Head and Neck Cutaneous Squamous Cell Carcinoma Workup

Although no specific laboratory analysis is required to confirm a diagnosis of squamous cell carcinoma (SCC), history and physical examination findings help determine specific laboratory and imaging needs. Any history of bleeding abnormalities, impaired healing, allergic reactions (eg, anesthetics, other medications), and significant cardiac or other systemic medical problems must be elicited.

Imaging is not routinely indicated for diagnosing cutaneous SCC. However, radiologic imaging should be obtained in patients with regional lymphadenopathy and/or neurologic symptoms suggestive of perineural involvement, for nodal staging, and for preoperative planning in patients in whom deep or extensive tissue involvement is suspected.

Computed tomography (CT) scanning, magnetic resonance imaging (MRI), ultrasonography, or positron-emission tomography (PET) scanning may be used depending on the specific question being addressed, although the selection of one modality over another is often based on clinician and institutional preference. Currently, no formal guidelines have been developed regarding the use of radiologic imaging in cutaneous SCC.

Few data are available to guide decisions about staging of nodal basins in high-risk squamous SCC. However, PET scanning, ultrasonography-guided fine need aspiration (FNA) biopsy for cytology or excisional biopsy, and sentinel lymph node biopsy (SLNB) all appear to offer a good chance of detecting subclinical nodal metastasis with low morbidity. Thus, nodal staging may be considered in patients with high-risk SCC. Development of prognostic models that better predict the risk of nodal metastasis will allow for more rational decisions about which patients should undergo nodal staging.

See the following for more information:

• Sentinel Lymph Node Biopsy for Squamous Cell Carcinoma
• Urogenital Squamous Cell Carcinoma
• Imaging of Nasopharyngeal and Laryngeal Squamous Cell Carcinoma
• Cell Biology of Head and Neck Squamous Cell Carcinoma
• Targeted Molecular Therapy in Head and Neck Squamous Cell Carcinoma.
• Mohs Micrographic Surgery
• Mohs Surgery

Perform routine hematologic examination to assess the overall medical condition of the patient and the possibility of spread to distant organs. Anemia may be detected with a complete blood cell (CBC) count with platelet count. Liver function tests help determine hepatic spread. Blood gases and pulmonary function tests in conjunction with chest radiographs are useful in heavy smokers.

Genetic analysis for xeroderma pigmentosum and/or a test for human immunodeficiency virus (HIV) infection may be helpful if patient is young and there is no history of occupational exposure or excessive sun exposure.

In advanced-stage cutaneous squamous cell carcinoma (SCC), anatomic imaging using computed tomography (CT) scanning or magnetic resonance imaging (MRI) can be helpful in defining the extent of disease. CT scanning is useful for determining the presence of bone or soft tissue invasion (see the first image below) and for evaluating cervical lymph nodes at risk for metastasis. Lung and liver scans or a full-body CT scan is performed if metastasis is suspected.

For evaluation of perineural invasion and orbital or intracranial extension, MRI with intravenous contrast enhancement is the preferred imaging modality (see the second image below).^[92] MRI is also the preferred method for staging SCC of the oral cavity and oropharynx.

Only a few studies have reported on the utility of radiologic imaging in cutaneous squamous cell carcinoma. One study of CT scanning and MRI in patients with histologically proven, perineurally invasive SCC showed that only 20% of asymptomatic patients have positive findings discovered from imaging studies.^[76] Thus, both modalities appear to be poor in detecting asymptomatic nerve involvement. However, positive imaging findings did correlate with worse outcomes. The 5-year survival rate was 50% if CT scanning or MRI findings were positive compared with 86% if they were negative.^[76]

Overall accuracy of nodal staging with CT scanning (90-95%) appears superior to the accuracy obtained by clinical nodal staging (75-80%). Thus, more metastases are detected when CT scanning is incorporated into the staging protocol of patients with primary head and neck SCC. The overall accuracy of MRI in staging lymph nodes is similar to that of CT scanning.

