Practical Head and Neck Pathology: Frequently Asked Questions

© Springer Nature Switzerland AG 2019

D. Elliott Range, X. Sara Jiang (eds.)Practical Head and Neck PathologyPractical Anatomic Pathologyhttps://doi.org/10.1007/978-3-030-10623-2_1

1. Oral Cavity

Sasha Jane Betz¹  and Ricardo J. Padilla²

(1)

Naval Medical Center San Diego, Department of Anatomic Pathology, San Diego, CA, USA

(2)

University of North Carolina School of Dentistry, Department of Diagnostic Sciences, Chapel Hill, NC, USA

Keywords

PapillaryVerrucousHuman papillomavirusSquamous papillomaMultifocal epithelial hyperplasiaVerruca vulgarisCondyloma acuminatumVerruciform xanthomaInflammatory papillary hyperplasiaLocalized juvenile spongiotic gingival hyperplasiaSquamous cell carcinomaVerrucous carcinomaToriExostosesOsseous choristomaEctopic thyroidDermoid cystPyogenic granulomaInfantile hemangiomaKaposi sarcomaLymphatic malformationVenous malformationArteriovenous malformationCaliber-persistent arteryVaricesPeripheral ossifying fibromaPeripheral giant cell granulomaEpulis fissuratumMultiple endocrine neoplasiaCowden syndromeNeurofibromatosis type 1Tuberous sclerosisAmyloidosisGingival hyperplasiaCongenital epulis of the newbornTraumatic neuromaMucosal neuromaSchwannomaNeurofibromaSolitary circumscribed neuromaNerve sheath myxomaAngioleiomyomaMyofibromaGranular cell tumorPeutz-Jeghers syndromePrimary adrenal insufficiencyMelanoacanthomaMucosal melanomaGranulomatous inflammationTraumatic eosinophilic granulomaLichenoidLichen planusVesiculo-erosivePemphigus vulgarisMucous membrane pemphigoidEBV-related ulcerAphthous ulcerIntraoral herpesSubmucous fibrosisLeukoplakiaDysplasiaGenodermatosisOral hairy leukoplakiaSquamous odontogenic tumorp16Geographic tongueLymphomaPlasmacytoidSpindle cell malignancyVesiculobullous

Frequently Asked Questions

1.

What are the most common developmental lesions of the oral cavity?

2.

What is the differential diagnosis of vascular lesions of the oral cavity?

3.

What is lichen planus and which entities are in the differential diagnosis of lichenoid lesions of the oral cavity?

4.

What is geographic tongue and its key histologic features?

5.

Which oral lesions are associated with a prominent eosinophilic infiltrate?

6.

What is the differential diagnosis of granulomatous inflammation of the oral cavity?

7.

What is the differential diagnosis of vesiculobullous conditions of the oral cavity and which ancillary tests are used to diagnose them?

8.

What is the differential diagnosis of ulcers of the oral cavity?

9.

What is the differential diagnosis of inflammatory gingival masses?

10.

What conditions are associated with generalized gingival enlargement and what are their histological features?

11.

What systemic conditions may present with multiple oral masses?

12.

What are the etiologies, presentations, and histologic features of amyloidosis? What stains aid in the diagnosis?

13.

What is the differential diagnosis of intraoral soft tissue masses in infants?

14.

What is the differential diagnosis of benign neural tumors of the oral cavity?

15.

What are the common muscle tumors of the oral cavity and which immunohistochemical studies differentiate them?

16.

What types of pigmented lesions are encountered in the oral mucosa?

17.

What are the features of oral cavity melanomas and how do they differ from cutaneous melanomas?

18.

What is the differential diagnosis of benign papillary and verrucous lesions of the oral cavity?

19.

Should lesions of the oral cavity be tested for HPV?

20.

Which benign lesions are commonly associated with pseudoepitheliomatous hyperplasia?

21.

What is the differential diagnosis of leukoplakic lesions of the oral cavity?

22.

What are the criteria used to diagnose oral epithelial dysplasia and how is it graded?

23.

What are the clinical and histologic characteristics of oral cavity squamous cell carcinoma and which features are related to prognosis?

24.

What are the subtypes of oral squamous cell carcinoma and their significance?

25.

How does squamous odontogenic tumor differ from squamous cell carcinoma?

26.

What are the common fibrous and fibroblastic lesions of the oral cavity?

27.

What are the common salivary gland tumors of the oral cavity?

28.

What are the characteristics of metastases to the oral cavity?

29.

Which hematolymphoid lesions show a predilection for the oral cavity?

1.

What are the most common developmental lesions of the oral cavity?

