Benign Neoplasms of the Larynx, Hypopharynx, and Trachea


Squamous Papillomas

Squamous papillomas are the most common benign neoplasms of the larynx and trachea, characterized by an exophytic squamous epithelium lining branching fibrovascular cores, often associated with human papillomavirus (HPV) infection. They may be solitary or may present in the setting of recurrent respiratory papillomatosis (RRP), a disorder characterized by numerous, multifocal, recurrent benign squamous papillomas of the respiratory tract. Squamous papillomas have a bimodal age distribution, with a peak in children younger than 5 years (i.e., juvenile papillomas), as well as one in adults from 20 to 40 years old (i.e., adult papillomas). There is a slight male predominance (3 : 2) in adult papillomas, but the sex distribution is equal for the juvenile form. RRP is more common in children, with approximately 25% of cases presenting in infancy. Squamous papillomas of the larynx are uncommon, with an estimated incidence of 4.3 cases per 100,000 children and 1.8 cases per 100,000 adults.

Squamous papillomas, especially those in the setting of RRP, are usually driven by specific types of HPV, especially types 6 and 11. These so-called low-risk types of HPV are biologically distinct from high-risk types that drive most cases of oropharyngeal carcinoma, largely due to different binding and signaling properties of their respective E6 and E7 proteins. In most pediatric cases the mode of transmission for the causative HPV is believed to be vertical (i.e., from mother to newborn via the birth canal). Indeed, an epidemiologic triad has been found to correlate with juvenile RRP cases: first-born child, vaginal delivery, and maternal age younger than 20. However, the mode of transmission in squamous papillomas that present in adults is unclear.

Squamous Papilloma—Disease Fact Sheet

Definition

  • Benign neoplasm composed of papillary fronds of squamous epithelium, usually caused by infection by low-risk human papillomavirus types 6 or 11

Incidence and Location

  • 4.3/100,000 in children, 1.8/100,000 in adults

  • True or false vocal cords, ventricles, subglottis, occasionally extending beyond the larynx

Morbidity and Mortality

  • Mortality 2%-14%, morbidity may be significant due to airway obstruction

Sex and Age Distribution

  • Affects sexes equally in children, slight male predominance in adults

  • Bimodal distribution with peaks in children <5 and adults 20-40 years

Clinical Features

  • Hoarseness, dysphonia, stridor, more severe in children

  • Exophytic masses, usually multiple, on laryngoscopic examination

Prognosis and Therapy

  • Multiple conventional or laser surgeries, with or without antiviral agents like cidofovir

  • Unpredictable course, although disease presenting in young children tends to be more progressive and more likely to transform into carcinoma

Clinical Features

Patients may present with dysphonia, hoarseness, and breathing difficulties. Symptoms are generally more severe in children, possibly in part because of the smaller diameter of their airways. On clinical examination, papillomas appear as friable, exophytic masses projecting into the airway ( Fig. 5.1 ). They tend to involve metaplastic areas where ciliated columnar transforms into squamous epithelium (squamocolumnar junction), for example, the true and false vocal cords, ventricles, and subglottis. As disease progresses, the papillomas may extend into the epiglottis and hypopharynx. Rarely (~5% of cases) papillomas can extend into the lower airway (bronchus and lung).

Squamous Papilloma—Pathologic Features

Gross Findings

  • Sessile or pedunculated, friable, exophytic tan-red mass with a lobulated surface. Often multiple

Microscopic Findings

  • Fingerlike fronds with fibrovascular cores lined by squamous epithelium

  • Epithelium often shows mild atypia in the form of basal or parabasal zone hyperplasia, increased mitoses, and “viral atypia” (koilocytes)

Ancillary Studies

  • Majority positive: low-risk human papillomavirus (especially types 6 or 11)

Pathologic Differential Diagnosis

  • Papillary carcinoma, dysplasia, verrucous hyperplasia, squamous cell carcinoma

FIGURE 5.1, This example of papillomatosis of the larynx shows numerous tan-pink fingerlike masses carpeting the right focal fold.

