Malignant Neoplasms of the Larynx, Hypopharynx, and Trachea


Precursor Squamous Lesions

Precursor lesions are difficult to define because they have an increased likelihood of progressing to squamous cell carcinoma (SCC). A constellation of architectural and cytologic features constitute dysplasia, but these features are not uniformly accepted or understood, thereby leading to differences in intra- and interobserver interpretation. It is wise to use the term atypia in the context of reactive, inflammatory, or regenerative changes, while reserving dysplasia for the premalignant group of lesions. The new World Health Organization (WHO) classification uses only two tiers, low and high grade, with carcinoma in situ (CIS) included in high-grade dysplasia. Terms like keratosis, squamous intraepithelial lesion (SIL) or neoplasia (SIN), laryngeal intraepithelial neoplasia (LIN), basal/parabasal hyperplasia , and atypical hyperplasia are preferentially replaced by the new two-tiered system for the sake of simplicity, reproducibility, and patient management. Keratinizing dysplasia is a potentially reversible alteration in epithelial cells that shows an increased likelihood of progressing to SCC. CIS is a noninvasive malignant alteration of the full thickness of the surface epithelium.

Clinical Features

Precursor Squamous Lesions—Disease Fact Sheet

Definition

  • Squamous lesions with an increased risk/likelihood of progressing to squamous cell carcinoma

Incidence and Location

  • From 2% to 40% of precursor lesions progress to carcinoma

  • Supraglottic and glottic regions are most commonly affected

Sex and Age Distribution

  • Males > females

  • Peak in 6th-7th decades

Clinical Features

  • Tobacco and alcohol abuse (with potentiating effect)

  • HPV very infrequently identified as a risk factor

  • Hoarseness, throat irritation, sore throat, chronic cough

Prognosis and Treatment

  • Progression to carcinoma is slow, but there is a well-defined risk of malignant transformation

  • Surgery, laser, and radiation, dependent upon lesion

HPV , Human papillomavirus.

Precursor lesions are mostly seen in the adult population (6th to 7th decades), with a male predilection that is especially pronounced after the 6th decade. There is a strong association with tobacco smoking and alcohol abuse, with a potentiating effect between the two; the increased risk is directly proportional to duration of use. The etiologic role of human papillomavirus (HPV) infection is very limited, detected in about 8% to 12% of cases. Symptoms depend on the location and severity of the disease and are usually present for at least a few months before they come to clinical attention. Hoarseness, voice changes, throat irritation, sore throat, and/or chronic cough are frequently reported. Endoscopically, dysplasia has a varied appearance, ranging from discrete to diffuse, leukoplakia to erythroplakia, and a small flat patch to a large warty plaque ( Fig. 6.1 ). Leukoplakia, in contrast to erythroplakia, tends to be well demarcated. Although inconsistent, leukoplakia alone seems to pose a lower risk of malignant transformation than pure erythroplakia.

FIGURE 6.1, Laryngoscopic view of true vocal cord leukoplakia ( arrow ), which represents a keratinizing dysplasia.

In general it is accepted that there is an increased risk of progression to invasive SCC over time. Low-grade dysplasia is potentially reversible if the inciting factor is removed. However, as the grade of dysplasia increases, it becomes more difficult to predict which dysplasia may be reversible and which may progress to invasive carcinoma. Although quite variable, low-grade dysplasia shows a 2% risk of progression to invasive carcinoma, whereas high-grade dysplasia ranges from 23% to 40% risk of progression. The progression is usually slow, with an average latency from low-grade dysplasia to invasive SCC of just under 4 years. It is important to realize that multifocal disease is a major factor in disease development, since the entire epithelium is exposed to the same etiologic risk agents.