Common developmental lesions of the oral cavity include choristomas, tori and exostoses, and dermoid cysts.

Bony exostoses are the most common developmental lesions of the oral cavity. They represent bony growths that arise from the cortical plates. The torus palatinus and torus mandibularis are found in approximately 20% and 6% of the population, respectively. The cause of tori is thought to be multifactorial, including genetic and environmental factors such as diet and bruxism. They may be removed for denture-planning procedures or to rule out more ominous pathologies. Not infrequently, tori become traumatized and infected, leading to bony necrosis and sequestration.

The histology is of normal-appearing, dense, lamellar bone.

Torus palatinus is a solitary bony protrusion located in the midline of the hard palate.

Torus mandibularis is located on the lingual surface of the mandible and usually occurs bilaterally.

Less frequent, is the torus maxillaris, found bilaterally in the buccal, maxillary, and premolar regions.

Choristomas are defined as normal tissue that is found in abnormal locations, where such tissue does not normally exist. In the oral cavity, they include lesions containing glial, gastrointestinal, and adnexal tissue. Choristomas typically present in the posterior dorsal tongue.

Females are affected twice as frequently as males with a wide age range from birth to the elderly.

The lesions present as smooth-surfaced, firm, sessile, or pedunculated masses. Gagging or dysphagia may be associated.

The most common tissue type in the oral cavity is bone or cartilage.

Histologically, mature bone or cartilage lies within connective tissue, deep to a normal epithelium. Haversian canals and marrow spaces may be identified.

Fordyce granules are another common lesion in this group. They are ectopic sebaceous glands (Fig. 1.1) usually found in the mucosa of the upper lip and cheek. Fordyce granules rarely form a mass. They are seldom biopsied given the classic clinical appearance of evenly distributed yellow-white, submucosal papules.

Ectopic thyroid tissue results from a disturbance in the descent of the thyroid from the foramen cecum to the anterior neck during embryogenesis. It presents early in life as a painless mass.

Females are affected four times more frequently than males.

90% occur in the posterior tongue.

In 75% of cases, a normal thyroid gland in the neck is absent, and patients require thyroid replacement therapy.

Histologically, normal-appearing thyroid follicles with colloid are identified in the lamina propria with possible extension into skeletal muscle. A capsule is usually absent. The tissue may undergo pathologic changes, including thyroiditis, nodular hyperplasia, and rarely, carcinoma.

Dermoid cysts most often occur in the midline floor of the mouth and are typically diagnosed within the first two decades of life.

Dermoid cysts located above the mylohyoid muscle present as a sublingual swelling and those located below the muscle present as a submental swelling.

Dermoid cysts contain tissue arising from both ectodermal and endodermal elements. Histologically, stratified, keratinized squamous epithelium lines a cystic lumen. The cyst wall contains dermal adnexa including hair follicles, sebaceous and sweat glands (Fig. 1.2).

The differential diagnosis includes an epidermal inclusion cyst which has a similar squamous lining but lacks adnexal structures and tends to occur in adults.

References: [1–6]

2.

What is the differential diagnosis of vascular lesions of the oral cavity?

Vascular lesions of the oral cavity range from localized caliber-persistent arteries to large hemangiomas. Vascular lesions are broadly divided into tumors and malformations (Table 1.1). A more comprehensive discussion of vascular lesions and how they are characterized can be found in Chap. 10.

Vascular tumors are characterized by a proliferation of endothelial cells. They may enlarge and later regress.

Vascular malformations are characterized by abnormal vascular channels. They are rare and typically do not regress.

The most common vascular lesions of the head and neck, in order of frequency, are:

1.

Infantile hemangioma.

2.

Lymphatic malformation – also known as cystic hygroma or lymphangioma. 75% occur in the head and neck.

3.

Venous malformation.

References: [7–14]

3.

What is lichen planus and which entities are in the differential diagnosis of lichenoid lesions of the oral cavity?

A lichenoid inflammatory infiltrate in oral mucosa biopsies (lichenoid mucositis) is a frequent finding with various etiologies and is characterized by a band-like inflammatory infiltrate in the lamina propria.

The classic lichenoid lesion of the oral cavity is lichen planus(LP). LP is a mucocutaneous, immune-mediated inflammatory process (Fig. 1.4). It affects middle-aged patients and shows a female predominance.

Patients present with erythematous, inflamed mucosal lesions, and ulcers which vary in appearance depending on type (Table 1.2).

As many as 25% of patients with mucosal lesions will have skin involvement.

The histologic features of LP are summarized in Table 1.3 and are characterized by a band-like, lichenoid chronic inflammatory infiltrate with interface mucositis and basal, vacuolar change (Fig. 1.4).

