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Authors: Engy Abdellatif, M.B.B.Ch., M.D., Ph.D., F. Zahra Aly, M.D., Ph.D., Saeed Asiry, M.D., Elizabeth Ann Bilodeau, D.M.D., M.D., M.S.Ed., Andrey Bychkov, M.D., Ph.D., Veronica Cheung, M.Ch.D., Patricia DeVilliers, D.D.S., M.S., Nella Cristina Fernandez, M.D., Timothy Fielder, M.B.B.S., B.Med.Sci., Jerad M. Gardner, M.D., Sarah H. Glass, D.D.S., Joshua Seth Goldfaden, D.D.S., Raul S. Gonzalez, M.D., Ruta Gupta, M.D., Katherine Hulme, M.B.Ch.B., Dia Kamel, M.D., Ph.D., Arash H. Lahoutiharahdashti, M.D., Nathan Lee, D.M.D., Abberly Lott Limbach, M.D., Kelly Magliocca, D.D.S., M.P.H., Zahra Maleki, M.D., Jose G. Mantilla, M.D., Anthony Martinez, M.D., Mark Mintline, D.D.S., Tony Ng, M.D., Ph.D., Aaron Niblock, M.B.B.Ch., M.Sc., Nat Pernick, M.D., S. Rajendran, M.B.B.Ch., M.Sc., Ph.D., Rema A. Rao, M.D., Vijay Shankar, M.D., Molly Housley Smith, D.M.D., Ivan J. Stojanov, D.M.D., M.M.Sc., Sally Tanakchi, M.D., Charu Thakral, M.D., Vasiliki Tzelepi, M.D., Michella Whisman, M.D., Bin Xu, M.D., Ph.D., Hillary Zalaznick, M.D.

Editorial Board Members: Kyle Devins, M.D., Ruta Gupta, M.D., Kelly Magliocca, D.D.S., M.P.H., Lisa Rooper, M.D., Molly Housley Smith, D.M.D., Bin Xu, M.D., Ph.D.

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Superpage Topics

Acinic cell carcinoma Actinic cheilitis Adenoid cystic carcinoma Adenomatoid hyperplasia of minor glands Adult type rhabdomyoma Amalgam tattoo Anatomy & histology Aphthous ulcers Caliber persistent artery (pending) Carcinoma cuniculatum (pending) Choristoma Chronic ulcerative stomatitis (pending) Congenital epulis of newborn Dermoid / epidermoid cyst Duplication cyst Dysplasia Ectomesenchymal chondromyxoid tumor Ephelis Erythema multiforme Fordyce granules Frictional keratosis (pending) Geographic tongue Giant cell fibroma Gingival hyperplasia Granulomatous inflammation Grossing & features to report Hairy tongue Hereditary benign intraepithelial dyskeratosis (pending) HPV associated HPV independent Infections-general Inflammatory fibrous hyperplasia (pending) Inflammatory papillary hyperplasia Irritation fibroma Kaposi sarcoma Leukoedema (pending) Leukoplakia Lichen planus Lingual thyroid Lingual tonsil Low grade myofibroblastic sarcoma Lymphoepithelial cyst Median rhomboid glossitis Melanotic neuroectodermal tumor of infancy (pending) Melanotic pigmentation Melkersson-Rosenthal syndrome Mucocele Mucoepidermoid carcinoma Multifocal epithelial hyperplasia Nasolabial cyst Necrotizing sialometaplasia Nicotine stomatitis (pending) Oral focal mucinosis (pending) Oral hairy leukoplakia Oral mucosal melanoma Oral mucosal neuroma (pending) Oral submucosal fibrosis Oropharnygeal neuroendocrine carcinoma (pending) Paraneoplastic pemphigus (pending) Parulis Pemphigoid Pemphigus vulgaris Peripheral giant cell granuloma Peripheral ossifying fibroma Plasma cell gingivitis Plasma cell gingivitis (pending) Pleomorphic adenoma Polymorphous adenocarcinoma Primary mucosal CD30 positive T cell lymphoproliferative disorder (pending) Proliferative verrucous leukoplakia (PVL) Pseudoepitheliomatous hyperplasia Pyogenic granuloma Pyostomatitis vegetans (pending) Salivary duct cyst SCC-general Schwannoma Smokeless tobacco keratosis Spongiotic gingival hyperplasia (pending) Squamous papilloma Stafne defect (pending) Staging features Staging-mucosal melanoma Staging-oral cavity Staging-oropharynx & hypopharynx Subgemmal neurogenous plaque Tonsillitis (pending) Transient lingual papillitis (pending) Traumatic ulceration with stroma eosinophilia (TUGSE) Varix / varicosities / varices Verruca vulgaris Verruciform xanthoma Verrucous carcinoma White sponge nevus (pending) WHO classification-oral cavity & oropharynx WHO classification-oral cavity & oropharynx

Acinic cell carcinoma

Actinic cheilitis

Table of Contents

Definition / general

Common premalignant alteration, usually of the lower lip vermilion, that results from chronic ultraviolet light exposure

Essential features

Clinically, this manifests as blurring of the demarcation between the vermilion and lip mucosa (Head Neck Pathol 2020;14:899)
Actinic cheilitis has a strong predilection for fair skinned (> 87%) men (> 70%) over the age of 55; colloquially known as farmer's lip or sailor's lip due to its association with such outdoor occupations (Head Neck Pathol 2020;14:899, AOCD: Actinic Cheilitis [Accessed 4 March 2024])
Surface epithelium is variably dysplastic and is low risk for malignant transformation (J Investig Clin Dent 2018;9:e12343, StatPearls: Actinic Cheilitis [Accessed 4 April 2024], J Dent Res Dent Clin Dent Prospects 2021;15:285)
- Hyperkeratosis, acanthosis and atrophy of the epithelium may also be present
Underlying connective tissue exhibits solar elastosis, which appears as a band of amorphous, acellular, basophilic change due to ultraviolet light induced degeneration of collagen and elastin fibers (Head Neck Pathol 2021;15:566)

Terminology

First described as "scurfy, scaly lip of the outdoor worker" by Montgomery and Culver in 1920, who attributed this to effects of wind and weather; Ayres coined the term chronic actinic cheilitis in 1923 to describe a chronic inflammatory disorder of the lips as a result of actinic or chemically active rays of sunlight (JAMA 1923;81:1183)
In 1997, Manganaro, Will and Poulos designated actinic cheilitis as a premalignant, irreversible pathosis that most often affects the lower lip vermilion (Gen Dent 1997;45:492)

ICD coding

ICD-10: L56.8 - other specified acute skin changes due to ultraviolet radiation
ICD-11: EK90.Y - other discrete epidermal dysplasias

Epidemiology

Actinic cheilitis has a strong predilection for fair skinned (> 87%) men (> 70%) over the age of 55 (Head Neck Pathol 2020;14:899)

Sites

Actinic cheilitis affects the vermilion of the lower lips in 95% of cases (Head Neck Pathol 2020;14:899)

Pathophysiology

Ultraviolet B (UVB) rays (290 - 320 nm) are the primary cause of actinic damage as 70% is absorbed by the skin (J Oral Med Oral Surg 2023;29:30)
- This form of radiation drives thymine and uracil dimer formation in DNA and RNA, respectively; additionally, UVB rays create 6 - 4 pyrimidine photoproducts and substitutions of cytosine thymine in DNA, which particularly results in mutations to the p53 protein (Photochem Photobiol 2008;84:422)

Etiology

Ultraviolet radiation from long term sun exposure

Clinical features

Actinic cheilitis manifests as a blurred demarcation between the vermilion and the mucosal lip, erythema and edema with subsequent dry scaling / a persistent, nonmigrating crust and in some cases, leukoplakia (BDJ Open 2017;3:17016, J Drugs Dermatol 2011;10:1240)
- Patients typically have a chief concern of persistent chapped lips or lip tightness (AOCD: Actinic Cheilitis [Accessed 4 March 2024])

Diagnosis

May be detected clinically as blurring between the vermilion and lip mucosa as an incidental finding
- Lip may also be erythematous, swollen or present with white patching
Biopsy is indicated

Prognostic factors

Chronic sun exposure without protective measures increases risk for malignant transformation
Weighted remission rate following surgical treatment (92.8%) is greater than nonsurgical treatment (65.9%)
- Additionally, the recurrence following surgery (8.4%) is lower in comparison to nonsurgical treatment (19.2%) (Oral Dis 2019;25:972)

Case reports

51 year old man with a chief concern of a lip lesion that was diagnosed by his dentist (Oral Surg Oral Med Oral Pathol Oral Radiol 2020;130:e203)
64 year old, fair skinned man with multiple crusted areas of the lower lip vermilion (Oral Surg Oral Med Oral Pathol Oral Radiol 1980;50:21)
67 year old woman with a 2 year history of dryness, thickening and scaling of the entire lower lip that was treated with photodynamic therapy (Phtodermatol Photoimmunol Photomed 2007;23:209)
76 year old man presented with a white, hyperkeratotic lesion of the lower lip (Dermatology 2016;232:1)

Treatment

Surgical treatments, particularly carbon dioxide laser ablation and vermilionectomy, are associated with the most favorable outcomes and the fewest recurrences (J Eur Acad Dermatol Venereol 2021;35:815)
Nonsurgical treatments for actinic cheilitis consist of a variety of topical therapies, including
- 5-fluorouracil
- Imiquimod
- Trichloroacetic acid
- Ingenol mebutate
- Diclofenac
Reference: Photodermatol Photoimmunol Photomed 2019;35:11

Clinical images

Contributed by James Guggenheimer, D.D.S.

Blurring of lip vermilion

Microscopic (histologic) description

Surface epithelium is variably dysplastic
Hyperkeratosis, acanthosis and epithelial atrophy may be noted
Underlying connective tissue exhibits solar elastosis, which appears as a band of amorphous, acellular, basophilic change due to ultraviolet light induced degeneration of collagen and elastin fibers (Head Neck Pathol 2021;15:566)
Chronic inflammatory cell infiltrate and dilated blood vessels are often present

Microscopic (histologic) images

Contributed by Joshua Seth Goldfaden, D.D.S.

Hyperkeratotic, dysplastic epithelium

Prominent solar elastosis and telangiectasia

Epithelium with dysplastic changes

Arising squamous cell carcinoma

Keratosis and solar elastosis

Epithelial dysplasia and dilated vessels

Positive stains

p53 is variable; may have extreme (loss or gain) staining of surface epithelium or may be nonextreme (nonmutated)
- MDM2 coexpression may also be increased (Oral Oncol 2008;44:878)
Ki67 and IMP3 may exhibit respective increased proliferation and expression within surface epithelium (Oral Maxillofac Surg 2022;26:587)

Negative stains

SOX10, MelanA / MART1, MITF and HMB45

Sample pathology report

Left lower lip, incisional biopsy:
- Actinic cheilitis (see comment)
- Comment: Actinic cheilitis is considered a premalignant condition. Long term monitoring is advised. Further, the patient should be cautioned against future unprotected sun exposure and smoking (if applicable) (Oral Surg Oral Med Oral Pathol Oral Radol and Endodontol 1999;88:181).

Differential diagnosis

Squamous cell carcinoma:
- Invasive tumor islands are seen within the connective tissue
- Abnormal mitotic figures and keratin pearl formation may be seen
Cheilitis glandularis:
- Inflammatory condition of the minor salivary glands and excretory duct dilation, particularly of the lower lip
- Nodular enlargement, reduced mobility and eversion of the affected lip(s) (J Am Dent Assoc 1989;118:317)
Basal cell carcinoma:
- Nests of basaloid cells with peripheral palisading associated with a fibromyxoid stroma
  - Basaloid cells have a high N:C ratio with hyperchromatic nuclei
Herpes labialis:
- Intraepidermal blisters with acantholytic epithelium and solitary keratinocytes within the blister pouch
  - Nuclei of the keratinocytes show nuclear changes, including margination of chromatin, multinucleation and nuclear inclusions
  - Nuclear viral inclusions are small, pink deposits with a clear halo
- Initial clinical lesions appear as blisters that rupture and ulcerate
- The condition is self limiting and recurrences may occur

Board review style question #1

A biopsy of the lower lip of a 65 year old man reveals high grade dysplastic change, solar elastosis and telangiectasia. Based on these findings, what is the most appropriate diagnosis?

Actinic cheilitis
Cheilitis glandularis
Keratoacanthoma
Squamous cell carcinoma

Board review style answer #1

A. Actinic cheilitis. High grade dysplasia in the context of solar elastosis and telangiectasias is consistent with actinic cheilitis. Answer B is incorrect because cheilitis glandularis appears as inflammation of the salivary glands and dilation of the excretory ducts. Answer C is incorrect because keratoacanthomas are nodular with a central keratin plug. Answer D is incorrect because squamous cell carcinomas appear as nests of atypical epithelial cells within the stroma that arise from the surface.

Comment Here

Reference: Actinic cheilitis

Board review style question #2

A 60 year old, fair skinned woman presents with blurring of the vermilion and mucosa of the lower lip with an associated white plaque with prominent, surrounding erythema. Based on the clinical image, what is the lesion?

Actinic cheilitis
Basal cell carcinoma
Cheilitis glandularis
Melanoma

Board review style answer #2

A. Actinic cheilitis. This clinical image depicts blurring of the lower lip vermilion that is consistent with chronic solar damage. Answer B is incorrect because basal cell carcinoma often appears as ulcerated, nodular lesions with associated telangiectasias. Answer C is incorrect because cheilitis glandularis presents as nodular enlargement and eversion of the affected lip(s). Answer D is incorrect because melanoma (cutaneous) often exhibits irregular, pigmented areas.

Comment Here

Reference: Actinic cheilitis

Adenoid cystic carcinoma

Adenomatoid hyperplasia of minor glands

Table of Contents

Definition / general

Uncommon benign entity first described in 1971 (Oral Surg Oral Med Oral Pathol 1991;71:583)

Terminology

Also called acinar adenomatoid hyperplasia (Barnes: Surgical Pathology of the Head and Neck, 3rd Edition, 2008 [p500])

Epidemiology

Most cases reported in Caucasians, uncommon in Asians (Barnes: Surgical Pathology of the Head and Neck, 3rd Edition, 2008 [p500])
Ages 9 to 79 years; 58% male (Oral Surg Oral Med Oral Pathol 1991;71:583)

Sites

80% on hard and soft palate

Etiology

Chronic, local trauma (smokers, denture wearers) may be contributing factor (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1995;79:482)

Clinical features

Presents as painless, sessile swelling at junction of hard and soft palate; may mimic a salivary gland tumor (Barnes: Surgical Pathology of the Head and Neck, 3rd Edition, 2008 [p500])

Prognostic factors

Does not appear to predispose to benign or malignant salivary gland neoplasia

Case reports

48 year old Asian man with painless swelling in palate (J Laryngol Otol 1996;110:167)

Treatment

Excision is curative (Barnes: Surgical Pathology of the Head and Neck, 3rd Edition, 2008 [p500])

Gross description

Localized swelling resembling a neoplasm, 0.5 - 2.7 cm

Microscopic (histologic) description

Multiple aggregates, varying in size, of normal appearing mucous acini surrounded by fibrous connective tissue stroma
Normal ductal structures
Overlying palatal epithelium is usually normal but may have lichenoid reaction or pseudoepitheliomatous hyperplasia
Occasionally, areas of interstitial mucous extravasation with associated inflammatory reaction (Barnes: Surgical Pathology of the Head and Neck, 3rd Edition, 2008 [p500]) but typically no significant inflammatory cell infiltrates (Oral Surg Oral Med Oral Pathol 1991;71:583)

Differential diagnosis

Idiopathic hyperplasia of the sublingual gland or "pouting" sublingual glands is seen as an enlargement in the floor of the mouth in totally or partially edentulous patients; sublingual glands may be otherwise normal or show nonspecific chronic inflammation

Adult type rhabdomyoma

Amalgam tattoo

Table of Contents

Definition / general

Iatrogenic implantation of exogenous foreign material, specifically dental amalgam, into the tissues of the oral cavity

Essential features

Deposition often occurs during oral procedures involving amalgam
Gray, blue or black macule on clinical exam in the oral cavity
Large black deposits or fine black granules in the connective tissue with affinity for reticulin fibers

Terminology

Foreign body tattoo

ICD coding

ICD-10: M79.5 - residual foreign body in soft tissue

Epidemiology

Person with history of amalgam tooth restorations (dental fillings)
Affects 3.3% of the U.S. adult population (Head Neck Pathol 2019;13:47)

Sites

Any location in the oral cavity, with gingiva and alveolar mucosa being the most common location due to proximity to the teeth

Pathophysiology

Implantation of dental amalgam into oral mucosa

Etiology

Implantation of dental amalgam can occur several ways, including contaminated mucosal abrasion during dental procedure, broken amalgam pieces in an extraction site and endodontic retrofill procedure (Neville: Oral and Maxillofacial Pathology, 4th Edition, 2015)

Clinical features

Gray, blue or black macule that is rarely raised
Multiple macules may occur
Borders may be well defined, irregular or diffuse
Enlargement can occur (Head Neck Pathol 2019;13:47)
May be useful as a means for person identifications (J Forensic Odontostomatol 1991;9:17)

Diagnosis

In some cases, the diagnosis may be presumed on clinical exam with corresponding historical information and radiographic features
If the diagnosis cannot be made confidently on clinical exam, a biopsy is recommended for definitive diagnosis (Head Neck Pathol 2019;13:47)

Radiology description

Radiopaque fragments may be noted on radiographic exam if amalgam particles are large; however, this is not common

Radiology images

Contributed by Sarah H. Glass, D.D.S. and Duane Schafer, D.D.S., M.S.

Radiopaque amalgam fragments

Prognostic factors

Excellent prognosis

Case reports

38 year old woman with amalgam in mucoperiosteal flap from endodontic surgery (J Conserv Dent 2016;19:280)
49 year old woman with a brown-gray macule on the ventral tongue noted after dental restoration (N Engl J Med 2016;374:e21)
53 year old man with black macule on alveolar ridge and remote history of tooth extraction (Indian J Med Res 2018;148:240)

Treatment

No treatment is needed once diagnosis is established
Conservative surgical excision can be recommended for esthetic concerns, especially for the anterior maxilla (J Esthet Restor Dent 2020;32:770)

Clinical images

Contributed by Sarah H. Glass, D.D.S. and Duane Schafer, D.D.S., M.S.

Buccal mucosa amalgam tattoo

Large maxillary amalgam tattoo

Alveolar ridge amalgam tattoos

Gross description

Well defined or diffuse black, gray or blue pigmentation in connective tissue on cross section

Gross images

Contributed by Sarah H. Glass, D.D.S.

Excisional biopsy specimen

Cross section

Microscopic (histologic) description

Large black deposits of foreign material with or without a chronic inflammatory response in the connective tissue
Fine black granules in the connective tissue; may demonstrate affinity for reticulin fibers (Head Neck Pathol 2019;13:47)

Microscopic (histologic) images

Contributed by Sarah H. Glass, D.D.S.

Extensive amalgam deposition

Scattered amalgam granules

Around blood vessels

Large amalgam fragment

Giant cell engulfment

Sample pathology report

Oral cavity, excisional biopsy:
- Foreign body tattoo (see comment)
- Comment: The histopathology and clinical information are consistent with an amalgam tattoo.

Differential diagnosis

Oral melanotic macule:
- Increased melanin in basal cell layer of the epithelium with melanin incontinence in the superficial connective tissue
- Multifocal presentation may be seen in a systemic disease, such as Addison disease or Peutz-Jegher syndrome (Head Neck Pathol 2019;13:47)
Foreign body tattoo or other exogenous material:
- Intentional tattoo pigment (shown above)
- Graphite from pencil (Dermatol Online J 2015;21:13030)
Drug related discolorations:
- Depending on the drug, histopathology features mimic those of melanotic macule or brown-yellow granules in connective tissue (Head Neck Pathol 2019;13:47)
Submucosal hemorrhage:
- Hemosiderin in the connective tissue from trauma
- Positive Prussian blue

Additional references

AAOMP: Atlas of Foreign Materials - Amalgam [Accessed 18 April 2022]

Board review style question #1

A biopsy from the oral cavity shows exogenous black foreign material around blood vessels and along collagen fibers in a patient with a history of amalgam dental fillings. What is the diagnosis?

Amalgam tattoo
Oral melanotic macule
Peutz-Jegher syndrome
Submucosal hemorrhage

Board review style answer #1

A. Amalgam tattoo. Although all answer choices can result in pigmented macules in the oral cavity, amalgam is the only exogenous material. This foreign material has a particular affinity for reticulin fibers and can be seen around blood vessels.

Comment Here

Reference: Amalgam tattoo

Board review style question #2

What is the etiology of an amalgam tattoo from the oral cavity?

Drug related discoloration
Iatrogenic implantation of dental filling material
Increased melanin production
Trauma induced hemosiderin deposition

Board review style answer #2

B. Iatrogenic implantation of dental filling material. A dental professional may inadvertently implant amalgam, an exogenous foreign material, into the oral mucosa during a dental procedure.

Comment Here

Reference: Amalgam tattoo

Anatomy & histology

Table of Contents

Anatomy

Oral cavity extends anteriorly from vermilion junction of lips to junction of hard and soft palate above and to line of circumvallate papillae on dorsal tongue below; communicates freely with oropharynx posteriorly
Oral cavity contains buccal mucosa, maxillary and mandibular arches, retromolar trigone, anterior two - thirds of tongue, floor of mouth and hard palate
Dorsal tongue: villous, normally exposed surface; contains papillae and specialized taste receptors
Ventral tongue: nonvillous, undersurface
Anterior two - thirds of tongue (oral tongue): freely mobile portion of tongue that extends anteriorly from line of circumvallate papillae to undersurface of tongue at junction of floor of mouth; composed of skeletal muscle, includes 4 areas: tip, lateral borders, dorsum and undersurface (nonvillous ventral surface of tongue)
Base of tongue (posterior one - third of tongue): bound anteriorly by circumvallate papillae, laterally by glossotonsillar sulci and posteriorly by epiglottis
Buccal mucosa: all of membrane lining inner surface of cheeks and lips from line of contact of opposing lips to line of attachment of mucosa of alveolar ridge (upper and lower) and pterygomandibular raphe; contains ostia of main duct of parotid gland (Stenson duct)
Floor of mouth: semilunar space of myelohyoid and hyoglossus muscles, extending from inner surface of lower alveolar ridge to undersurface of tongue; posterior boundary is base of anterior pillar of tonsil; divided into two sides by frenulum of tongue, contains ostia of submaxillary and sublingual salivary glands
Gingiva: mucosa in area of teeth and palate; extends from labial sulcus and buccal sulcus to a cuff of tissue around each tooth
Hard palate: forms roof of oral cavity; semilunar surface between upper alveolar ridge and mucous membrane covering palatine process of maxillary palatine bones; extends from inner surface of superior alveolar ridge to posterior edge of palatine bone
Lip: begins at junction of vermilion border (mucocutaneous junction) with skin, includes only vermilion surface or that portion of lip that comes into contact with opposing lip; upper and lower lip are joined at commissures of mouth; external surface is skin and mucous membrane; internally contains orbicularis oris muscle, blood vessels, nerves, areolar tissue, fat and small labial glands; inner surface of lip is connected to gum in midline by frenulum, a mucous membrane fold
Lower alveolar ridge: mucosa overlying alveolar process of mandible which extends from line of attachment of mucosa in lower gingivobuccal sulcus to line of free mucosa of floor of mouth; posteriorly extends to ascending ramus of mandible
Retromolar gingiva (retromolar trigone): mucosa overlying ascending ramus of mandible from level of posterior surface of last molar tooth to apex superiorly, adjacent to tuberosity of maxilla
Tonsillar area: anterior and posterior tonsillar pillars and tonsillar fossa
Upper alveolar ridge: mucosa overlying alveolar process of maxilla which extends from line of attachment of mucosa in upper gingivobuccal sulcus to junction of hard palate; posterior margin is upper end of pterygopalatine arch
Vermillion border: mucocutaneous junction of lip

Juxtaoral organ of Chievitz

Not actually a congenital anomaly but normal occurring neuroepithelial structure called organ of Chievitz, Chievitz paraparotid organ, juxtaoral organ or epithelial nests
Reported in 56% of adult autopsies without oral mucosal lesions
Within intraoral sensory nerve
May undergo nodular hyperplasia
Located bilaterally in buccotemporal fascia on medial surface of mandible, near angle
Rare examples of proliferative / hamartomatous masses of juxtaoral organ reported
May be interpreted as squamous cell carcinoma, mucoepidermoid carcinoma or metastasis especially during frozen sections (Am J Surg Pathol 1979;3:147)

Microscopic (histologic) description

Multilobulated nests of squamous-like epithelium without keratin formation, occasionally with lumen lined by cuboidal cells
Associated with small nerves and resembling perineural invasion

Case reports

Child with intraoral tumor (Int J Oral Maxillofac Surg 2003;32:101)
63 year old man with rare hamartomatous lesion (J Clin Pathol 2003;56:789)

Histology-oral cavity

Stratified squamous epithelium often with parakeratosis
No hair follicles or sweat glands present
Keratinization in areas most exposed to mastication (gingiva, hard palate, dorsum of tongue)
Lamina propria contains loose connective tissue, mucous glands, serous minor salivary type glands
Submucosa has dense collagenous fibrous tissue
Oral tongue mucosa: modified keratinized squamous epithelium with small papillae; papillae can be filiform (majority, conical projections of keratinized epithelium), fungiform (rounded elevations, nonkeratinized), foliate (along sides of tongue) or cirucumvallate (at junction of anterior 2/3 and posterior 1/3 tongue, largest papillae)
Taste buds: barrel shaped, lightly staining, intramucosal sensory receptors present in large numbers on circumvallate papillae and in lesser numbers elsewhere
Intraepithelial nonkeratinocytes: melanocytes (basal), Merkel cells (basal), Langerhans cells (suprabasal) and lymphocytes occur in oral mucosa
Ectopic sebaceous glands (Fordyce spots) increase with age in adults
Tonsillectomy specimens frequently contain skeletal muscle (Hum Pathol 2000;31:813)

Immunostains

Oral epithelium expresses cytokeratin 5 and 14, ABO blood group antigens
Taste buds express low molecular weight keratins, such as CK18 and CAM5.2

Histology-oropharynx

[Pending]

Drawings

Images hosted on other servers:

Sagittal section

Tongue surface

Tongue and oral cavity

Undersurface of tongue

Coronal section of tongue

Filiform papilla

Fungiform papilla

Circumvallate papilla

Diagrams / tables

Contributed by Katherine Hulme, M.B.Ch.B.

Oropharynx (frontal view)

Oropharynx (lateral view)

Aphthous ulcers

Table of Contents

Definition / general

Also called canker sores
Affect 40% in U.S.
More common up to 20 years
Painful, recurrent and familial

Case reports

26 year old HIV+ man with recurrent ulcer treated with laser therapy (Case Rep Med 2012;2012:695642)

Treatment

Symptomatic

Clinical images

Images hosted on other servers:

Aphthous ulcers

26 year old man:

Minor ulcer

Major ulcer

Laser therapy

After one week of laser treatment

Gross description

Single or multiple, shallow, hyperemic ulcerations covered by a thin exudate with hyperemic rim

Microscopic (histologic) description

Initially mononuclear infiltrate, then neutrophilic infiltrate from secondary bacterial infection

Caliber persistent artery (pending)

[Pending]

Carcinoma cuniculatum (pending)

[Pending]

Choristoma

Table of Contents

Definition / general

Choristoma is a tumor-like mass consisting of normal cells in an abnormal location (J Oral Maxillofac Surg 2012;24:110)
Hamartoma is a tumor-like malformation composed of mature normal cells in usual location but as a disorganized mass

Epidemiology

Most cases occur in adults but may occur at all ages
> 70% of lingual osseous and cartilaginous choristomas occur in females (Barnes: Surgical Pathology of the Head and Neck, 3rd Edition, 2008 [p822])

Sites

85% of osseous and cartilaginous choristomas occur on tongue (dorsal posterior third near foramen cecum)

Clinical features

Firm, exophytic, asymptomatic nodule covered by intact oral mucosa
Base may be sessile or pedunculated

Radiology images

Case #142

Xray images

Case reports

Glial choristomas of palate in newborn / one month old (J Oral Pathol Med 1997;26:147)
5 year old boy with buccal osseous choristoma (Oral Oncology 2005;41:198)
73 year old woman with asymptomatic ventral tongue lesion (Gerodontology 2009;26:78)

Treatment

Surgical excision

Clinical images

Images hosted on other servers:

Osseous choristoma

Gross description

Firm mass covered by oral mucosa, with smooth contour
Usually < 1.0 cm; lesions > 2.0 cm warrant careful microscopic examination (Barnes: Surgical Pathology of the Head and Neck, 3rd Edition, 2008 [p822])

Gross images

Case #142

Various images

Images hosted on other servers:

Osseous choristoma

Microscopic (histologic) description

Oral choristomas can be classified according to types of tissues they constitute (J Oral Maxillofac Surg 2012;24:110):
1. Salivary gland choristoma
  1. Central
  2. Gingival
  3. Both have ectopic salivary gland tissue appearing as a raised tumor-like mass; must not have any connection with normal minor or major salivary glands
2. Cartilagenous choristoma: composed of mature hyaline cartilage in fibrous tissue that resembles perichondrium; usually multilobulated; chondrocytes vary from small to large but lack atypia
3. Osseous choristoma: composed of dense mature bone; osteocytes are compact and unremarkable; no prominent osteoblastic rimming; occasionally bone and cartilage are present in same lesion
4. Lingual thyroid choristoma
5. Lingual sebaceous choristoma
6. Glial choristoma
7. Gastric / respiratory mucosal choristoma
  1. Solid
  2. Cystic

Microscopic (histologic) images

Case #142

Various images

Images hosted on other servers:

Osseous choristoma

Base of tongue

Differential diagnosis

Cartilaginous metaplasia:
- Usually occurs in soft tissue beneath ill fitting dentures, has diffuse deposits of calcium, scattered cartilaginous cells arranged in various stages of maturation in single or clustered foci
Pleomorphic adenoma:
- May have osteocartilaginous foci
Salivary gland tissue:
- Choristomas lack salivary gland ductal or myoepithelial components

Chronic ulcerative stomatitis (pending)

[Pending]

Congenital epulis of newborn

Table of Contents

Definition / general

Congenital granular cell tumor of alveolar mucosa of jaw in newborns
90% girls; 10% present as multiple lesions
Doesn't recur, even if incompletely excised
0.5 - 2 cm soft, pedunculated mucosal mass
Spontaneously regresses over first 8 months of life (Am J Surg Pathol 1981;5:37)

Terminology

Congenital granular cell myoblastoma, granular cell epulis of infancy and granular cell fibroblastoma

Sites

Exclusively on anterior alveolar ridge of maxilla and mandible, usually overlying future canine and lateral incisor teeth

Case reports

Newborn girl with 2 cm tumor (Pediatrics 2001;107:E22)
2 day old girl with 4 x 2 cm exophytic growth (Pan Afr Med J 2012;12:105)
3 week old girl with spontaneous regression (J Med Case Rep 2010;4:331)
3 week old girl had a pedunculated lesion of the anterior maxillary alveolar process, which was excised (Case of the Month #524)

Clinical images

Contributed by Dhiraj B. Nikumbh, M.B.B.S., M.D.

2 day old girl with
difficulty eating and
breathing due to
upper jaw lesion

Images hosted on other servers:

Lesion at 3 weeks

Lesion at 16 months

Tumor arising from anterior maxillary alveolus

Gross images

Contributed by Dhiraj B. Nikumbh, M.B.B.S., M.D.