Pathologic Features

Precursor Squamous Lesions—Pathologic Features

Gross Findings

  • Leukoplakia, erythroplakia, mixed (speckled), variegated

  • Diffuse or discrete

  • Flat patch or large warty plaque

  • Anterior true vocal cord most often, with frequent bilateral disease

Microscopic Findings

  • A continuum of architectural and cytologic features required, separated into low and high grade based on degree of involvement and cytologic features present

  • Increased cellularity, nuclear crowding, irregular maturation, lack of polarity, dyskeratosis, irregular cell pinking, intercellular edema (prominent spinous layer), keratin pearl formation, parakeratosis, increased mitoses, atypical mitoses

  • Increased nuclear-to-cytoplasmic (N:C) ratio, increased nuclear size, anisocytosis, poikilocytosis, anisonucleosis, nuclear pleomorphism, nuclear hyperchromasia, nuclear chromatin condensation, increased nucleolar size and number

  • Basement membrane intact

Pathologic Differential Diagnosis

  • Hyperplasia, regeneration, repair, inflammation, radiation changes, necrotizing sialometaplasia, SCC

SCC , Squamous cell carcinoma.

Gross Findings

There is no characteristic appearance of precursor lesions, which may be circumscribed or diffuse; smooth, granular, or irregular; flat or exophytic; and leukoplakic or erythroplakic. The anterior true vocal cords are involved most commonly (usually not the commissure), although no region of the larynx is exempt. Bilateral disease is common (30% to 60%). Invasive carcinoma may be concurrently present adjacent to or remote from the precursor lesion.

Microscopic Findings

Dysplasia is an alteration of surface epithelium that is more than hyperplasia but less than carcinoma. Needless to say, to identify the earliest forms of dysplasia and to arbitrarily separate and rigidly divide the dysplasias into different categories is fraught with tremendous intra- and interobserver variability and an overall lack of reproducibility.

Many architectural (maturation abnormalities) and cytologic features can be seen in dysplasia, although none in isolation is pathognomonic for dysplasia. In fact, many of these same features are more fully developed in carcinoma, so a rigid segregation between lesions is nearly impossible. In general, all of the various layers begin to cytologically resemble the basal layer cells (immature or uncommitted) as the lesion progresses from low-grade dysplasia ( Figs. 6.2–6.6 ) toward CIS. Moreover, on a continuous spectrum, there is a quantitative increase in architectural and cytologic features for the diagnosis of dysplasia ( Table 6.1 ).

FIGURE 6.2, A low-grade keratinizing dysplasia demonstrates limited disruption of the architecture and mild pleomorphism limited to the lower third of the mucosa.

FIGURE 6.3, Keratosis and a prominent granular cell layer is seen in this low-grade keratinizing dysplasia. There is loss of maturation in the lower half of the epithelium.

FIGURE 6.4, High-grade keratinizing dysplasia shows full-thickness replacement of the epithelium by markedly atypical cells, lacking any maturation to the surface. The basement membrane is intact.

FIGURE 6.5, High-grade keratinizing dysplasia with focal surface maturation. There is marked keratosis and parakeratosis as well as prominent intercellular spinous processes. Atypical mitoses are noted.

FIGURE 6.6, This atypical epithelium contains dyskeratosis throughout the epithelium and pleomorphism throughout the full thickness. Previously a moderate dysplasia, this would be placed in the category of high-grade dysplasia.

TABLE 6.1
Two-tiered system of grading laryngeal dysplasia
Low-grade dysplasia Architecture
  • Preserved stratification, with expansion of the basal layer, often with perpendicular orientation of the nuclei, transitioning to horizontal orientation at the surface

  • Increased spinous layer, but may be confined to the upper layers of the epithelium

  • May be limited to increased basal/parabasal layers

Cytology
  • Limited pleomorphism at the lowest end of the spectrum

  • Parabasal cells may have slight increased cytoplasm compared with the adjacent cells, with enlarged nuclei and occasional dyskeratotic cells

  • Rare normal mitoses in and around the basal layer

High-grade dysplasia Architecture a
  • Abnormal maturation that extends up to the full thickness of the epithelium

  • Pleomorphic epithelium affecting at least half to full thickness of the epithelium

  • Keratinizing (spinous cell process) to nonkeratinizing (basal cell process)

  • Rete may be irregular, including bulbous or downward extension (but intact basement membrane)

Cytology a
  • Pleomorphism is easily identified and sometimes profound, including marked variation in size, shape, and staining intensity

  • Dyskeratosis and apoptosis up to the whole epithelium

  • Increased nuclear-to-cytoplasmic ratio, irregular nuclear chromatin distribution (hyperchromasia), and prominent nucleoli

  • Increased mitoses at or above suprabasal level, with or without atypical forms

a Complete loss of polarity, profound pleomorphism and/or atypical mitoses qualifies as carcinoma in situ.