Dysplasia is not a feature of LP. However, there is conflicting data on the risk of malignancy in these patients which is reported to approximate 2%.

Direct immunofluorescence shows an irregular band of fibrinogen deposition on the basement membrane in nearly all cases.

There are a host of drugs and systemic conditions that can elicit a lichenoid mucositis and mimic LP (Table 1.4). Clinical history and careful application of diagnostic criteria can aid in arriving at the correct diagnosis.

References: [15–19]

4.

What is geographic tongue and its key histologic features?

Geographic tongue, also known as benign migratory glossitis, is a chronic, immune-mediated inflammatory process that affects approximately 3% of the population. It is the most common oral lesion associated with psoriasis.

The majority of cases are asymptomatic and present clinically as migrating areas of sharply demarcated erythematous mucosa rimmed by white, scalloped mucosa. The changes represent loss of filiform papillae.

Biopsies show a psoriasiform mucositis (Fig. 1.5). The white areas represent acanthosis with mild hyperparakeratosis, neutrophilic transmigration, and pseudo-abscesses filled with neutrophils within the upper half of the epithelium. The red areas correspond to areas of epithelial atrophy and loss of the filiform papillae. A mixed inflammatory cell infiltrate is usually seen in the lamina propria.

There is no premalignant potential associated with geographic tongue, but it is frequently biopsied and must not be confused with epithelial dysplasia.

Reference: [20]

5.

Which oral lesions are associated with a prominent eosinophilic infiltrate?

Eosinophils in the oral mucosa are associated with a host of lesions (Table 1.5) including, infectious, inflammatory, and neoplastic.

References: [17, 21]

6.

What is the differential diagnosis of granulomatous inflammation of the oral cavity?

Granulomatous inflammation can be encountered in oral biopsies as a result of local and systemic causes (Table 1.6).

The most frequently encountered lesion is secondary to foreign body implantation (Fig. 1.7).

Examination of all specimens under polarized light is mandatory.

In the absence of a foreign body, special stains for microorganisms should be performed.

Orofacial granulomatosis is a hypersensitivity reaction typically seen in young adults. Patients present with swelling of the lips and gingiva.

Histologic sections show non-necrotizing granulomas in the lamina propria with edema and chronic inflammation. Eosinophils may be seen. The granulomas may be subtle.

References: [22–24]

7.

What is the differential diagnosis of vesiculobullous conditions of the oral cavity, and which ancillary tests are used to diagnose them?

The oral mucosa is a frequent site of vesiculobullous diseases. The most common are mucous membrane pemphigoid and pemphigus vulgaris (Table 1.7).

Mucous membrane pemphigoid (Fig. 1.8) is the most common variant of a group known as the immune-mediated subepithelial blistering disorders.

Entities such as bullous pemphigoid, linear IgA disease, and pemphigoid gestationis are included in this group.

Pemphigus refers to a group of rare, autoimmune blistering disorders which include several variants. Pemphigus vulgaris (Fig. 1.9) is the most common. Other variants include:

Pemphigus foliaceus, IgA pemphigus, and paraneoplastic pemphigus

Diagnosis of vesiculobullous disorders relies on histologic confirmation with the aid of direct immunofluorescence (DIF).

Oral biopsies rarely include intact blisters due to the fragility of the oral mucosa.

If a blistering process is diagnosed, the patient must have a second biopsy of peri-lesional tissue for direct immunofluorescent studies in order to properly classify the disease and provide appropriate management.

References: [25–30]

8.

What is the differential diagnosis of ulcers of the oral cavity?

Oral ulcers can broadly be clinically divided into multiple ulcers and solitary ulcers.

Common conditions that manifest as multiple oral mucosal ulcerations are summarized in Table 1.8. Some of them have characteristic histologic features, but the majority require clinical correlation.

When reporting histologic findings in oral mucosal ulcers, it is important to:

Rule out infectious causes (fungal, viral, mycobacteria, etc.).

Characterize the type of the inflammatory infiltrate (chronic, granulomatous, etc.).

Recurrent aphthous ulcers have a variety of causes and associations. Diagnosis relies on clinical history and presentation. Treatment depends on the etiology, and unresolved lesions may be biopsied.

The ulcers will have a tan-gray pseudomembrane on examination.

Histology shows non-specific changes.

The mucosa is ulcerated with overlying fibrin and neutrophils.

Adjacent epithelium is spongiotic with inflammation.

The edge of the lesions may show granulation tissue and hyperkeratosis or parakeratosis.

Encountering single ulcerations of the oral mucosa is a frequent clinical situation. Most single ulcers are traumatic in origin.