Congenital granular cell tumor

Microscopic (histologic) description

Confluent to nodular submucosal growth of tumors composed of large polygonal cells with eosinophilic granular cytoplasm and small central nuclei
Overlying epithelium is atrophic; does NOT show pseudoepitheliomatous hyperplasia (common with granular cell tumor of adults)

Microscopic (histologic) images

Contributed by Dhiraj B. Nikumbh, M.B.B.S., M.D. and Kelly Magliocca, D.D.S., M.P.H. (Case #524)

Stratified squamous epithelium

Abundant granular eosinophilic cytoplasm

S100

Scanning magnification

Stroma and overlying surface epithelium

Sheet-like growth

Granular stromal cells

Images hosted on other servers:

Polygonal cells

Positive stains

Vimentin, acid phosphatase

Negative stains

S100 (in contrast to granular cell tumor of adults), laminin, Leu7, NSE

Differential diagnosis

Granular cell tumor:
- Adults, infiltrates deep tissues, overlying epithelial hyperplasia
- S100+
Verruciform xanthoma:
- Adults, overlying papillomatosis

Board review style question #1

Which of the following is a feature of congenital granular cell epulis?

Clinical presentation at ages 5 - 15
Detection within first trimester
Female predilection
Local recurrence after excision
Pseudoepitheliomatous hyperplasia

Board review style answer #1

C. Female predilection. The characteristic presentation of CGCE is the presence of a solitary, soft pedunculated mass on the anterior maxillary alveolar ridge in a female infant. The female to male ratio is striking at nearly 8:1. Pseudoepitheliomatous hyperplasia is not present (the overlying epithelium is attenuated) and recurrence has not been reported (J Neonatal Surg 2015;4:17).

Comment Here

Reference: Topic name

Dermoid / epidermoid cyst

Table of Contents

Definition / general

Midline in floor of mouth
Present at birth but asymptomatic until inflamed

Case reports

11 year old boy with sublingual epidermoid cyst (J Med Case Rep 2007;1:87)
21 year old woman with sublingual dermoid cyst and difficulty in swallowing food (Case Rep Otolaryngol 2012;2012:634949)
25 year old man with epidermoid cyst presenting as large sublingual swelling (J Can Dent Assoc 2007;73:525)

Treatment

Conservative surgical removal

Clinical images

Images hosted on other servers:

Submental swelling

Gross images

Contributed by Dhiraj B. Nikumbh, M.D.

Multiple tonsillar epidermoid cyst

Images hosted on other servers:

Sublingual dermoid cyst

Sublingual epidermoid cyst

Microscopic (histologic) description

Lined by squamous epithelium, contains skin adnexae if dermoid cyst

Microscopic (histologic) images

Contributed by Dhiraj B. Nikumbh, M.D.

Multiple tonsillar epidermoid cyst

Images hosted on other servers:

Cyst filled with keratin

Sebaceous gland and hair follicles

Duplication cyst

Table of Contents

Definition / general

Lined by indigenous mucosa of segment it is duplicating

Case reports

Newborn with cyst containing gastrointestinal and respiratory epithelium (Arch Pathol Lab Med 1989;113:1301)
Six infants with cysts of anterior tongue (Arch Otolaryngol Head Neck Surg 2001;127:1484)
7 year old girl with enteric duplication cyst of floor of mouth and base of tongue (Arch Pathol Lab Med 2000;124:614)

Treatment

Excision; may recur if incompletely excised

Clinical images

Images hosted on other servers:

Anterior floor
of the mouth
and base of tongue

Foregut duplication cyst

Gross images

Images hosted on other servers:

Foregut duplication cyst

Microscopic (histologic) images

Images hosted on other servers:

Forgut duplication cyst of anterior tongue

Dysplasia

Table of Contents

Definition / general

Abnormal proliferation of oral epithelial squamous cells showing cytologic and architectural atypia; associated with risk of progression to squamous cell carcinoma

Essential features

Oral epithelial dysplasia describes a spectrum of changes in the oral squamous mucosa, as it transforms from normal epithelium into a premalignant lesion with potential to develop invasive carcinoma (if not adequately treated)
Various grading systems have been proposed to capture this spectrum of changes, to reduce inter / intraobserver variability and to guide patient management; the current widely used system is a 3 tier system, with some authors advocating for a binary system to increase reproducibility
Clinical correlation and good communication with the surgeons / dentists is important in distinguishing dysplasia from mimics

Terminology

Oral epithelial dysplasia (OED): histologically defined entity indicating premalignant changes in the epithelium
Oral potentially malignant disorders (OPMD): clinically defined entities that may or may not show histologic features of dysplasia
- These include leukoplakia, erythroplakia, erythroleukoplakia, oral submucous fibrosis, oral dysplasia

ICD coding

ICD-O:
- 8077/0 - squamous intraepithelial neoplasia, low grade
- 8077/2 - squamous intraepithelial neoplasia, high grade

Epidemiology

Epidemiology for high grade dysplasia / carcinoma in situ is similar to oral squamous cell carcinoma (SCC) and includes:
- Gender: worldwide incidence higher among males than females
- Age: older adult population
- Geographic (IARC: Global Cancer Observatory [Accessed 28 February 2022])
  - Higher incidence of oral cavity cancer in southern Asia, Melanesia; associated with areca / betel nut use
  - High incidence also in Australia, eastern and western Europe; associated with smoking / tobacco use
Certain oral potentially malignant disorders (OPMD) have specific predilection:
- Leukoplakia: middle aged men (> 40 years old)
- Proliferative verrucous leukoplakia: older (> 60 years old), women
- Oral submucous fibrosis: Asian, broad age range, affects both male and female with betel nut chewing habits

Sites

Oral cavity
- Tongue: anterior two - thirds from circumvallate papillae to the junction at floor of mouth
- Floor of mouth: inner surface of lower alveolar ridge to ventral tongue
- Buccal: inner surface of cheek
- Labial: inner surface of lips
- Alveolar ridge: mucosa over the alveolar process of maxilla and mandible
- Retromolar trigone: mucosa over the ramus of the mandible, posterior to the last molar tooth
- Hard palate: area between the upper alveolar ridge extending to posterior edge of palatine bone (OED is rare on the hard palate)
Higher risk of malignant transformation in tongue (lateral / ventral) and floor of mouth dysplastic lesions

Pathophysiology

Progression of dysplasia to carcinoma is a stepwise event with accumulation of genetic changes with loss of heterozygosity, copy number variations, somatic mutations and hypermethylation leading to increasing severity of dysplasia and eventually to carcinoma

Etiology

Causes are similar to those of oral squamous cell carcinoma
Lifestyle factors:
- Smoking, tobacco use
- Areca nut chewing
- Excessive alcohol consumption
- Alcohol use has synergistic effect with smoking / areca nut chewing (Br J Cancer 2015;112:580, Eur J Cancer Prev 2010;19:431)
Medical background:
- Autoimmune disorders
- Immunosuppressed state
- Genetic syndromes (Cancers (Basel) 2021;13:3696):
  - Dyskeratosis congenita
  - Bloom syndrome (congenital telangiectatic erythema)
  - Xeroderma pigmentosum
  - Fanconi anemia
- Nutritional deficiencies (Cancers (Basel) 2021;13:3696):
  - Iron deficiency
  - Vitamin A, B and C deficiencies
HPV infection (HPV oncogenic type 16 and 18) (Anticancer Res 2010;30:3435, Mod Pathol 2017;30:1646, Mod Pathol 2013;26:1288):
- Prevalence of HPV in oral cavity SCC 4 - 6%
- Prevalence of HPV in OPMD and oral dysplasia reported 7 - 34%

Diagrams / tables

Contributed by Katherine Hulme, M.B.Ch.B.

Oral cavity (sagittal view)

Oral cavity (frontal view)

Clinical features

Presentation can be variable, ranging from asymptomatic lesions to nonhealing ulcers
Examination and detection require visual inspection and palpation for induration
OED can present clinically as leukoplakia or erythroplakia (Head Neck Pathol 2019;13:423)
- Leukoplakia:
  - Defined as white plaque of uncertain risk, provided that other known diseases / disorders with known cancer risk have been excluded
  - Localized leukoplakia more common in men and can present as
    - Homogeneous leukoplakia: uniform plaque, partially well delineated
    - Nonhomogeneous leukoplakia: warty / verrucous appearance with nodular or red areas, higher risk of dysplasia and carcinoma
  - Majority are keratosis of unknown significance but a proportion (40 - 46%) can show dysplasia, carcinoma in situ or invasive carcinoma at presentation (Oral Surg Oral Med Oral Pathol Oral Radiol 2014;118:713)
- Proliferative verrucous leukoplakia:
  - Affects older women
  - Presents as white plaque, verrucoid / warty keratotic surface and multifocal disease
  - May demonstrate a ring around the collar appearance, extending along the marginal gingiva (J Periodontol 2021;92:273)
  - Demonstrates a higher rate of malignant transformation
- Erythroplakia:
  - Granular red plaque, painless (much less common than leukoplakia)
  - More frequently associated with dysplasia, carcinoma in situ and invasive malignancy
- Oral submucous fibrosis:
  - Mucosal pallor
  - Palpable fibrous area
  - Burning sensation
  - Associated with areca nut chewing

Diagnosis

Diagnosis is based on histological examination of biopsy specimen of the lesion
Biopsies should aim to sample the most representative area with dysplasia / malignancy; e.g., thick white plaques, erythematous, indurated areas and adjacent to ulcer (J Can Dent Assoc 2008;74:283, J Can Dent Assoc 2012;78:c75)
Biopsies of the lesion periphery can be useful in certain cases (e.g., verruciform lesions) as it allows for comparison with adjacent normal mucosa
Large lesions may require multiple biopsy samples of heterogeneous area
Types of biopsies (J Can Dent Assoc 2012;78:c75):
- Incisional biopsy
  - Method of choice in examining representative area of tissue, especially where there is concern for malignancy
- Excisional biopsy
  - Complete removal of a lesion is usually more appropriate for benign lesions
- Punch biopsy
  - This technique can be used for incisional or excisional biopsy of a small lesion that is easy to access
- Laser technique
  - Greater value in wound management over scalpel biopsy where wound closure is difficult or inappropriate
  - Used for complete excision of lesions
  - Avoid use during incisional biopsy to avoid cytologic alterations, which may interfere with diagnosis

Prognostic factors

Presence of risk factors:
- Persisting lifestyle factors (smoking / tobacco, excess alcohol, areca nut) increases risk of recurrence / progression
Precursor lesions:
- Nonhomogeneous leukoplakia, erythroleukoplakia and erythroplakia are associated with higher risk of dysplasia and transformation
Multifocal disease increases risk of recurrence
Incomplete resection increases risk of recurrence
Size of the lesion (> 200 mm²) increases risk of malignant transformation (J Oral Pathol Med 2016;45:155)
Location of lesion:
- Higher risk of malignant transformation in tongue and floor of mouth lesions (J Oral Pathol Med 2016;45:155, Cancer 2001;91:2148)
Grade of dysplasia:
- Not all dysplastic lesions progress to invasive carcinoma
  - Transformation rate (annual) reported at 12% with higher rates associated with higher grades of dysplasia (Head Neck 2009;31:1600, Head Neck 2020;42:539)
  - Transformation rates over 15 year period:
    - Low grade (mild) dysplasia ~6%,
    - Moderate dysplasia ~18%,
    - High grade (severe) dysplasia ~39% (Cancer Prev Res (Phila) 2013;6:822)

Case reports

18 year old man with right lateral tongue leukoplakia (Oral Oncol 2021;122:105565)
39 year old woman (no history of smoking or alcohol use), on treatment for rheumatoid arthritis, develops a right lateral tongue lesion (J Oral Pathol Med 2005;34:447)
46 year old man with a left buccal mucosa nodule of several years duration (Int J Surg Pathol 2014;22:248)
54 year old man, with myeloma treated with hematopoietic stem cell transplantation, develops diffuse white lesions of the buccal, tongue and palate mucosa (Spec Care Dentist 2019;39:51)

Treatment

Surgical management is the treatment of choice
- Excision or laser ablation
- Does not completely eliminate the risk of recurrence or transformation; therefore, regular follow up is required
Nonsurgical management
- Topical and systemic treatments (e.g., bleomycin, cyclooxygenase [COX] inhibitors, vitamin A and beta carotene) have been examined but show no benefit in reducing risk of recurrence or malignant transformation (Cochrane Database Syst Rev 2016;7:CD001829, Periodontol 2000 2019;80:126)
Elimination of risk factors is essential to reduce the risk of recurrence

Clinical images

Contributed by Molly Housley Smith, D.M.D.

Floor of mouth leukoplakia

Buccal and labial leukoplakia

Images hosted on other servers:

Leukoplakia of buccal mucosa

Gross description

Identification of OED may be easier on excisions rather than small biopsies
Mucosal resections can show ill defined, pale areas or plaque-like lesions with / without ulceration
Thickened, verruciform appearance in lesions with verrucous hyperplasia
OED is confined to surface mucosa

Gross images

Contributed by Veronica Cheung, M.Ch.D.

Laser resection oral mucosa

Frozen section description

Dysplastic changes may be seen in mucosal margins of radical resections for oral squamous cell carcinoma (Cancer 2006;107:2792, Head Neck Oncol 2011;3:56)
Frozen sections should not be performed for diagnosis of OED as it can compromise evaluation of grade and invasion

Microscopic (histologic) description

Diagnostic criteria for epithelial dysplasia are divided into 2 types of features, architectural and cytological; various combinations of these features lead to a specific grade of dysplasia
Dysplasia is divided into 3 grades of severity ranging from:
- Mild / low: atypia involves < one - third
- Moderate / intermediate: atypia involves one to two - thirds of the mucosal thickness
- Severe / high: atypia involves > two - thirds of the epithelial thickness
- However, the degree of cytologic atypia can increase the grade even if involving lower part of mucosa
Carcinoma in situ is synonymous with severe dysplasia and involves full thickness of the oral mucosa
Diagnostic criteria for epithelial dysplasia adapted from WHO Classification of Head and Neck Tumors, 2017:
- Architectural features:
  - Basal hyperplasia and increased stratification
  - Loss of epithelial cell cohesion
  - Bulbous drop shaped rete ridges
  - Confluence of the rete
  - Keratin pearls within rete ridges
  - Abnormal superficial mitotic figures
  - Lack of maturation towards the surface
  - Verrucous / papillary architecture
  - Bulky epithelial hyperplasia
  - Sharp demarcation from the adjacent inflamed or normal mucosa
  - Extension of squamous atypia along minor salivary gland ducts
- Cytological features:
  - Abnormal variation in cell size
  - Abnormal variation in cell shape
  - Dyskeratosis and glassy cytoplasm
  - Abnormal variation in nuclear size
  - Abnormal variation in nuclear shape
  - Increased nuclear:cytoplasmic ratio
  - Increased number of mitotic figures
  - Atypical mitotic figures
  - Premature keratinization in single cells
  - Increased number and size of nucleoli
  - Hyperchromasia
Further additions to the architectural and cytologic criteria outlined in WHO have been proposed, including hyperkeratosis with epithelial atrophy (Head Neck Pathol 2019;13:423)
Purpose of grading dysplasia is for risk stratification and to direct appropriate patient management (when considered together with other risk / prognostic factors)
History of grading oral dysplasia (J Oral Biol Craniofac Res 2020;10:788):
- Smith and Pindborg 1969
  - Use of standardized photographs for each criterion of dysplasia (total of 13 criteria) (J Oral Maxillofac Pathol 2015;19:198)
  - Each criterion was graded as absent, slight and marked; then were assigned specific scores that were added to give a final epithelial atypia index
  - This system was found to be tedious and time consuming
- Ljubljana classification 2003
  - System proposed for classifying laryngeal dysplasia was also proposed for lesions of the oral cavity (J Craniomaxillofac Surg 2003;31:75)
  - Initial 4 grade system: squamous hyperplasia, basal parabasal hyperplasia, atypical hyperplasia and carcinoma in situ (Histopathology 1999;34:226)
  - Differences in interpretation of terminology for each grade led to variability in grading and difficulty in categorizing dysplasia in atrophic mucosa
- Brothwell 2003 (Community Dent Oral Epidemiol 2003;31:300)
  - 5 tier system: no dysplasia, mild, moderate, severe and carcinoma in situ
  - Diagnostic criteria for dysplasia based on 4 histologic features only: basal and parabasal hyperplasia, nuclear hyperchromasia, nuclear pleomorphism and bulbous retes
- WHO 2005
  - Recognized 5 stages of precursor lesion: squamous hyperplasia, mild dysplasia, moderate dysplasia, severe dysplasia and carcinoma in situ
  - Dysplasia was based on changes in architecture and cytology and the epithelium was divided into thirds in order to classify the lesion as mild, moderate or severe
- Binary system 2006
  - Due to the variability in interpretation of each cytological / architectural dysplasia criterion (presence of and degree of change), it was proposed that a 2 tier classification would increase concordance (J Oral Pathol Med 2008;37:127, Oral Oncol 2006;42:987)
- WHO 2017
  - Squamous hyperplasia and carcinoma in situ were removed (carcinoma in situ synonymous with high grade dysplasia in oral cavity), leaving a 3 tiered system
  - WHO recommends consensus grading by more than 1 pathologist to enhance reproducibility
HPV associated oral dysplasia (Mod Pathol 2017;30:1646, Mod Pathol 2013;26:1288)
- Predilection for tongue and floor of mouth location
- Associated with high risk HPV subtype 16
- Distinct histologic features include parakeratosis, epithelial hyperplasia, prominent karyorrhexis and apoptosis in all levels of the mucosa and conventional carcinoma in situ histology; koilocytes may be focal / few in number

Microscopic (histologic) images

Contributed by Veronica Cheung, M.Ch.D.

Basal cytologic and architectural change

Drop shaped rete

Dysplasia involving > two - third of mucosa

Dysplasia involving > two - thirds of mucosa

Severe cytologic, architectural atypia

Transition from normal to dysplastic mucosa

Floor of mouth dysplasia with skip lesion

Positive stains

While immunohistochemistry stains (p53, cyclin D1, Ki67, BCL2, EGFR) have been utilized in studying the progression of epithelial dysplasia and in an attempt to assess degree of dysplasia, the gold standard for diagnosis and grading of OED is based on routine histological examination (Anticancer Res 2008;28:2535, Int J Biol Markers 2007;22:132)

Molecular / cytogenetics description

Loss of heterozygosity (LOH) (Cancer Prev Res (Phila) 2012;5:1081, Clin Cancer Res 2000;6:357)
- LOH at 3p and 9p associated with dysplasia with slight increase in relative risk of developing invasive cancer
  - Increased risk of progression in the presence of LOH at other chromosomes including 4q, 8p, 11q, 13q and 17p
Other molecular alterations detected in premalignant lesions include increased expression of EGFR, cyclin D1 amplification, loss of Rb and disruption / overexpression of p53 (J Oral Pathol Med 2009;38:737, J Oral Pathol Med 2021;50:632, Mod Pathol 2022;35:177)

Sample pathology report

Lateral tongue, mucosal excision - stitch anterior:
- Low to high grade mucosal dysplasia (see comment)
- Comment: The entire specimen has been embedded and the sections studied through levels to show oral tongue mucosa with superficial skeletal muscle. There is a broad area of mucosal dysplastic changes ranging from low to high grade dysplasia. The latter is characterized by moderately thickened mucosa with atypical squamous cells involving almost full thickness of the epithelium. There is loss of polarity, increased nuclear size, hyperchromasia and pleomorphism with readily seen nucleoli. Suprabasal mitoses are noted including a few atypical forms. There is focal superficial excoriation and acute inflammation, with isolated fungal hyphae seen on dPAS stain. No invasive carcinoma is identified. The high grade dysplasia is 2 mm away from the closest peripheral margin, midline, while low grade dysplasia is seen focally at the anterior margin.

Differential diagnosis

Clinical history is often useful to distinguish OED from mimics
Traumatic / reactive keratoses:
- Clues to reactive keratosis: superficial changes, shredding keratin, shaggy parakeratosis, uniform cytologic atypia, balloon cells and intracellular edema
- Can show basal cell hyperchromasia and pleomorphism but usually less severe than true dysplasia
Candida:
- Causes hyperplasia, parakeratosis, superficial neutrophilic infiltrate
- Fungal hyphae: PAS and PAS diastase
Oral lichen planus (OLP):
- OLP tends to present as bilateral, multifocal, migrating / evolving lesions in contrast to an isolated, nonmigrating lesion of epithelial dysplasia
- Reactive atypia from lichenoid inflammation can be difficult to distinguish from mild dysplasia
- Look for classic features of OED: loss of polarity, drop shaped rete, mitoses, premature keratinization, sharp distinction from normal adjacent mucosa
- Lymphocyte predominant infiltrate versus mixed infiltrate in epithelial dysplasia with lichenoid features may be helpful
In some situations, it may be impossible to differentiate between reactive atypia and true dysplasia
Discussion with surgeon / dentist and recommend treatment or healing / resolution of inflammation before re-evaluation and rebiopsy, if clinically indicated
Good communication with the clinician is important in ensuring appropriate patient management

Additional references

Barnes: WHO Classfication of Head and Neck Tumours, 3rd Edition, 2005, El-Naggar: WHO Classification of Head and Neck Tumours, 4th Edition, 2017, Woo: Oral Pathology - A Comprehensive Atlas and Text, 2nd Edition, 2016

Board review style question #1

You receive a wedge biopsy from a 48 year old woman with a longstanding tongue lesion. Which of the following is true in relation to this histological finding?

Ensure the entire specimen is embedded and examined with levels
Following complete excision, the patient will no longer require any follow up
Immunohistochemistry for p16 can be used to confirm diagnosis
Presence of fungal hyphae will confirm the mucosal changes are reactive and are not dysplasia

Board review style answer #1

A. Ensure the entire specimen is embedded and examined with levels. Small mucosal biopsy / excisions should be entirely embedded and examined through levels to identify highest grade of dysplasia and the presence / absence of (micro) invasive disease.

Comment Here

Reference: Dysplasia

Board review style question #2

Which of the following is the most favorable prognostic factor for oral epithelial dysplasia?

45 year old woman with recurrent lateral tongue erythroplakia
Complete resection of low to intermediate grade dysplasia of lip buccal mucosa
Floor of mouth dysplasia recurrence
Multifocal intermediate to high grade dysplasia
Tobacco chewing in patient with previous tongue cancer

Board review style answer #2

B. Complete resection of low to intermediate grade dysplasia of lip buccal mucosa. The most favorable prognostic factor is the complete resection of a low risk lesion in a lower risk site (compared with tongue and floor of mouth sites that have higher risk of malignant transformation).

Comment Here

Reference: Dysplasia

Ectomesenchymal chondromyxoid tumor

Table of Contents

Definition / general

Rare, benign soft tissue tumor with striking predilection for the anterior dorsal tongue
First named by Smith et al. in 1995 (Am J Surg Pathol 1995;19:519)

Essential features

Most are found on the anterior dorsal tongue
Fewer than 120 well documented cases have been reported
Histopathologically demonstrates a well defined, often multilobulated tumor with ovoid, round, fusiform or polygonal cells within a sometimes myxoid, chondromyxoid or mucoid background
Reticular arrangement of cells is often noted
Characterized by RREB1::MRTFB (previously MKL2) fusion in 90% of cases (Am J Surg Pathol 2018;42:1297)
Conservative excision recommended; < 10% have recurred

Terminology

Ectomesenchymal chondromyxoid tumor of the anterior tongue (Am J Surg Pathol 1995;19:519)

ICD coding

ICD-10: D10.1 - benign neoplasm of tongue

Epidemiology

No sex predilection
Average age ~40 years
Age range is from 2.3 - 78 years (Cleft Palate Craniofac J 2022;59:932, Am J Surg Pathol 1995;19:519)

Sites

Striking predilection for anterior dorsal tongue
Rare cases reported in other oral locations
- Posterior tongue / base of tongue (Am J Surg Pathol 2018;42:1297, Cleft Palate Craniofac J 2022;59:932, Head Neck Pathol 2014;8:329, Oral Oncol 2017;67:192)
- Gingiva / anterior hard palate (Int J Oral Sci 2018;10:4, Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:154)
- Buccal mucosa (J Am Dent Assoc 2015;146:196)
- Mandible (Head Neck Pathol 2021;15:319)
Cases with the same RREB1::MRTFB fusion and overlapping morphologic features have been noted in extraoral sites
It is unclear whether these tumors are completely different entities or if they represent a variation of ectomesenchymal chondromyxoid tumor
- Mediastinum (Histopathology 2020;76:1023)
- Maxillo-ethmoidal angle, reported as a biphenotypic sinonasal sarcoma (Genes Chromosomes Cancer 2021;60:565)
- Oropharynx, reported as a biphenotypic oropharyngeal sarcoma (Genes Chromosomes Cancer 2018;57:203)

Etiology

Currently considered as tumors of uncertain histogenesis by WHO classification
Most authors support neural crest origin (Am J Surg Pathol 1995;19:519)
- Supported by the fact that the anterior tongue derives from the neural crest mesenchyme of the first branchial arch (Head Neck Pathol 2015;9:315)
- Pluripotency of the neural crest may explain the significant immunohistochemical variability (Oral Surg Oral Med Oral Pathol Oral Radiol 2021;132:4, Oral Oncol 2006;42:1026)
- Markers for undifferentiated embryonic stem cells (OCT 3/4, SOX2, Nanog, MAP2, CD105 mRNAs) have been found in ectomesenchymal chondromyxoid tumors (Oral Surg Oral Med Oral Pathol Oral Radiol 2013;115:233)
Some authors cite potential link between ectomesenchymal chondromyxoid tumor and myoepithelioma of soft parts (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005;99:581, Histopathology 2016;69:607)

Clinical features

Slow growing, usually asymptomatic, firm submucosal nodule on anterior dorsal tongue
Purulent drainage noted in one case report (Anticancer Research 2010;30:4685)
Tumor size ranges from 0.3 - 4.0 cm (Am J Surg Pathol 1995;19:519, Oral Oncol 2017;67:192)
Pain is rarely noted (Advances in Oral and Maxillofacial Surgery 2021;1:100006)

Diagnosis

Diagnosis is made on histopathological examination

Radiology description

Isointense signal or low intensity signal on T1 weighted MRI and hyperintense signal on T2 weighted MRI (Oral Surg Oral Med Oral Pathol Oral Radiol 2013;115:233, Oral Oncol 2017;67:192, BMJ Case Rep 2019;12:e231278)
Case detailing CT scan without contrast shows cystic appearing lesion with hemorrhagic areas (Head Neck Pathol 2014;8:329)

Radiology images

Images hosted on other servers:

Cystic appearing mass

T1 weighted image, MRI

T2 weighted image, MRI

Prognostic factors

5 cases (< 10% of reported cases with follow up information) are reported to have recurred (Am J Surg Pathol 2018;42:1297, Am J Surg Pathol 1995;19:519, Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009;108:e20)
Local re-excision appears curative (Oral Dis 2008;14:390)

Case reports

26 year old woman with slow growing nodule on the anterior dorsal tongue (Advances in Oral and Maxillofacial Surgery 2021;1:100006)
37 year old woman with expansile radiolucency in the body of the mandible (Head Neck Pathol 2021;15:319)
43 year old man with mass on posterior dorsal tongue (Head Neck Pathol 2014;8:329)
46 year old man with anterior dorsal tongue mass, present for 5 years (BMJ Case Rep 2019;12:e231278)

Treatment

Conservative surgical excision is recommended (Int J Surg Case Rep 2017;41:162, Oral Dis 2008;14:390)

Clinical images

Images hosted on other servers:

Submucosal nodule

Gross description

Firm, well defined tumor
White, tan, yellow or gray in color (Am J Surg Pathol 1995;19:519, Acta Cytol 2010;54:82, Oral Surg Oral Med Oral Pathol Oral Radiol 2021;132:4)
Cystic, gelatinous or hemorrhagic areas often are described (Virchows Arch 2003;442:302, Int J Surg Pathol 2016;24:586, Oral Surg Oral Med Oral Pathol Oral Radiol 2021;132:4)

Gross images

Images hosted on other servers:

Well circumscribed, tan, hemorrhagic mass

Microscopic (histologic) description

Well demarcated tumor, often entrapped within skeletal muscle and frequently multilobulated (Am J Surg Pathol 2018;42:1297, Head Neck Pathol 2015;9:315)
Stromal background may be hyalinized or demonstrate mucoid, myxoid or chondromyxoid areas
Cords, strands or sheets of oval, round, fusiform or polygonal bland cells, sometimes arranged in a reticular / net-like or globoid pattern (Am J Surg Pathol 2018;42:1297)
Myxoglobulosis-like changes have been noted (Virchows Arch 2003;442:302)
May focally demonstrate fine calcifications, cellular atypia, necrosis, multinucleated giant cells (Am J Surg Pathol 2018;42:1297, Head Neck Pathol 2015;9:315, Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;82:417)
Cystic, slit-like spaces or hemorrhagic areas often noted (Head Neck Pathol 2014;8:329)
Mitotic figures not seen (Head Neck Pathol 2015;9:315)

Microscopic (histologic) images

Contributed by Molly Housley Smith, D.M.D.

Prominent hemorrhagic areas

Entrapment within muscle

Focal papillary growth pattern

Chondromyxoid stroma

Hemosiderin breakdown products

Sheets of ovoid cells

Reticular pattern

Chondromyxoid stroma

Ovoid nuclei

GFAP

Virtual slides

Images hosted on other servers:

Multilobulated tumor

Cytology description

Overlapping features with pleomorphic adenoma (Acta Cytol 2010;54:82, Oral Oncol 2003;39:83)
Cellular, with abundant thick to myxoid fibrillary stromal elements (Acta Cytol 2010;54:82)
Clusters of oval, spindled or polygonal cells with uniform nuclei (Acta Cytol 2010;54:82)
Lacking mitotic figures (Acta Cytol 2010;54:82)

Positive stains

Glial fibrillary acidic protein (GFAP) ~90% (Head Neck Pathol 2015;9:315)
S100 protein > 90%
CD56 and CD57 > 50% (Head Neck Pathol 2015;9:315)
Authors often attribute the immunodiversity to the pluripotency of the neural crest origin
Many other markers, such as SMA, p63, cytokeratin, desmin and SOX10, are positive in a subset (< 50%) (Head Neck Pathol 2015;9:315, Int J Surg Pathol 2016;24:586, Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010;110:e48)

Negative stains

EMA typically negative

Electron microscopy description

Electron microscopy is not specific (Int J Surg Pathol 2016;24:586)
Lobulated, concave nuclei; well developed rough endoplasmic reticulum; intermediate filament bundles (Int J Surg Pathol 2016;24:586, Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;82:417)

Molecular / cytogenetics description

RREB1::MRTFB (previously MKL2) gene fusion (RNA sequencing and FISH) (Am J Surg Pathol 2018;42:1297)
EWSR1::CREM fusion product found in 1/21 cases and 3/11 cases showed EWSR1 rearrangement on FISH (Am J Surg Pathol 2018;42:1297, Histopathology 2016;69:607)
- Unclear at this point whether EWSR1 rearranged ectomesenchymal chondromyxoid tumors represent a separate entity or part of the spectrum of ectomesenchymal chondromyxoid tumors

Molecular / cytogenetics images

Images hosted on other servers:

FISH rearrangement of RREB1 and MRTFB

Sample pathology report

Anterior tongue, excision:
- Ectomesenchymal chondromyxoid tumor

Differential diagnosis

Soft tissue myoepithelioma:
- Due to the overlapping morphologic, immunohistochemical and molecular findings (EWSR1 rearrangements), some authors note significant overlap or potential link between soft tissue myoepithelioma and ectomesenchymal chondromyxoid tumor (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005;99:581, Histopathology 2016;69:607)
Pleomorphic adenoma / salivary myoepithelioma:
- Do not occur on the anterior dorsal tongue due to the lack of salivary glands in this area
- PLAG1 aberrations not found in ectomesenchymal chondromyxoid tumors (Histopathology 2016;69:607)
Oral focal mucinosis:
- Stroma positive for PAS and Alcian blue (Head Neck Pathol 2015;9:315)
- Less cellular than ectomesenchymal chondromyxoid tumors
- Most commonly found on the gingiva
Neurothekeoma:
- Positive with NKI / C3 (CD63), MITF (Head Neck Pathol 2015;9:315)
- Negative with S100, GFAP, CD57, cytokeratin (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;82:417)
Reticular perineurioma:
- EMA positive (Virchows Arch 2005;447:677)
- GLUT1 and claudin1 often positive
- Negative with S100, GFAP, CD57, cytokeratin
Clinical differential diagnosis for a submucosal nodule on the dorsal tongue most often includes fibroma / fibrous hyperplasia, granular cell tumor or cartilaginous / osseous choristoma, all of which can easily be differentiated from an ectomesenchymal chondromyxoid tumor by biopsy
GLI1 altered mesenchymal tumors:
- Both tumors have a propensity to oral tongue location, multilobulated to nodular growth pattern and immunopositivity of SMA, S100 and keratins
- GLI1 altered mesenchymal tumors have epithelioid morphology, arborizing capillary network and show GLI1 amplification or GLI1 translocation at molecular level (Am J Surg Pathol 2020;44:729)

Board review style question #1

The following tumor is found in the anterior dorsal tongue. Lesional cells are strongly and diffusely positive for GFAP and S100 protein. What is the diagnosis?