Architectural features of dysplasia include increased cellularity, nuclear crowding ( Fig. 6.2 ), irregular maturation toward the surface, lack of polarity, dyskeratosis ( Fig. 6.2 ), keratin pearl formation within rete, parakeratosis ( Fig. 6.3 ), and pseudoepitheliomatous hyperplasia (PEH) or acanthosis with irregular rete extending into the submucosa. In general, dysplasia starts in the basal/parabasal zone and moves toward the surface ( Fig. 6.4 ). Cytologic features of dysplasia include increased N:C ratio, increased nuclear size, anisocytosis, poikilocytosis, anisonucleosis, nuclear pleomorphism, nuclear hyperchromasia, nuclear chromatin condensation and contour irregularities, and increased number and size of nucleoli ( Figs. 6.5 and 6.6 ). Mitoses are increased; they are identified above the basal zone and may include atypical mitotic figures (misalignment of chromosomes, unbalanced distribution of chromosomes, and multipolar figures). Atypical mitoses and profound pleomorphism, when present, are features of high-grade dysplasia. Obviously the basement membrane is intact. The term carcinoma in situ is sometimes limited to lesions that truly lack any maturation at the surface; for the most part, however, high-grade dysplasia encompasses the previous moderate and severe dysplasia and CIS. Nearly all laryngeal lesions are keratinizing dysplasia, with only isolated cases of nonkeratinizing dysplasia. An inflammatory infiltrate, occasionally intense, is common.

A commonly asked question is: How many features are necessary for the diagnosis? Here the art of pathology comes into play, with interpretation incorporating the clinical, gross, and histologic features. Other considerations include the fact that a synchronous invasive SCC is frequently present. Furthermore, invasive carcinoma may develop from a nondysplastic surface epithelium.

Technical factors are important to accurate diagnosis. Multiple biopsies of sufficient size from within the diseased area are necessary to assess the full extent of the lesion. Avoiding tangential sections is paramount, which usually precludes frozen-section diagnoses. Additional deeper sections may be needed to fully demonstrate diagnostic features of dysplasia. Glandular/duct extension must not be interpreted as invasive disease. Various immunohistochemical and molecular studies have been proposed to separate hyperplasia, dysplasia, and carcinoma, including p53 (increased, Fig. 6.7 ), p21, p27 (decreased), cyclin D1, bcl-2, p16, ß-catenin, EGFR, and Ki-67 (increased); but in practical application these are currently too inconsistent and have too much overlap to be clinically meaningful in an individual case.

FIGURE 6.7, A strong and nearly diffuse nuclear p53 reaction in the dysplasia epithelium may help in assessing dysplasia (note the absent staining in the normal epithelium).

Differential Diagnosis

Reactive, regenerative, reparative, or hyperplastic squamous proliferations (e.g., in response to trauma, inflammation, irradiation, or ulceration) may manifest architectural and cytologic atypia. However, morphologic changes suggestive of the inciting event (e.g., ulceration, inflammation, hemorrhage, radiation-induced mesenchymal and/or endothelial nuclear enlargement and hyperchromasia) may be present. Infectious agents resulting in inflammatory infiltrates should be excluded with special stains or cultures. In addition, stratification and maturation is usually present and atypical mitotic figures are absent. The clinical history may also be helpful. Transitional vocal cord epithelium is sometimes confused with dysplasia, but knowledge of the normal histology will help make this separation. Basal zone hyperplasia has a columnar arrangement to the basal cells, which maintain a vertical polarity and hyperchromatic nuclei. There is an abrupt termination of the process at the upper edge of the prickle layer with a very sharp horizontally oriented zone of transition (see laryngeal reactive lesions, Fig. 4.22 ). Granular cell tumor can cause atypical epithelial changes, most importantly PEH, which often mimics invasion but is usually limited to the extent of the granular cell tumor below. Identification of large eosinophilic cells with abundant granular cytoplasm in the stroma should confirm the diagnosis. Definitive evidence of dissociated squamous cells below the basement membrane confirms invasive SCC.