In many occasions, the greatest value of pathologic examination of single ulcers is to rule out infectious processes or malignancy.

Entities in the differential diagnosis of a single aphthous ulcer includes:

CMV-associated mucosal ulcer (Fig. 1.10).

Syphilitic chancre.

Deep fungal infection.

Mucosal ulcer secondary to jaw disease or malignancy.

EBV-associated mucocutaneous ulcer – this is a hematolymphoid entity which is discussed later in question 29.

References: [31, 32]

9.

What is the differential diagnosis of inflammatory gingival masses?

Inflammatory masses of the gingiva are common (Table 1.9). The pluripotent capacity of gingival cells results in a spectrum of inflammatory lesions comprising reactive proliferations of bone, vessels, and mesenchymal cells.

The most common of these lesions is a pyogenic granuloma. This lesion differs from lobular capillary hemangioma in that the vascular proliferation is not organized in a lobular arrangement but instead grows in a radiating fashion from a central stalk or area.

References: [33–35]

10.

What conditions are associated with generalized gingival enlargement and what are their histological features?

Gingival overgrowth is usually triggered by an inflammatory response to dental plaque and poor oral hygiene. If the inflammatory response is clinically exaggerated, clinicians may biopsy these lesions to rule out other etiologies. There are multiple causes of gingival hyperplasia (Table 1.10); the histologic findings can be non-specific, and clinical correlation is usually required to arrive at a specific diagnosis.

References: [36–42]

11.

What systemic conditions may present with multiple oral masses?

Oral soft tissue masses may be manifestations of inherited syndromes, immune-mediated conditions, infections, or systemic diseases. Multiple oral lesions should raise suspicion for systemic diseases and prompt further clinical workup based on the histologic findings.

Inherited syndromes presenting with oral masses are highlighted in Table 1.11.

Immune-mediated conditions, specifically the granulomatous disorders, vary in their clinical manifestation of oral masses (see question 6).

Sarcoidosis may present as submucosal nodules, while Crohn’s disease may present with mucosal tags.

Biopsies of both reveal noncaseating granulomatous inflammation.

Among the infectious processes, multifocal epithelial hyperplasia (Heck’s disease) is most commonly associated with multiple oral masses.

Other HPV-associated lesions occurring in multiples may be seen in immune-deficient states, such as HIV-infected patients.

Amyloidosis can appear in the oral cavity as multiple oral masses, macroglossia, or induration of the buccal mucosa, lips, or tongue (see question 12).

References: [43–48]

12.

What are the etiologies, presentations, and histologic features of amyloidosis? What stains aid in the diagnosis?

Amyloid deposits comprise proteinaceous material with a variety of biochemical compositions. Amyloidosis of the oral cavity most commonly results from monoclonal gammopathies and the overproduction of immunoglobulin light chains (AL amyloid). Other etiologies include infection and rheumatic disease as a result of overproduction of acute phase proteins (AA amyloid). Rarely, amyloidosis is associated with familial syndromes.

Patients may present with induration, generalized nodularity, or isolated nodules of the oral mucosa.

The tongue is affected in 20% of patients with amyloidosis and presents as macroglossia with reduced mobility.

Histologic sections show amorphous, paucicellular, pale pink depositions within the lamina propria. The deposits may appear globular or diffuse, and perivascular or perineural patterns may be identified. Plasma cell infiltrates and a multinucleated giant cell reaction may be seen in association with the deposits.

Amyloid deposits stained with Congo red demonstrate apple-green birefringence under polarized light microscopy. If plasma cell infiltrates are identified, kappa and lambda immunohistochemistry (IHC) may be used to demonstrate monoclonal light chain restriction.

References: [49, 50]

13.

What is the differential diagnosis of intraoral soft tissue masses in infants?

The most common intraoral soft tissue masses in infants are vascular (see question 4). Others include ectopic thyroid tissue and hamartomas (see question 3), as well as congenital epulis of the newborn.

Congenital epulis of the newborn shows a female predominance and presents as a slightly red or mucosa-colored, pedunculated soft tissue mass. It is usually located on the mucosa of the anterior alveolus, with occurrence in maxilla approximately twice as frequent as the mandible.

Histologically, unencapsulated sheets of large cells with abundant, eosinophilic, granular cytoplasm and small, eccentric nuclei lie within normal adjacent connective tissue. The cells are morphologically identical to those of a granular cell tumor; however, S100 and SOX10 staining is negative. Excision is curative.

References: [51, 52]

14.

What is the differential diagnosis of benign neural tumors of the oral cavity?