Ectomesenchymal chondromyxoid tumor
Glomus tumor
Granular cell tumor
Pleomorphic adenoma

Board review style answer #1

A. Ectomesenchymal chondromyxoid tumor. This tumor is well defined and comprised of ovoid cells set within a mucoid background.

B. While glomus tumors may show a similar morphology, the immunohistochemical profile is not compatible with glomus tumor.
C. While the dorsal tongue is a common location for granular cell tumor and S100 is positive, the morphology of the cells is inconsistent with granular cell tumor.
D. While the histomorphology is highly suggestive of pleomorphic adenoma, pleomorphic adenomas do not occur on the anterior dorsal tongue due to the lack of salivary glands in the area.

Comment Here

Reference: Ectomesenchymal chondromyxoid tumor

Ephelis

Table of Contents

Definition / general

Also called freckle
Solitary melanotic macules, usually of lower lip
More common in women; associated with Peutz-Jeghers syndrome

Case reports

4 patients with labial melanotic macule (Dermatology 2012;224:209)

Clinical images

Images hosted on other servers:

55 year old woman

60 year old man

26 year old woman

37 year old woman

Microscopic (histologic) description

Hyperpigmentation of basal layer with elongation of rete ridges

Microscopic (histologic) images

Images hosted on other servers:

Keratinocytes (fig d)

Differential diagnosis

Melanoacanthoma:
- Melanocytes mixed with keratinocytes
Melanosis:
- Pigmented patches in hard palate or gingiva

Erythema multiforme

Table of Contents

Definition / general | Case reports | Clinical images | Microscopic (histologic) description

Definition / general

Part of spectrum of reactive mucocutaneous disorders with maculopapular vesiculobulbous eruptions that includes erythema multiforme (EM - minor and major), Stevens-Johnson syndrome (SJS, if more mucosal involvement and epidermal necrosis) and toxic epidermal necrolysis (TEN)
Due to cancer, collagen vascular disorder, drugs, infection
Oral erythema multiforme: variant with only oral lesions and no skin involvement

Case reports

21 and 23 year old women with drug induced lip and oral ulcerations (J Oral Maxillofac Pathol 2012;16:145)
40 year old man with oral variant precipitated by alcohol (Indian J Otolaryngol Head Neck Surg 2011;63:9)

Clinical images

Images hosted on other servers:

21 year old woman:
irregular lip uclerations and buccal mucosal

23 year old woman:
palatal ulcerations

40 year old man:
hemorrhagic bullae and target lesions

Microscopic (histologic) description

Necrotic keratinocytes, spongiosis, basal layer liquefaction, dermal edema, perivascular or interface lymphocytes

Fordyce granules

Table of Contents

Definition / general

Ectopic sebaceous glands within oral cavity or on vermillion border of lips

Essential features

Appear as yellow-white, asymptomatic 1 - 3 mm papules in the oral cavity or lip vermillion
May be hyperplastic and nodular
Neoplastic transformation very rare but reported (Oral Surg Oral Med Oral Pathol 1991;72:709, Head Neck 2016;38:E20, Case Rep Dent 2018;2018:3054931)
Have been associated with Lynch and Muir-Torre syndromes (Gut 2005;54:1279, J Oral Pathol Med 2015;44:552)
Present in ~80 - 90% of the population (Med Clin North Am 2014;98:1281)

Terminology

Fordyce granules
Fordyce spots

ICD coding

ICD-10: Q38.6 - other congenital malformations of the mouth

Epidemiology

No sex or racial predilection
Often most prominent after puberty (Med Clin North Am 2014;98:1281)
Hyperplastic examples have been associated with Lynch and Muir-Torre syndromes (Gut 2005;54:1279, J Oral Pathol Med 2015;44:552)
Patients with high densities of Fordyce granules may have higher lipid profiles (Dent Res J (Isfahan) 2014;11:553)

Sites

Buccal mucosa (often bilateral), upper lip vermilion border, mandibular retromolar pad and tonsillar areas
Similar anomalies affect the areolae, glans penis and labia minora

Etiology

Congenital
Considered benign sebaceous hamartomas

Clinical features

Yellow-white, asymptomatic, floral appearing 1 - 3 mm papules that remain constant throughout life
May be hyperplastic and nodular

Diagnosis

Diagnosed clinically
Rarely may require biopsy for identification when hyperplastic or nodular

Treatment

No treatment necessary unless for cosmetic reasons

Clinical images

Contributed by Molly Housley Smith, D.M.D.

Yellow, floral papules

1 - 3 mm yellow-white papules

Image hosted on other servers:

Yellow-white papules

Microscopic (histologic) description

Similar to normal sebaceous glands of skin but lack hair follicles and almost always lack ductal communication with surface
Parakeratotic stratified squamous epithelium overlies the sebaceous lobules

Microscopic (histologic) images

Contributed by Molly Housley Smith, D.M.D.

Oral mucosa containing sebaceous lobules

Sebaceous lobules adjacent to mucous glands

Sebaceous lobules

Positive stains

Although associated with Lynch and Muir-Torre syndromes, which demonstrate defects in DNA mismatch repair (MMR) proteins leading to microsatellite instability, preservation of MMR proteins is noted upon immunostaining of Fordyce granules (Appl Immunohistochem Mol Morphol 2017;25:209)

Sample pathology report

Left buccal mucosa, incision:
- Fordyce granules (see comment)
- Comment: Microscopic examination reveals parakeratotic stratified squamous epithelium overlying mesenchymal tissue. Within the mesenchymal stroma are numerous sebaceous gland lobules. Hair follicles are not appreciated.

Differential diagnosis

Clinically diagnostic and doesn't have a differential diagnosis; often are not even biopsied but found only incidentally on pathology
Usually noted on routine examination

Additional references

J Cutan Dis 1896;14:413

Board review style question #1

Which of the following is true about this oral mucosal entity?

Immunohistochemistry is necessary to define this process
It is found in higher frequency in those who have Lynch and Muir-Torre syndromes
Neoplastic transformation occurs in the majority of cases
This entity is most frequently found on the tongue

Board review style answer #1

B. It is found in higher frequency in those who have Lynch and Muir-Torre syndromes

Comment here

Reference: Fordyce granules

Board review style question #2

A 43 year old female patient presents to the clinic for a routine head and neck cancer screening. Upon examination, numerous yellow-white papules (approximately 1 - 3 mm in diameter) are present along the upper lip vermillion border and on the right and left buccal mucosa. The patient states that the spots are asymptomatic and thinks that they have always been there. Which is the most likely diagnosis?

Actinic cheilitis
Fordyce granules
Morsicatio buccarum
Salivary gland hyperplasia

Board review style answer #2

B. Fordyce granules

Comment here

Reference: Fordyce granules

Frictional keratosis (pending)

[Pending]

Geographic tongue

Table of Contents

Definition / general

Inflammatory disorder characterized by asymptomatic erythematous patches with serpiginous borders
Local loss of filiform papillae leads to ulcer-like lesions that rapidly change color and size
Associated with common cold, work / home stress
Associated with tongue fissures

Terminology

Also called benign migratory glossitis, glossitis migrans

Epidemiology

1 - 2% of population, usually adults

Case reports

77 year old man and woman successfully treated with topical tacrolimus (J Dermatol Case Rep 2010;4:57)

Treatment

Usually none in asympomatic patients

Clinical images

Images hosted on other servers:

Before and after therapy

Geographic tongue

Gross description

Erythematous flat zone on tongue dorsum due to loss of filiform papillae

Microscopic (histologic) description

Acanthosis with neutrophils throughout epithelium and surface microabscesses, plus inflammatory infiltrate in lamina propria
Resembles psoriasis

Microscopic (histologic) images

Images hosted on other servers:

Psoriform epidermal hypertrophy

Giant cell fibroma

Table of Contents

Definition / general

Benign fibrous proliferation of the oral cavity mucosa with distinct stellate fibroblasts

Essential features

Fibrous nodule that most commonly presents on the gingiva and can have a papillary appearance
Histologic features include large, plump stellate fibroblasts in the superficial connective tissue
Treatment is conservative excision and recurrence is rare

ICD coding

ICD-10: benign neoplasm of mouth
- D10.0 - benign neoplasm of lip
- D10.1 - benign neoplasm of tongue
- D10.39 - benign neoplasm of other parts of mouth

Epidemiology

2 - 5% of all oral benign fibrous growths (Neville: Oral and Maxillofacial Pathology, 4th Edition, 2015)
Increased frequency in (Case Rep Dent 2014;2014:864512):
- Patients' first to third decade
- Caucasians

Sites

Most common location is the gingiva followed by the tongue, palate, buccal mucosa and lip (Oral Surg Oral Med Oral Pathol 1982;53:582)

Pathophysiology

Fibrous proliferation generally considered to be reactive process (Braz J Otorhinolaryngol 2019;85:399, Case Rep Dent 2014;2014:864512)
Giant cell fibroma shows limited growth potential, local recurrence would be considered exceptional and microscopic appearance is indistinguishable from nonneoplastic retrocuspid papilla; on balance, some authors have suggested the possibility that the lesion represents a neoplasm (Acta Histochem 2016;118:451, Head Neck Pathol 2019;13:71)

Etiology

Unclear etiology but less likely to be associated with chronic mild trauma (Head Neck Pathol 2019;13:71)

Clinical features

Dome shaped sessile or pedunculated fibrous nodule
Surface may be smooth, pebbly, bosselated, nodular or papillary
Most lesions are less than 1 cm in diameter (Head Neck Pathol 2019;13:71)
Asymptomatic unless secondarily traumatized

Diagnosis

Definitive diagnosis is made on histopathology

Prognostic factors

Excellent prognosis and recurrence is rare

Case reports

7 year old boy with a pedunculated soft tissue nodule on the mandibular gingiva (J Oral Maxillofac Res 2013;4:e5)
19 year old man with a small growth on the tip of the tongue (Case Rep Dent 2014;2014:864512)
30 year old man with a growth on gingiva in the retromolar area (J Oral Maxillofac Pathol 2017;21:429)
40 year old man with a sessile mass of the buccal mucosa (J Dent Sci 2021;16:552)

Treatment

Conservative surgical excision

Clinical images

Contributed by Sarah H. Glass, D.D.S.

Bosselated gingival mass

Small tongue mass

Gross description

Firm tan nodule with white cut surface

Gross images

Contributed by Sarah H. Glass, D.D.S.

Dome shaped mass

White cut surface

Microscopic (histologic) description

Varying numbers of large, plump angular and stellate fibroblasts that may demonstrate multiple nuclei in the superficial connective tissue (Oral Surg Oral Med Oral Pathol 1974;37:374)
Proliferation of collagen bundles
Overlying surface epithelium with narrow and elongated epithelial rete ridges
Absence of inflammation

Microscopic (histologic) images

Contributed by Sarah H. Glass, D.D.S.

Nodular fibrous proliferation

Elongated rete ridges

Stellate fibroblasts

Multinucleated fibroblasts

Positive stains

Vimentin

Negative stains

S100, GFAP, neurofilament, desmin, SMA, CD31, CD68 (J Oral Pathol Med 1994;23:284)

Sample pathology report

Oral cavity, excisional biopsy:
- Giant cell fibroma

Differential diagnosis

Retrocuspid papillae (Head Neck Pathol 2019;13:71):
- Normal anatomic structure, therefore clinicopathologic correlation required
- Histopathologically identical to giant cell fibroma
Oral squamous papilloma:
- Epithelial proliferation with koilocytes related to low risk human papillomavirus
Verruciform xanthoma:
- Foam cells in the superficial connective tissue with overlying clefts of orange keratin
Irritation fibroma:
- Reactive fibrous proliferation with chronic inflammation and without large stellate fibroblasts
Other clinically noted common masses of the gingiva include pyogenic granuloma, peripheral ossifying fibroma and peripheral giant cell granuloma:
- Diagnosis made with histopathologic examination

Board review style question #1

A 30 year old patient presents with a 5 mm bosselated soft tissue mass on the mandibular gingiva. Histopathology shows a benign fibrous proliferation with stellate fibroblasts in the superficial connective tissue with no inflammation. There is no history of trauma. What is the diagnosis?

Giant cell fibroma
Irritation fibroma
Papilloma
Pyogenic granuloma

Board review style answer #1

A. Giant cell fibroma. All of the answer choices could be included on a clinical differential diagnosis of a gingival mass. Giant cell fibromas demonstrate stellate fibroblasts on microscopic exam. These lesions are not associated with trauma and do not routinely demonstrate inflammation unless secondarily traumatized.

Comment Here

Reference: Giant cell fibroma

Board review style question #2

Which of the following is true regarding giant cell fibromas of the oral cavity?

Features of human papillomavirus in the epithelium
History of repeated trauma to the site
Majority of lesions are larger than 1 cm
Stellate fibroblasts in the superficial connective tissue

Board review style answer #2

D. Stellate fibroblasts in the superficial connective tissue. Defining histologic feature of a giant cell fibroma is the presence of large, plump angular and stellate fibroblasts that may demonstrate multiple nuclei in the superficial connective tissue. These lesions generally have limited growth potential, are not associated with trauma and are not related to human papillomavirus.

Comment Here

Reference: Giant cell fibroma

Gingival hyperplasia

Table of Contents

Definition / general

Also called fibrous hyperplasia
Associated with diphenylhydantoin (Dilantin) ingestion; also cyclosporine A, nifedipine and other drugs
May require surgical excision

Granulomatous inflammation

Table of Contents

Definition / general | Case reports | Treatment | Clinical images | Microscopic (histologic) images

Definition / general

Associated with chronic recurrent tonsillitis
Usually benign course, no specific organism recovered
Must rule out infectious causes (tuberculosis, tertiary syphilis, salmonella, mycotic granulomas), systemic causes (sarcoidosis, Crohn's, Granulomatosis with polyangiitis (Wegener's), eosinophilic granuloma), foreign body reaction, cholesterol granuloma
Idiopathic orofacial granulomatosis: condition restricted to oral and maxillofacial region without any identifiable systemic granulomatous disease

Case reports

9 year old girl with idiopathic orofacial granulomatosis (J Oral Maxillofac Pathol 2012;16:432)
11 year old boy with idiopathic orofacial granulomatosis (J Indian Soc Periodontol 2012;16:469)

Treatment

Individualized and often needs to change for each patient; includes corticosteroids or other drugs, gingivectomy

Clinical images

Images hosted on other servers:

9 year old girl:

Preoperative

1 year follow up

11 year old boy:

Preoperative

Postoperative

Microscopic (histologic) images

Images hosted on other servers:

Multiple granulomas

Lip and gingival biopsies

Granulomatous lesion and infiltrates

Grossing & features to report

Table of Contents

Grossing | Features to Report | Measurements

Grossing

At least one section per 1 cm of tumor for large tumors, including tumor center and periphery
Submit entire tumor if can do so in 5 sections or less
Resection margins
Save intervening levels on biopsies for special stains

Features to Report

Tumor histologic type and pattern
Tumor size and location
Tumor histologic grade
Depth of invasion (not used for TNM staging)
Pattern of invasion (noncohesive irregular cords, infiltrative single cells, well defined blunt pushing borders, thick rounded invasive cords)
Tumor extension to adjacent structures
Status of resection margins
Vascular invasion
Perineural invasion
Lymph nodes: for each level, number obtained, number involved by tumor, size of nodal metastases and presence of extracapsular spread
Dysplasia
References: Mod Pathol 2000;13:1038

Features to report by organization:

Measurements

Endophytic tumors: measure perpendicularly from surface of invasive carcinoma to deepest area of involvement, using nontangential sections with a clearly recognizable surface component
Exophytic tumors: measure tumor thickness from surface to deepest area
Ulcerated tumors: measure from ulcer base to deepest area as well as from surface of most lateral extent of invasive carcinoma to deepest area

Hairy tongue

Table of Contents

Definition / general

Benign condition of the dorsal tongue characterized by elongation and often staining of the filiform papilla, imparting a hairy appearance

Essential features

Marked elongation of the lingual filiform papillae
Hairy appearance of the dorsal tongue
Associated with cigarette use, electronic cigarette use, xerostomia, oxidizing mouthwashes, hyposalivation, radiation, older age, general debilitation, medication use, lack of coarse foods in diet and poor oral hygiene

Terminology

Oral hairy tongue
Black hairy tongue
Foliate papillae hypertrophy
Lingua villosa nigra
Melanoglossia
Similar to coated tongue
Not to be confused with oral hairy leukoplakia, an unrelated entity

ICD coding

ICD-10: K14.3 - hypertrophy of tongue papillae

Epidemiology

Slight male predominance
Prevalence varies from 0.6 - 11.3% of the general population (World J Gastroenterol 2014;20:10845)

Sites

Dorsal tongue, often posterior midline area

Pathophysiology

Elongation of filiform papillae due to decreased sloughing or increased production of keratin

Etiology

Associated with cigarette use, electronic cigarette use, xerostomia, oxidizing mouthwashes, hyposalivation, radiation, older age, general debilitation, medication use, lack of coarse / crunchy foods in diet and poor oral hygiene (J Evid Based Dent Pract 2019;19:101318, World J Gastroenterol 2014;20:10845)
Associated medications include bismuth, penicillin, chlorpromazine, ranitidine, tetracycline, linezolid, olanzapine, interferon, prednisolone (Head Neck Pathol 2019;13:47)
Pigment often is caused by pigment producing bacteria or exogenous substances, such as food, medicines or tobacco

Clinical features

Hair-like projections of the dorsal tongue (Head Neck Pathol 2019;13:47)
Brown, black, green or yellow discoloration may be present

Diagnosis

Diagnosis is made clinically; biopsy is not necessary

Prognostic factors

Asymptomatic, although some patients may experience gagging sensation, malodor or foul taste

Case reports

54 year old woman smoker with hairy tongue occurring concurrently with respiratory infection (Cleve Clin J Med 2017;84:434)
56 year old white man with black hairy tongue associated with linezolid (J Med Case Rep 2013;7:46)
60 year old woman with hairy tongue after prednisolone use (Arch Rheumatol 2019;34:348)
63 year old man with amyotrophic lateral sclerosis and hairy tongue (J Int Soc Prev Community Dent 2016;6:80)
64 year old woman with hairy tongue associated with interferon therapy for hepatitis C (Ann Hepatol 2015;14:414)

Treatment

Treatment is not urgent or immediately necessary
Patients may seek treatment for foul breath, abnormal sensation
Includes tongue scraping / brushing, elimination of offending / contributing agents (e.g. tobacco, medications), addition of crunchy / coarse foods to diet and oral hygiene improvement (Head Neck Pathol 2019;13:47)

Clinical images

Contributed by Molly Housley Smith, D.M.D.

Black hairy tongue

Brown hairy tongue

Yellow hairy tongue

Microscopic (histologic) description

Markedly elongated filiform papillae with hair-like spires of keratin (World J Gastroenterol 2014;20:10845)
Basophilic bacterial colonies often adhered to keratin surface

Microscopic (histologic) images

Contributed by Molly Housley Smith, D.M.D.

Hyperparakeratosis

Superficial bacterial colonies

Elongated filiform papilla

Molecular / cytogenetics description

Negative in situ hybridization for Epstein-Barr virus (EBER); there is no association with EBV

Sample pathology report

Dorsal tongue, incisional biopsy:
- Hyperkeratosis and elongation of filiform papillae (see comment)
- Comment: The histologic findings are compatible with hairy tongue.

Differential diagnosis

Coated tongue:
- White, brown, black, yellow discoloration of the dorsal tongue without prominent elongation of the filiform papillae
Oral hairy leukoplakia:
- Only included in differential diagnosis due to similarity of terminology
- Most often presents as furrowed white plaques on lateral tongue
- Associated with Epstein-Barr virus
- Positive upon in situ hybridization with EBER

Board review style question #1

Which of the following is true about hairy tongue, shown in the image?

Hairy tongue is positive upon in situ hybridization for Epstein-Barr virus (EBER)
Hairy tongue is strongly correlated with smoking and medication use
Microscopic examination reveals eosinophilic condensation in a perinuclear arrangement in the superficial aspects of the epithelium
Treatment varies based on the histologic grade

Board review style answer #1

B. Hairy tongue is strongly correlated with smoking and medication use

Comment Here

Reference: Hairy tongue

Board review style question #2

A tongue biopsy is shown above. What is the diagnosis for this patient with marked elongation of the lingual filiform papillae and prominent superficial bacterial colonization?

Acanthosis nigricans
Hairy tongue
Oral hairy leukoplakia
White sponge nevus

Board review style answer #2

B. Hairy tongue

Comment Here

Reference: Hairy tongue

Hereditary benign intraepithelial dyskeratosis (pending)

[Pending]

HPV associated

Table of Contents

Definition / general

An increasing subset of oropharyngeal carcinomas caused by high risk human papillomaviruses (HPV) (El-Naggar: WHO Classification of Head and Neck Tumours, 4th Edition, 2017)

Essential features

Oropharyngeal squamous cell carcinoma caused by high risk HPV
Mostly present as a cystic or solid neck mass, enlarged cervical lymph node, or rarely enlarged tonsil
Variable squamous differentiation characterized by orangeophilic keratinized squamous cells in Papanicolaou stain
p16 immunostain, a surrogate marker for high risk HPV, is considered positive when expressed in ≥ 70% of tumor cells with both nuclear and cytoplasmic staining; occasionally p16 is focal / patchy positive or negative
High risk HPV can be detected by different methods such as RNA in situ hybridization
High risk HPV testing can be performed on both primary or metastatic tumor
No tumor grading
Overall favorable prognosis despite early local lymph node metastasis (Cancer Epidemiol Biomarkers Prev 2019;28:1660)
Rare cases associated with distant metastasis and poor prognosis
HPV+ squamous cell carcinoma is associated with better prognosis than HPV- squamous cell carcinoma

Terminology

Also known as HPV+ squamous cell carcinoma of oropharyngeal origin (El-Naggar: WHO Classification of Head and Neck Tumours, 4th Edition, 2017)

Epidemiology

Affects both males and females, more common in white males, mostly younger than 65
Incidence is growing rapidly (J Clin Oncol 2011;29:4294)
U.S. incidence of oropharyngeal HPV+ squamous cell carcinoma is higher than the incidence of HPV- cases, 4.62 versus 1.82 per 100,000 (Cancer Epidemiol Biomarkers Prev 2019;28:1660)
Patients are younger, predominantly Caucasians and higher socioeconomic status compered to HPV- squamous cell carcinoma

Sites

Most common in oropharynx (tonsils, base of tongue and adenoids) and posterior pharyngeal wall
Arise from the tonsillar crypts

Pathophysiology

Etiologic agent is high risk HPV
Arises from the tonsillar crypts
Initial step is infection of the epithelial basal layer by HPV through microabrasions or trauma
HPV double stranded DNA genome encodes oncoproteins such as Early genes E1, E2, E6 and E7 after integration into the host cell nucleus (J Dent Res 2015;94:1532)
E1 and E2 genes activate viral replication
E6 binds to p53 and inactivates tumor suppressor protein p53 and E7 binds to pRB and inactivates tumor suppressor protein pRB
E6 and E7 expression promotes cellular proliferation and increases chance of malignancy (J Am Soc Cytopathol 2016;5:203)

Etiology

Caused by high risk HPV, mostly commonly associated with HPV16 and HPV18 strains
Also includes high risk HPV strains 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 82, as well as others (Cancer Epidemiol Biomarkers Prev 1996;5:567)
Oral sexual contact is a major risk factor, but not alcohol or tobacco (smoking or chewing)

Clinical features

Initial presentation in most cases is a neck mass or cervical lymphadenopathy
Occasionally presents with a unilateral enlarged tonsil
May have distant metastases to the lungs, mediastinal lymph nodes, brain, liver, bone, skin, duodenum (J Am Soc Cytopathol 2016;5:203)

Diagnosis

Tissue findings in which morphology, along with nuclear and cytoplasmic expression of p16 in ≥ 70% of tumor cells or detection of high risk HPV in tumor cells, is required for the diagnosis

Radiology description

Imaging findings, including ultrasound, such as enlargement, loss of the central fatty hilum, irregular cortical thickening, increased vascularity and loss of elongated shape are suspicious characteristics for metastatic HPV related squamous cell carcinoma; however, they are nonspecific
Central necrosis appears as a cystic area within the node, demonstrating an anechoic, or completely black, echo texture enhanced through transmission (AJR Am J Roentgenol 2005;184:1691)

Radiology images

Contributed by Zahra Maleki, M.D.

Ultrasound

Prognostic factors

Distant metastasis, although rare, is associated with poor prognosis

Case reports

18 year old woman with larynx tumor (Head Neck 2019;41:E59)
52 year old man with metastasis to the pleura (J Oral Maxillofac Surg 2018;76:2577)
61 year old man with solitary dural metastasis (Head Neck 2014;36:E103)

Treatment

Resection of primary tumor with or without ipsilateral or bilateral neck dissection
Radiation therapy or systemic therapy in cases with extranodal extension, positive margins or other high risk associated features such as pT3 or pT4 primary, one positive node > 3 cm or multiple positive nodes, nodal metastasis in levels IV or V, perineural invasion, vascular invasion and lymphatic invasion (National Comprehensive Cancer Network, J Am Soc Cytopathol 2016;5:203)

Microscopic (histologic) description

Variable squamous differentiation including:
- Basaloid features with no squamous differentiation, most common pattern
- Focal keratinization
- Abundant keratinization
Other morphology types:
- Nonkeratinizing squamous cell carcinoma with maturation
- Hybrid variant
- Keratinizing SCC
- Cystic / microcystic, ciliated
- Papillary SCC
- Adenosquamous SCC
- Spindle cell carcinoma (sarcomatoid)
- Undifferentiated SCC (Am J Surg Pathol 2015;39:1591)
No tumor grade or differentiation status should be reported (CAP: Human Papillomavirus Testing in Head and Neck Carcinomas [Accessed 24 September 2019])

Microscopic (histologic) images

Contributed by Zahra Maleki, M.D. and @AnaPath10 on Twitter

Infiltrating tumor

Basaloid cells

HPV positive oropharynx squamous cell carcinoma

Cytology description

Non / minimally keratinized squamous cell carcinoma, fragments of basaloid cells with high N/C ratio and hyperchromatic nuclei
Fragments of cohesive malignant squamous cells with dense cytoplasm
Variable squamous differentiation, tadpole, snake cells and squamous cells with orangeophilic cytoplasm in Papanicolaou stain and blue in Romanowsky stain, respectively
Individual keratinized cells with marked pleomorphism
Necrosis, cystic degeneration and macrophages, common

Cytology images

Contributed by Zahra Maleki, M.D.

Atypical squamous cells

Pleomorphism

Focal keratinization

Cohesive fragments

Basaloid features

Cyst aspiration

Cell block

p63

p16

Positive stains

p16 in ≥ 70% of tumor cells with both nuclear and cytoplasmic staining (Arch Pathol Lab Med 2018;142:559), a surrogate marker
p40, p63, CK5/6

Molecular / cytogenetics description

Positive for high risk HPV by hybrid captured II assay, DNA in situ hybridization, RNA in situ hybridization, PCR (J Am Soc Cytopathol 2016;5:203)
EBER-

Molecular / cytogenetics images

Contributed by Zahra Maleki, M.D.

High risk HPV DNA ISH

HPV16 DNA ISH

HPV RNA ISH

Sample pathology report

Lymph node, right level II, ultrasound guided fine needle aspiration:
- Metastatic HPV related squamous cell carcinoma (see comment)
- Comment: An immunostain for p16 is positive in 80% of the tumor cells. In situ hybridization for high risk HPV RNA is positive.

Differential diagnosis

HPV- squamous cell carcinoma of oropharynx
- History of heavy alcohol consumption or chewing / smoking tobacco
- Shows higher degree of squamous differentiation in most cases
- p16-, high risk HPV-
Metastatic squamous cell carcinoma of skin
- Older patients
- Shows higher degree of squamous differentiation in most cases
- p16-, high risk HPV-
Lymphoepithelial cyst
- Overall less cellularity
- Unilateral and single cyst
- p16 focally positive, HPV-
Nasopharyngeal carcinoma
- Presents as keratinizing squamous cell carcinoma or nonkeratinizing squamous cell carcinoma including basaloid squamous cell carcinoma and undifferentiated subtype (El-Naggar: WHO Classification of Head and Neck Tumours, 4th Edition, 2017)
- Syncytial growth pattern, vesicular nuclei with prominent central nucleoli and reactive lymphocytes in stroma
- Usually positive for Epstein-Barr virus (EBV) / Epstein-Barr encoded RNA (EBER)
- p16-, high risk HPV-
Metastatic squamous cell carcinoma of lung
- Prior relevant clinical history
- Variable squamous differentiation
- p16-, HPV-
Metastatic HPV related anogenital squamous cell carcinoma including uterine cervix
- Prior relevant clinical history
- Cytomorphologic overlap
- Also p16+ and high risk HPV+
Adenoid cystic carcinoma, solid type
- Basaloid tumor cells with high N/C ratio and angulated nuclei
- CD117 (c-kit)+
- p16-, high risk HPV-
Metastatic small cell carcinoma of the lung
- Chest imaging useful to differentiate these two entities
- Same morphology with small cell variant of oropharyngeal carcinoma
- CD56+, chromogranin+, synaptophysin+
- High risk HPV-
Metastatic large cell neuroendocrine carcinoma
- Sheets and three dimensional fragments of cohesive cells with large pleomorphic nuclei and vesicular chromatin
- Mitoses, molding and necrosis common
- Neuroendocrine markers (chromogranin, synaptophysin, CD56)+, HPV-, p40-

Additional references

Head Neck Pathol 2017;11:41

Board review style question #1

10% nuclear and cytoplasmic
40% nuclear and cytoplasmic
50% nuclear
60% cytoplasmic
70% nuclear and cytoplasmic

Board review style answer #1

E. 70% nuclear and cytoplasmic

Comment Here

Reference: HPV related oropharyngeal squamous cell carcinoma

Board review style question #2

Extranodal extension has no impact on treatment
Distant metastasis is very common
High risk HPV testing can be performed on primary or metastatic tumor
The prognosis is poor in most cases
Tumor differentiation must be reported for all cases

Board review style answer #2

C. High risk HPV testing can be performed on primary or metastatic tumor

Comment Here

Reference: HPV related oropharyngeal squamous cell carcinoma

HPV independent

Table of Contents

Definition / general

A subset of oropharyngeal squamous cell carcinomas that are not associated with high risk human papillomaviruses (HPV)

Essential features

Squamous cell carcinoma involving the oropharynx
Oropharynx includes the soft palate, uvula, palatine tonsils, posterior third (base) of the tongue and posterior wall of the pharynx
Associated with smoking and alcohol
Not associated with HPV
Resembles squamous cell carcinoma (SCC) and its morphologic variants observed in other head and neck mucosal sites; can show surface dysplasia, keratinization and desmoplasia

Terminology

Keratinizing squamous cell carcinoma

ICD coding

ICD-0: 8086/3 - squamous cell carcinoma, HPV negative
ICD-10: C10 - malignant neoplasm of oropharynx

Epidemiology

Age: mean 61 years (standard deviation 10.49) (Cancer 2019;125:761)
M:F = 3.2:1 (Cancer 2019;125:761)
Higher incidence in Indian subcontinent, French Polynesia, New Caledonia and Papua New Guinea, Eastern Europe, North America, Australia and Brazil

Sites

Oropharynx
- Most commonly soft palate
- Arises in the surface mucosa and invades neighboring structures with metastases to draining regional nodes

Pathophysiology

Invasive lesion is typically preceded by progressively severe dysplasia
Chronic insult with abrogation of DNA repair mechanisms and mutations in tumor suppressor genes, such as gatekeeper p53 (J Oncol 2011;2011:603740)

Etiology

Most commonly chewing or smoking tobacco, heavy alcohol use and poor oral hygiene (J Natl Cancer Inst 2008;100:407)
Also reported in association with syphilis, other infections (bacterial, fungal or viral) and Fanconi anemia (Int J Epidemiol 1994;23:381, Sci Rep 2017;7:4036, Arch Otolaryngol Head Neck Surg 2003;129:106)

Diagrams / tables

Contributed by Katherine Hulme, M.B.Ch.B.