Prognosis and Therapy

Some precursor lesions are self-limiting and reversible, others persist, and some progress to SCC, with notable differences in incidence based on site of involvement and the presence or absence of dysplasia. Lesions that arise in the anterior commissure nearly always convert to invasive SCC, whereas other topographic sites convert only about 15% of the time. Lesions classified as low-grade dysplasia have an approximately 2% rate of malignant transformation, implying the need for close clinical follow-up. Patients with CIS usually require more extensive management, including close follow-up, as there is a progression rate of closer to 40%. Treatments are not standardized but include the elimination of contributing factors, biopsy, vocal cord stripping, laser ablation, cordectomy, hemilaryngectomy and radiation, used individually or in various combinations. Recurrence or persistence may develop from gland-duct extension left behind in a stripping or ablation or as a result of persistent etiologic factors.

Squamous Cell Carcinoma

SCC is the most common malignancy of the head and neck, accounting for more than 95% of all laryngeal carcinomas. However, it still accounts for only about 1% of all carcinomas, showing remarkable geographic variation between and even within countries. About 1 in 10,000 men and 1 in 100,000 women are affected. The most important risk factors are, independently and synergistically, tobacco and alcohol abuse, while susceptibility (immunologic factors and age), gastroesophageal reflux, environmental influences (including radiation), and occupational factors also play a role. Viruses (HPV, Epstein-Barr virus) are uncommonly linked to the development of laryngeal SCC. Associated genetic disorders include Lynch, Bloom, and Li-Fraumeni syndromes, among others. All of these factors interact in a multistep process.

As a malignant neoplasm characterized by squamous differentiation, SCC demonstrates infiltration into the stroma, abnormal keratinization, irregular nests of squamous epithelium, and cellular pleomorphism. Most laryngeal SCCs develop from a precursor lesion, with an arc of development, culminating in invasive SCC. But, not all dysplasias progress to invasive carcinoma.

Clinical Features

Conventional Squamous Cell Carcinoma—Disease Fact Sheet

Definition

  • A malignant epithelial neoplasm characterized by squamous differentiation

Incidence and Location

  • About 1% of all cancers, but 90% of head and neck cancers

  • Marked geographic variation

  • Glottic and supraglottic regions are most common

Morbidity and Mortality

  • Loss of phonation

  • Up to 25% mortality (site- and stage-dependent)

Sex and Age Distribution

  • Males > females (6 : 1)

  • 6th-7th decades; rare in children

Clinical Features

  • Tobacco and alcohol abuse

  • Hoarseness, dysphagia, dysphonia, changes in phonation

Prognosis and Treatment

  • Site-, size-, and stage-specific, with ∼90% 5-year survival for T1 vs. less than 50% for T4 lesions

  • Glottic tumors: 80%-85%, but subglottic: 40%

  • Surgery and radiation therapy

Men are affected much more frequently than women (M > F = 6 : 1), although there has been an increased incidence in women over recent years. All ages are affected, but patients usually present in the 6th to 7th decades of life. Patients present with symptoms referable to the anatomic site of the primary, including hoarseness, dysphagia, dysphonia, dyspnea, changes in phonation, foreign-body sensation in the throat, difficulty swallowing, and stridor.

Radiographic imaging is usually done before endoscopy, as endoscopy may decrease the sensitivity of imaging. Imaging highlights the extent of the disease, shows submucosal invasive patterns, and helps with staging (extent of disease and lymph node status). There is a high incidence of regional lymph node metastasis due to lymphovascular invasion. Endoscopy is recommended to evaluate the extent of the disease, rule out other synchronous primaries (seen in up to 10% of patients), and obtain a biopsy.