Positron emission tomography (PET) scanning has been proposed as an additional diagnostic tool to improve the accuracy of computed tomography (CT) scanning. In early radiologic studies, the combination of CT and PET scanning resulted in improved accuracy of staging, but this is not yet the standard of care.^[93]

PET scanning and ultrasonography-guided fine-needle aspiration (FNA) biopsy may be capable of detecting many cases of subclinical nodal metastasis.^{[94, 95]} In a small study of PET scanning in 9 patients with high-risk SCC, this modality detected subclinical nodal metastasis in 3 of 9 patients.^[95]

A study of vulvar squamous cell carcinoma (SCC) indicated that ultrasonography followed by fine-needle aspiration (FNA) biopsy for suspicious nodes was superior to computed tomography (CT) scanning in staging subclinical nodal metastasis, with ultrasonography-guided FNA biopsy demonstrating 80% sensitivity and 100% specificity.^[94]

Echography can be used to assess any suspicion of intraocular invasion.^[96]

A biopsy should be performed for any lesion suspected of being a cutaneous neoplasm. For most lesions, the biopsy can be readily accomplished in the clinic or physician’s office under local anesthesia. The type of biopsy performed depends on the size of the lesion. Small skin lesions in noncritical areas may be amenable to excisional biopsy, where the entire area of concern is removed. This method has the benefit of being diagnostic as well as potentially therapeutic without the need for a second procedure. For larger lesions or those located in cosmetic or functionally critical areas, confirming the diagnosis before embarking on surgical excision that may be extensive and require reconstruction is often preferable (eg, eyelid lesions suggestive of squamous cell carcinoma [SCC]). In these cases, an incisional or punch biopsy should be performed initially with further treatment based on the pathology results.

Whatever biopsy method chosen, several principles should be followed, such as:

• The biopsy should contain the full thickness of the skin in order to evaluate the depth of the lesion and to allow for a determination of the presence or absence of invasive disease. Given recent information about depth being an important prognostic factor (analogous to melanoma), a large punch biopsy through the center of the lesion or excisional biopsy may be best, particularly in high-risk lesions or immunosuppressed patients.^[4] Therefore, a shave biopsy is generally not recommended when malignancy is suspected.
• The biopsy should be centered over the transition point between normal and involved skin, thereby providing a reference for comparison by the pathologist.
• When possible, incisions should be made parallel to the natural lines of skin tension (Langer lines) for optimal cosmetic outcome. For punch biopsies, stretching the skin perpendicular to the Langer lines creates an ellipse oriented in this optimal direction and facilitates closure.
• For high-risk lesions, a larger sample may be helpful to assess for perineural invasion and other histologic features that confer a greater risk of metastasis.

Toluidine blue, which clinically stains malignant lesions dark blue but does not stain normal mucosa, is recommended for early detection as a guide for optimal biopsy. The dye is absorbed by the nuclei of malignant cells with increased DNA synthesis.

If the diagnosis of carcinoma is made, endoscopic examination should proceed under general anesthesia with random biopsies of Waldeyer ring, the hypopharynx, nasopharynx, and other common sites of metastasis and any suspicious lesions. Subglottis, esophagus, and tracheobronchial tree are routinely evaluated to rule out synchronous primaries, which may have an incidence of 20%.

Patients with regional lymphadenopathy identified by clinical examination or imaging studies should undergo a lymph node biopsy or fine-needle aspiration (FNA) biopsy for histologic evaluation.

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

Selection of the biopsy site

Squamous cell carcinomas (SCCs) typically appear as a surface abnormality visible to the eye, such as a surface with decreased 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.

Obtaining the specimen

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.

Excisional 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, such as the following:

• With serial sectioning and histologic examination, the entire lesion can be evaluated.
• 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.
• 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.
• 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.