Oropharynx (frontal view)

Oropharynx (lateral view)

Clinical features

Presents as nonhealing mucosal ulcer identified by patient or clinician and confirmed with nasoendoscopy and biopsy
Difficulty and pain while swallowing
Metastasis to ipsilateral or bilateral neck nodes may rarely be the initial presenting feature

Diagnosis

Clinical examination with biopsy of primary lesion
Biopsy of primary lesion may require examination under anesthesia of the oropharynx
Cytology of lymph node metastases followed by biopsy of the primary lesion identified on diagnostic CT and PET scan

Radiology description

Primarily used for staging of nodal drainage sites and distant spread
PET may identify primary lesion in the rare setting of neck nodal disease of unknown origin

Prognostic factors

Overall survival at 3 years 57% (N Engl J Med 2010;363:24)
Prognostic factors
- Clinical
  - Tobacco use (N Engl J Med 2010;363:24)
  - Overall patient health, comorbidity and lifestyle factors
  - Women have worse overall survival and cancer specific survival than men (Expert Rev Anticancer Ther 2020;20:813)
- Histological
  - Size
  - Depth of invasion
  - Perineural invasion (J Surg Oncol 2015;111:352, Head Neck 2019;41:3992)
  - Worst pattern of invasion (Am J Surg Pathol 2005;29:167)
  - Completeness of resection
  - Lymph node involvement
  - Extranodal extension
  - Stage as per the AJCC 8th edition chapter 11 oropharynx (p16) and hypopharynx (AJCC: Cancer Staging Manual [Accessed 12 December 2020])

Case reports

49 year old man with a lymphoepithelial carcinoma in the soft palate and uvula (Head Neck Pathol 2011;5:327)
58 year old woman with a spindle cell carcinoma of the palatine tonsil (Am J Otolaryngol 2008;29:123)
65 year old man with a basaloid squamous cell carcinoma of the retromolar trigone (J Oral Maxillofac Pathol 2011;15:192)

Treatment

Surgical resection of the primary along with ipsilateral or bilateral elective neck dissection (N Engl J Med 2015;373:521)
Surgical resection can be through transoral robotic surgery (TORS)
Adjuvant radiotherapy and platinum based chemotherapy
Immune check point inhibitors have demonstrated response in 25 - 29% patients (Future Oncol 2020;16:1235)

Clinical images

Images hosted on other servers:

Preoperative soft palate tumor

Gross description

Macroscopic appearance varies with the morphologic type
Common conventional squamous cell carcinoma shows an ulceroproliferative mucosal lesion with a firm gray-white infiltrative surface
Verrucous and papillary squamous cell carcinomas demonstrate prominent exophytic, finger-like projections
Spindle cell carcinoma generally presents as a mucosal polypoid lesion

Gross images

Contributed by Ruta Gupta, M.B.B.S., M.D.

Verrucous mucosal lesion

Ulceroproliferative
mucosal lesion

Frozen section description

Not routinely done
Value with confirming clearance of margins of primary lesion

Microscopic (histologic) description

Squamous cell carcinoma, conventional
- Most common and typical morphology of conventional keratinizing squamous cell carcinoma at any site
- Large polygonal malignant cells with intercellular bridges
- Cytoplasmic or extracellular eosinophilic keratin
- Dyskeratotic cells and squamous pearls
- Nuclear size, pleomorphism, hyperchromasia and mitoses increase with increasing grade
Other morphological types
- Verrucous carcinoma
  - Pronounced exophytic growth of well differentiated squamous epithelium
  - Bulbous enlargement of the rete ridges with elephant foot appearance
  - Broad pushing border
  - Does not metastasize; good prognosis
- Carcinoma cuniculatum
  - Well differentiated exophytic verruciform lesion with broad front of burrowing invasion
  - Generally involves mucoperiosteal sites; rare in the oropharynx
- Papillary squamous cell carcinoma
  - Well differentiated keratinocytes forming exophytic organized papillary structures with fibrovascular cores
  - 70% of tumor must show papillary architecture
  - Better prognosis than conventional squamous cell carcinoma
- Acantholytic squamous cell carcinoma (Head Neck Pathol 2012;6:438)
  - Keratinocytes with loss of adhesion molecules appear "falling apart"
  - May have pseudolumina mimicking glands or vessels but no mucin
- Adenosquamous carcinoma (Head Neck Pathol 2016;10:486)
  - True glandular and squamous differentiation close but distinct and separate
  - Poor prognosis with frequent metastases
- Basaloid squamous cell carcinoma (J Oral Maxillofac Pathol 2011;15:192)
  - Cells with minimal cytoplasm
  - Enlarged, angulated, hyperchromatic nuclei
  - Basement membrane-like matrix
  - Solid pattern with lobular configuration
  - May have prominent peripheral palisading
  - May have comedo type necrosis
  - May have abrupt change to differentiated component
- Lymphoepithelial carcinoma (nonnasopharyngeal) (Head Neck Pathol 2011;5:327)
  - Cohesive tumor nests of nonkeratinising epithelioid cells with prominent intermixed reactive lymphoplasmacytic infiltrate
  - Present at high stage with metastases
- Spindle cell / sarcomatoid squamous cell carcinoma (Am J Otolaryngol 2008;29:123)
  - Most commonly occurs postradiotherapy or as second primary
  - Mesenchymal in appearance
  - Atypical plump spindled cells arranged in fascicles or storiform pattern
  - May have metaplastic or neoplastic cartilage or bone

Microscopic (histologic) images

Contributed by Ruta Gupta, M.B.B.S., M.D.

Well differentiated SCC

Moderately differentiated SCC

Poorly differentiated SCC

Verrucous SCC

Papillary SCC

Lymphoepithelial carcinoma

p40 in lymphoepithelial carcinoma

Spindle cell / sarcomatoid carcinoma

CK5/6 in spindle cell SCC

p40 in spindle
cell / sarcomatoid
carcinoma

Adenosquamous carcinoma

Mucicarmine in adenosquamous carcinoma

Virtual slides

Images hosted on other servers:

75 year old woman

Cytology description

Role of cytology only in investigation of regional or distant metastases
Appearance depends on type and differentiation
Conventional squamous cell carcinoma shows sheets and small clusters of large polygonal malignant cells with intercellular bridges and cytoplasmic or extracellular eosinophilic keratin

Cytology images

Contributed by Ruta Gupta, M.B.B.S., M.D.

Keratin and dyskeratotic cells

Clusters of keratin and dyskeratotic cells

Clusters of well differentiated squamous cells

CK5/6 in cell block

Positive stains

Diffusely and strongly positive:

Negative stains

Molecular / cytogenetics description

Negative for presence of high risk HPV DNA / RNA
EBV ISH negative

Sample pathology report

Right soft palate and uvula and bilateral neck dissection levels I - IV, excision:
- Moderately differentiated squamous cell carcinoma (T = 28 mm, pT2) arising on a background of carcinoma in situ (see comment)
- Comment: Extensive perineural involvement is present. Local excision complete, closest margin: anterior mucosal 3 mm away. Bilateral neck dissection shows 2/66 lymph nodes with metastatic squamous cell carcinoma. The larger involved node is present in the right neck, measures 25 mm and shows extranodal extension (pN3b). AJCC 8th Ed pT2pN3b group stage 4. The tumor cells lack immunostaining with p16 excluding an HPV related oropharyngeal squamous cell carcinoma. HPV negative oropharyngeal squamous cell carcinoma is frequently associated with smoking and alcohol and does not carry the good prognosis described in HPV related oropharyngeal squamous cell carcinoma.

Differential diagnosis

HPV+ oropharyngeal squamous cell carcinoma:
- p16+ or high risk HPV+
- Nonkeratinizing morphology with scanty cytoplasm
- Tumor cells embedded in lymphoid stroma
- High mitotic and apoptotic activity
HPV related oral diseases: squamous papilloma, verruca vulgaris, condyloma acuminatum
- Usually low risk HPV+
Nasopharyngeal carcinoma:
- Arising in the nasopharynx
- Usually EBV+
Verrucous hyperplasia / proliferative verrucous leukoplakia:
- Exophytic growth only
- Mature keratinocytes with marked acanthosis
- Can be multifocal and widespread
Squamous dysplasia:
- No invasive component
- Dysplastic keratinocytes with variable level of thickness involvement

Additional references

WHO Oral Health Programme: Global Data on Incidence of Oral Cancer [Accessed 25 October 2021], El-Naggar: WHO Classification of Head and Neck Tumours, 4th Edition, 2017

Board review style question #1

A 67 year old man with 15 pack year smoking history and social alcohol presented with a nonhealing ulcer on the soft palate. A histologic image of the biopsy is provided above. Which of the following immunostains is most likely to be negative in this lesion?

CK5/6
p16
p40
p53
p63

Board review style answer #1

B. p16

Comment Here

Reference: HPV negative

Board review style question #2

Which of the following risk factors apply to HPV negative oropharyngeal squamous cell carcinoma?

Asbestos exposure
HHV8
Oral sexual contact
Smoked foods
Smoking and alcohol

Board review style answer #2

E. Smoking and alcohol

Comment Here

Reference: HPV negative

Infections-general

Table of Contents

Actinomycosis

See Skin nontumor - Actinomycosis

Blastomycosis

See Skin nontumor - Blastomycosis

Candidiasis (thrush)

Definition / general

Normal flora that overgrows due to AIDS, antibiotics, diabetes, immunosuppression, neutropenia, xerostomia (Med Oral Patol Oral Cir Bucal 2013;18:e381)

Case reports

45 year old HIV+ man (Case Rep Dent 2011;2011:929616)

Clinical images

Images hosted on other servers:

Pseudomembranous
candidiasis
on palate

White plaques and reddened regions of tongue

Retrocommissural area

Palate

Angular cheilitis

Gross description

Superficial curdy, gray-white membranes that easily wipe off (pseudomembranous candidiasis) or painful erosions (erythematous candidiasis)

Microscopic (histologic) description

PAS+ hyphae within keratin layer in neutrophilic background; prominent inflammatory infiltrate along the lamina propria

Microscopic (histologic) images

Images hosted on other servers:

Candidal hyphae

Herpes simplex virus

Definition / general

Also called cold sore
Usually HSV1
Lasts 3 - 4 weeks, then virus tracks along regional nerves and becomes dormant in trigeminal or other local ganglia
Most infected adults have latent HSV1 that is activated by upper respiratory infection, excessive exposure to cold, wind, sun, allergies
Acute herpetic gingivostomatitis:
- Rare, children 2 - 4 years with diffuse involvement of oral and pharyngeal mucosa, tongue, gingiva
- Fiery red mucosa and swelling with clusters of vesicles
Recurrent herpetic stomatitis:
- Groups of 1 - 3 mm vesicles on the lips, nasal orifices, buccal mucosa
- Lesions heal in 7 - 10 days
Tzanck test: microscopic examination of vesicle fluid shows giant cells, inclusions

Gross description

Vesicles or bullae with clear serous fluid, painful shallow ulcers

Microscopic (histologic) description

Intra and intercellular edema (acantholysis), intranuclear inclusions, multinucleate polykaryons (giant cells)

Herpes simplex / zoster

See Skin nontumor - Herpes simplex / zoster

Histoplasmosis

See Skin nontumor - Histoplasmosis

Infectious mononucleosis

Definition / general

Acute pharyngitis and tonsillitis with gray-white exudate, lymphadenopathy in neck
Due to Epstein-Barr virus infection

Microscopic (histologic) description

Tonsil: reactive lymphoid hyperplasia (polymorphous transformed lymphocytes) with extensive immunoblastic proliferation in sheets and nodules, marked atypia resembling Reed-Sternberg cells (Am J Surg Pathol 1987;11:122)

Microscopic (histologic) images

Images hosted on other servers:

Peripheral blood lymphocytosis

Reactive lymphocytes

Negative stains

CD15, CD30

Syphilis

See Skin nontumor - Syphilis

Verruca vulgaris

Definition / general

Associated with HPV

Microscopic (histologic) description

Cup shaped margins, prominent hyperkeratinized spires

Microscopic (histologic) images

Contributed by Joseph Christopher Castillo, M.D.

Oral cavity

Inflammatory fibrous hyperplasia (pending)

Inflammatory papillary hyperplasia

Table of Contents

Definition / general

Common, usually involves palate or lingual mandibular gingiva
Called palatal papillomatosis in palate
Middle aged and older persons, 2/3 female
Associated with ill fitting dentures or partial dentures (Braz Dent J 2009;20:243), wearing prostheses at night, poor oral hygiene; also candidiasis
Not a premalignant condition

Treatment

Removal of offending agent; proper fitting dentures
Complete excision

Clinical images

Images hosted on other servers:

Multiple small nodules on palate

Gross description

Multiple red polyp-like projections, often under ill fitting dentures and usually in palate

Microscopic (histologic) description

Exophytic mucosal epithelial hyperplasia, including pseudoepitheliomatous hyperplasia and submucosal fibrous hyperplasia
Islands of hyperplastic squamous mucosa may appear in submucosa
May have chronic inflammation of accessory salivary glands; no dysplasia

Microscopic (histologic) images

Images hosted on other servers:

Inflamed bulbous projection

Irritation fibroma

Table of Contents

Definition / general

Fibrous nodule of oral cavity, often considered a reactive hyperplasia to trauma or local sources of irritation

Essential features

Common reactive fibrous hyperplasia of oral cavity
Typically affects buccal mucosa along the line of occlusion / bite line
Conservative surgical excision is recommended and recurrences are rare

Terminology

Irritation fibroma
Oral fibroma
Traumatic fibroma
Focal fibrous hyperplasia

ICD coding

Reactive fibrous tissue:
- ICD-10: K13.79 - Other lesions of oral mucosa
True benign fibrous tumor with continuous growth:
- ICD-10: D10.0 - Benign neoplasm of lip

Epidemiology

Any age, although most common in fifth and sixth decades (Iran J Otorhinolaryngol 2015;27:137)
About twice as common in women

Sites

Most common along the bite line on the buccal mucosa (may be bilateral)
Also seen on the labial mucosa, tongue, palate and gingiva (Iran J Otorhinolaryngol 2015;27:137, Am Fam Physician 2007;75:509)

Pathophysiology

Considered to be a reactive proliferation rather than a true neoplasm, although true fibrous neoplasms of unlimited growth potential are possible (Neville: Oral and Maxillofacial Pathology, 4th Edition, 2016)

Etiology

Thought to be induced by recurrent local irritants of the oral cavity, which may include bite trauma, denture irritation, food impaction, poor oral hygiene, broken teeth or overhanging dental restorations (Iran J Otorhinolaryngol 2015;27:137)

Clinical features

Smooth, round, flesh colored nodule (Am Fam Physician 2007;75:509)
Asymptomatic unless painful due to bite trauma
May be ulcerated or demonstrate a thickened white surface (hyperkeratosis)
Often 1 - 2 cm in diameter (Indian J Dent Res 2018;29:61)

Diagnosis

Definitive diagnosis is made upon histopathological review, although irritation fibromas may be highly suspected based on clinical features (Braz J Otorhinolaryngol 2019;85:399)

Prognostic factors

Excellent prognosis with infrequent recurrence after conservative surgical excision

Case reports

23 year old man with dermoscopic features of oral fibroma (Skin Res Technol 2019;25:768)
53 year old man with oral fibroma of the tip of his tongue (Postepy Dermatol Alergol 2019;36:125)

Treatment

Conservative surgical excision with removal of local irritants (J Indian Soc Periodontol 2017;21:258)

Clinical images

Contributed by Brandon Stapleton, D.M.D., Molly Housley Smith, D.M.D. and Jimmy Vellis, D.D.S., M.S.

Fibroma of buccal mucosa

Fibroma of the tongue

Ulcerated irritation fibroma

Gross description

Tan or gray nodule of soft tissue with white cut surface
Surface ulceration or thickened keratin surface may be present

Gross images

Contributed by Molly Housley Smith, D.M.D.

Tan to gray nodule

Cut surface

Microscopic (histologic) description

Nonencapsulated nodular mass
Mass composed of fibrous connective tissue with collagen bundles interspersed with fibroblasts, blood vessels and scattered chronic inflammatory cells
Overlying surface of squamous epithelium (J Oral Maxillofac Pathol 2015;19:330)

Microscopic (histologic) images

Contributed by Molly Housley Smith, D.M.D.

Nodular mass

Hyperkeratotic surface

Scattered chronic inflammatory cells

Positive stains

Vimentin

Negative stains

Negative for markers of other mesenchymal origins (S100, SMA, CD34, desmin, etc.)

Sample pathology report

Right buccal mucosa, excisional biopsy:
- Focal fibrous hyperplasia (irritation fibroma)

Differential diagnosis

Clinical:
- Nodules of neural, muscular, lipomatous, vascular or salivary gland origins, as well as fibrous proliferations associated with embedded foreign material (e.g. dermal fillers); proper diagnosis is made upon histopathological review
- Multiple fibrous nodules may be associated with various syndromes (e.g. Cowden syndrome) (Cancers (Basel) 2019;11:844)
- Multiple endocrine neoplasia, type 2B (MEN 2B):
  - Bilateral flesh colored nodules in the oral commissure regions or multiple nodules of the tip of the tongue are highly suggestive of MEN 2B (Head Neck Pathol 2017;11:364)
  - Biopsy of the nodules reveals a diagnosis of mucosal neuroma
Histopathological:
- Giant cell fibroma (which is of little consequence):
  - Papillary surface architecture and plump, stellate shaped fibroblasts within the connective tissue (J Oral Maxillofac Pathol 2012;16:359)

Board review style question #1

A 56 year old man presents with a chief complaint of a bump inside the oral cavity. On clinical exam, a pink, smooth surfaced nodule is noted along the patient’s bite line. He states that the mass interferes with chewing and speaking. The microscopic appearance is pictured. What is the diagnosis?

Irritation fibroma
Lipoma
Neurofibroma
Pleomorphic adenoma

Board review style answer #1

A. Irritation fibroma. Although all of the entities listed fall under the clinical differential diagnosis list, the histology demonstrates a nodular mass of fibrous connective tissue with scattered fibroblasts, blood vessels and chronic inflammatory cells, which rules out all of the listed entities except irritation fibroma.

Comment Here

Reference: Irritation fibroma

Board review style question #2

A 61 year old woman presents with a solitary nodular mass of the oral buccal mucosa that has been present over 5 years with minimal change. Histopathological review of the mass reveals a fibrous mass containing collagen bundles interspersed with fibroblasts and blood vessels. Which of the following is true regarding this pathological entity?

Lesional tissue is positive upon immunohistochemistry with S100
The patient should be evaluated for multiple endocrine neoplasia, type 2B
This entity represents most likely represents a reactive hyperplasia rather than a true tumor
Without surgical excision, this mass will continue to grow to enormous size

Board review style answer #2

C. This entity represents most likely represents a reactive hyperplasia rather than a true tumor. The pathological entity described is an irritation fibroma. Irritation fibromas are the most common oral reactive lesion. While irritation fibromas would be positive upon immunohistochemical staining with vimentin, they are negative with S100, SMA, CD34 and other soft tissue markers. MEN 2B should be considered in a patient with bilateral flesh colored nodules in the commissures of the mouth or multiple nodules of the tip of the tongue, although the biopsy results would reveal a mucosal neuroma rather than purely fibrous connective tissue. Because irritation fibrous are not considered true tumors, they often do not grow with unlimited potential. They most frequently measure 1 - 2 cm in diameter and may increase or decrease in size depending on local irritating factors.

Comment Here

Reference: Irritation fibroma

Kaposi sarcoma

Leukoedema (pending)

[Pending]

Leukoplakia

Table of Contents

Definition / general

Hyperkeratotic (white) plaque / patch of mucosa exhibiting clonality and representing precursor lesion to squamous cell carcinoma
- Approximately 40% of leukoplakias exhibit keratinizing dysplasia (Oral Surg Oral Med Oral Pathol Oral Radiol 2014;118:713)
- Remaining exhibit hyperkeratosis / parakeratosis characterized genomically by KMT2C, TP53, TIAM1 or other mutations (Oral Dis 2019;25:1707)
Term leukoplakia / leukoplakic also used descriptively in clinical setting to denote any white lesion without a readily apparent diagnosis
- Such use may skew understanding of leukoplakia biology / behavior due to preponderance of frictional / reactive keratoses in oral cavity, which are not always recognizable clinically but have no malignant potential (Head Neck Pathol 2019;13:423)
Defined by WHO as a white plaque of questionable risk having excluded (other) known diseases or disorders that carry no increased risk for cancer (J Oral Pathol Med 2007;36:575)
Leukoplakia may occur throughout the upper aerodigestive tract

Essential features

Hyperkeratotic (white) plaque / patch of mucosa exhibiting clonality and representing precursor lesion to squamous cell carcinoma
Approximately 40% of leukoplakias exhibit keratinizing dysplasia; the remainder are characterized by hyperkeratosis alone
Annual malignant transformation rate is 3% and most strongly predicted by presence of dysplasia on biopsy; increasing duration, increasing size and nonhomogenous appearance also associated with malignant transformation
Leukoplakia exhibiting hyperkeratosis that is not frictional / reactive exhibits a malignant transformation rate of approximately 5%, similar to that of mild epithelial dysplasia
Histologic appearance of leukoplakia indistinguishable from proliferative (verrucous) leukoplakia and requires clinical correlation
Surgical excision reduces risk of malignant transformation approximately 3 times

Terminology

Leukoplasia, erythroleukoplakia, erythroplakia

ICD coding

ICD-10: K13.21 - Leukoplakia of oral mucosa, including tongue

Epidemiology

Worldwide prevalence approximately 0.5% (Oral Oncol 2003;39:770, Oral Oncol 2009;45:317)
Characteristically a disease of older males (M:F = 3:1)

Sites

May present on any mucosal surface
Associated with highest incidences of malignant transformation when occurring on ventrolateral tongue or floor of mouth (Oral Oncol 2009;45:317)

Pathophysiology

Leukoplakia exhibiting keratinizing dysplasia characterized by genomic alterations including TP53 mutations and loss of heterozygosity at 3p and 9p (Cancer Prev Res (Phila) 2012;5:1081)
Leukoplakia exhibiting hyperkeratosis alone characterized by genomic alterations including KMT2C, TP53 and TIAM1 mutations (Oral Dis 2019;25:1707)
Genetic progression model of head and neck cancer not well worked out, particularly with regards to early precursor lesions (Clin Cancer Res 2000;6:347)

Etiology

Associated with smoking / smokeless tobacco, alcohol and areca nut (betel quid) use
HPV associated with only a very small percentage of cases (Mod Pathol 2017;30:1646)

Clinical features

Hyperkeratosis on mucosal sites not amenable to frictional / factitial trauma, particularly when sharply demarcated, considered clinically concerning (J Oral Maxillofac Surg 2017;75:723)
Biopsy proven leukoplakia may clinically appear homogenous or nonhomogenous (Oral Oncol 2009;45:317)
- Homogenous leukoplakia: uniformly thin or thick hyperkeratosis, frequently sharply demarcated
- Nonhomogenous leukoplakia: irregular texture with fissuring, nodular / verrucous components or erythematous components (erythroleukoplakia)
Proliferative (verrucous) leukoplakia: uncommon and significantly more aggressive (60 - 100% malignant transformation rate) disease characterized by multifocal oral mucosal involvement and a predilection for middle aged / elderly females with no / minimal history of tobacco or alcohol exposure (Oral Dis 2018;24:749)
- Best considered a separate disease on the basis of differing demographic / clinical presentation, biologic behavior and patient management considerations

Diagnosis

Biopsy required for diagnosis and risk stratification
Leukoplakia with dysplasia readily diagnosed on basis of conventional histopathologic features of epithelial dysplasia (Head Neck Pathol 2019;13:423)
Leukoplakia without dysplasia requires clinicopathologic correlation and exclusion of frictional / factitial features as identified clinically or histopathologically

Prognostic factors

Annual malignant transformation rate 3% (Oral Oncol 1998;34:270)
Presence of epithelial dysplasia most significant risk factor for malignant transformation (Oral Oncol 2009;45:317, Mod Pathol 2017;30:S112)
- Severe epithelial dysplasia: 28.4% risk
- Moderate epithelial dysplasia: 22.5% risk
- Mild epithelial dysplasia: 5.7% risk
- Hyperkeratosis: 4.9% risk
Reported overall malignant transformation rates of 0.36 - 34% difficult to interpret due to historical inclusion of frictional / reactive keratoses in leukoplakia cohorts and variability in followup duration (J Oral Pathol Med 2016;45:155)
Length of duration, increasing size and nonhomogenous appearance associated with increased risk of malignant transformation

Case reports

21 year old man with amalgam associated leukoplakia (J Oral Sci 2016;58:445)
59 and 66 year old men with tongue leukoplakia and squamous cell carcinoma (Mol Med Rep 2017;16:6780)
75 year old man with tongue lesion (Cleve Clin J Med 2020;87:133)

Treatment

Surgical excision results in 3 times reduction in risk of malignant transformation (Head Neck 2009;31:1600)
Leukoplakia with high grade (moderate / severe) dysplasia should be excised whenever possible
Close clinical observation may be appropriate for extensive leukoplakia or patients with comorbidities but otherwise appears to have a limited role when conservative surgical management is possible (J Oral Maxillofac Surg 2017;75:723)

Clinical images

Contributed by Ivan J. Stojanov, D.M.D., M.M.Sc.

Left posterior maxillary leukoplakia

Right posterior maxillary leukoplakia

Left ventral tongue leukoplakia

Extensive leukoplakia of tongue

Microscopic (histologic) description

Leukoplakia with dysplasia exhibits characteristic architectural and cytological features of keratinizing dysplasia
- Features include hyperkeratosis / parakeratosis, epithelial atrophy or hyperplasia with bulbous rete ridges, basal cell hyperplasia with nuclear hyperchromasia or increased nuclear cytoplasmic ratio, variable suprabasal or atypical mitoses, dyskeratosis or glassy cytoplasm, dyscohesion
- Approximately 33% of dysplasias are characterized by an inflammatory infiltrate and should not be misdiagnosed as lichen planus (Oral Surg Oral Med Oral Pathol Oral Radiol 2014;117:511)
Leukoplakia without dysplasia exhibits hyperkeratosis with no histologic features of a frictional / reactive process but is otherwise less well characterized
- Histologic features include (Head Neck Pathol 2019;13:423):
  - Compact hyperkeratosis with hypergranulosis
  - Subtle verrucoid architecture
  - Epithelial atrophy or hyperplasia
- If the periphery of the leukoplakia is sampled, hyperkeratosis will appear sharply demarcated
Some leukoplakias without dysplasia may exhibit prominent verrucous architecture and be reported as verrucous hyperplasia

Microscopic (histologic) images

Contributed by Ivan J. Stojanov, D.M.D., M.M.Sc.

Undulating / verrucoid surface architecture

Absence of epithelial atypia

Sharply demarcated hyperkeratosis

Verrucous hyperplasia

Leukoplakia periphery

Moderate dysplasia

Leukoplakia with no dysplasia

Parakeratosis and epithelial hyperplasia

Hyperkeratosis and epithelial atrophy

Minimal cytologic dysplastic features

Cytology description

Currently limited role for cytology:
- Difficulty sampling adequate tissue in unanaesthetized patients
- Epithelial atypia, if present, difficult to classify as reactive or dysplastic in absence of architectural features
- Patterns of keratinization cannot be assessed
- Oral cavity sites readily amenable to incisional biopsy

Molecular / cytogenetics description

See Pathophysiology

Molecular / cytogenetics images

Images hosted on other servers:

CGH leukoplakia versus SCC

Genes implicated in malignant transformation

Sample pathology report

Mandible, gingiva, incisional biopsy:
- Hyperkeratosis, epithelial atrophy and mild chronic inflammation, not reactive (see comment)
- Comment: The hyperkeratosis exhibits no features of a frictional / reactive process and resembles the surface keratinization commonly seen in epithelial dysplasias. Cytologic atypia is minimal / absent in this specimen but leukoplakia without dysplasia (hyperkeratosis that is not reactive) has malignant transformation rates of approximately 5%, similar to that of leukoplakia with mild dysplasia. The findings are consistent with the clinically observed leukoplakia, which in approximately 60% of cases presents without dysplasia. If the clinical context is appropriate, proliferative (verrucous) leukoplakia may also be considered.

Differential diagnosis

Benign alveolar ridge keratosis:
- Histologic features similar to lichen simplex chronicus
- Epithelial hyperplasia with verrucous / undulating surface and wedge shaped hypergranulosis
- Compact hyperkeratosis that tapers towards the edges and is not sharply demarcated
- Elongated rete ridges, occasionally confluent at tips
- No epithelial atypia
- Fibrosis and sparse chronic inflammation
Chronic frictional / factitial keratosis:
- Shaggy / macerated parakeratosis with superficial bacterial colonization
- Epithelial hyperplasia with keratinocyte edema but no epithelial atypia
- Variable fibrosis, acute and chronic inflammation and leukocyte exocytosis
Lichen planus / lichenoid mucositis:
- Squamatization / degeneration of the basal cell layer with Civatte bodies (dyskeratotic keratinocytes)
- Band-like lymphoplasmahistiocytic infiltrate in the superficial lamina propria with leukocyte exocytosis and spongiosis
Proliferative (verrucous) leukoplakia:
- Characterized clinically by multifocal leukoplakia
  - Gingival involvement common
- Predilection for middle aged / elderly females and with no / minimal tobacco or alcohol exposure
  - Reason for this association is unclear
- Indistinguishable histologically from leukoplakia
- Verrucous epithelial architecture common but not necessarily present

Board review style question #1

A 57 year old male smoker presents with a leukoplakia on the left ventral tongue. What is the most important predictor of malignant transformation?

Duration
Homogenous appearance
Nonhomogenous appearance
Presence of epithelial dysplasia on biopsy
Size

Board review style answer #1

D. Presence of epithelial dysplasia on biopsy

Comment Here

Reference: Leukoplakia

Board review style question #2

Which of the following is true regarding leukoplakia without dysplasia?