Pathologic Features

Conventional Squamous Cell Carcinoma—Pathologic Features

Gross Findings

  • Glottic, supraglottic, subglottic, transglottic

  • Flat, well defined, raised edge, polypoid, exophytic

  • Surface ulceration

Microscopic Findings

  • In situ, superficially or deeply invasive

  • Well, moderately, or poorly differentiated

  • Keratinizing or nonkeratinizing

  • Disorganized growth, lack of maturation, dyskeratosis, keratin pearl formation, intercellular bridges, increased N:C ratio, irregularities in nuclear chromatin distribution, prominent nucleoli, increased mitotic figures, atypical mitotic figures

  • Inflammatory infiltrate and stromal desmoplasia

Pathologic Differential Diagnosis

  • Hyperplasia, dysplasia, radiation changes, necrotizing sialometaplasia, squamous papilloma, variants of SCC

SCC , Squamous cell carcinoma.

Gross Findings

The anatomic sites—supraglottis, glottis, and subglottis—are embryologically distinct and separately compartmentalized ( Fig. 6.8 ), resulting in unique lymphatic drainage; consequently they have implications for the type of surgery and oncologic management. Glottic tumors for the most part are smaller (due to early clinical presentation), whereas supraglottic tumors are often clinically silent, resulting in a much larger tumor at the time of diagnosis. Interestingly, in Europe, supraglottic tumors predominate, while glottic tumors are most common in the United States. SCCs can be ulcerative, endophytic, flat, polypoid, verrucous, or exophytic. They range from minute areas of mucosal thickened to large masses filling the luminal space, although they are usually smaller than 2 cm. The borders are rolled, raised to irregular, and abrupt. Tumors can be erythematous to tan to white and are frequently firm.

FIGURE 6.8, Laryngectomy specimens showing the various locations of tumor: transglottic ( A ), supraglottic ( B ), and subglottic ( C ).

Microscopic Findings

SCC is generally divided into two groups: superficially or deeply invasive, with additional modifiers based on histologic grade, including well differentiated (closely resembles normal squamous mucosa), moderately differentiated (distinct nuclear pleomorphism and less keratinization), or poorly differentiated (immature cells with little maturation or keratinization), along with the presence or absence of keratinization ( Figs. 6.9–6.12 ). “Conventional” SCC is composed of a variable degree of squamous differentiation, with the neoplastic cells invading through and disrupting the basement membrane ( Fig. 6.8 ). The overlying surface may not be atypical, yet invasion may develop from the base ( Fig. 6.9 ). Broad infiltration may give way to small islands, irregular nests, jagged cords, or individual cells, the last correlating with a worse prognosis. SCC shows disorganized growth, a loss of polarity, dyskeratosis, keratin pearls (including paradoxical keratinization at the base), intercellular bridges, an increased N:C ratio, nuclear chromatin irregularities, prominent eosinophilic nucleoli, and increased mitoses (including atypical forms). The keratinizing type ( Fig. 6.11 ) is seen more frequently than nonkeratinizing or poorly differentiated types, while clear cell changes may be seen. Mitoses and necrosis tend to increase as the grade of the tumor becomes more poorly differentiated ( Fig. 6.12 ). A rich inflammatory infiltrate (usually of lymphocytes and plasma cells) is seen at the junction of tumor and stroma, along with a dense, desmoplastic fibrous stroma. Perineural and lymphovascular invasion may be seen, the latter specifically correlated to metastatic potential. Tumors may directly extend into cartilage ( Fig. 6.13 ), adjacent structures, or organs. Margins are often difficult to assess, as shrinkage (up to 50%) may be seen after removal, and there may also be differences between frozen versus permanent sections . Special studies are rarely needed to document the epithelial nature of the tumor, although specific keratin subtypes may relate to histologic grade, degree of keratinization, and likelihood of metastasis . p53 mutations are an early event in carcinogenesis and may therefore help in separating benign from malignant lesions. Tumor site, size, histology (poorly differentiated), degree of invasion, positive surgical margins of resection, lymph node metastasis (especially when there is extranodal extension), and multifocal disease all correlate with a poorer prognosis. Separation of residual carcinoma from radiation changes in the postradiation sample may be difficult. Although cellular enlargement is common, radiation usually does not change the N:C ratio, as carcinoma does ( Fig. 6.14 ).

FIGURE 6.9, Squamous cell carcinoma (SCC) with uneven, finger-like infiltration of the SCCs into the underlying stroma. A desmoplastic stroma is noted ( A ). There is moderate nuclear pleomorphism and cellular disarray ( B ).