The following images are examples from excisional biopsies.

Fine-needle aspiration biopsy

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

Sentinel lymph node biopsy

Sentinel lymph node biopsy (SLNB) has been used to identify micrometastasis in patients with high-risk SCC and clinically negative nodes, with 21% positivity.^[63] Although SLNB appears to be able to detect most subclinical metastasis, whether early detection of lymph node metastasis leads to enhanced survival in SCC is unknown, because controlled studies have not been conducted.

A review of 85 reported cases of SLNB in high-risk, nonanogenital cutaneous squamous SCC showed that 21% of cases were positive based on SLNB findings. This indicates that SLNB likely can detect many cases of subclinical nodal metastasis. How the sensitivity of SLNB compares with that of positron emission tomography (PET) scanning or ultrasonography-guided fine-needle aspiration (FNA) biopsy and whether detection of subclinical nodal metastasis impacts survival are unknown.^[63] However, because the 5-year survival rate of patients with nodal metastasis is as high as 73% with aggressive treatment,^[62] early detection of nodal metastasis may prove more beneficial in SCC than in melanoma.

Complete lymphadenectomy of the draining nodal basin has also been suggested for high-risk tumors with an estimated metastatic risk of 20% or greater. However, because prognostic models do not exist, knowing precisely which patients fall into this category is difficult. Thus, when it is feasible, SLNB offers a low-morbidity approach to accurately staging high-risk SCC.

Open biopsy

Do not perform open biopsy of neck masses unless findings from fine-needle aspiration (FNA) biopsy, 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.

If 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.

Pathologic analyses may be completed by a dermatologist or a general pathologist, but they are preferably completed by a dermatopathologist with extensive experience in squamous cell carcinoma (SCC). Most SCCs have a gelatinous surface on gross inspection, which frequently is permeated by fibrovascular cores, giving it a papillomatous appearance.

The histologic hallmark of SCC is the presence of keratin or "keratin pearls." These are well-formed desmosome attachments and intracytoplasmic bundles of keratin tonofilaments. The term epidermoid can be substituted for squamous.

Conventional cutaneous SCC can be divided into 3 histologic grades based the degree of nuclear atypia and keratinization found. Well-differentiated cutaneous SCC is characterized by more normal-appearing nuclei with abundant cytoplasm and extracellular keratin pearls. In contrast, poorly differentiated cutaneous SCC shows a high degree of nuclear atypia with frequent mitoses, a greater nuclear-cytoplasmic ratio, and less keratinization, and it may be difficult to distinguish from mesenchymal tumors, melanoma, or lymphoma. Moderately differentiated cutaneous SCC shares exhibits features of both well-differentiated and poorly differentiated lesions. See the following images.

Histopathologic features of cutaneous SCC remain important for the clinician, as they carry prognostic value and help to define the most appropriate treatment for patients. Pathologic features, including poor differentiation, perineural invasion, and lymphovascular involvement, are more likely to be seen with regional lymph node involvement. Poorly differentiated cutaneous SCC demonstrates rates of metastatic spread significantly higher than those of other grades (17% vs 4%). Those exhibiting perineural and lymphovascular invasion also exhibit higher rates of metastasis.

SCC in situ

SCC in situ (SCCIS), sometimes referred to as Bowen disease, is a precursor to invasive cutaneous SCC. This lesion is characterized by an intraepidermal proliferation of atypical keratinocytes. Keratinization results in the production of squamous eddies or keratin pearls. The neoplastic cells may demonstrate varying degrees of squamous differentiation and atypia.

Hyperkeratosis, acanthosis, and confluent parakeratosis are seen within the epidermis, and the keratinocytes lie in complete disorder, resulting in the classic "windblown" appearance. Cellular atypia, including pleomorphism, hyperchromatic nuclei, and frequent mitoses, is prominent. Atypical keratinocytes may be found in the basal layer and often extend deeply down hair follicles, but they do not invade the dermis. SCCIS is differentiated from actinic keratosis, a similar precancerous skin lesion, by full-thickness involvement of the epidermis. See the image below.