It can be readily recognized by histologic features of a frictional / reactive process
It can undergo malignant transformation
It is usually associated with HPV infection
It is diagnostic of proliferative (verrucous) leukoplakia
It is rarely encountered in leukoplakia biopsies

Board review style answer #2

B. It can undergo malignant transformation

Comment Here

Reference: Leukoplakia

Lichen planus

Table of Contents

Definition / general

Chronic, T cell mediated inflammatory mucocutaneous disorder of uncertain etiology and pathogenesis
Characterized by relapses and remissions

Essential features

Common oral mucosal disease with multifocal, bilateral and symmetrical involvement
Characterized by white, lace-like lesions (Wickham striae) with or without atrophic or erosive areas
Accurate identification is challenging and often requires clinicopathological correlation
Histopathology is nonspecific but includes hyperkeratosis, interface mucositis, hydropic degeneration and apoptotic keratinocytes
Direct immunofluorescence is nonspecific with a shaggy deposition of fibrinogen at the basement membrane zone

Terminology

Lichen planus

ICD coding

ICD-10: L43.9 - oral lichen planus
ICD-11:
- EA91.40 - nonerosive lichen planus of oral mucosa
- EA91.41 - erosive oral lichen planus
- EA91.42 - oral lichen planus, unspecified

Epidemiology

Global oral lichen planus prevalence is 1.01% (Oral Dis 2021;27:813)
Most commonly seen in middle aged adults (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103:S25.e1)
Rarely seen in pediatric populations (Pediatr Dermatol 2014;31:59)
F > M (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103:S25.e1)
May be associated with hepatitis C (varies geographically) (Br J Dermatol 2004;151:1172)

Sites

Intraoral
- Oral lichen planus is typically multifocal and bilateral with a symmetric distribution of lesions
- Most common site is buccal mucosa; oral lichen planus usually involves the buccal mucosa bilaterally
- May affect the gingiva, vestibule and labial mucosa; tongue involvement is uncommon (J Cancer Prev 2016;21:55)
Extraoral
- Skin (flexor, wrists and forearms, dorsal hands, shins, presacral area), mucous membranes (oral mucosa, genitalia), hair, nails, esophagus (rare)
- 16% of oral lichen planus patients also have cutaneous involvement (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;88:431)

Pathophysiology

Unknown pathogenesis (Oral Surg Oral Med Oral Pathol Oral Radiol 2016;122:72)

Etiology

Believed to be a T cell mediated chronic inflammatory oral mucosal disease of unknown etiology (J Oral Pathol Med 2010;39:729)

Clinical features

Most common clinical patterns of oral lichen planus are the reticular and erosive forms (Head Neck Pathol 2020;14:192)
- Reticular pattern: characterized by thin, interlacing and white lines (Wickham striae); lesions typically wax and wane over weeks or months (Oral Maxillofac Surg Clin North Am 2013;25:93)
- Erosive pattern: characterized by atrophic and erythematous areas with central ulceration
Other clinical patterns include atrophic, papular, plaque and bullous forms (Clin Dermatol 2016;34:495)
Reactive pigmentation may be seen, particularly in persons of color (Oral Surg Oral Med Oral Pathol Oral Radiol 2016;122:332)
Multiple forms may be seen in one patient; clinical forms represent the same disease process
Worse symptoms / lesions tend to be in areas of trauma, chronic irritation, poor oral hygiene

Diagnosis

Diagnosis is based on both clinical and histopathologic features (J Oral Pathol Med 2021;50:520)
- Histopathologic features of oral lichen planus may mimic numerous pathologic processes with an inflammatory infiltrate (Oral Surg Oral Med Oral Pathol Oral Radiol 2016;122:332)
- Adjunct direct immunofluorescence may be beneficial to differentiate oral lichen planus from conditions with similar histomorphology (e.g., chronic ulcerative stomatitis) or clinical features (e.g., mucous membrane pemphigoid and pemphigus vulgaris) (Oral Surg Oral Med Oral Pathol Oral Radiol 2016;122:332)
  - Direct immunofluorescence does not distinguish lichen planus from oral dysplasia (Oral Surg Oral Med Oral Pathol Oral Radiol 2015;119:675)

Prognostic factors

Oral lichen planus is characterized by relapses and remissions
Uncertain malignant potential
- Small subset of patients with oral lichen planus (1.1%) develops oral squamous cell carcinoma (Oral Oncol 2017;68:92)

Case reports

8 year old boy with oral ulcerations (J Oral Maxillofac Pathol 2020;24:S128)
57 year old man with bilateral white lesions of the buccal mucosa (Head Neck Pathol 2020;14:192)
77 year old woman with desquamative gingivitis (Case Rep Dent 2019;2019:4659134)

Treatment

Reticular oral lichen planus is often asymptomatic; no treatment is needed, although management includes monitoring patients at regular intervals to ensure the lesions are migrating or changing patterns
- Photographic documentation is beneficial (Head Neck Pathol 2019;13:423)
- Lesions that do not migrate are concerning for evolving oral dysplasia or contact related lichenoid lesions
Erosive oral lichen planus is often bothersome due to open sores; typically managed with topical or systemic corticosteroids (Cochrane Database Syst Rev 2020;2:CD001168)

Clinical images

Contributed by Mark Mintline, D.D.S., Sahar Mirfarsi, D.D.S. and Molly Housley Smith, D.M.D.

Reticular oral lichen planus

Erosive lichen planus

Desquamative gingivitis

Ulceration

Cutaneous plaques

Papular lichen planus

Reactive pigmentation

Cutaneous papules

Nail changes

Gross description

Nonspecific
Often tan wedge of mucosa with white striations, papules, erosions or ulcerations

Gross images

Contributed by Molly Housley Smith, D.M.D.

White striations

Microscopic (histologic) description

2003 modified WHO criteria may have more specificity than the 1978 WHO criteria (Int J Prev Med 2021;12:126, J Oral Pathol Med 2003;32:507):
- Orthokeratosis or parakeratosis
- Epithelial thickness varies, sawtooth rete ridges occasionally seen
- Colloid (civatte) bodies in the epithelium or superficial lamina propria
- Thin band of eosinophilic material in the basement membrane
- Well defined, band-like zone of cellular infiltration consisting mainly of lymphocytes and confined to the superficial lamina propria
- Liquefactive degeneration in the basal cell layer (hydropic degeneration)
- Absence of epithelial dysplasia
Additional criteria proposed by Cheng et al. 2016 (Oral Surg Oral Med Oral Pathol Oral Radiol 2016;122:332):
- Band-like or patchy, predominantly lymphocytic infiltrate in the lamina propria that is confined to the interface of the epithelium and lamina propria
- Lymphocytic exocytosis
- Absence of epithelial dysplasia
- Absence of verrucous epithelial architectural changes
Histopathologic features of oral lichen planus are nonspecific and should be correlated with clinical features (Oral Surg Oral Med Oral Pathol Oral Radiol 2016;122:332)

Microscopic (histologic) images

Contributed by Mark Mintline, D.D.S. and Molly Housley Smith, D.M.D.

Interface mucositis

Hydropic degeneration

Sawtooth rete ridges

Colloid bodies

Melanin pigmentation

Virtual slides

Images hosted on other servers:

Oral lichen planus

Immunofluorescence description

Direct immunofluorescence is nonspecific
IgG, IgA, IgM and complement (C3) are characteristically negative
Shaggy, linear deposition of fibrinogen may be seen at the basement membrane zone
- Fibrinogen positivity at the basement membrane zone may also be seen in epithelial dysplasia and squamous cell carcinoma (Oral Surg Oral Med Oral Pathol Oral Radiol 2015;119:675)
Colloid bodies may be positive for immunoglobulins
Indirect immunofluorescence is negative

Immunofluorescence images

Contributed by Molly Housley Smith, D.M.D.

Fibrinogen deposition

Positive stains

PAS (colloid bodies)

Sample pathology report

Buccal mucosa, incisional biopsy:
- Chronic interface mucositis and hyperparakeratosis (see comment)
- Comment: The histomorphology of interface mucositis combined with the clinical presentation of bilateral, migrating erosions with Wickham striae is most consistent with oral lichen planus.

Differential diagnosis

Oral lichenoid drug reaction:
- Oral mucosal immunoinflammatory disorder characterized by erythematous plaques, vesiculation, ulceration or hyperkeratosis in response to a medication (Dermatol Ther 2010;23:251)
- Time range between initiation of medication and onset of reaction can vary widely
- Resembles oral lichen planus; mixed inflammation may extend into the deep lamina propria, may show perivascular inflammation
- Epithelium may have a greater number of colloid bodies (Int J Dermatol 2012;51:1199)
- Infiltrate may be more diffuse or mixed with plasma cells
- Indirect immunofluorescence may detect circulating antibodies directed to basal cells in a string of pearls pattern (Am J Dermatopathol 1982;4:155)
- Common implicated medications: nonsteroidal anti-inflammatory drugs, anticonvulsants, antihypertensives, antimalarials and antiretrovirals
Oral lichenoid contact hypersensitivity reaction:
- Oral mucosal immunoinflammatory disorder characterized by erythematous plaques, vesiculation, ulceration or hyperkeratosis in response to a local agent (Oral Surg Oral Med Oral Pathol Oral Radiol 2017;123:559)
- May present with pain, burning sensation or itchiness (Oral Surg Oral Med Oral Pathol Oral Radiol 2017;123:559)
- Lichenoid interface mucositis; mixed inflammation may extend into the deep lamina propria, may show perivascular inflammation (Eur J Dermatol 2004;14:284)
- Common implicated agents: mouthwashes, foods, spices (particularly cinnamon), gloves, rubber dams and dental materials (Eur J Dermatol 2004;14:284)
Chronic ulcerative stomatitis:
- Rare, autoimmune disorder that affects the oral mucosa (J Oral Pathol Med 2022;51:501)
- Patients develop autoantibodies against nuclear protein ΔNp63α (an isoform of p63) (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2011;111:742)
- Clinically, lesions often respond to antimalarial medications and are less responsive to corticosteroid therapy than oral lichen planus (Oral Surg Oral Med Oral Pathol Oral Radiol 2016;122:332, Oral Dis 2008;14:383)
- Histopathological features may be indistinguishable from oral lichen planus; often demonstrates marked epithelial atrophy (Head Neck Pathol 2019;13:386)
- Direct immunofluorescence: specific antinuclear antibody (SES ANA) pattern; IgG antibodies present in the nuclei of basal and parabasal cells (Head Neck Pathol 2019;13:386)
Oral graft versus host disease:
- Clinical and histopathological presentations are similar to oral lichen planus
- Develops as a result of allogeneic hematopoietic cell transplantation
Lupus erythematosus:
- Oral involvement in ~25% of cases (Expert Rev Mol Diagn 2014;14:169)
- Majority of cases have cutaneous involvement or systemic inflammatory disease
- Histopathology resembles oral lichen planus; may have perivascular inflammation
- Direct immunofluorescence: linear band or continuous granular IgG, IgM, IgA or C3 at the basement membrane zone
Proliferative verrucous leukoplakia:
- Multifocal, aggressive form of oral leukoplakia with a tendency to recur and undergo malignant transformation (Head Neck 2014;36:1662)
- Clinicopathological diagnosis (Head Neck Pathol 2021;15:572)
- Early lesions may mimic oral lichen planus clinically and microscopically
- Histopathology may have inflammatory infiltrate (Head Neck Pathol 2021;15:572)
- Oral lichen planus should lack a prominent corrugated architecture (Oral Surg Oral Med Oral Pathol Oral Radiol 2016;122:332)
Evolving / early dysplasia:
- Clinical correlation is necessary to distinguish from oral lichen planus
- Oral dysplastic lesions may demonstrate lichenoid inflammatory infiltrate in superficial lamina propria
- Clinically, the lesion does not migrate or change patterns
Foreign body gingivitis:
- White, progressing, verrucous / corrugated clinical lesions (mimicking proliferative verrucous leukoplakia) were recently found to be strongly associated with granules of embedded foreign material (Oral Surg Oral Med Oral Pathol Oral Radiol 2019;128:250)
- Similar histomorphology to oral lichen planus; however, inflammatory infiltrate is often mixed and patchy, containing minuscule granules of foreign material
- Silica is the most common element found in the embedded foreign material (Oral Surg Oral Med Oral Pathol Oral Radiol 2019;128:250)

Board review style question #1

A 54 year old woman presents to her dentist for a routine examination. Clinical examination reveals thin, interlacing white lines on the buccal mucosa. The lesions present bilaterally. The patient reports that the lesions are asymptomatic and that she had them for years. She reports that the lesions tend to wax and wane. What is the most likely diagnosis?

Lichen planus
Mucous membrane pemphigoid
Oral candidiasis
Pemphigus vulgaris
Squamous cell carcinoma

Board review style answer #1

A. Lichen planus. The prevalence of oral lichen planus is 0.1% to 2.2%. The 2 most common clinical patterns of oral lichen planus are reticular and erosive. Reticular oral lichen planus is named because of its characteristic pattern of interlacing white lines (Wickham striae).

Comment Here

Reference: Lichen planus

Board review style question #2

Which direct immunofluorescence finding is most supportive of oral lichen planus?

IgG in the basal and parabasal epithelial nuclei
Intracellular IgG deposition
Linear IgG deposition at the basement membrane zone
Shaggy, linear deposition of fibrinogen at the basement membrane zone

Board review style answer #2

D. Shaggy, linear deposition of fibrinogen at the basement membrane zone. Direct immunofluorescence studies may be necessary to differentiate oral lichen planus from autoimmune blistering diseases. Shaggy deposition of fibrinogen at the basement membrane zone and the absence of immunoglobulin is seen in oral lichen planus.

Comment Here

Reference: Lichen planus

Lingual thyroid

Table of Contents

Definition / general

Developmental anomaly in which ectopic thyroid gland is located at the base of tongue
Tongue is the most common site for total thyroid ectopia
First reported by Hickman in 1869 (AMA Arch Otolaryngol 1953;57:60)

Epidemiology

Prevalence in general population is 1 per 10,000 - 100,000 people (Endocr Pract 2016;22:343)
Historically, thyroid tissue has been found in the tongue in 10% of autopsies (J Pathol 1970;102:239, Oral Surg Oral Med Oral Pathol 1972;34:781)
F:M = 3 - 7:1
Mean age at presentation is about 40 years, ranging from infancy to 83 years (Eur J Endocrinol 2011;165:375)
Some studies report a bimodal age distribution, with peaks in 2nd and 4th decades (Br J Surg 1979;66:537)

Sites

Most cases arise superficially or submucosally along the midline of base of the tongue between foramen cecum and epiglottis
Sublingual types (body of the tongue) are rarer and may be suprahyoid, infrahyoid or at the level of the hyoid bone

Pathophysiology / etiology

Failure of thyroid gland to descend from the foramen cecum to its normal prelaryngeal location
Pathogenesis is unclear, but there are speculations that maternal antithyroid immunoglobulin may stop thyroid gland descent (Barnes: Surgical Pathology of the Head and Neck, 3rd Edition, 2008)
Hypothyroidism is commonly seen in patients with lingual thyroid and some have hypothesized that lingual thyroid is a hyperplastic physiologic response by small thyroid remnants in the tongue to a low thyroid hormone level
Mutation in the genes of thyroid specific transcription factors TTF1, TTF2 (FOXE1) and PAX8 might be involved in thyroid arrest in tongue, as was shown in animals (Nat Genet 1998;19:395); however, no mutation in known genes has so far been associated with the human ectopic thyroid

Clinical features

Most lingual thyroids are asymptomatic
Symptomatic lingual ectopia is often manifested in women during puberty, pregnancy or menstruation
Most common symptoms are dysphagia, dyspnea and upper airway obstruction; other symptoms are foreign body sensation, pain, hemoptysis, dysphonia, snoring and sleep apnea (Endocr Pract 2016;22:343)
In more than 75% of patients, orthotopic thyroid is absent (total migration failure) and lingual thyroid represents the only thyroid tissue; as a result, 70% of patients with symptomatic lingual thyroid are hypothyroid; hyperthyroidism is exceptionally rare (Int J Surg 2014;12:S3)
Malignant neoplasms may arise in up to 1% of lingual thyroids; 50+ cases have been reported (J Clin Endocrinol Metab 2011;96:2684)
- Most are follicular carcinomas
- However, recent reports more often encounter papillary carcinomas, which probably reflects greater recognition of the follicular variant of papillary carcinoma (Nikiforov: Diagnostic Pathology and Molecular Genetics of the Thyroid, 2nd Edition, 2012)

Diagnosis

Radionuclide scan with technetium or radioiodine
CT, MRI and angiography are important for the preoperative assessment of patients
FNA helps to differentiate benign from neoplastic conditions
Incisional biopsy is discouraged due to risk of complications, e.g. infection, necrosis or hemorrhage (Wenig: Atlas of Head and Neck Pathology, 3rd Edition, 2015)

Laboratory

Hypothyroidism (low T3 and T4, high TSH)

Radiology description

MRI is useful in estimating extent of a lesion, because it can clearly distinguish thyroid tissue (low-intermediate T2 signal) from the tongue muscle (Hormones (Athens) 2011;10:261)

Radiology images

Images hosted on other servers:

CT and laryngoscopy

SPECT / CT

CT scan:

Distinct margins

Lingual thyroid

Well defined mass

Aberrant thyroid tissue

48-year-old white female with obstructive lingual thyroid

MRI:

Axial MRI: lingual thyroid

38 year old female

Radionuclide scan:

Scintigraphy with Tc-99m

Tc99m pertechnetate planar image

99mTcO4 radionuclide thyroid scan

Thyroid scintigraphy

Angiography:

External carotid artery angiogram

Ectopic thyroid

Carotid arteriography

Prognostic factors

Prognosis is good, since resection of lingual thyroid achieves significant improvement in patient symptoms with low rates of recurrence (Wenig: Atlas of Head and Neck Pathology, 3rd Edition, 2015)

Case reports

7 year old girl with Hashimoto thyroiditis in lingual thyroid (BMJ Case Rep 2013;2013:bcr2013200247)
12 year old girl with ectopic lingual thyroid (Case Rep Pediatr 2015;2015:252357)
12 year old boy with hyperfuctioning lingual thyroid (J Anaesthesiol Clin Pharmacol 2013;29:132)
15 year old girl with lingual thyroid and TSH secreting pituitary adenoma (Case Rep Endocrinol 2013;2013:570847)
24 year old woman with follicular adenoma of sublingual ectopic thyroid gland (J Med Case Rep 2014;8:270)
25 year old woman with fine needle aspiration diagnosis of hyperfunctioning ectopic thyroid (Acta Cytol 2005;49:228)
26 year old man with hemoptysis caused by ectopic lingual thyroid (Quant Imaging Med Surg 2015;5:480)
31 year old man with ectopic lingual goiter (Acta Otorhinolaryngol Ital 2013;33:343)
40 year old woman with lingual thyroid (Ann Maxillofac Surg 2015;5:104)
45 year old woman with dyspnea caused by lingual thyroid (N Engl J Med 2012;366:e15)
60 year old man with ectopic lingual thyroid with a multinodular goiter (Surgery 2013;153:294)
63 year old woman with differentiated thyroid carcinoma in lingual thyroid (Endocrine 2016;51:189)

Treatment

Small lesions without symptoms usually require no therapy
Nonsurgical treatment includes thyroid hormone and radioiodine ablation to induce tissue regression (Int J Surg 2014;12:S3)
Major indications for surgical excision are airway obstruction and repeated significant hemorrhage
- Transoral robotic surgery (TORS) is the most advanced surgical technique (Thyroid 2013;23:466)
- Most patients with lingual thyroid have no other thyroid tissue and acute hypothyroidism may occur after surgical removal
- Autotransplantation of pieces of lingual thyroid into the neck soft tissues may be considered

Clinical images

Images hosted on other servers:

Tongue mass:

Endoscopy:

Flexible and rigid

Swelling

Lingual thyroid in surgery:

Exposed tumor

Intraoperative photograph and surgical specimen

Gross description

Midline of base of tongue, usually between circumvallate papillae and epiglottis
Dome shaped, soft to firm mass with smooth surface, rarely ulcerated
Several mm to several cm in size (mean 2 - 3 cm)
Red, smooth to lobulated to nodular, either well or ill defined on sectioning

Gross images

Images hosted on other servers:

Excised specimen

Microscopic (histologic) description

Thyroid tissue appears normal, with normofollicular and microfollicular patterns
Follicular cells are benign in appearance, without nuclear features of papillary carcinoma
Thyroid tissue usually grows between skeletal muscle and minor salivary glands of tongue, which may simulate tumor invasion
Circumscribed and encapsulated arrangement is rare
Diagnosis of primary thyroid carcinoma in a lingual site requires vascular invasion, unequivocal infiltration with desmoplastic response or metastasis in the absence of another primary site (Endocr Pathol 2002;13:353)

Microscopic (histologic) images

Contributed by Andrey Bychkov, M.D., Ph.D. and AFIP

Enlarged thyroid follicles

Resembles malignancy

Images hosted on other servers:

With skeletal muscle

Thyroid follicles

Papillary thyroid
carcinoma in
lingual thyroid

Virtual slides

Images hosted on other servers:

Lingual thyroid with follicular carcinoma

Cytology description

Clusters of follicular cells and colloid, with usual hemorrhagic background (Acta Cytol 2005;49:228)
Features of associated pathological conditions, e.g. inflammatory and neoplastic, if such are present (Cytopathology 2013;24:275)

Cytology images

Images hosted on other servers:

Follicular cells

Positive stains

Immunophenotype of thyroid tissue: thyroglobulin, TTF1 in follicular cells and calcitonin in C cells (J Clin Endocrinol Metab 2012;97:951)

Molecular / cytogenetics description

Mutations typical for thyroid cancer (BRAF V600E, NRAS, HRAS, KRAS) are absent in benign appearing ectopic thyroid tissue (Int J Surg Pathol 2015;23:170)

Videos

Ectopic thyroid in a 6 year old child

Differential diagnosis

Lingual thyroglossal duct cyst
Lymphoepithelial cyst of oral cavity
Some tumors in oral cavity may mimic papillary thyroid carcinoma (Wenig: Atlas of Head and Neck Pathology, 3rd Edition, 2015)
- Cribriform adenocarcinoma of minor salivary glands of oral cavity: thyroglobulin-, TTF1-
- Low grade nasopharyngeal papillary adenocarcinoma: thyroglobulin-, TTF1+

Lingual tonsil

Table of Contents

Definition / general

Collection of reactive submucosal lymphoid nodules situated on the dorsal or lateral aspects of the tongue base, which presents clinically as red papules or nodules
One of the three sets of tonsils present within Waldeyer ring, along with the pharyngeal and palatine tonsils

Essential features

Clinically presents as red papules or nodules posterior to the circumvallate papillae
Often clinically diagnostic, although asymmetric, hyperplastic nodules may warrant biopsy to rule out lymphoma, HPV-positive squamous cell carcinoma, or other pathology
Hyperplastic lingual tonsil is associated with obesity, obstructive sleep apnea, acid reflux disease, younger age, allergic rhinitis and smoking (Am J Rhinol Allergy 2020;34:87)

Terminology

Hyperplastic lingual tonsil
Hyperplastic lymphoid aggregates
Lingual tonsillar hypertrophy

ICD coding

ICD-10: J35.1 - hyperplastic lingual tonsil

Epidemiology

Normal anatomical structure
Hyperplastic lingual tonsils demonstrate higher incidence in younger patients (Am J Rhinol Allergy 2020;34:87)
Associated with obesity, obstructive sleep apnea, laryngopharyngeal reflux, younger age, allergic rhinitis and smoking (Am J Rhinol Allergy 2020;34:87)

Sites

Base of tongue, dorsal or lateral aspects, posterior to the circumvallate papillae
Anterior to the epiglottis

Diagrams / tables

Images hosted on other servers:

Lingual tonsil anatomy

Clinical features

Red papules or nodules on the dorsal or lateral aspects of the base of the tongue
Size ranges from a small papule to a large mass (Clin Otolaryngol 2017;42:144)
Patients with hyperplastic lingual tonsils may present with dysphagia, chronic cough, voice changes, globus sensation, snoring, lingual tonsillitis or rarely airway compromise (Am J Rhinol Allergy 2020;34:87, Cureus 2020;12:e8309, BMJ Case Rep 2019;12:e229555)
May contribute to the pathogenesis of acid reflux or obstructive sleep apnea in children who are obese (J Otolaryngol Head Neck Surg 2017;46:32)
Hyperplastic lingual tonsils may cause difficulty in face mask ventilation or tracheal intubation (Clin Otolaryngol 2017;42:144, Anesthesiology 2010;112:746)

Diagnosis

Diagnosis is made upon clinical features or awake endoscopy (Otolaryngol Head Neck Surg 2018;158:391)
Biopsy rarely is indicated to rule out other pathological causes of submusocal masses (e.g. lymphoma)
Head and neck computed tomography (CT), magnetic resonance imaging (MRI), skull lateral radiographs may prove useful in diagnosis and staging of lingual tonsil hypertrophy (Otolaryngol Head Neck Surg 2017;157:898)

Radiology description

Head and neck computed tomography (CT), magnetic resonance imaging (MRI) and skull lateral radiographs demonstrate lingual tonsils at the level of the epiglottis on the tongue base (Otolaryngol Head Neck Surg 2017;157:898)

Radiology images

Contributed by Molly Housley Smith, D.M.D.

Sagittal T1 weighted MRI

Case reports

17 year old girl and 26 and 30 year old women present with eosinophilic lingual tonsillitis following sublingual immunotherapy for allergic rhinitis (Clin Case Rep 2020;8:2211)
48 year old woman with lingual tonsil abscess contributing to rapidly progressing sore throat (BMJ Case Rep 2019;12:e229555)
70 year old woman with hyperplastic lingual tonsil leading to partial airway obstruction (Cureus 2020;12:e8309)

Treatment

Nonsurgical medical management or surgical debulking / removal may be indicated in cases of hyperplastic lingual tonsil contributing to sleep apnea (Clin Otolaryngol 2017;42:144)
- Nonsurgical management most often entails treating symptoms of acid reflux to prevent inflammation of the tonsil tissue (Clin Otolaryngol 2017;42:144)
- Surgical debulking or removal includes a number of different techniques including sharp dissection, coblation, cryotherapy, laser ablation, suction diathermy, ultrasonographic coagulating dissection and bipolar radiofrequency plasma excision (JAMA Otolaryngol Head Neck Surg 2013;139:1032, Clin Otolaryngol 2017;42:144)

Clinical images

Contributed by Molly Housley Smith, D.M.D.

Posterior dorsal tongue

Posterior lateral tongue

Numerous enlarged papules

Gross images

Images hosted on other servers:

Inferior view

Superior view

Microscopic (histologic) description

Aggregates of benign lymphoid tissue, often with germinal center formation; germinal centers lack capsules and sinusoidal spaces
May contain crypts lined by specialized keratinized stratified squamous epithelium (termed reticular epithelium) that invaginate from the surface; crypts are often filled with desquamated epithelial cells and bacteria, which may calcify
Often surrounded by other normal structures of the tongue, including striated muscle, mucinous glands and serous glands
Reference: Anat Histol Embryol 2005;34:27

Microscopic (histologic) images

Contributed by Molly Housley Smith, D.M.D.

Germinal center formation

Epithelial crypt formation

Diffuse lymphocytic tissue

Reticular epithelium

Videos

Histology of the lingual tonsil

Lingual tonsillectomy for obstructive sleep apnea

Sample pathology report

Tongue base, incisional biopsy:
- Hyperplastic lingual tonsil (see comment)
- Comment: Microscopic examination reveals surface stratified squamous epithelium and supporting connective tissue. The surface epithelium contains scattered taste buds and focally invaginates into the mesenchymal tissue forming deep crypts containing keratin flakes. Within the supporting connective tissue is a well defined area of lymphoid tissue. Germinal center formation is noted. Lobules of minor salivary glands and associated ductal structures are noted in the surrounding stroma.

Differential diagnosis

Lymphoepithelial cyst:
- Often clinically presents as an opaque yellow-white nodule that easily ruptures upon manipulation
- Microscopically similar to lingual tonsil, although an enlarged cystic space is seen rather than an crypt-like invagination of surface epithelium (J Clin Exp Dent 2017;9:e1035)

Human Papilloma Virus-Positive Squamous Cell Carcinoma (HPV-positive SCCa):
- Since HPV positive SCCa often originates deep within the tonsillar crypt epithelium, it may clinically present as an enlarged, smooth surfaced, red / pink nodule within the area of the lingual tonsils (Statpearls: Oropharyngeal Squamous Cell Carcinoma [Accessed 23 June 2021])
- Firm / indurated on palpation
- Typically larger in size when compared to the contralateral side of the tongue
- Microscopically, islands of epithelium arising from the tonsillar crypt epithelium are seen invading into the connective tissue in HPV-pos SCCa; P16^ink4a or cytokeratin immunohistochemical markers may be used to highlight the invasive islands when dense inflammation obscures the presence of overt invasion

Additional references

Wenig: Atlas of Head and Neck Pathology (Atlas of Surgical Pathology), 3rd Edition, 2015

Board review style question #1

Oral examination of a patient reveals an asymmetric 4 mm red nodule at the dorsal tongue base. The patient is asymptomatic and was unaware of the finding. Biopsy of the lesion is shown. Which of the following is true regarding the diagnosis?

Diagnosis of this entity relies heavily on immunohistochemical findings
Diagnosis represents reactive hyperplasia of a normal structure
Significant clinical follow up is recommended, since malignant transformation occurs in the majority of patients with this finding
This entity is more commonly found in older adults

Board review style answer #1

B. Diagnosis represents reactive hyperplasia of a normal structure

Comment Here

Reference: Lingual tonsil

Board review style question #2

A patient presents with a focal collection of red papules on the posterior lateral tongue. Biopsy demonstrates a well defined aggregate of lymphocytes showing germinal center formation. An epithelial lined crypt containing keratin is seen in the central aspects of the lymphocytic nodule. What is the most likely diagnosis?

Fibroma
HPV related squamous cell carcinoma
Lingual tonsil
Lymphoma

Board review style answer #2

C. Lingual tonsil

Comment Here

Reference: Lingual tonsil

Low grade myofibroblastic sarcoma

Lymphoepithelial cyst

Table of Contents

Definition / general

Lymphoepithelial cysts are uncommon benign oral cavity cysts

Essential features

Oral lymphoepithelial cysts are most common in the lateral tongue and floor of mouth
Histologic features include a squamous epithelial lined cyst filled with keratin debris and stromal lymphoid tissue
Treatment is conservative surgical excision with no recurrence

Terminology

Oral lymphoepithelial cyst
Intraoral lymphoepithelial cyst
Benign lymphoepithelial cyst

ICD coding

ICD-10:
- K09.8 - other cysts of oral region, not elsewhere classified
- K09.9 - cyst of oral region, unspecified

Epidemiology

< 1% of all lesions in oral cavity
Occurs in adults
- Most common in fifth to sixth decade
- F > M (Head Neck Pathol 2021 Jun 29 [Epub ahead of print])

Sites

Oral cavity (Head Neck Pathol 2021 Jun 29 [Epub ahead of print], J Oral Pathol Med 2020;49:219)
- Most common site: ventral and posterolateral tongue
- Second most common site: floor of mouth
- Other sites in the oral cavity: buccal mucosa, palate, tonsillar pillar, lip

Etiology

Unknown:
- Leading theory: pseudocysts develop from obstruction of tonsil crypt of oral tonsil tissue (Oral Surg Oral Med Oral Pathol 1970;29:295)
- Another theory postulates traumatic implantation of epithelium into deeper tissues, forming cyst (Oral Surg Oral Med Oral Pathol 1963;16:1214)
- A third theory postulates lymphoid tissue with ectopic foci of entrapped glandular epithelium (Oral Surg Oral Med Oral Pathol 1966;21:120)
Oral lymphoepithelial cyst is not associated with human immunodeficiency virus (HIV), unlike a subset of lymphoepithelial cysts of the major salivary glands

Clinical features

Small, white-yellow submucosal nodule
< 1 cm
Often painless and asymptomatic
References: Head Neck Pathol 2021 Jun 29 [Epub ahead of print], J Oral Pathol Med 2020;49:219

Diagnosis

Combination of clinical and histologic findings

Prognostic factors

Good prognosis
No recurrence after excision

Case reports

21 year old man with lymphoepithelial cyst in the palatine tonsil (Int J Clin Exp Pathol 2015;8:4264)
42 year old woman with multiple lymphoepithelial cysts (Indian J Pathol Microbiol 2013;56:473)
55 and 57 year old women with oral lymphoepithelial cysts (Bull Tokyo Dent Coll 2012;53:17)

Treatment

Conservative surgical excision

Clinical images

Images hosted on other servers:

Lymphoepithelial cyst in tonsil

Lymphoepithelial cyst, floor of mouth

Gross description

Cystic structure, well demarcated, filled with yellowish keratin-like material

Gross images

Images hosted on other servers:

Lymphoepithelial cyst, floor of mouth

Microscopic (histologic) description

Well circumscribed cyst lined by parakeratinized stratified squamous epithelium with lymphoid stroma
- May have connection to overlying epithelium but not always identified
- Other cyst linings: nonkeratinized squamous epithelium, respiratory metaplasia or ciliated pseudostratified epithelium (or any combination)
- Cyst contents: predominantly keratin debris, amorphous eosinophilic material and inflammatory cells
- Lymphoid stroma may or may not have germinal centers
- Rarely subgemmal neurogenous plaques have been reported near the cyst (Head Neck Pathol 2021 Jun 29 [Epub ahead of print], J Oral Pathol Med 2020;49:219)

Microscopic (histologic) images

Contributed by John Kalmar, D.M.D., Ph.D.