Benign neural tumors of the oral cavity are not uncommon (Table 1.12). They may be trauma-induced, neoplastic, or syndrome-related. They are seen in various head and neck sites including soft tissues, ear, and salivary gland. With overlapping histologic features and immunohistochemical profiles, achieving the correct diagnosis may be challenging.

References: [53–57]

15.

What are the common muscle tumors of the oral cavity and which immunohistochemical studies differentiate them?

Angioleiomyoma is the most common oral smooth muscle tumor. It arises from the smooth muscle of vessel walls. In the oral cavity, it is most commonly found on the lower lip and presents as a painless or painful, mucosa-colored mass.

Myofibromas occur less frequently but may overlap in clinical and histological presentations. Rarely, multiple lesions are seen in infants and termed myofibromatosis.

Rhabdomyoma occurs in adults and children. It is a benign tumor derived from skeletal muscle. There is an adult and fetal type. Most are solitary but multifocal disease has been described.

The head and neck account for over 85% of the extracardiac rhabdomyomas.

The head and neck variant is not associated with tuberous sclerosis.

A comparison of the clinical, histologic, and immunohistochemical features of these lesions is outlined in Table 1.13.

References: [58–60]

16.

What types of pigmented lesions are encountered in the oral mucosa?

Pigmented lesions of the oral cavity may represent foreign body deposition, vascular lesions with hemorrhage, or melanocytic lesions. They are typically biopsied to exclude atypical and malignant melanocytic tumors.

Amalgam tattoos represent foreign body deposition of amalgam debris from silver-colored dental fillings.

Tissue sections show black to brown coarse, granular material tracking along collagen fibers and within vessels of the lamina propria (Fig. 1.15). Minimal to no inflammatory response is elicited.

Vascular pigmentation results from bleeding of vascular lesions and extravasation of blood.

Lesions show hemosiderin-laden macrophages singly or in clusters, resulting in clinical ecchymoses.

Traumatic lesions are often on the palate as a result of heavy snoring and emesis; inflammation may be present

Localized melanocytic lesions and their histologic findings are outlined in Table 1.14.

Generalized melanocytic lesions are usually associated with increased melanin production (melanosis) rather than melanocyte hyperplasia or proliferation.

The histologic findings are non-specific and typically show increased melanin in the basal layers of epithelium.

Causes of generalized melanocytic lesions include racial pigmentation, smoker’s melanosis, Addison’s disease, and various inherited syndromes that result in melanotic macules.

References: [61–63]

17.

What are the features of oral cavity melanomas and how do they differ from cutaneous melanomas?

Mucosal melanomas of the head and neck are most common in the nasal cavity and sinuses. Oral melanomas are rare and commonly affect the maxillary gingiva and hard palate. Patients are typically in the fifth to seventh decades.

The majority of cases show a radial growth phase in the form of a pigmented macule with or without a nodular component.

The radial proliferation comprises basally located atypical melanocytes. The vertical growth phase shows invasive nests of atypical melanocytes in the lamina propria.

Tumor cells show a variety of morphologies, as in other sites, including spindled, epithelioid, pleomorphic, and small round blue cells. Nuclei range from round to spindled with prominent nucleoli and brisk mitotic activity. Cells are generally pleomorphic and may contain fine, dusty brown, or coarse intracytoplasmic pigment and intranuclear inclusions (Fig. 1.18).

Melanin production is seen in about two-thirds of cases.

In contrast to cutaneous melanomas, oral melanomas:

Are not associated with ultraviolet light exposure as a risk factor.

Do not harbor BRAF-V600E mutations.

Uniformly have a poor prognosis that is not related to histologic parameters commonly identified in skin melanomas (e.g., depth, ulceration, etc.).

Usually arises de novo and is not preceded by a pre-existing, noninvasive pigmented lesion.

Five-year disease-free survival rates range from 0% to 20%. Over 50% of mucosal melanoma patients have nodal metastases at diagnosis, and over 25% present with distant metastases.

References: [61, 64, 65]

18.

What is the differential diagnosis of benign papillary and verrucous lesions of the oral cavity?

The descriptive terms verrucous and papillary overlap clinically and histologically in that both depict an exophytic architecture with surface projections. Due to the overlap, these lesions may be considered together for the purposes of generating a differential diagnosis.

Verrucous lesions are generally spikey and hyperkeratotic, appearing white clinically.

Papillary lesions have more rounded projections with parakeratosis and typically have fibrovascular cores imparting a more pink color on clinical inspection.

The etiologies of papillary and verrucous lesions of the oral cavity (Fig. 1.19) include human papillomavirus (HPV), inflammatory reactions, and neoplasia.