SCCIS 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, SCCIS does not metastasize; and (2) full-thickness atypia must demonstrate atypia that includes the surface.

The second point is of clinical importance. The surface atypia of SCCIS 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 SCCIS of the head and neck are: (1) SCC in situ may develop into invasive SCC, and (2) given the concept of field defect (see Anatomy), frankly invasive carcinoma in proximity frequently accompanies SCCIS.

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 novo invasive SCC.

Invasive SCC

Invasive cutaneous SCC is differentiated from SCCIS and actinic keratosis by the invasion of the basement membrane by malignant-appearing cells (see the following images). With invasive cutaneous SCC, nests of atypical cells are found within the dermis, surrounded by an inflammatory infiltrate 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.

For 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, such as the following:

• Whether the tumor is invasive: The report states "SCC in situ, no invasion identified" or "SCC, invasive." The simple designation "SCC" should not be accepted, because it may indicate an oversight on the part of the pathologist or the typist of the report. The assessment of invasion, or its lack, must be mentioned.
• Invasion: If possible, the pathology report must state the structures that are invaded. Simply stating "invasive" informs the clinician that the tumor has breached the natural basement membrane. This is most often the case. However, it is not too unusual for the pathologist to state that perineural invasion, lymphatic invasion, or vascular invasion is present. By convention, "vascular invasion" indicates vascular and not lymphatic invasion.
• Degree of differentiation: This is a difficult and debated topic. Strict criteria that are universally accepted simply do not exist. In addition, on examination of many fields of any given tumor, one often identifies considerable variability. Fields that most pathologists agree are well differentiated may be adjacent to fields that they would agree are poorly differentiated. Therefore, the degree of differentiation is subjective.

Many pathologists accept the subjective nature of the degree of differentiation 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 histologic appearance of a usual invasive SCC varies with the degree of differentiation. In common to all are the following:

• Atypical squamous cells with enlarged, angulated nuclei
• Increased nuclear diameter–to–cytoplasmic diameter ratio
• Evidence of keratinization, more in well-differentiated and less in poorly differentiated lesions
• Intercellular bridges or cytoplasmic projections that radiate outward from the cytoplasm and connect adjacent cells
• Increased mitotic figures: No specific number is diagnostic of malignancy
• Atypical mitotic figures: These are mitotic figures that do not fit into any of the known phases of cell division. Even anaphaselike mitotic figures demonstrate multipolarity, whereas normal cell division has 2 poles that the genetic material is oriented toward; atypical mitotic figures may have 3 or more poles.
• Hyperchromasia: The nuclei are darkly staining because of increased ploidy.
• Invasion below the usual level of the basement membrane: This may be in a large pushing front of dozens of cohesive squamous cells. It may also invade as small cell nests containing 5-10 cells per cluster, often with an elongated stabbing pattern. Finally, individual cells may be percolating through the stroma.
• Inflammation: Invasive carcinomas almost always have a surrounding and/or intermingling inflammatory response. This response may be exclusively of 1 cell type (eg, lymphocytes or plasma cells), or it may be a mixture of any combination of cells, including macrophages, neutrophils, eosinophils, lymphocytes, and plasma cells.

SCC histologic variants

Several variants of SCC can be distinguished by clinical and/or histologic criteria. In some cases, these tumors may be difficult to distinguish from other malignancies based on routine histology findings alone. Therefore, immunohistochemical staining with antibodies to cytokeratins and epithelial membrane antigen is often used to confirm the epithelial (ie, keratinocyte) origin of the tumor. The salient features of keratoacanthoma, spindle cell SCC, acantholytic (adenoid) SCC, and verrucous carcinoma are highlighted in Table 3, below.