Pathologic Features

Gross Findings

Squamous papillomas are friable, exophytic tan-red masses with a lobular surface. They may be broad based or pedunculated with a stalk. They are often multiple ( Fig. 5.1 ).

Microscopic Findings

Squamous papillomas are characterized histologically by a complex proliferation of fingerlike growths consisting of delicate fibrovascular cores lined by squamous epithelium ( Fig. 5.2 ). There is typically little or no keratinization. Uncommonly there may also be a component of ciliated, respiratory-type epithelium. The lining epithelium is typically hyperplastic (i.e., thickened) and often exhibits mild atypia in the form of parabasal cell hyperplasia with mitotic figures elevated slightly above the basal zone ( Fig. 5.3 ). In addition, koilocytic changes such as nuclear hyperchromasia, irregular (raisinoid) nuclear membranes, and perinuclear haloes are often identified in the superficial epithelial layers ( Fig. 5.3 ). These types of changes should not be overinterpreted as squamous dysplasia. With that being said, in very rare instances, squamous papillomas can undergo malignant transformation into squamous cell carcinoma ( Fig. 5.4 ).

FIGURE 5.2, Squamous papillomas at low power consist of fingerlike projections of squamous epithelium surrounding a fibrovascular core. In patients with papillomatosis, it is typical for specimens to contain numerous fragments of papillomas in the container.

FIGURE 5.3, Squamous papillomas commonly exhibit mild atypia in the form of basal and parabasal layer hyperplasia and mitotic figures just above the basement membrane. In addition, cells in the superficial layers often exhibit “viral” atypia with crinkled nuclear membranes and perinuclear “haloes.” These cells can usually be shown to be positive for low-risk human papillomavirus by in situ hybridization ( inset ).

FIGURE 5.4, Very rarely, squamous cell carcinomas can arise in the setting of papillomatosis. In this case, an invasive squamous cell carcinoma is seen in the submucosa ( center ) surrounded by benign-appearing papilloma ( A ). At high power the squamous cell carcinoma is well differentiated, consisting of angulated nests of squamous epithelium eliciting a desmoplastic stromal reaction ( B ).

Ancillary Studies

Squamous papillomas are usually diagnostically straightforward and ancillary studies are rarely required. Low-risk HPV types (especially 6 or 11) can be demonstrated by HPV testing techniques, most often RNA or DNA in situ hybridization in more than 90% of cases. The signals are diffuse, nuclear, and usually confined to the most superficial layers of the epithelium ( Fig. 5.3 ). This testing is occasionally diagnostically useful (see Differential Diagnosis later) or may be requested by clinicians (e.g., for enrollment into specific clinical trials). p16 immunohistochemistry is not a useful surrogate for low-risk HPV.

Differential Diagnosis

Adult-onset squamous papillomas may be difficult to distinguish from squamous dysplasia (typically induced by smoking), which can sometimes exhibit papillary or exophytic architecture. As described previously, cellular changes that would be consistent with squamous dysplasia in some settings (e.g., parabasal hyperplasia, mitotic figures above the basal layer) are acceptable in benign squamous papillomas. In this setting, HPV 6/11 testing may be diagnostically useful, as a positive result is reassuring that the process is viral and likely not truly dysplastic. Similarly, the papillary variant of squamous cell carcinoma may be architecturally identical to squamous papilloma ( Fig. 5.5A ). However, this carcinoma variant exhibits overtly malignant cellular findings that are unlikely to be confused with a benign process ( Fig. 5.5B ). Verrucoid lesions such as verrucous hyperplasia, verruca vulgaris, or verrucous carcinoma may be considerations because there are also exophytic squamous lesions; however, these proliferations are broad based, lack papillary fronds with fibrovascular cores, and by definition demonstrate considerable surface keratosis.