HPV-related lesions are commonly associated with low-risk subtypes including types 2, 4, 6, 11, and 32. The histological and clinical presentations vary widely (Table 1.15).

Inflammatory reactions with a papillary appearance may mimic the HPV-associated lesions clinically (Table 1.16).

Premalignant lesions and carcinomas with papillary or verrucous architecture are also in the differential diagnosis and will be discussed separately in question 24. They include lesions such as proliferative verrucous hyperplasia as well as papillary and verrucous carcinomas.

References: [66–72]

19.

Should lesions of the oral cavity be tested for HPV?

While the incidence of HPV-related squamous cell carcinoma is rising in the oropharynx, the majority of squamous cell carcinomas (SCC) of the oral cavity remain tobacco- and alcohol-related. It is estimated that only 5–9% of oral cavity squamous cell carcinomas are associated with high-risk HPV.

There is no evidence of benign HPV-associated oral lesions progressing to malignancy.

The correlation between clinical outcomes and the presence of HR-HPV in oral cavity SCC is not well proven.

Given the need for more definitive data, HPV testing for benign and malignant oral cavity lesions is not currently indicated.

References: [73, 74]

20.

Which benign lesions are commonly associated with pseudoepitheliomatous hyperplasia?

Pseudoepitheliomatous hyperplasia (PEH) is an exuberant, reactive, proliferation of squamous epithelium that is usually cytologically bland. Etiologies include fungal infection, underlying tumors or chronic irritation.

A granular cell tumor (GCT) is the prototypic tumor associated with PEH (Fig. 1.21). The most common site of granular cell tumors is the dorsal tongue.

GCT demonstrates sheets, cords, or nests of polygonal cells with abundant, eosinophilic, granular cytoplasm. The nucleus is small, normochromatic, and often eccentric.

PEH may show atypia and an irregular proliferation of epithelial nests at its deep border. This can be mistaken for squamous cell carcinoma. However, PEH is usually devoid of atypia, and the nests should not extend beyond the deep border of the granular cell tumor.

Tumor cells stain strongly and diffusely for S100 and SOX10.

Oral candida infection should be considered in the absence of a GCT. It is another common cause of PEH.

Microorganisms should be seen in the deep epithelium to exclude surface colonization.

References: [54, 75]

21.

What is the differential diagnosis of leukoplakic lesions of the oral cavity?

Leukoplakia is a white lesion involving the oral mucosa. It is a purely descriptive, clinical term which gives no indication of etiology or pathogenesis. There are many pathologic conditions that can present as a leukoplakia. Some of the most frequently encountered lesions that clinically may be described as leukoplakia are outlined in Table 1.17.

Most leukoplakic lesions show hyper-, ortho-, or parakeratosis of the surface epithelium, which conveys an opaque, white discoloration to the mucosa.

Biopsy is typically done to exclude dysplasia or carcinoma.

The prevalence of dysplasia ranges from 16% to 39%.

The rate of malignant transformation is 8–18%.

References: [76–85]

22.

What are the criteria used to diagnose oral epithelial dysplasia and how is it graded?

Oral epithelial dysplasia (OED) is a premalignant lesion of epithelium which shows architectural and cytologic atypia (Fig. 1.22). It may appear clinically as a leukoplakic or erythematous mucosal lesion. The criteria for OED (Table 1.18), established by the WHO in 2005, uses a set of cytologic and architectural features.

Grading of oral dysplasia traditionally encompasses a three-tiered system based on the amount of epithelium involved by the atypical changes.

Corresponding rates of malignant transformation increase with the degree of dysplasia.

Application of these criteria in a 3-tiered system had high inter- and intraobserver variability. As a result, a two-tiered system is advocated by some authors (Table 1.19) with a proposed point system applied based on the number of features present.

This binary system has improved observer variability and shows better correlation with disease progression to carcinoma. However, it will require additional validation.

References: [86–89]

23.

What are the clinical and histologic characteristics of oral cavity squamous cell carcinoma and which features are related to prognosis?

Oral squamous cell carcinoma (SCC) may affect any site in the oral cavity that is lined by stratified squamous epithelium.

Patients are typically males in the fifth to seventh decades.

The lip and oral tongue are the most frequent sites, followed by the floor of mouth.

Smoking is an important risk factor for the development of oral SCC and shows a dose-dependent effect. Alcohol imparts a synergistic effect.

Additional risk factors vary by site:

Lip: sun exposure.

Buccal vestibule, floor of mouth: smokeless tobacco, betel quid.

Oral SCC shows morphologic features similar to those seen at other head and neck sites (Fig. 1.23):

Nests and cords of polygonal cells with moderate to abundant, eosinophilic cytoplasm, distinct cell borders.