FIGURE 6.10, A well-differentiated squamous cell carcinoma is noted arising from an unremarkable surface epithelium, underscoring the necessity for a biopsy of adequate size and depth.

FIGURE 6.11, ( A ) A moderately differentiated squamous cell carcinoma with loss of polarity, disorganization, increased nuclear-to-cytoplasmic ratio, and areas of keratinization. ( B ) There is clearing of the cytoplasm in many of the cells, but keratinization is still noted.

FIGURE 6.12, A poorly differentiated squamous cell carcinoma is arranged in a sheet-like distribution with only occasional cells showing dyskeratosis.

FIGURE 6.13, A moderately differentiated squamous cell carcinoma approaches but does not invade the perichondrium of the laryngeal cartilage. Inflammation is noted.

FIGURE 6.14, Radiation can induce changes in residual carcinoma, resulting in bizarre cells and nuclei, but the cells do not appear degenerated nor do they have a low nuclear-to-cytoplasmic ratio. Nucleoli are frequently obvious in a squamous cell carcinoma after radiation therapy.

Differential Diagnosis

The diagnosis of SCC is usually clear-cut, although occasionally other lesions—such as hyperplasia, dysplasia, radiation changes, necrotizing sialometaplasia, squamous papilloma, and the variants of SCC—are included in the differential diagnosis. Marked PEH may be mistaken for SCC. However, the reactive nature of the proliferation, lack of “finger-like” invasion, and the association with infectious agents and granular cell tumor will help to make this distinction. Radiation changes may affect the epithelium, endothelial cells, and stroma. Glands may become atrophic. There is often profound nuclear pleomorphism; however, these cells maintain a very low N:C ratio ( Fig. 6.14 ). Necrotizing sialometaplasia has a preserved lobular architecture despite the degree of cytologic atypia (see Nonneoplastic Larynx chapter, Fig. 4.30, Fig. 4.31, Fig. 4.32 ). A biopsy of sufficient size is necessary to secure this diagnosis. A squamous papilloma does not have disorganized growth and unequivocal morphologic features of malignancy. SCC should be separated from SCC variants (discussed further on), as there is often a difference in management and prognosis.

Prognosis and Therapy

Prognosis is heavily influenced by anatomic site, tumor stage, and age, while differentiation, invasive pattern, lymphovascular invasion, perineural invasion, margin status, and extranodal extension also contribute to outcome. The TNM tumor classification correlates closely with both disease-free and overall survival. Overall, 5-year survival rates approach 90% for T1 lesions, whereas they are less than 50% for T4 tumors. Glottic tumors have an 80% to 85% survival, while subglottic tumors are at about 40%, with an intermediate 65% to 75% for supraglottic tumors. Regional lymph node metastases are relatively common; extracapsular extension is associated with a worse prognosis. A number of prognostic factors are available ( EGFR, CCND1, CDK4, CDKN2A ), although not yet commonly employed. Larynx function–preserving treatment is the goal, with negative resection margins (3 to 5 mm). Laser excision, limited resection, and radical resection along with radiation therapy are variably employed to achieve the best potentially curative voice-sparing outcome. There is a movement toward noninvasive management. Occasionally neoadjuvant chemotherapy and radiation therapy are used to maintain laryngeal function. However, if these modalities fail, delayed, salvage, partial or total laryngectomy can still achieve a good patient outcome.

Variants of Squamous Cell Carcinoma

Variants make up in aggregate about 4% of all SCCs and include among others verrucous, exophytic or papillary, spindle cell, basaloid, and adenosquamous carcinomas (ASCs; Table 6.2 ). Rather than give an exhaustive review, only the unique features of each variant are presented here.