Floor of mouth cyst

Squamous epithelial lining

Lateral tongue cyst

Germinal center in stroma

Positive stains

Cyst lining: p40+
Lymphoid stroma: CD20+ cells predominant, rare CD3+ (J Oral Pathol Med 2020;49:219)

Sample pathology report

Floor of mouth, biopsy:
- Oral lymphoepithelial cyst

Differential diagnosis

Epidermal inclusion cyst (epidermoid cyst):
- Squamous lined cyst without lymphoid stroma
Sebaceous cyst:
- Squamous lined cyst with adnexal structures, lacking lymphoid stroma
Fordyce granules:
- Clusters of sebaceous glands
Sialolith:
- Calcified material with surrounding ductal epithelium (with squamous metaplasia)
Mucocele:
- Pseudocyst filled with mucin, lined by histiocytes and lymphocytes
Foreign body reaction:
- Numerous multinucleated giant cells with poorly formed granulomas with foreign material
Squamous cell carcinoma:
- Invasive proliferation of squamous nests

Board review style question #1

A 45 year old patient presents with a painless 0.5 cm white nodule on the left lateral tongue. A biopsy is performed and a representative image from the histology is shown above. What is the diagnosis?

Fordyce granule
Lymphoepithelial cyst
Lymphoid aggregate
Mucocele
Sialolith

Board review style answer #1

B. Lymphoepithelial cyst

Comment Here

Reference: Oral lymphoepithelial cyst

Board review style question #2

Which of the following is seen in the stroma surrounding the cyst lining of a lymphoepithelial cyst?

Collagen
Lymphoid tissue
Mucin
Sebaceous glands
Seromucinous glands

Board review style answer #2

B. Lymphoid tissue

Comment Here

Reference: Oral lymphoepithelial cyst

Median rhomboid glossitis

Table of Contents

Definition / general

Inflammation or beefy red tongue associated with deficiency states
Due to atrophy of tongue papillae, thinning of mucosa and exposure of underlying vasculature

Terminology

Also called central papillary atrophy, posterior lingual papillary atrophy

Epidemiology

1% population, usually males, ages 30 - 50 years

Clinical features

Usually a clinical diagnosis
Causes: pernicious anemia (vitamin B12 deficiency), deficiency of riboflavin, niacin or pyridoxine; sprue, iron deficiency anemia; also associated with jagged teeth, ill fitting dentures, rarely syphilis, burns and ingestion of corrosive chemicals
Susceptible to recurring or chronic atrophic candidiasis
Plummer-Vinson / Paterson-Kelly syndrome: iron deficiency anemia, glossitis and esophageal webs
Median rhomboid glossitis: red patch, usually 2 - 3 cm long, in posterior midline dorsal tongue just anterior to V shaped grouping of circumvallate papillae with loss of papillae or taste buds; associated with candidiasis and diabetes mellitus (Eur J Dent 2011;5:367)

Treatment

Usually none
Antifungal therapy to reduce clinical erythema of candidiasis

Clinical images

Images hosted on other servers:

Median rhomboid glossitis

Diabetic patient

Microscopic (histologic) description

Atrophic stratified squamous epithelium overlying moderately fibrosed stroma with chronic inflammation
Also chronic candida infection with associated pseudoepitheliomatous hyperplasia

Melanotic neuroectodermal tumor of infancy (pending)

[Pending]

Melanotic pigmentation

Table of Contents

Definition / general | Clinical / microscopic (histologic) images

Definition / general

Associated with Addison disease, fibrous dysplasia of bone (Albright syndrome), hemochromatosis, Peutz-Jeghers syndrome
Oral mucosal pigmented lesions are divided into 2 groups:
- Melanin associated lesions - racial pigmentation, syndrome associated, melanotic macules, melanocytic nevi, melanoma
- Nonmelanin associated lesions - blood related pigmentations, metallic pigmentation

Clinical / microscopic (histologic) images

Images hosted on other servers:

Labial melanotic macule

Melanoacanthoma

Peutz-Jeghers syndrome

Melkersson-Rosenthal syndrome

Table of Contents

Definition / general

Rare neurological disorder characterized by orofacial swelling (usually of upper lip), peripheral facial nerve paralysis and plicated tongue
No known cause; onset in childhood or early adolescence
After recurrent attacks, swelling may persist and eventually become permanent
Lips become hard, cracked and fissured with a reddish brown discoloration
Cheilitis granulomatosa: may be a variant, sometimes considered to be a monosymptomatic form of Melkersson-Rosenthal syndrome

Case reports

14 year old girl with monosymptomatic form of Melkersson-Rosenthal syndrome (Rom J Morphol Embryol 2012;53:851)
30 year old man with Down syndrome (Dermatol Online J 2012;18:7)

Treatment

Symptomatic

Clinical images

Images hosted on other servers:

Diffuse swelling of lip

Microscopic (histologic) description

Granulomatous inflammation of lip stroma

Microscopic (histologic) images

Images hosted on other servers:

Nonnecrotizing granulomas

Giganto-epithelioid granuloma

Differential diagnosis

Mucocele

Table of Contents

Definition / general

Reactive lesion to mucus extravasation that attracts muciphages without any epithelial lining

Essential features

Mucus extravasation into the surrounding tissue secondary to salivary gland duct trauma
Pseudocyst with epithelioid macrophages (muciphages) forming the periphery
Found on oral mucosal sites with minor salivary glands or sublingual gland
May recur if feeding salivary gland is not also removed

Terminology

Mucus extravasation phenomenon
Ranula (if on the floor of mouth arising from the sublingual gland)
Plunging ranula (if the mucin dissects through the mylohyoid muscle to involve the cervical area)
Mucus escape reaction
Not to be confused with salivary duct cyst / salivary retention cyst / mucus retention cyst / mucus duct cyst / sialocyst

ICD coding

ICD-10: K11.6 - mucocele of salivary gland

Epidemiology

No gender predilection (J Oral Maxillofac Surg 2011;69:1086)
Reported in patients of all ages but more common before the third decade due to association with trauma to oral mucosa containing salivary glands (J Oral Maxillofac Surg 2011;69:1086)

Sites

Lower labial mucosa > floor of the mouth > ventral tongue > buccal mucosa (J Oral Maxillofac Surg 2011;69:1086)
Superficial mucoceles are most common at the soft palate, retromolar pad and buccal mucosa (J Oral Maxillofac Surg 2011;69:1086)
Very rare at the upper labial mucosa as it is difficult to traumatize that site; neoplastic minor salivary gland lesions should be considered (J Oral Maxillofac Surg 2011;69:1086)

Pathophysiology

Local mechanical trauma, such as biting that injures a salivary gland excretory duct (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003;95:467)
When the duct is severed, mucus escapes into the adjacent tissue (J Oral Maxillofac Surg 2008;66:2050)
Extravasated mucin attracts macrophages that attempt to phagocytose the foreign material (Acta Histochem 2014;116:40)
Not associated with primary obstruction of a salivary gland excretory duct, which will lead to mucus retention within a salivary duct cyst (J Oral Maxillofac Surg 2007;65:855)

Etiology

Trauma to salivary gland excretory duct (Laryngoscope 1988;98:296)

Clinical features

Dome shaped, sessile nodule measuring a few millimeters to several centimeters (especially ranula) in diameter (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003;95:467)
Fluctuant to palpation but painless, some may feel firmer (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003;95:467)
Blue tinge due to the Tyndall effect (J Oral Maxillofac Surg 2008;66:2050)
Waxes and wanes over time; patient may report “popping” of lesion, may also resolve spontaneously (Laryngoscope 1988;98:296)
Superficial mucoceles are associated with hyposalivation and lichenoid lesions such as oral lichen planus, lichenoid drug reaction and chronic graft versus host disease (J Oral Maxillofac Surg 2011;69:1086)

Diagnosis

Based on patient reported history and clinical examination with definitive diagnosis made by histopathologic evaluation under light microscopy

Prognostic factors

Benign with good prognosis

Case reports

11 month old boy with a 3 month history of difficulty suckling and lower labial mucosal nodule (Case Rep Dent 2014;2014:723130)
9 year old boy with a nail-biting habit and deep anterior overbite with a recurrent vesicle at the lower labial mucosa (BMJ Case Rep 2016;2016:bcr2016216354)
9 year old boy with a history of local trauma resulting in an enlarging left lower lip swelling (J Pharm Bioallied Sci 2015;7:S731)
35 year old woman with complicated medical history presenting with an upper labial mucosal nodule (Braz Dent J 2017;28:405)

Treatment

Excision along with the feeding salivary gland is curative
- Iatrogenic intraoperative damage to neighboring salivary gland parenchyma may contribute to recurrence
Removal of the sublingual gland with marsupialization of Wharton's duct can reduce the risk of recurrence for large ranulas (J Oral Maxillofac Surg 2008;66:2050)
Laser ablation, superpotent topical corticosteroids and gamma-linolenic acid have been reported to be effective in isolated case reports for superficial mucoceles (J Oral Maxillofac Surg 2007;65:855)

Clinical images

Contributed by Nathan Lee, D.M.D.

Oral cavity mucocele

Gross description

Nodular mass resembling gelatinous material if removed intact (Acta Histochem 2014;116:40)

Gross images

Images hosted on other servers:

Intact lesions

Microscopic (histologic) description

If removed intact
- Pseudocyst cavity containing mucin, abundant epithelioid foamy histiocytes (muciphages), neutrophils and granulation tissue (Acta Histochem 2014;116:40)
If removed ruptured
- Fragments of granulation tissue containing epithelioid foamy histiocytes (muciphages) and neutrophils, may see mucinous material (Acta Histochem 2014;116:40)
Removed salivary gland parenchyma showing obstructive changes
- Acinar atrophy, ductal dilatation with periductal hyalinization, interstitial lymphoplasmacytic infiltrate and interstitial fibrosis at late stage (J Oral Maxillofac Surg 2008;66:2050)
May see ruptured feeding salivary duct with squamous metaplasia (J Oral Maxillofac Surg 2008;66:2050)
Long standing lesions organize into fibrosis resembling a fibroepithelial polyp (Acta Histochem 2014;116:40)
No epithelial cyst lining, may see overlying surface oral mucosa with variable atrophy in superficial mucoceles (J Oral Maxillofac Surg 2011;69:1086)

Microscopic (histologic) images

Contributed by Vancouver General Hospital

Early mucocele removed intact

Late mucocele removed ruptured

Mucocele mimicking mucoepidermoid carcinoma

Early mucocele removed intact

Late mucocele removed ruptured

Positive stains

Note: stains typically not needed to make the diagnosis
CD68
PAS-D
Mucicarmine
Alcian blue

Negative stains

Sample pathology report

Right lower labial mucosa, excision:
- Mucous extravasation phenomenon (mucocele)
- Minor salivary gland parenchyma showing chronic sialoadenitis

Differential diagnosis

Salivary duct cyst / salivary retention cyst / mucus retention cyst / mucus duct cyst / sialocyst:
- True salivary gland duct epithelial lining that may show an oncocytic bilayer or squamous metaplasia
Mucoepidermoid carcinoma
- 3 populations of atypical cells (mucous, intermediate, epidermoid) invading the surrounding stroma
Autoimmune sialadenitis (Sjögren syndrome)
- Minimal obstructive changes such as salivary gland duct dilation and the lymphocytic inflammation is not periductal
Glandular odontogenic cyst
- True epithelial cystic lining with goblet cells, no extravasated mucin and this lesion is not within the orofacial soft tissues
Oral focal mucinosis
- No mucin and instead is a well localized non encapsulated collection of myxomatous connective tissue in the stroma

Additional references

Head Neck 1990;12:316

Board review style question #1

CD68 positive
Cytokeratin positive
PAX8 positive
S100 positive
SMA positive

Board review style answer #1

A. CD68 positive (this is a mucocele)

Comment Here

Reference: Mucocele

Board review style question #2

Gingiva
Intrabony, within the maxillary or mandibular bone
Labial commissure
Parotid gland
Upper labial mucosa

Board review style answer #2

C. Labial commissure

Comment Here

Reference: Mucocele

Mucoepidermoid carcinoma

Multifocal epithelial hyperplasia

Table of Contents

Definition / general

Also called Heck disease
Discrete, recurrent papillary lesions on oral mucosa in Native American and Inuit children, associated with HPV 1, 13, 32 (Eur J Dermatol 2011;21:396)

Case reports

7 year old girl with HPV 32 related disease (J Maxillofac Oral Surg 2011;10:357)

Clinical images

Images hosted on other servers:

Slightly elevated

Multiple lesions

Lesions on tongue and lip

Gross description

Well circumscribed, sessile and pale elevation of buccal mucosa

Microscopic (histologic) description

Balloon cells in Malpighian layers, localized areas of mucosal epithelial hyperplasia with marked acanthosis and parakeratosis

Microscopic (histologic) images

Images hosted on other servers:

Parakeratosis

Typical nuclear changes

Nasolabial cyst

Table of Contents

Definition / general

A rare, developmental non-odontogenic cyst that occurs in the soft tissues of the upper lip lateral to midline

Terminology

Klestadt cyst
Nasal alveolar cyst
Nasoalveolar cyst
Nasal wing cyst
Nasal vestibule cyst
Mucoid cyst of the nose

Epidemiology

Rare, represents:
- < 1% of jaw cysts
- 2.5% of non-odontogenic cysts
Adults, peak prevalence in fourth and fifth decades
3:1 predilection for women

Sites

Nasolabial region of the facial soft tissues
Does not involve the underlying bone, therefore nasoalveolar cyst is a misnomer

Etiology

Unsettled, but two main theories:
First suggests remnants of the embryonic nasolacrimal ridge, duct or rod as origin
- Support for this theory is the immunohistochemical protein expression pattern which is very similar to the physiologic pattern of normal nasolacrimal duct epithelium
Second theory, now less favored:
- Suggests entrapped epithelial remnants along fusion line of medial nasal, lateral nasal and maxillary processes as an origin

Clinical features

Benign, slow growing cystic mass usually less than 3 cm in size
Usually asymptomatic, rarely nasal obstruction or reports of pain if infected
Most common patient concern is swelling
Mass effect results in distention of nasolabial fold and elevation of the ala of the nose, extraorally
Presentation could result in clinical differential diagnosis of odontogenic infection
Intraorally, obliterates the mucolabial fold
10% of cysts are bilateral

Diagnosis

Diagnosis dependent of clinical, radiologic and pathologic correlation

Prognosis and treatment

Malignant transformation has never been reported

Radiology description

On CT, will appear as ovoid, well circumscribed lesion, distortion of the affected nasolabial area / base of the nose
Aside from subtle surface saucerization of bone, bone changes are not identified with this soft tissue cyst

Case reports

45 year old woman with Klestadt cyst visualized with radiographic contrast medium (J Clin Diagn Res 2014;8:ZD33)
54 year old woman with nasolabial cyst (Head Neck Pathol 2013;7:155)
69 year old woman with bilateral nasolabial cysts (J Oral Maxillofac Pathol 2013;17:443)

Treatment

Surgical excision, performed intraorally, is most common
Transnasal marsupialization has also been performed

Clinical images

Images hosted on other servers:

Lateral cephalograph

Raised left ala of nose

Extraoral swelling

Obliteration of labial sulcus

Endoscopic view

Gross description

Rubbery, smooth surfaced mass, ballotable soft tissue cyst
Sectioning reveals cystic and fibrous areas, without internal surface papillary projections

Gross images

Images hosted on other servers:

Surgical specimen

Microscopic (histologic) description

Histologic examination often reveals lining of multilayered or pseudostratified, cuboidal to columnar epithelium
Presence of true 'ciliated' epithelium has been described but there is a question whether true cilia remains
Other combinations possible:
- Bilayered epithelium with a cuboidal basal layer and a columnar luminal layer that contains interspersed scattered mucinous goblet cells
- Both stratified squamous and cuboidal epithelium
- Cuboidal epithelial lining only
- A minority exhibit pseudostratified columnar, stratified squamous and cuboidal epithelium together
Scattered interspersed luminal goblet cells are common
Focal squamous metaplasia or apocrine changes may be present
Cyst wall is composed of hypocellular fibrous connective tissue and may include skeletal muscle
Inflammation may be present if a history of secondary infection

Microscopic (histologic) images

Images hosted on other servers:

Pseudostratified cylindrical epithelium

Cyst lining

Stratified squamous epithelium

Immunohistochemistry & special stains

Positive:
- Epithelial cells: CK7, CK19 and high molecular weight cytokeratins
- Basal layer cells: CK5/6 and p63
- Goblet cells: MUC2 (weakly), MUC5AC (strongly)
Negative:
- Epithelial cells: CK20 expression

Electron microscopy description

Bilayered structure of the lining epithelium with cuboidal basal layer and columnar luminal cells and mucous (goblet) cells
Nonmucous luminal cells frequently feature prominent rough endoplasmic reticulum and numerous submembranous secretory granules, some with electron dense cores
Microvilli decorated with glycocalix, but no true cilia present, which is in keeping with the newer literature

Differential diagnosis

Cyst of the incisive papilla:
- Soft tissue cyst with similar histologic features to nasolabial cyst, but distinguished by anatomic site
- Cyst of the incisive papillae occurs within the soft tissue of the anterior hard palate only and shows no communication with the upper lip or nasal area
Cystic salivary gland neoplasms (benign or malignant) could show overlapping features with nasolabial cyst, particularly on small biopsies:
- Mucoepidermoid carcinoma
- Mammary analogue secretory carcinoma
- Pleomorphic adenoma
- Cystadenoma
Dilated salivary duct due to obstruction:
- Soft tissue cystic proliferation, typically associated with inflammation in fibrous connective tissue wall
Epidermal inclusion cyst:
- Soft tissue cyst distinguished from nasolabial cyst by keratinizing epithelium
Glandular odontogenic cyst:
- Is an intraosseous cyst
- If bony cortical perforation has occurred, then a sampling of the 'soft tissue' component of the cyst lining will create a diagnostic dilemma
Hidrocystoma:
- Soft tissue cyst of the skin, usually occurring in the periorbital region. Thin, uniform lining, usually 2 cell layers
Nasopalatine duct cyst:
- Is an intraosseous cyst with histologic features similar to nasolabial cyst
- If bony cortical perforation has occurred, then a sampling of the 'soft tissue' component of the cyst lining will create a diagnostic dilemma
- Contents of incisive foramen typically identified in the surgically resected specimen (peripheral nerve, cartilaginous rests, vascular channels)

Necrotizing sialometaplasia

Nicotine stomatitis (pending)

[Pending]

Oral focal mucinosis (pending)

[Pending]

Oral hairy leukoplakia

Table of Contents

Definition / general | Microscopic (histologic) description | Electron microscopy description

Definition / general

White, confluent patches of fluffy (hairy) mucosa, bilateral, along lateral tongue
Associated with HIV+ patients (AIDS may appear within 2 - 3 years) but actually due to EBV infection

Microscopic (histologic) description

Hyperkeratotic oral mucosa due to piling of keratotic squamous epithelium
Cowdry type A intranuclear inclusions
Balloon cells with margination of chromatin (nuclear beading); EBV present in clear cells of spinous layer
Variable koilocytosis, superimposed Candida infection, without inflammatory response

Electron microscopy description

Herpes type virions

Oral mucosal melanoma

Table of Contents

Definition / general

Rare; annual incidence of 1.2 cases per 10 million; more common in Japanese, black Africans, Native Americans and Hispanics
Median age 61 years, 78% men
Differs from cutaneous melanoma due to lack of association with sun damage, family history or atypical nevi and difference in prognostic factors
Nodal and distant metastases are common
References: Am J Surg Pathol 2001;25:782, Am J Surg Pathol 2002;26:883

Prognostic factors

Extremely poor prognosis, with median survival 2 - 3 years; some lower grade tumors without vascular invasion had median survival of 8 years
Poor prognostic factors: vascular invasion, polymorphous tumor cell population and necrosis
No prognostic value: tumor thickness, ulceration and level of invasion

Case reports

17 year old girl with tender lesion of hard palate (Arch Pathol Lab Med 2002;126:1110)
47 year old man with tumor after low dose radiation therapy for lichen planus (Arch Pathol Lab Med 1985;109:290)
71 year old man with multiple firm left submandibular swellings for two months (Case #419)

Gross description

Mucosa covering maxillary bone (62%), labial mucosa (13%) and lower gingiva (8%)
Usually flat, erythematous or pigmented, less commonly presents as a mass

Microscopic (histologic) description

Mean 3 mm thick; pigmented or frequently amelanotic; morphology includes epithelioid, fusiform and polymorphous cells
Some tumor giant cells in almost all cases; 90% have associated melanoma in situ; usually mitotic figures
Frequent ulceration, necrosis, vascular invasion and perineural invasion; may have desmoplastic features, particularly if lower lip

Microscopic (histologic) images

Case #419

Nests and nodules
of tumor cells with
melanin pigments

Tumor cells with
extensive necrosis
and melanin
pigments

PAP

HMB45 (cell block)

Giemsa

Positive stains

S100 (97%), tyrosinase / T311 (94%), MelanA / Mart1 / A103 (85%), microphthalmia associated transcription factor / MITF (D5, 74%) and HMB45 (71%)
Desmoplastic melanoma: S100, tyrosinase

Negative stains

Keratin, CD34 and muscle specific actin

Differential diagnosis

Amelanotic melanomas:
- Large cell lymphoma, poorly differentiated carcinoma

Board review style question #1

What do primary mucosal melanoma and cutaneous melanoma have in common?

Both commonly have BRAF mutations
Both use the same staging criteria
Sun exposure is a risk factor for both
They have a similar prognosis
They have the same immunohistochemical profile

Board review style answer #1

E. They have the same immunohistochemical profiles. Primary mucosal melanomas share histologic and immunohistochemical features with cutaneous melanomas but differ in terms of risk factors, aggressiveness, molecular profiles and staging criteria.

Comment Here

Reference: Melanoma

Oral mucosal neuroma (pending)

[Pending]

Oral submucosal fibrosis

Table of Contents

Definition / general

Mainly in India and Pakistan due to smokeless tobacco / chewing of betel quid
Reactive but risk factor for squamous cell carcinoma
Early lesions show blanching, mottled, marble-like appearance; later fibrous bands lead to stiffness, restricting ability to open mouth (trismus)

Sites

Buccal mucosa, lips, retromolar areas, soft palate

Case reports

10 year old boy and 12 year old girl (J Indian Soc Pedod Prev Dent 2012;30:85)
38 year old man with successful reconstruction using skin graft in buccal mucosa (Case Rep Dent 2012;2012:628301)

Treatment

None, irreversible once it develops
Cessation of quid chewing reduces risk of oral cancer but fibrosis is not altered

Clinical images

Images hosted on other servers:

Blanching and fibrosis

With verrucous leukoplakia

38 year old man:
preoperative, after suturing graft and 1 year followup

10 year old boy:
difficulty in mouth opening

12 year old girl:
shrunken uvula, pretreatment and posttreatment

Microscopic (histologic) description

Subepithelial fibrosis, chronic inflammation, often with eosinophils, hyalinization and loss of vascularity
Overlying epithelium is atrophic or hyperplastic and hyperkeratotic

Microscopic (histologic) images

Images hosted on other servers:

Dense fibrosis

Advanced

Differential diagnosis

Amyloidosis

Oropharnygeal neuroendocrine carcinoma (pending)

[Pending]

Paraneoplastic pemphigus (pending)

[Pending]

Parulis

Table of Contents

Definition / general

Localized collection of acute inflammation and edematous granulation tissue on the gingiva, which represents the intraoral opening of a draining odontogenic (dental) infection

Essential features

Reactive soft tissue swelling of the gingiva
By definition, must be associated with draining dental abscess / infection (periapical or periodontal fistula)
Similar to pyogenic granuloma but contains linear tracks or accumulations of neutrophils
Must treat the source of infection, since surgical removal of the parulis alone likely will lead to recurrence

Terminology

Gum boil
Dental fistulous tract / dental fistula
Dental abscess with sinus tract

ICD coding

ICD-10: K04.6 - periapical abscess with sinus

Sites

Exclusively occurs on the gingiva; attached or unattached gingiva

Etiology

Associated with dental infection
- Pulpal necrosis, abscess (Eur Endod J 2020;5:54)
- Infection associated with an untreated dental cavity
- Infection surrounding dental implant, embedded foreign material or other oral prosthesis

Clinical features

Smooth and sometimes lobulated exophytic polypoid lesion on the gingiva
Yellow, red or pink (when fibrosed) in color (Case Rep Dent 2018;2018:4850901)
Often fluctuant
Light pressure may reveal drainage of purulent exudate

Diagnosis

Diagnosis is most often made upon clinical evaluation of fluctuant / draining gingival nodule associated with adjacent dental infection; histopathologic confirmation is useful but may not be needed
Pulpal necrosis is evaluated with electric pulp testing or thermal evaluation in combination with radiographic correlation
Intraoral sinus track can be traced with gutta percha to help confirm etiologic origin (J Clin Diagn Res 2013;7:2392)

Radiology description

Parulides may be accompanied by an ill or well defined radiolucency at or around the apex of a nonvital tooth (Eur Endod J 2020;5:54)

Radiology images

Contributed by Molly Housley Smith, D.M.D.

Periapical radiolucency

Case reports

40 year old woman with multiple parulides (intraoral draining sinus tracts) all associated with a single necrotic tooth (J Clin Diagn Res 2013;7:2392)
53 year old woman with parulis forming around dental implant (J Oral Implantol 2016;42:505)
59 year old man presents with a large exophytic mass of the gingiva adjacent to a necrotic tooth (Case Rep Dent 2018;2018:4850901)

Treatment

While the gingival nodule may be removed surgically, the nodule will recur without effective treatment of the underlying associated infection (e.g., root canal therapy, dental extraction, etc.) (Eur Endod J 2020;5:54)
Antibiotics not indicated unless systemic spread is present (Fertil Steril 1986;45:75)

Clinical images

Contributed by Molly Housley Smith, D.M.D.

Fluctuant gingival nodules

Yellow gingival nodule

Gross description

Tan / gray / brown nodule that often collapses upon sectioning and contains yellow exudate

Microscopic (histologic) description

Nodule or collapsed nodule surfaced by keratinized squamous epithelium and comprised of edematous granulation tissue (World J Clin Cases 2015;3:779)
Collections or linear tracts of neutrophils are present and often extend to the base of the specimen

Microscopic (histologic) images

Contributed by Molly Housley Smith, D.M.D.

Exophytic nodule

Loose, inflamed mesenchymal stroma

Dense collections of neutrophils

Virtual slides

Images hosted on other servers:

Subacutely inflamed nodule

Videos

Etiology and treatment of a dental fistulous tract / parulis

Tracing a dental fistulous tract with gutta percha

Sample pathology report

Gingiva, excisional biopsy:
- Granulation tissue with linear tracts of neutrophils (see comment)
- Comment: When combined with the clinical information, the histomorphology is compatible with a parulis (draining fistulous tract).

Differential diagnosis

Histopathologic:
- Pyogenic granuloma:
  - May be histopathologically identical / similar, although parulis tends to demonstrate dense accumulations or linear tracts of neutrophils that may extend to the base of the specimen
  - Clinical correlation is vital in the differentiation of the two entities
  - Distinguishing pyogenic granuloma from parulis is essential for appropriate treatment
  - Local excision of the polypoid lesion is sufficient for pyogenic granuloma
  - Parulides require treatment of the underlying infection to prevent recurrence
Clinical:
- Clinical differential diagnosis for a red, yellow or pink nodule on the gingiva is exhaustive and may include pyogenic granuloma, peripheral giant cell granuloma, peripheral ossifying fibroma, peripheral odontogenic fibroma, localized accumulation of dermal filler, metastatic disease or other malignant or benign tumors (Head Neck Pathol 2019;13:4, World J Clin Cases 2015;3:779, Head Neck Pathol 2013;7:241)
  - Identification of a soft tissue gingival nodule, in combination with underlying dental infection, favors diagnosis of parulis
  - Excisional biopsy may be used to confirm diagnosis

Additional references

Neville: Oral and Maxillofacial Pathology, 4th Edition, 2015

Board review style question #1

Cone beam computed tomography (CBCT) of the patient shown above demonstrates a well defined, nonexpansile radiolucency surrounding the root of the associated necrotic maxillary incisor. Biopsy shows a nodule of granulation tissue demonstrating dense accumulations of neutrophils at the base of the specimen. What is the most likely diagnosis?

Foreign body granuloma due to dermal filler
Leukoplakia
Parulis
Pyogenic granuloma

Board review style answer #1

C. Parulis. The main distractor for this gingival nodule comprised of inflamed granulation tissue is a pyogenic granuloma; however, the description of dense accumulations of neutrophils at the base of the specimen favors a parulis, a soft tissue mass representing the intraoral opening of a draining odontogenic (dental) infection. Although both entities are benign, differentiating the two entities is important, as treatment modalities are different.

Although accumulations of dermal filler may present as a yellow nodule in the oral cavity, dermal filler accumulates under unattached mucosa rather than attached gingiva. Past medical history regarding previous cosmetic injections may also aid in excluding this entity from the differential diagnosis.

Leukoplakia is a flat, white patch of the oral cavity and does not clinically present as a nodule or histopathologically as granulation tissue.

Comment Here

Reference: Parulis

Board review style question #2

A patient presents with a gingival nodule near a necrotic tooth. The histopathology demonstrates loose granulation tissue with linear tracts of neutrophils at the base of the specimen. What is the diagnosis?

Parulis
Peripheral giant cell granuloma
Peripheral ossifying fibroma
Pyogenic granuloma

Board review style answer #2

A. Parulis. The main distractor for this gingival nodule comprised of inflamed granulation tissue is a pyogenic granuloma; however, the presence of dense accumulations of neutrophils at the base of the specimen favors a parulis, a soft tissue mass representing the intraoral opening of a draining odontogenic (dental) infection. Although both entities are benign, differentiating the two entities is important, as treatment modalities are different.

Peripheral giant cell granulomas contain osteoclast type giant cells, not appreciated within the present biopsy.

Peripheral ossifying fibromas contain focal to large islands of vital bone, not appreciated within this biopsy.