FIGURE 5.5, At low power, papillary variant of squamous cell carcinoma is virtually identical to squamous papilloma, with numerous papillary tissue fragments ( A ). However, at high power the lining epithelium of papillary variant of squamous cell carcinoma is overtly malignant at the cytologic level, with marked disorganization, nuclear pleomorphism, and atypical mitoses ( B ).

Prognosis and Therapy

The clinical course of patients with squamous papillomas is rather unpredictable and is often marked by alternating periods of active disease and remissions, with longitudinal studies showing viral persistence in greater than 95% (same strain at the beginning and in follow-up). Although papillomas are technically benign neoplasms, they can cause considerable morbidity due to airway obstruction and result in death in a small subset (2% to 14%) of patients. The aggressiveness of RRP is associated with age of onset, with disease presenting earlier in life being more progressive and more likely to undergo malignant transformation. The rare examples of malignant transformation tend to be associated with some other risk factor, such as smoking or radiation exposure, and are more often seen in RRP-induced by HPV type 11.

Patients with RRP are treated with multiple conventional or laser surgeries, often with injection of antiviral agents (e.g., cidofovir). It is hoped that widespread use of the HPV vaccine will reduce the incidence of RRP, but the vaccine effects are not yet known.

Granular Cell Tumor

Granular cell tumor is an uncommon, benign mesenchymal neoplasm of Schwann cell origin showing polygonal, large, granular cells.

Granular Cell Tumor—Disease Fact Sheet

Definition

  • Benign mesenchymal neoplasm of Schwann cell origin, composed of polygonal cells with abundant granular cytoplasm

Incidence and Location

  • Uncommon

  • Larynx is one of the more common sites of occurrence, where it usually affects the posterior vocal folds

Sex, Race, and Age Distribution

  • No sex predilection for laryngeal tumors

  • Black patients are disproportionately affected

  • Third to fifth decades

Clinical Features

  • Usually hoarseness, sometimes cough, hemoptysis, dysphagia

  • Small rounded nodule on the vocal cords

Prognosis and Therapy

  • Simple excision alone

  • Excellent prognosis

Clinical Features

Granular cell tumor can be seen in a wide age range but most commonly affects patients in their 3rd to 5th decades. There is no predilection for either sex for laryngeal tumors, but tracheal granular cell tumors are seen more often in women. There is a predilection for black patients. In the head and neck, it is most frequently encountered in the skin, oral cavity (especially tongue), and larynx. Patients with laryngeal granular cell tumor tend to present with hoarseness, dysphagia, cough, or hemoptysis, and a small, nontender posterior vocal fold nodule is seen on laryngoscopic examination. Tracheal tumors generally occur in the cervical region of the trachea ( Fig. 5.6 ). Approximately 10% of patients have more than one tumor.

Granular Cell Tumor—Pathologic Features

Gross Findings

  • Rounded submucosal nodule, nonulcerated, with tan-white or yellow appearance on cut section

Microscopic Findings

  • Unencapsulated, poorly circumscribed proliferation of large polygonal to vaguely spindled cells with abundant pale granular cytoplasm

  • Nuclei small, round, and without significant atypia

  • May induce striking pseudoepitheliomatous hyperplasia of the surface epithelium

  • Involvement of nerves may be seen and is not significant

  • Rare malignant examples exhibit prominent spindling, elevated mitotic rates, necrosis, nuclear pleomorphism

Ancillary Studies

  • Positive : S100 protein, SOX10, inhibin, CD68

  • Negative : epithelial and muscle markers

Pathologic Differential Diagnosis

  • Adult rhabdomyoma, paraganglioma, alveolar soft parts sarcoma, PEComa, malignant granular cell tumor, squamous cell carcinoma (when pseudoepitheliomatous hyperplasia is prominent)

FIGURE 5.6, Endoscopic examination of a patient with granular cell tumor of the trachea. The nodular tumor has a whitish-yellow appearance (arrow) .

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