Verrucous Squamous Cell Carcinoma

Definition

  • Well-differentiated exophytic/verrucous growth with a pushing border of infiltration in a cytologically bland, amitotic squamous epithelium

Prognosis and Treatment

  • 85%-95% 5-year survival (20% recurrence/persistence)

  • Surgery alone; radiation employed for nonsurgical candidates

Gross Findings

  • Broad-based, warty, exophytic, fungating mass

Microscopic Findings

  • Broad border of pushing infiltration

  • Multiple projections of well-differentiated squamous epithelium with club-shaped to filiform projections

  • Maturation toward surface

  • Abundant keratosis (ortho- and parakeratosis; “church spire” keratosis), parakeratotic crypting

  • Limited mitotic figures, if present at all (limited to basal zone)

Pathologic Differential Diagnosis

  • Verrucous hyperplasia, squamous papilloma, papillary/exophytic SCC, conventional SCC

SCC , Squamous cell carcinoma.

TABLE 6.2
Clinical and histologic features of squamous cell carcinoma variants
Feature Variant
Verrucous Papillary/Exophytic Spindle Cell (Sarcomatoid) Basaloid Adenosquamous
Sex M > F, except oral M > > F M > > > F M > > F M slight > F
Location Oral > larynx Larynx > mouth > nose Larynx > mouth> nose Base of tongue > supraglottic larynx Tongue > floor of mouth > nose
Frequency (of all SCC) ~ 3% ~ 1% ~ 3% < 1% < 1%
Etiologic agent? HPV ? HPV ? Radiation Unknown Unknown
Macroscopic Broad, based warty and fungating mass Polypoid, exophytic, bulky, papillary, fungiform Polypoid mass Firm to hard with central necrosis Indurated submucosal nodule
Size (cm) Up to 10 1-1.5 (mean) 2 (mean) Up to 6 1 (mean)
Microscopic Pushing border of infiltration; abrupt transition with normal; large, blunt club-shaped rete pegs; no pleomorphism; limited mitotic activity; abundant keratin, including parakeratin crypting and “church spire” keratosis >70% exophytic or papillary architecture; “cauliflower-like” vs. “celery-like;” unequivocal cytomorphologic malignancy; surface keratinization; invasive, but difficult to demonstrate; koilocytic atypia Biphasic: SCC present but ulcerated, blended/ transition with atypical spindle cell population; hypercellular; variable patterns of spindle cell growth; pleomorphism; opacified cytoplasm; increased mitotic figures Biphasic: invasive, lobular, basaloid component most prominent; palisaded; high N:C ratio; abrupt squamous differentiation (metaplasia, dysplasia, CIS or invasive); ↑ mitotic figures; comedonecrosis; hyaline material Biphasic: SCC and adenocarcinoma, undifferentiated component, separate or intermixed with areas of transition; infiltrative; ↑ mitotic figures; sparse inflammatory infiltrate
Special studies HPV identified None ~70% + with epithelial markers Keratin, EMA, CK7, and K903 Mucin-positive
Differential diagnosis Verrucous hyperplasia, SCC In situ SCC, squamous papilloma, reactive hyperplasia Benign and malignant mesenchymal process, melanoma, synovial sarcoma Adenoid cystic carcinoma, neuroendocrine carcinoma (small cell carcinoma) BSCC, mucoepidermoid carcinoma, adenocarcinoma with squamous metaplasia
Treatment Surgery Surgery and/or radiation Surgery with radiation Surgery, radiation, chemotherapy Surgery with neck dissection
Prognosis 75% 5-year survival ~ 70% 5-year survival ~ 70% 5-year survival ~ 40% 2-year survival ~ 55% 2-year survival
Pitfalls Inadequate biopsy, tangential sectioning, radiation is acceptable Orientation, adequacy of specimen No surface, mesenchymal markers, needs “excisional” biopsy initially Association with second primary, high chance of nodal metastases Separation on small biopsies from adenocarcinoma or SCC
BSCC , Basaloid squamous cell carcinoma; CIS , carcinoma in situ; HPV , human papillomavirus; SCC , squamous cell carcinoma.

Verrucous Squamous Cell Carcinoma

Verrucous SCC (VSCC; Ackerman tumor) comprises about 3% of all SCCs, and is related to tobacco smoking, with no significant association with HPV. It is usually affects the anterior true vocal cords and measures up to 10 cm.