Round, irregular nuclei with coarse chromatin or hyperchromasia.

Dyskeratosis and keratin pearl formation can be seen in deep portions of the epithelium.

Associated dysplasia or in situ carcinoma and stromal desmoplasia may be present.

Oral SCC is locally aggressive and demonstrates early nodal disease. Poor prognostic factors include:

Depth of invasion greater than 4 mm.

Perineural, lymphovascular, and bone invasion.

Extranodal extension of lymph node metastases.

Two or more LN metastases.

Low-level nodal involvement (levels IV or V).

Satellite foci of tumor greater than 1 mm away from main tumor mass (WPOI 5: worst pattern of invasion 5).

References: [86, 90]

24.

What are the subtypes of oral squamous cell carcinoma and their significance?

The oral cavity is one of the most common sites for head and neck squamous cell carcinomas. Not surprisingly, it is also one of the more common sites for the different variants of SCC as well (Table 1.20).

Most of these variants are relatively rare. Their correlation with prognosis appears to be more closely related to tumor site rather than histologic type.

Verrucous and papillary carcinomas are notable for their improved prognosis over conventional SCC.

As a result of the better prognosis, strict criteria should be applied when diagnosing either of these variants.

Verrucous carcinomas are very well-differentiated and characterized by bland cytology, demonstrating essentially no atypia and a pushing border. Areas of small nest infiltration should be absent or minimal.

Papillary carcinomas are exophytic with well-developed papillary projections which demonstrate upward growth that extends beyond the surrounding uninvolved epithelium. It has a largely pushing border with scattered, infiltrative nests at the base. The lack of surface keratinization is a strict criteria that has been inconsistently applied to reports in the literature.

Awareness of the different variants is important for the prognostic value and to distinguish them from their histologic mimics.

References: [91–100]

25.

How does squamous odontogenic tumor differ from squamous cell carcinoma?

Squamous odontogenic tumor (SOT) is a benign neoplasm of odontogenic origin that most frequently arises in the medullary cavity of the jaws but occasionally presents as a peripheral/extraosseous lesion.

Radiographs show a radiolucent defect with well-delineated margins.

The tumor is composed of small islands and nests of bland squamous epithelium with occasional but not prominent keratinization. The tumor islands are haphazardly arranged in a fibrous stroma and may impart a jigsaw puzzle appearance (Fig. 1.24).

There is no connection with the surface epithelium except in cases in which the cortical bone is broken or when the lesion arises in the gingiva (peripheral squamous odontogenic tumor).

Differential diagnosticconsiderations include:

Squamous cell carcinoma – lacks the bland tumor cytology of SOT.

Acanthomatous ameloblastoma – stellate reticulum, cystic change, and nuclear palisading at the periphery of tumor nodules are not seen in SOT.

Reference: [101]

26.

What are the common fibrous and fibroblastic lesions of the oral cavity?

Mesenchymal lesions of the oral cavity include those derived from neural, muscular, adipose, and fibrous tissue. Most of the common tumors in the former categories have already been discussed. This current section will address a few miscellaneous entities found in the oral cavity (Table 1.21).

References: [102–111]

27.

What are the common salivary gland tumors of the oral cavity?

Salivary gland neoplasms arise from the numerous minor salivary glands found throughout the oral cavity. These tumors, along with their intraoral distribution and frequency, are discussed in greater detail in Chap. 5. A few important facts about intraoral salivary gland tumors include:

The oral cavity is the second most frequent site of salivary gland neoplasms after the parotid gland.

The palate is the most common intraoral location for salivary gland tumors.

Pleomorphic adenoma is the most common benign intraoral salivary gland neoplasm.

Mucoepidermoid carcinoma is the most common malignant intraoral salivary gland neoplasm.

References: [112]

28.

What are the characteristics of metastases to the oral cavity?

Metastatic tumors to the oral cavity are rare, comprising 1–2% of all neoplastic lesions at this site.

25% of oral cavity metastases represent unknown primary tumors.

25% of oral cavity metastases represent the first sign of metastatic disease and are a harbinger of advanced, late-stage disease.

Average interval from diagnosis of metastases to death is 5–6 months.

The most common oral site of metastasis is the gingiva.

The most common primary tumor is lung followed by breast. Kidney, liver, and colorectal carcinomas are among the five most frequent sites, but frequency varies by study.

References: [113–119]

29.

Which hematolymphoid lesions show a predilection for the oral cavity?

Hematopoietic tumors of the oral cavity are rare.

Lymphoma is the second most common malignant tumor of the oral cavity; non-Hodgkin lymphoma comprises <4% of all malignancies at this site.

