute and chronic inflammation, and scant peripheral epithelium. The pathologist sends a report stating, "Ulcer, acute and chronic inflammation, and scant squamous epithelium with mild atypia, probably benign reactive change. No evidence of malignancy."

The surgeon's secretary informs the patient that immediate follow-up is not needed and that the patient can go on the 4-month vacation he had planned. The patient leaves on vacation but returns a month early and immediately goes to the surgeon because the lesion is enlarged and painful, and a neck mass is probably present. The surgeon performs repeat biopsy of the lesion. The pathology report now states, "Squamous cell carcinoma, moderately differentiated, invasive, keratinizing."

Once again, the problem was miscommunication. Despite the requisition, the surgeon's real question was, "Should I be concerned at all about this or simply follow it at a later date?" However, the pathologist read, "Does this biopsy contain definite cancer?"

In this case, the problem is a bit more complicated than that in example 1. The pathologist was definitely correct in what was seen and reported. However, the statement, "No evidence of malignancy," misleads the surgeon into thinking, "Do not worry about this. This is probably a bite-induced lesion." What is misleading is that ulceration and acute and chronic inflammation are evidence of malignancy. However, they are nonspecific findings that can be seen in trauma and certain vasculitic conditions as well as malignancy.

At 1 AM, a 60-year-old man presents to the emergency department with uncontrolled esophageal hemorrhage, and emergency esophagectomy is considered. A biopsy specimen of the esophagus is sent to pathology with the question, "Malignancy?"

The pathologist comes in from home and by 2 AM is reviewing the slides, which demonstrate bizarre cells that meet the criteria of a poorly differentiated malignancy. A peculiarity in the vascular walls strikes the pathologist as interesting and provokes a call to the surgeon with the question, "Has this patient ever received radiation in this area?"

The somewhat angry pathologist replies, "Why didn't you tell me this? I was about to call this a sarcoma, but these are radiation-related fibroblasts! No malignancy is present."

The surgeon later apologized and explained, "I didn't want to give you too much information and prejudice you."

The key is imparting all the news that is necessary to treat this patient. This requires an active participation of both parties, not the, unfortunately too common, black box approach to pathology. This is the term pathologists use for the one question to the pathologist and one answer back to the surgeon.

To actively participate, the pathologist should ask himself or herself the following questions:

To actively participate, the surgeon should ask himself or herself the following questions:

The age old expression "I am responsible for what I say. I am not responsible for what you hear" is not acceptable in interactions between the surgeon and the pathologist. An appropriate expression is, "I am responsible for the other physician's understanding of what I mean to say."

Pathology report

The pathology report describes the pathologist's interpretation of the evidence offered for examination. It indicates the disease, which, like any other indicator, may not be correct. Close cooperation between the surgeon and the pathologist optimizes factors (eg, biopsy specimen, clinical information) that influence interpretation of the results.

Specimen collection

The biopsy specimen must be representative of the lesion and processed properly.

SCCs typically appear as a surface abnormality visible to the eye, such as a surface with decrease reflectivity, the white discoloration of keratosis or ulceration, the red and velvety appearance of erythroplasia, or elevation or umbilication of the surface. However, some SCCs demonstrate relatively little in terms of visual anomaly. Easily elicited bleeding is also often an important clue to an underlying malignancy. A carcinoma may appear as a subepithelial mass. In this case, a papule may be visible, or the lesion may be detected only on the detection of firmness to palpation.

A supravital stain, such as toluidine blue, reliably indicates surface atypia, which is not deeper than 5 cell layers from the surface. Avoid biopsy of a healing area because rapidly growing tissue mimics malignancy in many morphologic ways.

A specimen from the oral cavity, nasal cavity, palate, tonsil, and pharynx can be obtained by using topical or local anesthesia in the office setting. Lesions in the tongue base, pharynx, or larynx are best evaluated and sampled with the patient under general anesthesia. Excisional biopsy is preferred when possible. After the procedure, the wound is left to heal without sutures.

A sharp instrument, such as a basket punch or a scalpel, is used to cut rather than tear the specimen. Use of a sharp instrument prevents stretch artifact in the histologic specimen. The specimen should always include the marginal adjacent tissue as well as the tumor itself. A biopsy sample from the center of the lesion is usually of least value, especially if the lesion is ulcerated.

Methods of biopsy

Excisional biopsy is en bloc excision of the entire lesion, including a narrow margin of the normal tissue. It is particularly suited for evaluating superficial lesions without obvious fixation to underlying muscle.

Excisional biopsy has several advantages: (1) With serial sectioning and histologic examination, the entire lesion can be evaluated. (2) If the lesion is completely excised, no further treatment is required. When only microinvasion is present, positive mucosal margins may be observed safely. When the biopsy wound heals, clinical evidence of atypia often clears. If not, further excision is performed. (3) If the entire lesion cannot be excised, further treatment is needed. The type of treatment is selected on the basis of the information obtained during attempted excisional biopsy. (4) Excisional biopsy is consistent with the goals of minimal treatment. This approach allows for the removal of no more tissue than necessary to treat the disease, preserving as much tissue as possible. Therefore, the benefit-cost ratio is high.

A suitable candidate for excisional biopsy is a patient who can undergo anesthesia and who has a lesion that is entirely visible. A patient with early glottic cancer is particularly suited for excisional biopsy. Glottic cancer has a predilection for the ventricular surface of the vocal fold, where removal of the mucosa interferes minimally with the vocal wave (voicing). The ventricular surface has typically undergone polypoid degeneration (Reinke edema) with a marked accumulation of fluid just below the surface, which makes dissection easy and safe.

Fine-needle aspiration biopsy (FNAB) can aid in evaluating a neck mass of uncertain origin, including most non-Hodgkin lymphomas. This procedure is easy to perform and helps provide a quick, reliable diagnosis when the results are positive for cancer; however, it is not reliable when the results are negative. FNAB does not complicate later attempts at curative surgery. Of note, FNAB of a parotid mass releases digestive enzymes into the gland that may make histologic evaluation of the excised gland unreliable.

Do not perform open biopsy of neck masses unless findings from FNAB, paranasal sinus radiographs, and panendoscopy with random biopsy of the Waldeyer ring under general anesthesia fail to confirm a diagnosis. The surgeon who has ultimate responsibility for the patient's care and who will select an incision site that can be included in any future resection is best suited to make the incision for open biopsy.

A small specimen ( <1 cm) that is to be fixed must be uncurled, flat, and oriented during fixation so that the histotechnologist can mount and section the specimen properly. The surgeon flattens the specimen and attaches it to a carrier. A suitable carrier is a slice of preserved cucumber pressed to the inside of the specimen bottle lid, which has been sprayed with benzoin and then allowed to dry and become sticky. After it is well positioned on the carrier, the specimen is flooded with 10% formalin as a fixative, and the specimen bottle is screwed onto the lid (ie, the lid remains topside down on the table) and transported to the laboratory in the upside-down position. The surgeon and/or a map drawing of the lesion and the biopsy site should accompany the specimen to the laboratory to explain its location and orientation in the patient.

The diagnosis of lymphoma rather than carcinoma is suspected, the lymph node should be sent to the pathologist immediately after its removal when it is fresh, moist, and not preserved. Otherwise, the node should be immersed in a 10% formalin fixative.

When the specimen's representation of the lesion is doubted, frozen sectioning is helpful.