VSCC is a highly differentiated type of SCC that lacks cytologic features of malignancy, grows slowly, and is locally aggressive but does not usually metastasize. It is composed of an exophytic warty tumor ( Fig. 6.15 ) with multiple filiform projections, which are thickened, club-shaped, and lined by well-differentiated squamous epithelium ( Fig. 6.16 ). The advancing margins of the tumor are usually broad or bulbous rete ridges with a blunt, pushing rather than infiltrative appearance, occasionally showing coalescing rete ( Fig. 6.17 ). The downward-dipping epithelium may create a “cup” or “arms” around the periphery of the tumor, which is noted below the level of the adjacent normal basal cell layer. There is often a dense inflammatory response in the subjacent tissues, but desmoplasia is usually absent. The epithelium is extraordinarily well differentiated without any of the normally associated malignant criteria identified in SCC. The cells are arranged in an orderly maturation toward the surface, with abundant surface keratosis (parakeratosis and/or orthokeratosis; “church spire” keratosis; Fig. 6.18 ). Parakeratotic crypting (collections of parakeratotic cells with debris) is a common feature. Mitotic figures are not easy to identify; when found, they are not atypical ( Fig. 6.19 ). If dysplasia is present, it is focal and limited to the basal zone. A foreign-body giant cell reaction may develop to extravasated keratin. Overexpression of p53 is seen in about 40% of cases. A benign keratinizing hyperplasia (verrucous hyperplasia), squamous papilloma, and a very well differentiated SCC can share all of these features somewhere in the tumor, making separation of these lesions a most vexing problem. The relationship of the lesion to the stroma must be adequately assessed in a sample of sufficient size that has been accurately oriented (not tangential) before a definitive diagnosis can be rendered.

FIGURE 6.15, ( A ) Laryngoscopy shows a large verruciform mass projecting into the lumen. ( B ) Multiple projections are seen in this macroscopic view of a large transglottic verrucous carcinoma.

FIGURE 6.16, The broad, pushing border of infiltration is noted below the adjacent uninvolved epithelium (far left). Keratosis and parakeratosis are noted in verrucous carcinoma.

FIGURE 6.17, The size of the lesion is often a helpful indicator in verrucous carcinoma. Seen here is a broad, pushing border of infiltration with extensive “church spire” keratosis and parakeratotic crypting.

FIGURE 6.18, The proliferation in verrucous carcinoma is cytologically bland; it shows maturation and appropriate polarity, demonstrating a broad, bulbous type of infiltration into the stroma with associated inflammation.

FIGURE 6.19, The epithelium of this verrucous carcinoma lacks pleomorphism and has inconspicuous mitoses. Keratosis is noted, with a prominent granular cell layer.

The major differential diagnosis rests between verrucous hyperplasia and conventional SCC. It is argued that the difference between verrucous hyperplasia and VSCC is only in stage and size, the lesions representing a developmental spectrum. The distinction on histologic features alone is often impossible. True verrucous hyperplasia must be diagnosed only on a large sampling, with caution to avoid underinterpreting the extent of the lesion ( Fig. 6.20 ). A papillary or exophytic SCC (ESCC) has pleomorphism and increased mitoses, showing lack of maturation toward the surface. VSCC can include an invasive component of “ordinary” SCC at the base or demonstrate atypical cytologic features; these are hybrid carcinomas and are managed as well-differentiated SCC. Squamous papilloma has thin, well-formed papillae, limited keratinization, and koilocytic atypia.

FIGURE 6.20, Verrucous hyperplasia with fronds of squamous epithelium covered with keratin and lacking architectural and cytologic features of malignancy. The separation of verrucous hyperplasia from verrucous carcinoma is often difficult, demanding clinical correlation.

Biologically, VSCC behaves as an “extremely well differentiated squamous cell carcinoma,” with an ∼85% to 95% 5-year survival depending upon site and stage. Most tumors are pT1 at presentation without lymph node metastases. Persistence/recurrence is seen in up to 20% of patients, usually as a function of the type of treatment. Voice-preservation techniques are encouraged, with surgery alone the mainstay of therapy . Radiation is sometimes used for functional preservation in nonsurgical candidates.

Exophytic and Papillary Squamous Cell Carcinoma

Definition

  • Exophytic or papillary architecture in a SCC

Prognosis and Treatment

  • Recurrences in about 35%

  • Better prognosis than conventional SCC (site- and stage-dependent)

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