Comment Here

Reference: Parulis

Pemphigoid

Table of Contents

Definition / general

Chronic, immune mediated, subepithelial blistering disease that predominantly affects mucous membranes
Autoantibodies directed at components of the basement membrane zone

Essential features

Second most common immune mediated, subepithelial blistering disease, after bullous pemphigoid (J Invest Dermatol 2016;136:2495)
Most often presents in the oral cavity
Autoimmune (IgG, IgA or C3) attack of hemidesmosomes / basement membrane zone
May affect the oral cavity, conjunctiva, subglottis, larynx, nose, esophagus, penis, vulva, anal mucosa or skin

Terminology

Mucous membrane pemphigoid
Benign mucous membrane pemphigoid (BMMP)
Cicatricial pemphigoid
Mucosal pemphigoid

ICD coding

ICD-10: L12.1 - benign mucous membrane pemphigoid

Epidemiology

Wide age range; predilection for middle aged to older adults
Slight female predominance

Sites

Affects the oral cavity (96.7%), conjunctiva (42.2%), subglottis, larynx, nose, esophagus, skin or anogenital regions (27.9%) (J Eur Acad Dermatol Venereol 2016;30:72)
Oral cavity is the most commonly affected site
- Gingiva > buccal mucosa > palate > alveolar ridge > tongue > lower lip

Pathophysiology / etiology

Likely an autoantibody induced and complement mediated sequestration of leukocytes (predominantly neutrophils) with release of cytokines and leukocyte enzymes leading to detachment of epithelium at the basement membrane zone (Br J Oral Maxillofac Surg 2008;46:358)
Combination of IgG (94.6%), C3 (85.8%) or IgA (16.5%) autoantibodies directed against epithelial basement membrane zone components BP180, BP230, alpha 6 integrin, beta 4 integrin or laminin 332 (laminin-5) (J Eur Acad Dermatol Venereol 2016;30:72, Acta Derm Venereol 2004;84:381)
- BP180 is the most frequently affected target, in ~75% (Br J Dermatol 2006;154:90)
- Oral only subset: α6 integrin target antigen (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;85:37)
- Ocular only subset: β4 integrin (J Invest Dermatol 2006;126:2631)
Mechanism that links the binding of autoantibodies to the basement membrane zone and the subsequent scarring process is unknown (Clin Dermatol 2012;30:34)
Association with HLA-DQB1*0301 (Br J Dermatol 2001;145:805, Br J Dermatol 2001;145:406, Br J Oral Maxillofac Surg 2008;46:358)
Emerging association with anti-PDL1 medications (Front Med (Lausanne) 2018;5:268, J Immunother 2019;42:359, J Eur Acad Dermatol Venereol 2019 Oct 29 [Epub ahead of print], Br J Dermatol 2018;179:993)

Diagrams / tables

Images hosted on other servers:

Epidermal / dermal junction

Table 2 MMPDA Index

Clinical features

General: erythematous or ulcerated mucous membranes +/- blood blister formation (+ Nikolsky sign); periodic episodes leading to potential scarring (Br J Oral Maxillofac Surg 2008;46:358)
Ocular: scarring on the conjunctiva may produce a symblepharon or blindness
Oropharynx: dyspnea, hoarseness
Esophagus: difficulty swallowing or bleeding; stenosis
Nose: nosebleeds
Skin: rare; vesicles / bullae
Laryngeal involvement can lead to airway loss

Diagnosis

Diagnosis made on routine H&E histological examination and biopsy for direct immunofluorescence
Direct immunofluorescence is gold standard for diagnosis
Cases may be followed with indirect immunofluorescence, immunoblotting or enzyme-linked immunosorbent assay (ELISA) testing
2015 consensus group created a disease area index table to standardize diagnosis (J Am Acad Dermatol 2015;72:168)

Laboratory

IgG autoantibodies against basement membrane zone components (BP180, BP230, alpha 6 integrin, beta 4 integrin or laminin 332) detected
IgG titers correlate with disease severity (Br J Dermatol 1999;140:645)
Laminin-332 is detected in up to 20% of patients (J Invest Dermatol 2001;116:348, Br J Dermatol 2019;180:149)

Prognostic factors

Detection of both IgG and IgA autoantibodies associated with more severe disease (Br J Dermatol 1998;138:602)
Laminin-332 is associated with more severe disease and solid organ tumors in up to 30% (J Invest Dermatol 2001;116:348, Br J Dermatol 2019;180:149)

Case reports

58 year old man presents with painful mouth sores, cutaneous blisters, paronychia and onychomadesis (BMC Dermatol 2019;19:3)
83 year old patient presenting with oral blisters and erosions after taking pembrolizumab (Front Med (Lausanne) 2018;5:268)

Treatment

Mild-to-moderate disease:
- Topical therapies, including betamethasone, fluticasone propionate or clobetasol propionate
- Dapsone (Br J Oral Maxillofac Surg 2008;46:358) or sulfapyridine

Moderate-to-severe disease:
- Mycophenolate mofetil, azathioprine, sulfa drug or prednisolone

Severe, recalcitrant disease:
- Pulsed IV cyclophosphamide, IV immunoglobulin and rituximab (Clin Exp Dermatol 2019;44:732)
Rituximab (anti-CD20 therapy) in combination with conventional immunosuppressive therapy leads to more rapid and sustained disease control with fewer potential adverse events (J Am Acad Dermatol 2016;74:835)
Encourage excellent oral hygiene habits and regular ophthalmologic examinations

Clinical images

Contributed by Molly Housley Smith, D.M.D. and Sonal Tuli, M.D.

Diffuse gingival involvement

Localized gingival ulceration

Bullae development

Buccal mucosa involvement

Symblepharon

Gross description

Thin wedge of white-tan surface epithelium with underlying tan-brown connective tissue
Epithelium occasionally separated from underlying connective tissue

Microscopic (histologic) description

Surface epithelium cleanly detached from the underlying connective tissue at the point of the basement membrane zone
Superficial lamina propria contains a variable amount of inflammation that may contain lymphocytes, eosinophils and neutrophils (Br J Oral Maxillofac Surg 2008;46:358)
Aggregates of erythrocytes may be present in area of bullae formation

Microscopic (histologic) images

Contributed by Molly Housley Smith, D.M.D. and @reportesVilla on Twitter

Subepithelial separation

Subepithelial cleft
contains fibrin,
erythrocytes and
inflammatory cells

Subepithelial separation

Minimal inflammation

Pemphigoid

Immunofluorescence description

Direct immunofluorescence (DIF): linear deposits of IgG, IgA or C3 along the basement membrane zone (Br J Oral Maxillofac Surg 2008;46:358)
Indirect immunofluorescence (IIF): IgG autoantibodies against the basement membrane zone with known target antigens including BP180, BP230, alpha 6 integrin, beta 4 integrin or laminin 332 (laminin-5)

Immunofluorescence images

Contributed by Molly Housley Smith, D.M.D.

IgG

IgA

Videos

Clinical, histology, laboratory findings with discussion on pathophysiology

Sample pathology report

Buccal gingiva, incisional biopsy:
- Subepithelial vesiculo-erosive condition consistent with benign mucous membrane pemphigoid (see comment)
- Comment: On H&E, there is a clean separation of the superficial stratified squamous epithelium from the underlying connective tissue at the layer of the basement membrane zone. On direct immunofluorescence, a shaggy and linear deposition of IgG, C3 and IgA is present in the basement membrane zone.

Differential diagnosis

Bullous pemphigoid (BP)
- Most common immune mediated, subepithelial blistering disease
- Widespread skin lesions
- Persistent mucosal lesions are not seen
- Propensity to scar is less frequent
- Infrequent in the oral cavity

Pemphigus vulgaris
- Autoimmune bullous disease directed against desmosomes
- Skin lesions heal without scarring
- Buccal mucosa > palate > tongue > labial mucosa > gingiva
- Suprabasilar clefting with acantholysis
- Direct immunofluorescence shows intracellular IgG and C3 staining
- Enzyme-linked immunosorbent assay demonstrates antibodies directed against desmoglein 1 and 3

Paraneoplastic pemphigus
- Autoimmune blistering condition that indicates an underlying benign or malignant disease
- Patient may be unwell at time of diagnosis
- Intraepidermal-acantholytic bullae
- Direct immunofluorescence may demonstrate intracellular or basement membrane zone IgG and C3 staining
- Immunoblotting reveals antibodies to desmoglein 3 (Dsg3), BP230, envoplakin, plectin, periplakin or epiplakin

Erosive lichen planus
- T-cell mediated autoimmune disease
- Interface mucositis with Civatte bodies
- Subepithelial band of lymphocytes
- Direct immunofluorescence shaggy fibrin deposition at basement membrane zone

Linear IgA disease
- Rare immune mediated, subepithelial blistering disease
- Mainly on skin; oral lesions less common
- Demonstrates prominent linear IgA deposition (+/- IgG or IgM) along basement membrane zone on direct immunofluorescence

Epidermolysis bullosa acquisita
- Immune mediated, subepithelial blistering condition
- Differentiate using salt split testing or enzyme-linked immunosorbent assay
- Enzyme-linked immunosorbent assay detects antibodies against type VII collagen
- Antibodies bind to the connective tissue floor of the bullae in epidermolysis bullosa acquista rather than the roof of the bullae as seen in metalloproteinases

Lichen planus pemphigoides
- Generally younger
- Lichenoid lesions along with bullae
- Also has lichenoid characteristics
- Similar direct immunofluorescence with IgG, C3 or IgA+ at basement membrane zone

Bullous lichen planus
- Least common variant of oral lichen planus
- Extremely rare
- Demonstrates clinical features similar to lichen planus and lichen planus pemphigoides; vesicles or bullae on pre-existing lichen planus lesions
- Histopathologic and immunofluorescent antibody studies are similar to lichen planus

Angina bullosa hemorrhagica
- Often traumatic in nature
- Blood filled blisters on the soft palate
- Can be a mimicker on H&E
- Direct immunofluorescence is usually negative (Dermatol Reports 2014;6:5282)

Erythema multiforme
- Self limiting blistering condition
- Lesions typically last 2 - 4 weeks
- Triggers may include infections (HSV, mycoplasma) or medications
- May demonstrate target lesions on the skin
- Lichenoid infiltrate in basement membrane zone
- Epithelium is edematous and spongiotic with necrosis of basal and suprabasal epithelial cells (intraepithelial and subepithelial bullae formation)
- Direct immunofluorescence shows diffuse granular staining of C3 in basement membrane zone

Board review style question #1

Affected patients are often young, in the second to third decades of life
Gingiva is the most commonly affected location
Patients demonstrate significant ulceration and blistering of mucous membranes without subsequent scarring
This entity mimics erosive lichen planus on direct immunofluorescence

Board review style answer #1

B. Gingiva is the most commonly affected location. This is mucous membrane pemphigoid.

Comment Here

Reference: Mucous membrane pemphigoid

Board review style question #2

BP180
BP230
Desmoglein 1
Laminin-332
α6 integrin

Board review style answer #2

C. Desmoglein 1

Comment Here

Reference: Mucous membrane pemphigoid

Board review style question #3

BP 180
BP 230
Desmoglein 3
Laminin-332
Type VII collagen

Board review style answer #3

D. Laminin-332

Comment Here

Reference: Mucous membrane pemphigoid

Pemphigus vulgaris

Table of Contents

Definition / general

Autoimmune disease with antigen antibody complexes at desmosomes; produces vesicles and bullae prone to rupture, leaving erosions covered with exudate

Case reports

36 year old woman with gingival pemphigus vulgaris preceding cutaneous lesion (J Indian Soc Periodontol 2012;16:588)
52 year old woman with lesion presenting as gingival involvement (Indian Dermatol Online J 2012;3:202)

Treatment

Steroids

Clinical images

Images hosted on other servers:

36 year old woman:

Intra oral lesion

After 15 days

52 year old woman:

Erosive lesions

Erythematous gingivae

Microscopic (histologic) description

Intraepithelial blister with acantholysis and chronic inflammation

Microscopic (histologic) images

Images hosted on other servers:

36 year old woman

52 year old woman

Peripheral giant cell granuloma

Table of Contents

Definition / general

Reactive gingival mass resembling pyogenic granuloma, which pushes teeth aside and may erode alveolar bone or involve periodontal membrane
Arises from periodontal ligament enclosing root of tooth
Central giant cell granuloma: similar to peripheral giant cell granuloma but multiloculated

Terminology

Also called giant cell epulis, giant cell reparative granuloma, osteoclastoma, myeloid epulis

Epidemiology

Usually women, 30s to 50s, although may involve children or elderly patients without teeth

Case reports

22 year old woman with lesion in maxillary anterior region (Contemp Clin Dent 2012;3:S118)
53 year old man, 57 and 81 year old women with lesion in same location as edentulous mandible (Eur J Dent 2010;4:329)

Central giant cell granuloma:

15 year old girl with lesion mimicking adenomatoid odontogenic tumor (Contemp Clin Dent 2011;2:249)

Treatment

Excision with curettage of base of lesion extending into adjacent periodontal membrane
Recurs if not completely excised or source of irritation not removed (10% recurrence rate)

Clinical images

Images hosted on other servers:

Resembes pyogenic granuloma

22 year old woman:
preoperative, excision and postoperative

53 year old man:
pre and postoperative

57 year old woman:
pre and postoperative

81 year old woman:
pre and postoperative

Central giant cell granuloma:
swelling, extended to midline and excisional biopsy

Gross description

Nodular, pedunculated, inflammatory lesion up to 1.5 cm that protrudes from gingiva at site of chronic inflammation
Covered by gingival mucosa or ulcerated

Gross images

Images hosted on other servers:

22 year old woman

Microscopic (histologic) description

Nonencapsulated aggregates of foreign body giant cells and fibroangiomatous stroma with hemorrhage, hemosiderin, acute and chronic inflammatory cells
Alveolar bone often expanded in edentulous patients, leading to superficial bone loss with peripheral cuffing
Variable mitotic activity

Microscopic (histologic) images

Contributed by Tim Bracey, M.B.Ch.B., Ph.D.

28 year old woman with rapidly growing lesion

Images hosted on other servers:

22 year old woman

81 year old woman

53 year old man

Central giant cell
granuloma: irregular
giant cells

Differential diagnosis

Peripheral ossifying fibroma

Table of Contents

Definition / general

Reactive gingival proliferation characterized by spindle cell proliferation with calcification or ossification

Essential features

Reactive gingival lesion; thought to be associated with chronic irritation
Spindle cell proliferation with calcification or ossification within gingival connective tissue

Terminology

Other terms include peripheral cementifying fibroma, peripheral cemento-ossifying fibroma, ossifying fibrous epulis, calcifying fibrous epulis (J Indian Soc Periodontol 2014;18:527)
Should not be confused with odontogenic / central bone tumors, such as ossifying fibroma and cemento-ossifying fibroma

ICD coding

ICD-10:
- K06.8 - other specified disorders of gingiva and edentulous alveolar ridge
- K13.6 - irritative hyperplasia of oral mucosa

Epidemiology

More common in females (F:M = ~2:1) (Oral Surg Oral Med Oral Pathol 1987;63:452, Med Oral Patol Oral Cir Bucal 2022;27:e460, J Indian Soc Periodontol 2015;19:83, Pediatr Dent 2001;23:245)
Second to fourth decades (children and young adults) (Oral Surg Oral Med Oral Pathol 1987;63:452, Med Oral Patol Oral Cir Bucal 2022;27:e460, Br J Oral Maxillofac Surg 2019;57:1081)
Can occur at any age, reports range from 2 months to 87 years (Oral Surg Oral Med Oral Pathol Oral Radiol 2020;130:e74, Med Oral Patol Oral Cir Bucal 2022;27:e460)
~5% of oral hyperplastic lesions (Braz J Otorhinolaryngol 2019;85:399, Indian J Dent Res 2018;29:61, Acta Odontol Latinoam 2015;28:103)
~20% of gingival hyperplastic lesions (Quintessence Int 2007;38:103, J Oral Pathol Med 2010;39:631)

Sites

Arise exclusively on the gingiva
Maxilla more common than mandible (Oral Surg Oral Med Oral Pathol 1987;63:452, Pediatr Dent 2001;23:245)
~67% in incisor cuspid region (Oral Surg Oral Med Oral Pathol 1987;63:452, Med Oral Patol Oral Cir Bucal 2022;27:e460, J Indian Soc Periodontol 2015;19:83)

Pathophysiology

Unknown, likely a reaction to chronic irritation (J Indian Soc Periodontol 2015;19:83)
Hormonal influence has been proposed since the lesion is common in adolescents and young women (Niger Med J 2011;52:35)
- However, lesional cells do not express estrogen or progesterone receptors (ER / PR) (J Oral Sci 2010;52:95)

Etiology

Associated with chronic irritation, poor dentition and dental prosthetics, especially if poorly fitted (J Indian Soc Periodontol 2015;19:83)
Thought to arise from the periodontal ligament (Ann Diagn Pathol 2020;46:151510)

Clinical features

Slow growing nodule with a mean time to presentation of 16 months (Med Oral Patol Oral Cir Bucal 2022;27:e460)
Generally painless or causing mild discomfort (J Indian Soc Periodontol 2015;19:83)
May ulcerate (Oral Surg Oral Med Oral Pathol 1987;63:452)
Indolent clinical course but in some cases, the size and location may interfere with normal oral function, displace teeth and distort local anatomy (Int J Surg Case Rep 2021;84:106127, Ann Maxillofac Surg 2016;6:300, Head Neck Pathol 2013;7:356)
Recurrence in ~15% despite surgical excision (Oral Surg Oral Med Oral Pathol 1987;63:452, Br J Oral Maxillofac Surg 2019;57:1081, J Indian Soc Periodontol 2015;19:83)
Multifocal disease is rare (Indian J Dent Res 2014;25:220)

Diagnosis

Difficult to distinguish clinically from other entities (pyogenic granuloma, oral irritation fibroma, giant cell fibroma, peripheral giant cell granuloma, metastatic lesions)
Readily diagnosed histologically with high interobserver concordance (Med Oral Patol Oral Cir Bucal 2022;27:e460)

Radiology description

May show irregular radiopacity due to calcification / ossification or show mild alveolar bone resorption (Dentomaxillofac Radiol 2007;36:180, Med Oral Patol Oral Cir Bucal 2022;27:e460, Head Neck Pathol 2013;7:356)

Radiology images

Contributed by Molly Housley Smith, D.M.D.

Visible ossification

Prognostic factors

Benign but may recur
Recurrence is more likely if offending irritant is not removed (J Indian Soc Periodontol 2015;19:83)

Case reports

2 month old girl with peripheral ossifying fibroma (Oral Surg Oral Med Oral Pathol Oral Radiol 2020;130:e74)
24 year old man with multifocal disease (Indian J Dent Res 2014;25:220)
25 year old woman with 4 cm tumor interfering with oral function (Int J Surg Case Rep 2021;84:106127)

Treatment

Surgical excision (J Indian Soc Periodontol 2015;19:83)
Removal of irritants including plaque / calculus or poorly fitted prosthetics (J Indian Soc Periodontol 2015;19:83)

Clinical images

Contributed by Molly Housley Smith, D.M.D.

Nodular mass

Multilobular red growth

Images hosted on other servers:

Typical clinical appearance

17 year old boy

21 year old man

25 year old man

26 year old man

31 year old man

Gross description

Exophytic mass that may be sessile or pedunculated (Med Oral Patol Oral Cir Bucal 2022;27:e460, J Indian Soc Periodontol 2015;19:83)
Mean size of < 2 cm but sizes up to 10 cm have been reported (Med Oral Patol Oral Cir Bucal 2022;27:e460, J Indian Soc Periodontol 2015;19:83, Ann Maxillofac Surg 2016;6:300)

Gross images

Contributed by Molly Housley Smith, D.M.D.

Partially calcified mass

Microscopic (histologic) description

Variably cellular fibroblastic spindle cell proliferation in subepithelial connective tissue in variably collagenous background (J Indian Soc Periodontol 2015;19:83)
- Collagen deposition is more prominent in the deep aspect (J Indian Soc Periodontol 2015;19:83)
Dystrophic calcification, lamellar or woven bone formation is essential for diagnosis (J Indian Soc Periodontol 2015;19:83)
Overlying hyperplastic epithelium with hyperkeratosis (J Indian Soc Periodontol 2015;19:83)
- Surface epithelium may be ulcerated (J Indian Soc Periodontol 2015;19:83, Oral Surg Oral Med Oral Pathol 1987;63:452)
Background contains variable chronic inflammatory infiltrate, predominantly lymphoplasmacytic and proliferating small capillary sized vessels (J Indian Soc Periodontol 2015;19:83, Med Oral Patol Oral Cir Bucal 2022;27:e460)

Microscopic (histologic) images

Contributed by Timothy Fielder, M.B.B.S., B.Med.Sci., Ruta Gupta, M.D. and Molly Housley Smith, D.M.D.

Well demarcated mucosal lesion

Ulceration

Metaplastic ossification

Ossification and calcification

Lamellar bone

Collagenous matrix

Woven bone

Peripheral cemento-ossifying fibroma

Cementum-like bone

Positive stains

Not used in routine diagnosis
SMA in 73% (Br J Oral Maxillofac Surg 2019;57:1081)
CD68 in 54% (Br J Oral Maxillofac Surg 2019;57:1081)
SATB2 in 100% (Head Neck Pathol 2022;16:339, Ann Diagn Pathol 2020;46:151510)
Positive for osteoblastic / cementoblastic proteins RUNX2, BMP2, CAP in one study and osterix (OSX) in another (J Oral Pathol Med 2015;44:628, Braz Oral Res 2017;31:e53)

Negative stains

Sample pathology report

Gingiva, excision:
- Peripheral ossifying fibroma (see comment)
- Comment: Sections include oral squamous mucosa with underlying connective tissues and show features of a peripheral ossifying fibroma. The mucosa shows focal ulceration with organizing granulation tissue. The submucosal tissues show a well demarcated but unencapsulated lesion composed of areas of fibrosis and metaplastic ossification. There is no dysplasia or malignancy.

Differential diagnosis

Oral irritation fibroma:
- Clinically difficult to distinguish
- Histologically lacks calcification or bone formation
Peripheral giant cell granuloma:
- Clinically difficult to distinguish
- Stromal multinucleated giant cells are seen on histology
Pyogenic granuloma:
- Clinically difficult to distinguish
- Lobulated vascular proliferation on histology
Giant cell fibroma:
- Clinically difficult to distinguish
- Lacks bone formation

Board review style question #1

Which of the following is true regarding peripheral ossifying fibroma?

It is a reactive gingival proliferation thought to occur in response to irritation or trauma
It is histologically characterized by lobulated growth of capillary sized vessels with a central feeder vessel
It is molecularly characterized by recurrent internal tandem duplication of BCOR
It is most common in males over 50

Board review style answer #1

A. It is a reactive gingival proliferation thought to occur in response to irritation or trauma

Comment Here

Reference: Peripheral ossifying fibroma

Board review style question #2

A 24 year old woman presents with a 1 cm anterior maxillary gingival nodule. What is the favored diagnosis?

Central ossifying fibroma
Oral irritation fibroma
Peripheral ossifying fibroma
Pyogenic granuloma

Board review style answer #2

C. Peripheral ossifying fibroma

Comment Here

Reference: Peripheral ossifying fibroma

Plasma cell gingivitis

Table of Contents

Definition / general

Plasma cell gingivitis (PCG) is a rare, idiopathic, nonneoplastic plasma cell proliferative disorder of the gingiva

Essential features

Plasma cell gingivitis is a distinctive pattern of gingival inflammation of unknown etiology
Inflammatory infiltrate is dense and composed predominantly of nonneoplastic plasma cells
The most common clinical presentation is diffuse erythema and oedema of the gingiva
While this condition is widely considered to be idiopathic, hypersensitivity reactions to various types of antigens including flavoring agents, spices, mouthwash, tobacco, alcohol, chewing gum, candy and medications have been previously proposed in the literature (J Periodontol 1971;42:709, CDS Rev 1995;88:22, Br Dent J 1990;168:115, Oral Surg Oral Med Oral Pathol 1992;73:690, SADJ 2008;63:394)
Therapeutic strategies are based mainly on symptom control and removal of the offending substance
Surgical intervention has proven successful in severe cases (BMJ Case Rep 2015;2015:bcr2014207013, Int J Surg Case Rep 2022;93:106998)

Terminology

Atypical gingivostomatitis
Idiopathic gingivitis / gingivostomatitis
Allergic gingivitis / gingivostomatitis
Plasma cell gingivitis / gingivostomatitis

ICD coding

ICD-10: K05.10 - chronic gingivitis NOS
ICD-11: DA0B.Y - plasma cell gingivitis

Epidemiology

Based on limited data in the literature, the average age of onset is 45 years and there is a higher prevalence in males (J Clin Med 2021;10:830)

Sites

This condition typically affects the gingiva but additional sites of involvement may be seen, including lips, tongue and larynx

Pathophysiology

There is a diffuse and dense infiltrate of polyclonal plasma cells in the superficial lamina propria
Plasma cells show no cytological atypia
No nodular architecture is seen
The overlying squamous epithelium is hyperplastic but there is no disruption of normal architecture
Plasma cells show no affinity for vasculature
References: J Clin Med 2021;10:830, J Indian Soc Periodontol 2022;26:434

Etiology

Unclear
This condition may arise in the context of a hypersensitivity reaction to environmental antigens
- Previously reported antigens include flavoring agents, spices, mouthwash, tobacco, alcohol, chewing gum, candy and medications
On follow up of cases in the literature there is no increased rate of myeloma, monoclonal gammopathy of undetermined significance (MGUS) or amyloid
Due to the rarity of the condition and relatively small number of cases in the literature, it is not possible to classify the full extent of this condition and confirm if this is a purely localized phenomenon or if infiltration exists elsewhere
References: J Clin Med 2021;10:830, J Indian Soc Periodontol 2022;26:434

Diagrams / tables

Image moved to Clinical images

Clinical features

This condition most commonly presents as diffuse swelling and redness of the gingiva
- Tenderness and bleeding have been frequently reported
- Ulceration is rare and several case reports have described alveolar bone loss (BMJ Case Rep 2015;2015:bcr2014207013, J Oral Maxillofac Pathol 2021;25:S54, J Indian Soc Periodontol 2013;17:527)

Diagnosis

Diagnosis is made by clinicopathological correlation
Clinical history of antigen exposure
Characteristic clinical features of erythema and swelling of the gingiva
Biopsy of the gingiva, which classically shows a diffuse benign infiltrate of plasma cells in the subepithelial space with no light chain restriction
References: J Clin Med 2021;10:830, J Indian Soc Periodontol 2022;26:434

Laboratory

Not applicable

Radiology description

Not applicable

Radiology images

No information provided

Prognostic factors

Type of offending stimulus
Extent of stimulus exposure
Condition may resolve following removal of offending stimulus
On follow up of cases in the literature there is no increased incidence of myeloma, MGUS or amyloid
References: J Clin Med 2021;10:830, J Indian Soc Periodontol 2022;26:434

Case reports

17 year old girl with severe alveolar bone loss related to herbal toothpaste (J Indian Soc Periodontol 2013;17:527)
18 year old man with cheilitis that was managed by gingivectomy (Case Rep Dent 2019;2019:2939126)
38 year old woman mistakenly treated as aggressive periodontitis (Int J Surg Case Rep 2022;93:106998)
42 year old man presenting with severe alveolar bone loss, which was managed by surgical intervention (BMJ Case Rep 2015;2015:bcr2014207013)
64 year old man treated with photobiomodulation with no evidence of recurrence after 5 years (Case Rep Dent 2022;2022:2992656)

Treatment

Treatment is based mainly on symptom control and removal of the offending agent
Patients are advised to keep a complete dietary history and avoid potential allergens
Allergy testing and elimination diet may prove helpful
Other strategies including topical and systemic immunosuppressive therapies, antibiotics, radiation and tissue destruction by liquid nitrogen, carbon dioxide laser and electrocoagulation have had variable results in the literature
Surgical treatments including gingivectomy may be effective in severe cases
References: J Clin Med 2021;10:830, J Indian Soc Periodontol 2022;26:434

Clinical images

Images hosted on other servers:

Diffuse erythema and edema of the gingiva

Gross description

Not applicable

Gross images

Not applicable

Frozen section description

Not applicable

Frozen section images

Not applicable

Microscopic (histologic) description

Diagnostic criteria: nonneoplastic proliferation of predominantly plasma cells
Histology shows hyperplastic and spongiotic squamous epithelium
Ulceration may rarely be seen
The juxtaepithelial tissues contain a dense inflammatory infiltrate rich in mature plasma cells
Granulomatous inflammation, blister formation and vasculitis are absent
References: J Clin Med 2021;10:830, J Indian Soc Periodontol 2022;26:434

Microscopic (histologic) images

Contributed by S. Rajendran, M.B.B.Ch., M.Sc., Ph.D.

Diffuse plasma cell infiltrate

CD138

MUM1

CD56

CD20

Kappa

Lambda

Virtual slides

Not applicable

Cytology description

Not applicable

Cytology images

Not applicable

Immunofluorescence description

Not applicable

Immunofluorescence images

Not applicable

Positive stains

CD138, MUM1

Negative stains

CD20, CD56, cyclin D1, Treponema pallidum IHC

Electron microscopy description

Not applicable

Electron microscopy images

Not applicable

Molecular / cytogenetics description

Not applicable

Molecular / cytogenetics images

Not applicable

Videos

Not applicable

Sample pathology report

Gingiva, biopsy:
- Plasma cell gingivitis (see comment)
- Hyperplastic and spongiotic squamous epithelium
- Dense and diffuse proliferation of mature plasma cells in the superficial lamina propria, in close juxtaposition with the squamous epithelium.
- Kappa and Lambda immunohistochemistry or ISH shows a polyclonal plasma cell population.
- Plasma cells are negative for CD56.
- Relevant negative findings: No granulomas, spirochete infection, vasculitis or blister formation.
- Comment: The differentials include an allergic or hypersensitivity phenomenon (plasma cell gingivitis), response to medication or other agents (lichenoid reaction) and a nonspecific reaction to injury. Of these, plasma cell gingivitis is felt the most likely. Does the clinical impression support this interpretation?

Differential diagnosis

Multiple myeloma:
- Clonal plasma cell population and 70% of cases are positive with CD56
Solitary plasmacytoma:
- Clonal plasma cell population
Chronic hyperplastic gingivitis:
- Absence of diffuse plasma cell infiltrate
Granulomatous gingivitis:
- Absence of diffuse plasma cell infiltrate
- Granulomas are present
Spirochete infection

Additional references

J Clin Med 2022;11:6550

Board review style question #1

A 50 year old man presented with redness and swelling of the gums. He has a history of smoking. Histological details are shown in the image above. Which immunophenotype would be in keeping with plasma cell gingivitis?

CD20-, CD68+
CD20-, CD138+, CD56-
CD138+, CD56+
Kappa and lambda ratio 20:1

Board review style answer #1

B. CD20-, CD138+, CD56-. Plasma cell gingivitis is gingival inflammation composed predominantly of a population of nonneoplastic plasma cells. These cells show polyclonal pattern of staining with Kappa and Lambda. CD138 would be positive in both nonneoplastic and neoplastic plasma cell populations. Answer A is incorrect because CD20 and CD68 are negative in plasma cells. CD20 is a B cell marker which is retained on mature B cells until plasma cell differentiation so is not expressed by mature plasma cells. CD68 highlights histiocytes which would be positive in granulomatous gingivitis. Answer C is incorrect because CD56 is positive in 70% of neoplastic plasma cells and negative in nonneoplastic plasma cells. Answer D is incorrect because in a normal or reactive plasma cell population, the ratio of Kappa to Lambda light chains is approximately 2:1. Immunoglobulins from a neoplastic (clonal) plasma cell population contain either Kappa or Lambda light chains. Light chain restriction or monoclonality can therefore be used to distinguish between reactive / nonneoplastic and neoplastic plasma cell proliferations.

Comment Here

Reference: Plasma cell gingivitis

Board review style question #2

Which antibodies could be used to highlight the plasma cells in plasma cell gingivitis?

CD20 and CD3
CD56
Cyclin D1
MUM1 / IRF4 and CD138

Board review style answer #2

D. MUM1 / IRF4 and CD138 are positive in both neoplastic and nonneoplastic plasma cells populations. Answers B and C are incorrect because CD56 and cyclin D1 are expressed in neoplastic plasma cells. Overexpression of cyclin D1 by either translocation t(111;14) (most common) or gene amplification is a well recognized oncogenic event in both mantle cell lymphoma and myeloma (Indian J Med Paediatr Oncol 2013;34:283). CD56 is positive in 70% of neoplastic plasma cells and is usually negative in nonneoplastic plasma cells (Histopathology 2004;44:375). Answer A is incorrect because CD20 and CD3 are usually negative in plasma cells. CD20 is a B cell marker which is retained on mature B cells until plasma cell differentiation so is not expressed by mature plasma cells. CD3 is a T cell marker and is typically not expressed by B cells and plasma cells or their neoplastic counterparts.