Primary lymphomas in this location account for less than 2% of all extranodal lymphomas. Diffuse large B-cell lymphoma is the most common subtype.

A few rare hematolymphoid tumors have a particular predilection for the oral cavity and are highlighted in Table 1.22.

References: [32, 86, 120–127]

Fig. 1.1

Fordyce granules. Ectopic sebaceous glands underlie a normal squamous epithelium and show aggregates of pale, finely vacuolated cells with central, small nuclei

Fig. 1.2

Dermoid cyst. The cystic lumen is lined by stratified squamous epithelium with keratinization and adnexal structures in the cyst wall

Fig. 1.3

Lobular capillary hemangioma. (a) A vascular proliferation with surface ulceration and a (b) vaguely lobular pattern

Table 1.1

Vascular lesions of the oral cavity

H/N head and neck, GLUT glucose transporter, RBC red blood cell, HHV human herpes virus, LANA latency-associated nuclear antigen

Table 1.2

Clinicopathologic features of the different types of lichen planus

Fig. 1.4

Oral lichen planus. (a) Acanthotic squamous mucosa with a band-like lymphocytic infiltrate along the interface between the epithelium and lamina propria. (b) The lymphocytes obscure the basement membrane, eroding the basal keratinocytes. Exocytosis into the epithelium is present, and a dyskeratotic keratinocyte (Civatte body) is present (arrow)

Table 1.3

Histologic features of lichen planus

Table 1.4

Lichenoid conditions of the oral cavity

TKI tyrosine kinase inhibitors, SLE systemic lupus erythematosus, BMT bone marrow transplant, HLA human leukocyte antigen, GVHD graft-versus-host disease, OK orthokeratosis, PK parakeratosis, LP lichen planus, HK hyperkeratosis, BM basement membrane, DIF direct immunofluorescence, dsDNA double-stranded DNA, RNP ribonucleic protein

Fig. 1.5

Geographic tongue . The surface epithelium exhibits acanthosis, collections of neutrophils, and the absence of the usual filiform papillae of the dorsal tongue

Fig. 1.6

Traumatic ulcerative granuloma with stromal eosinophilia (TUGSE). (a) The ulcerated oral mucosa is rimmed by reactive epithelium. (b) The granulation tissue extends into the underlying striated muscle and contains enlarged fibroblasts, endothelial cells, and (c) eosinophils which may vary in number but are a constant feature

Table 1.5

Lesions of the oral cavity with prominent eosinophilia

Table 1.6

Disorders that present as granulomatous lesions of the oral cavity

Fig. 1.7

Foreign body granulomatous inflammation. (a) The lamina propria has non-necrotizing granulomas that lack microorganisms. (b) Fragments of pigmented, finely granular foreign body material are present

Table 1.7

Vesiculobullous conditions of the oral cavity

Fig. 1.8

Mucous membrane pemphigoid . The mucosa shows separation of the entire epithelium at the basement membrane level with subepithelial bulla formation and no evidence of acantholysis

Fig. 1.9

Pemphigus vulgaris . The mucosa shows acantholysis with retention of the basal keratinocytes along the basement membrane and suprabasal blistering

Table 1.8

Conditions presenting with multiple oral ulcers

Fig. 1.10

CMV ulcer base. Large, infected stromal cells show intracytoplasmic granules (arrow) and intranuclear inclusions with the characteristic clear halo (arrowhead). An immunohistochemical stain for CMV is positive in scattered cells (inset)

Fig. 1.11

Peripheral ossifying fibroma. (a) Sessile, hypercellular nodule composed of (b) bland fibroblasts and deposition of cementum and calcifications

Fig. 1.12

Peripheral giant cell granuloma. (a) Hypercellular, sessile lesion composed of (b) plump, monotonous spindle cells and multinucleated giant cells in a vascular stroma

Table 1.9

Inflammatory gingival masses

Fig. 1.13

Plasma cell gingivitis. (a) Slightly hyperplastic epithelium with sheets of inflammatory cells that do not efface the normal lamina propria architecture. (b) The inflammatory cell infiltrate is composed of mature, reactive plasma cells with no atypical features

Table 1.10

Conditions associated with generalized gingival enlargement

Fig. 1.14

Palisaded encapsulated neuroma. (a) A well-circumscribed spindle cell proliferation arranged in a vaguely lobular pattern with areas of tissue clefting. (b) Higher magnification shows short, plump, spindled cells with vague palisading and indistinct cell borders

Table 1.11

Inherited syndromes presenting with multiple oral masses

GI gastrointestinal

Table 1.12

Histologic features and immunohistochemical profiles of benign neural tumors of the oral cavity

var variable,