Table 3. Histologic and Clinical Features of Squamous Cell Carcinoma (SCC) Variants (Open Table in a new window)

Spindle cell carcinoma, basaloid SCC, papillary SCC, mucoepidermoid carcinoma, and nasopharyngeal carcinoma are variants of SCC and will be discussed in this section.

Spindle cell carcinoma

Spindle cell carcinoma may contain intercellular bridges and incipient keratinization. In other cases, spindle cells are intermingled with collagen and may be arranged in whorls. In such cases, special stains for cellular markers can be used to distinguish SCC from other cancers. For example, an S100 stain returns negative results for SCC and positive results for melanoma. Specifically, synaptophysin, CD99, leukocyte common antigen, nonspecific esterase, S100, homatropine methylbromide, and neurofilament stains return negative findings for SCCs, whereas cytokeratin, vimentin, and epithelial membrane antigen stains return positive findings.

This morphologically deceptive and unusual tumor has also 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.

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.

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.

Basaloid SCC

Basaloid SCC is less common than conventional SCC of the head and neck; men are 4 times more likely than women to have this cancer, and most patients are aged 40-70 years. This tumor 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. The 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.

Almost all basaloid SCCs have regions in common 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.

Increasing evidence suggests that human papillomavirus (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 SCC is less aggressive than any other type of SCC in the same anatomic location.

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, SCCIS) 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.

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.

Table 4 below summarizes the epithelial, invasive and inflammatory characteristics of benign squamous papillomas, papillary SCCIS, invasive papillary SCC, and verrucous carcinoma.

Table 4. Summary of Characteristics of Papillary Epithelial Lesions and Verrucous Carcinoma (Open Table in a new window)

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 theoretic 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.

Although mucoepidermoid tumors preferentially metastasize to the regional lymph nodes of the neck, they also frequently metastasize to distant sites (eg, lungs, bones, skin and subcutis) by the time the disease is diagnosed.

Nasopharyngeal Carcinoma

In more than 50% of cases of nasopharyngeal carcinoma 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.

Nasopharyngeal carcinoma 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.

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, nasopharyngeal carcinoma 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). These are discussed below

Keratinizing SCC

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 nasopharyngeal carcinoma. In addition, Epstein-Barr virus (EBV) may well be identified in these tumors but not as frequently as it is in nonkeratinizing carcinoma of the nasopharynx.

Differentiated and undifferentiated nonkeratinizing SCC

The nonkeratinizing SCC 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 nasopharyngeal undifferentiated type is the type of nasopharyngeal carcinoma that has been responsible for much of the early confusion of the origin of nasopharyngeal tumors. 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.

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.

On a practical level, certain aspects of squamous cell carcinomas (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.

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.

Example 1

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; that is, 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 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 left the operating room and went to the pathology laboratory to review the slide with the pathologist. Only then, 45 minutes after the start of the procedure, did a 20-second discussion with the pathologist resolve the situation. The surgeon was then return to the original operation.

The breakdown in communication was the clear cause of the 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?"

Example 2

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 frequently has 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 1 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 a 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 the first example. 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.

Example 3

At 1 AM, a 60-year-old man presents to the emergency department with uncontrolled esophageal hemorrhage. 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 surgeon tells the pathologist "Yes, for previous malignancy 10 years ago."

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 “black box approach” to pathology, an unfortunately too common occurrence. This is the term pathologists use for the “one question to the pathologist and one answer back to the surgeon” scenario.

Questions to ask

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."

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

• What is the surgeon really asking me?
• What is prompting this question? That is, what observation led to this question?
• What information is essential for optimal treatment of this patient?
• Did I make myself clear enough for the surgeon to understand exactly what he or she needs to know?

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

• Am I giving the pathologist all the information he or she needs to answer my specific questions?
• Might I be misunderstood? How can I make myself clear?
• Am I (tactfully) reminding the pathologist what information I need?
• Is the information from the pathologist consistent with the clinical findings?