Comment Here

Reference: Plasma cell gingivitis

Plasma cell gingivitis (pending)

[Pending]

Pleomorphic adenoma

Polymorphous adenocarcinoma

Primary mucosal CD30 positive T cell lymphoproliferative disorder (pending)

[Pending]

Proliferative verrucous leukoplakia (PVL)

Table of Contents

Definition / general

An oral potentially malignant disorder that shows slow growing, persistent and often multifocal proliferations of white, verruciform lesions of the oral cavity, particularly the gingiva

Essential features

Diagnosis requires clinical - pathologic correlation
Shows high rates (~50%) of recurrence and progression to squamous cell carcinoma (Head Neck Pathol 2021;15:572, Cancers (Basel) 2021;13:4085)
Older women are most affected

Terminology

Leukoplakia: white patch of the mucous membrane that is not clinically diagnostic
Verrucous hyperplasia: a term used by Shear and Pindborg in 1980 for lesions having a histopathologic pattern similar to the bulky hyperkeratotic epithelial proliferation seen in proliferative verrucous leukoplakia and appearing histopathologically and clinically similar to verrucous carcinoma (Cancer 1980;46:1855)

ICD coding

ICD-10: K13.21 - leukoplakia of oral mucosa

Epidemiology

Middle aged to older women are most affected (Cancers (Basel) 2021;13:4085)

Sites

Any oral site
Gingiva / alveolar ridge mucosa is the most common site for hyperkeratotic PVL lesions and for malignant transformation of PVL lesions (Cancers (Basel) 2021;13:4085)

Pathophysiology

Little is known about the molecular pathways and biologic factors associated with PVL (Head Neck Pathol 2021;15:572)

Etiology

Etiology is unknown
Tobacco and alcohol do not appear to be significant etiologic factors, as seen in other oral precursor lesions (Cancers (Basel) 2021;13:4085)

Diagrams / tables

Images hosted on other servers:

Major histologic categories

Clinical features

Clinical criteria proposed by Villa et al. in 2018 (Oral Dis 2018;24:749):
- White, hyperkeratotic lesions that are smooth, fissured, verrucous or erythematous with or without ulcers
- Multifocal, noncontinuous lesions or a single, large lesion > 4 cm involving 1 site or a single, large lesion > 3 cm involving continuous sites
- Lesions that progress, expand in size or develop multifocality over time
White / keratotic lesions of the gingiva that often demonstrate a ring around the collar appearance, where the lesion appears to follow the marginal gingiva around the tooth (Head Neck Pathol 2021;15:572)

Diagnosis

Diagnosis is made upon clinical examination; however, biopsy is required to determine transformation of hyperkeratotic lesions into cytologic dysplasia or carcinoma
Biopsy from uninflamed and nonulcerated sites is recommended (Head Neck Pathol 2021;15:572)

Prognostic factors

Women have a 3 times higher risk of developing oral squamous cell carcinoma in PVL compared to men with PVL (Cancers (Basel) 2021;13:4085)

Case reports

38 year old man with carcinomatous transformation in a setting of PVL (J Indian Soc Periodontol 2017;21:499)
60 year old man presented with multifocal white patches (Contemp Clin Dent 2013;4:258)
84 year old woman treated with high dose rate brachytherapy (Cureus 2021;13:e15696)

Treatment

There is no current treatment for PVL; however, management includes the following:
- Close clinical follow up (every 3 - 6 months) (Oral Dis 2018;24:749)
- Lesions should be photographed at each clinical visit and photographs should be submitted to the pathologist along with any biopsy specimens (Oral Dis 2018;24:749)
- Biopsies are taken periodically, particularly when lesions have changed character (e.g., increased significantly in size, become nodular, exophytic, indurated or more verrucoid) or when destruction of adjacent structures or tooth mobility is noticed
- Early detection and patient education is critical to management
Early success with laser assisted photodynamic therapy has been reported (Photodiagnosis Photodyn Ther 2022;39:103002)
Although no standard of care exists for treatment, cases of PVL with cytologic dysplasia or those diagnosed as bulky hyperkeratotic epithelial proliferation (with or without suspicion for invasion) are generally excised with conservative, assured margins when clinically feasible

Clinical images

Contributed by Molly Housley Smith, D.M.D., Michael Piepgrass, D.M.D.,
John McGehee, D.M.D., Michael Menis, D.D.S. and Trent Clifton, D.M.D., M.D.

Patchy mandibular leukoplakia

Verrucoid surface texture

Ring around the collar

Diffuse leukoplakia

Buccal mucosa

Tongue lesion

Nonmigrating white lesions

Carcinomatous transformation

Gross description

White lesions demonstrate well demarcated borders, contrasting with adjacent tan, unaffected mucosa
Pebbled, papillary, verrucoid or sometimes smooth surface texture

Gross images

Contributed by Molly Housley Smith, D.M.D.

Ring around the collar

Multifocal lesions

Microscopic (histologic) description

Microscopic features may be subtle; clinical correlation or photographs are vital to diagnosis
The following histopathologic categories of proliferative verrucous leukoplakia are taken directly from the Consensus Guideline by Thompson et al., 2021 (Head Neck Pathol 2021;15:572, see table)
- Corrugated ortho(para)hyperkeratotic lesion, not reactive
  - Disproportionate orthokeratosis
    - Orthokeratosis that is > half of adjacent epithelial thickness
    - Troughs and crests of keratosis or epithelium, i.e., corrugation
    - Wave-like undulation commonly seen in sentinel lesions
    - Prominent crests or spikes in clinically worrisome lesions (formerly Christmas tree keratosis)
    - Minor subgroup in this category shows flat, dense, markedly thickened orthokeratin with atrophic underlying spinous layer (proliferative leukoplakia)
    - Usually prominent granular layer
    - Skip segments of ortho and parahyperkeratosis
    - Absent to scant acute surface inflammation
  - Loss of rete pegs or atrophic epithelium for site
  - Sharp demarcation / abrupt transitions
  - Architectural distortion is greater than cytologic atypia
- Bulky hyperkeratotic epithelial proliferation, not reactive
  - Amplified bulkiness of the epithelial proliferation that accounts for the lesion's thickness rather than keratosis (usually orthokeratosis)
  - Bulbous rete pegs that sometimes coalesce to appear confluent, with architectural abnormalities overshadowing cytologic findings
  - Separation artifact between epithelium and stroma
  - Lichenoid inflammation at advancing epithelial front is sometimes present
  - Consider risky sites in order: gingiva > soft palate > floor of mouth > buccal > tongue
- Suspicious for or squamous cell carcinoma
  - Voluminous squamous epithelial proliferation with acanthotic endophytic appearing columns with complex folding and invaginations that is > 3 - 4 times the adjacent uninvolved epithelial thickness
  - Thick, clubby, bulbous, blunt, downwardly directed rete peg projections:
    - May or may not extend below level of adjacent epithelium and often lacking classical invasion or extension below adjacent epithelium
    - Basement membrane is often intact
    - Intraepithelial microabscesses, sometimes with keratin pearls
    - Increased intraepithelial eosinophils
    - Muscle abutment / displacement
  - Parakeratotic crypting
  - Occasional church spire hyperkeratosis in some
  - Focal dysplasia may be present but is usually limited

Microscopic (histologic) images

Contributed by Molly Housley Smith, D.M.D.

Corrugated hyperorthokeratosis

Skip pattern

Prominent granular cell layer

Skip pattern

Cytologic dysplasia

Dysplastic and elongated epithelium

Bulky hyperkeratotic epithelial proliferation

Suspicion for invasion

Verrucous carcinoma transformation

Deceptively benign

Squamous cell carcinoma transformation

Sample pathology report

Gingiva, biopsy:
- Corrugated hyperorthokeratosis and chronic mucositis (see comment)
- Comment: When combined with the clinical description and photographs, the histomorphology is compatible with proliferative verrucous leukoplakia.

Differential diagnosis

Lichen planus / lichenoid reaction:
- Histopathologic features
  - Degeneration of the epithelium at the stromal - epithelial junction with blurring of the basal cells with the superficial lamina propria
  - Band of lymphocytes within the superficial lamina propria (although lichenoid reactions often have plasma cells, histiocytes or eosinophils as well)
  - Sawtooth rete ridges or atrophy
  - Degenerated keratinocytes, termed Civatte, colloid or hyaline bodies
  - Parakeratosis or minimal to absent orthokeratosis
  - Ulceration or subepithelial separation may be present
  - Cytologic dysplasia is absent
- Because lichen planus may show overlapping histopathologic features with PVL, diagnosis requires clinical - pathologic correlation (Head Neck Pathol 2021;15:572)
  - Lichen planus and medication related lichenoid reactions should migrate or change patterns; although contact related reactions (e.g., due to an adjacent amalgam restoration) may remain in one place, the lesion should not progress and should ameliorate upon elimination of the adjacent irritant
  - May be painful, particularly when eating acidic foods
  - May show lace-like striations, papules, plaques, ulcerations / erosions or erythema
  - Should respond to steroid therapy (although medication related lichenoid reactions may be recalcitrant)
Foreign body gingivitis with hyperkeratotic lesions:
- Recently, white, progressing, verrucous clinical lesions (mimicking PVL) were found to be strongly associated with granules of embedded foreign material (Oral Surg Oral Med Oral Pathol Oral Radiol 2019;128:250)
- Silica is the most common element found in the embedded foreign material (Oral Surg Oral Med Oral Pathol Oral Radiol 2019;128:250)
- It is uncertain whether this embedded foreign material plays a role in the pathogenesis of PVL or if it represents a separate disease process
Alveolar ridge keratosis:
- White plaque without erythema or ulceration, present on the edentulous alveolar ridge or the retromolar pad
- Clinically exhibits fading margins rather than well demarcated margins seen in PVL (Head Neck Pathol 2021;15:572)
- White lesions that extend off the alveolar ridge are more concerning
- Histopathologically demonstrates a corrugated layer of orthokeratin but has elongated rete ridges and the inflammatory component is insignificant
- Fibrous stroma is often densely fibrotic
Traumatic hyperkeratosis (morsicatio):
- Lesions that arise from chronic biting, nibbling or rubbing of the area
- Often arise on the buccal mucosa or lateral tongue along the line of occlusion
- Patients may or may not be aware of the biting habit
- Clinically, lesions are white and often demonstrate a shaggy or shredded surface texture; the lesions blend in with the surrounding mucosa
- Microscopic examination shows thickened parakeratin, often with bacterial surface colonies, areas of plasma / serum pooling, edema within the keratinocytes and thickening of the spinous cell layer; scattered inflammatory cells are seen within the underlying connective tissue
Tobacco pouch keratosis:
- Mucosal alterations due to habitual use of chewing tobacco or snuff
- Clinically, the mucosa is thickened and fissured with a white-gray sheen
- Histopathologic examination reveals thickening of the spinous cell layer, basilar hyperplasia and a thickened layer of edematous ortho or parakeratin which forms epithelial peaks or chevrons; a dense band of eosinophilic hyalinization may be seen in the superficial lamina propria with use of wet snuff
Epithelial dysplasia / unifocal leukoplakia, not attributable to PVL:
- M > F
- Associated with tobacco and alcohol use (Cancers (Basel) 2021;13:4085)
- Histopathologically shows bulbous or teardrop shaped rete ridges with variable degree of pleomorphism, hyperchromasia, hypercellularity, increased and abnormal mitotic figures, increased nuclear size and individual cell keratinization

Board review style question #1

A 73 year old woman presents with multiple, asymptomatic white patches of the attached gingiva that have progressed over a few months. The lesions do not change pattern and do not migrate. Histopathologic examination reveals epithelium with a thickened, corrugated layer of orthokeratin devoid of overt cytologic dysplasia. What condition does this patient have?

Alveolar ridge keratosis
Proliferative verrucous leukoplakia
Squamous cell carcinoma
Tobacco pouch keratosis

Board review style answer #1

B. Proliferative verrucous leukoplakia

Comment Here

Reference: Proliferative verrucous leukoplakia

Board review style question #2

Which of the following is true of the condition proliferative verrucous leukoplakia?

Chewing tobacco is a common etiologic factor
Males are most frequently affected
Microscopic examination of the associated white lesions shows frank cytologic dysplasia during early stages
Patients demonstrate a ~50% risk of developing oral squamous cell carcinoma

Board review style answer #2

D. Patients demonstrate a ~50% risk of developing oral squamous cell carcinoma

Comment Here

Reference: Proliferative verrucous leukoplakia

Pseudoepitheliomatous hyperplasia

Table of Contents

Definition / general

Histopathological pattern characterized by the benign, reactive elongation of the epithelial rete ridges, which deceivingly may mimic squamous cell carcinoma
Seen in a variety of conditions / tumors, namely granular cell tumor, candidiasis (median rhomboid glossitis, chronic hyperplastic candidiasis), necrotizing sialometaplasia, blastomycosis, granulomatosis with polyangiitis, etc. (Oral Dis 2020;26:573)

Essential features

Microscopic pattern rather than a distinct diagnosis
Benign hyperplasia of the epithelial rete ridges
May be misdiagnosed as squamous cell carcinoma
Seen in a wide variety of infectious, inflammatory, traumatic and neoplastic conditions (Am J Dermatopathol 2012;34:165)

Terminology

Pathologists often use the acronym PEH
Pseudocarcinomatous hyperplasia

Sites

Not site specific; site predilection depends on the primary diagnosis
- Oral granular cell tumors most commonly occur on the dorsal tongue, necrotizing sialometaplasia is most commonly on the hard palate and median rhomboid glossitis occurs on the posterior dorsal tongue at the midline (Oral Dis 2020;26:573)

Pathophysiology

Unknown
Possible role of transforming growth factor alpha (TGF alpha) in PEH development via autocrine growth effect or by blocking downregulation of epidermal growth factor receptor (EGFR) (Ann Diagn Pathol 2003;7:73, Am J Dermatopathol 2012;34:165)

Etiology

Reported in a variety of conditions / tumors
- Granular cell tumor (Oral Dis 2020;26:573)
- Candidiasis (median rhomboid glossitis, chronic hyperplastic candidiasis) (J Int Oral Health 2015;7:148)
- Reactive proliferations, such as epulis fissuratum (J Int Oral Health 2015;7:148)
- Necrotizing sialometaplasia (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;89:600)
- Deep chronic infections, such as blastomycosis (Am J Dermatopathol 2011;33:112)
- Granulomatosis with polyangiitis (Intractable Rare Dis Res 2022;11:93)
- Oral submucous fibrosis (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;106:556)
- Melanocytic nevi (Int J Oral Maxillofac Surg 2002;31:330)
- Melanoma (J Cutan Pathol 2000;27:153)

Clinical features

Clinical appearance dictated by the condition / background setting in which PEH is found
- For example, PEH in chronic hyperplastic candidiasis may manifest as a well demarcated plaque
- Granular cell tumors present as dome shaped, often yellow nodules (Am J Dermatopathol 2011;33:112)

Diagnosis

Biopsy with clinicopathologic correlation, sometimes with review of multiple levels (Am J Dermatopathol 2011;33:112)
Diagnosis of PEH is made with significant caution, as atypical epithelial processes (e.g., verrucous carcinoma, proliferative verrucous leukoplakia, squamous cell carcinoma) may imitate PEH
Misdiagnosis of PEH as squamous cell carcinoma may lead to radical surgery or surgery related morbidity (J Cutan Aesthet Surg 2014;7:232)
Double reporting or obtaining a second opinion aids in preventing misdiagnosis of PEH for squamous cell carcinoma and vice versa (Eur Arch Otorhinolaryngol 2014;271:847)
Special stains may be necessary to diagnose infections

Prognostic factors

Prognosis dictated by primary diagnosis

Case reports

27 year old woman with PEH in necrotizing sialometaplasia (Dermatol Online J 2020;26:13030)
32 year old man with granulomatosis with polyangiitis of the gingiva showing PEH on biopsy (Intractable Rare Dis Res 2022;11:93)
44 year old white man with granular cell tumor showing PEH (BMC Res Notes 2017;10:14)
62 year old man with PEH in an intramucosal nevus (Int J Oral Maxillofac Surg 2002;31:330)

Treatment

Depends on primary diagnosis

Clinical images

Contributed by Molly Housley Smith, D.M.D.

Median rhomboid glossitis

Images hosted on other servers:

Granular cell tumor

Gross description

Depends on the underlying diagnosis (e.g., granular cell tumor, blastomycosis, etc.) but in general, thickening of the epithelium is noted
Tan, although may be pigmented if overlying a nevus or melanoma (Am J Dermatopathol 2011;33:112)

Microscopic (histologic) description

Thick elongation of the overlying epithelium with bulbous or sometimes jagged / sharp, interconnecting rete ridges (Am J Dermatopathol 2011;33:112)
May exhibit keratin pearl formation: concentric layers of keratinocytes with central keratinization (Am J Dermatopathol 2011;33:112)
Lacks significant nuclear atypia; although mitotic figures may be seen, they are not numerous or atypical (Am J Dermatopathol 2011;33:112)
Awareness of microscopic features seen in conditions / tumors associated with PEH is paramount for proper diagnosis
- Prominent leukocytic exocytosis or extravasated red blood cells should alert the pathologist to look for infection (candidiasis, blastomycosis, etc.) or granulomatosis with polyangiitis (Am J Dermatopathol 2011;33:112)
- Replacement of underlying fibrous stroma with sheets of pale, basophilic, plump granular cells suggests that the overlying epithelial proliferation is likely associated with granular cell tumor
- Connection with metaplastic salivary ducts and presence of spilled mucin suggests necrotizing sialometaplasia
- Underlying stromal fibrosis may be seen in oral submucous fibrosis (in a patient who uses betel quid) or in median rhomboid glossitis, as the posterior dorsal tongue is a region that tends to exhibit prominent fibrosis of the stroma

Microscopic (histologic) images

Contributed by Molly Housley Smith, D.M.D.

PEH in granular cell tumor

PEH in chronic hyperplastic candidiasis

PEH in median rhomboid glossitis

PEH in blastomycosis

PEH in epulis fissuratum

PEH in necrotizing sialometaplasia

PEH in melanoma in situ

PEH in granulomatosis with polyangiitis

Virtual slides

Images hosted on other servers:

Pseudoepitheliomatous Hyperplasia in Blastomycosis Infection of the Skin

PEH in blastomycosis infection of the skin

Positive stains

Usually not utilized for diagnosis as clinicopathologic correlation is often the most valuable
Special stains PAS or GMS may highlight the underlying infectious process
p53 reportedly positive only in basilar portion of epithelium (differentiated keratinocytes not stained) (Am J Dermatopathol 2011;33:112, Arch Pathol Lab Med 2005;129:1032, Cancer 1994;73:2317)

Videos

PEH in excision of skin lesion

Definition, causes and histologic appearance of PEH

PEH in granular cell tumor

Sample pathology report

Dorsal tongue, incisional biopsy:
- Hyperparakeratosis, epithelial hyperplasia and superficial candidal colonization (see comment)
- Comment: The microscopic pattern of epithelial hyperplasia is suggestive of pseudoepitheliomatous hyperplasia, likely caused by the presence of candidiasis. If lesional tissue persists after adequate antifungal therapy, however, rebiopsy is recommended in order to rule out atypical epithelial processes that may mimic pseudoepitheliomatous hyperplasia.

Differential diagnosis

Squamous cell carcinoma (SCC):
- May be difficult to differentiate from PEH on small biopsies or without supplemental clinical information
- Demonstrates significant cellular atypia and increased / abnormal mitotic figures
- Frankly invasive islands that lack surrounding basement membrane
- May show perineural, lymphovascular, skeletal muscle or ductal invasion
- p53 reportedly positive throughout full thickness in SCCs as opposed to in PEH, where it highlights only the basilar portion (Arch Pathol Lab Med 2005;129:1032, Am J Dermatopathol 2011;33:112)
- In cases with secondary candidiasis, repeat biopsy after antifungal therapy may aid in determining a more definitive diagnosis
Verrucous carcinoma:
- May be difficult to differentiate from PEH on small biopsies or without supplemental clinical information
- Church spire-like or papillary hyperkeratosis with deep keratin clefting
- Broad, bulbous, plunging rete ridges that demonstrate pushing encroachment on muscle or other deep submucosal structures, below the level of intact normal epithelium (Head Neck Pathol 2021;15:572)
- Persists despite antifungal therapy
- In cases with secondary candidiasis, repeat biopsy after antifungal therapy may aid in determining a more definitive diagnosis
Bulky hyperkeratotic epithelial proliferation in proliferative verrucous leukoplakia (PVL) (Head Neck Pathol 2021;15:572):
- May be difficult to differentiate from PEH on small biopsies or without supplemental clinical information
- Generalized thickened epithelium
- Bulbous rete pegs that sometimes coalesce
- Lichenoid inflammation may be present
- High risk of progression into malignancy if untreated
- Associated with multifocal lesions
- Persists despite antifungal therapy
- High risk sites in order: gingiva > soft palate > floor of mouth > buccal > tongue

Board review style question #1

The above biopsy was taken from the posterior dorsal tongue at the midline. What is the microscopic pattern of the epithelium called?

Pseudoepitheliomatous hyperplasia
Squamous cell carcinoma
Squamous ductal metaplasia
Verrucous carcinoma

Board review style answer #1

A. Pseudoepitheliomatous hyperplasia. When combined with the clinical information / photograph, the overall diagnosis of this case is median rhomboid glossitis, which is a particular diagnosis made in a patient with a red patch on the middle portion of the posterior dorsal tongue. The epithelium often shows elongated, bulbous shaped rete ridges (pseudoepitheliomatous hyperplasia) and superficial candidal colonization, as highlighted here by a PAS stain. Answer B is incorrect because the epithelium does not show significant atypia or detached islands of invasive epithelium. Answer C is incorrect because there are no salivary ducts pictured above; however, squamous ductal metaplasia may be seen in association with pseudoepitheliomatous hyperplasia in a setting of necrotizing sialometaplasia, a condition most often diagnosed on the hard palate. Answer D is incorrect because although the epithelium is bulbous and hyperplasic, a prominent verrucoid surface architecture and keratin clefting are not identified.

Comment Here

Reference: Pseudoepitheliomatous hyperplasia

Board review style question #2

A patient presents with a yellow nodule on the tongue. What is the diagnosis?

Frictional keratosis
Granular cell tumor with overlying pseudoepitheliomatous hyperplasia
Squamous cell carcinoma
Verrucous carcinoma

Board review style answer #2

B. Granular cell tumor with overlying pseudoepitheliomatous hyperplasia (PEH). Microscopic sections show a dome shaped mass of pale, basophilic, plump granular cells surfaced by hyperkeratotic and hyperplastic epithelium. Although the rete ridges are significantly proliferative and demonstrate keratin pearls, overt cytologic atypia is not appreciated. This proliferative pattern of the epithelium is termed pseudoepitheliomatous hyperplasia and is known to be associated with granular cell tumors. Answer A is incorrect because although there is a thickened layer of parakeratin, this answer choice ignores the replacement of the fibrous stroma by plump granular cells. Answer C, a common pitfall in the diagnosis of this tumor, is incorrect because although the epithelium is proliferative, prominent cytologic atypia is not appreciated. The pathologist must be keen in recognizing the underlying replacement of the fibrous stroma with plump granular cells and must know that granular cell tumors characteristically show PEH in many cases. Answer D is incorrect because verrucous carcinoma would show keratin clefting and prominent, bulbous, plunging rete ridges that push into the underlying muscle.

Comment Here

Reference: Pseudoepitheliomatous hyperplasia

Board review style question #3

The above biopsy was taken from a patient with a large, indurated ulceration on the tongue. What is the diagnosis?

Blastomycosis with pseudoepitheliomatous hyperplasia
Granulomatosis with polyangiitis
Pyogenic granuloma
Squamous cell carcinoma

Board review style answer #3

A. Blastomycosis with pseudoepitheliomatous hyperplasia. Blastomycosis is one of the conditions that characteristically shows pseudoepitheliomatous hyperplasia (PEH) in which the epithelium is thickened and forms elongated and anastomosing rete ridges. Answer D is incorrect because although blastomycosis has often been misdiagnosed as squamous cell carcinoma (SCC) due to this prominent PEH, neutrophilic abscesses throughout the epithelium should prompt the pathologist into getting infectious stains, such as the GMS shown above. The GMS stain highlights the thick walled blastomycosis organisms, which show broad based budding. SCC is a common pitfall in the diagnosis of blastomycosis but is incorrect because fungal stains are negative for deep organisms in SCC. Answer B is incorrect because granulomatosis with polyangiitis (GPA) also demonstrates dense inflammation and PEH; however, GPA has evidence of vasculitis and a lack of deep fungal organisms. Answer C is incorrect because pyogenic granulomas can also show dense inflammation and some degree of PEH; however, the epithelium is often not this prolific and microorganisms would not be present on GMS staining.

Comment Here

Reference: Pseudoepitheliomatous hyperplasia

Pyogenic granuloma

Table of Contents

Definition / general

Benign and often reactive vascular proliferation of the oral mucosa, most commonly found on the gingiva

Essential features

Benign red / vascular soft tissue proliferation, most commonly found on the anterior maxillary gingiva
Associated with poor oral hygiene, chronic trauma, pregnancy, medications
Form of capillary hemangioma that is most often considered reactive and may demonstrate a lobular architecture histopathologically
May demonstrate rapid growth and clinically mimic malignancy (Clin Case Rep 2018;6:690, Case Rep Dent 2021;2021:5575896)
Constitutes 3.8 - 7% of oral biopsy diagnoses (J Oral Maxillofac Surg 2010;68:2185)

Terminology

Lobular capillary hemangioma, subtype
Pregnancy tumor
Epulis gravidarum / granuloma gravidarum: pyogenic granuloma occurring in a setting of pregnancy
Epulis granulomatosum: pyogenic granuloma located in an extraction socket

ICD coding

ICD-10:
- K06.8 - pyogenic granuloma of the gingiva
- K13.4 - granuloma and granuloma-like lesions of the oral mucosa
- K13.6 - irritative hyperplasia of the oral mucosa

Epidemiology

Large age range; most common in the second and third decades of life (J Oral Maxillofac Surg 2010;68:2185, Oral Maxillofac Surg 2012;16:305)
Female predilection (J Oral Maxillofac Surg 2010;68:2185, Pathol Int 2005;55:391, Oral Maxillofac Surg 2012;16:305)

Sites

Gingiva affected most often (maxillary anterior) (J Oral Maxillofac Surg 2010;68:2185, Head Neck Pathol 2019;13:4)
May also affect lips, buccal mucosa, tongue or palate

Pathophysiology

Largely unknown, although in pregnancy, estrogen enhances vascular endothelial growth factor (VEGF) production in macrophages, likely contributing to the development of pyogenic granulomas (J Dermatol Sci 2005;38:1)
Also in pregnancy, progesterone may function as an immunosuppressant in gingiva, preventing an acute inflammatory reaction against oral bacteria and resulting in proliferative gingival inflammation (J Clin Periodontol 1991;18:262)
Increased estrogen and progesterone in pregnancy increases concentrations of Prevotella intermedia in the subgingival biofilm, decreases the host response to the bacteria and increases the vascular permeability and infiltration of fluids into the gingival tissues, contributing to formation of pyogenic granulomas (J Appl Oral Sci 2013;21:215)
2018 International Society for the Study of Vascular Anomalies (ISSVA) Classification of Vascular Anomalies lists BRAF, RAS and GNA14 as causal genes for the lobular capillary hemangioma (pyogenic granuloma) (ISSVA: ISSVA Classification for Vascular Anomalies [Accessed 11 August 2021])

Etiology

Associated with chronic irritation (J Oral Maxillofac Surg 2010;68:2185, Head Neck Pathol 2019;13:4)
- Poor oral hygiene
- Ill fitting oral appliances or overhang margins of dental restorations
- Persistent bite trauma
May be seen in patients with drug induced gingival overgrowth from use of calcium channel blockers, calcineurin inhibitors, antiseizure medications or anticancer medications (e.g. TNF alpha antagonists, BRAF inhibitors, tyrosine kinase inhibitors, epidermal growth factor receptor inhibitors, mTOR inhibitors, taxanes, pyrimidine analogs) (Case Rep Dent 2021;2021:5575896, Pediatr Transplant 2020;e13947)

Clinical features

Smooth or lobulated exophytic mass
Ranges from red / pink to deep red / blue / purple in color (Head Neck Pathol 2019;13:4)
Frequently ulcerated or crusted (Pathol Int 2005;55:391)
Often pedunculated, although the lobular capillary hemangioma variant is more commonly sessile (Pathol Int 2005;55:391)
May bleed easily upon gentle manipulation
May exhibit rapid growth (Case Rep Dent 2021;2021:5575896)
1 mm to several centimeters in diameter
Lesions tend to become more fibrotic / pink / rubbery over time and with elimination of irritating factors (termed sclerosed pyogenic granuloma or inflammatory fibrous hyperplasia) (J Oral Maxillofac Surg 2010;68:2185)

Diagnosis

Made upon histopathological examination of the excisional specimen

Prognostic factors

Good prognosis with low recurrence rate (8.2%) (J Oral Maxillofac Surg 2010;68:2185)

Case reports

15 and 26 year old women with large, progressive pyogenic granulomas (Clin Case Rep 2018;6:690)
51 year old woman with pyogenic granuloma treated with diode laser (Saudi Med J 2016;37:1395)
57 year old man taking amlodipine with rapid development of an epulis granulomatosum (Case Rep Dent 2021;2021:5575896)

Treatment

Conservative excision, extending to periosteum, with subsequent histopathologic examination (J Oral Maxillofac Surg 2010;68:2185, Neville: Oral and Maxillofacial Pathology, 4th Edition, 2015)
Elimination of precipitating factors
Granuloma gravidarum (pyogenic granuloma) should be excised after pregnancy, unless significant esthetic or functional concerns are present (J Appl Oral Sci 2013;21:215)
In pregnancy, pyogenic granulomas may spontaneously regress after removal of local irritants or after childbirth (J Appl Oral Sci 2013;21:215)

Clinical images

Contributed by Brittany Camenisch, D.M.D., Nehal Almehmadi, B.D.S., Sana Naheed, B.D.S., Evan Lynch, M.D., Ph.D.,
Justin Kolasa, M.D., D.M.D., Molly Housley Smith, D.M.D. and Susanna Goggin, D.M.D.

Gingival pyogenic granuloma

Reactive pyogenic granuloma

Pedunculated vascular nodule

Red ulcerated pyogenic granuloma

Nodular red pebbly masses

Epulis granulomatosum

Ulcerated gingival pyogenic granuloma

Gross description

Tan / brown mass, often pedunculated or lobulated
May demonstrate hemorrhagic foci on cut surface (Case Rep Dent 2016;2016:1323798)
Often exhibits ulcerated surface

Gross images

Contributed by Molly Housley Smith, D.M.D.

Lobulated and hyperkeratotic mass

Lobulated and hyperkeratotic mass, sectioned

Deep inflammatory infiltrate

Ulcerated pyogenic granuloma

Ulcerated pyogenic granuloma, sectioned

Microscopic (histologic) description

Highly vascularized proliferation of granulation tissue (J Oral Maxillofac Surg 2010;68:2185)
Often demonstrates surface ulceration and a subacute inflammatory cell infiltrate comprised of neutrophils, lymphocytes and plasma cells
May demonstrate a lobular arrangement of capillary vessels and proliferating endothelial cells delineated by fibrous septae (termed lobular capillary hemangioma)
May be pedunculated
May show brisk mitotic rate (up to 10 mitotic figures per high power field); however, lacks pleomorphism (Ann Diagn Pathol 2020;46:151506)

Microscopic (histologic) images

Contributed by Molly Housley Smith, D.M.D.

Pedunculated mass

Prominent vasculature

Prominent blood vessels

Acute inflammation

Lobular arrangement

Lobular and exophytic architecture

Capillary proliferation

Virtual slides

Images hosted on other servers:

Pyogenic granuloma of the skin

Positive stains

Immunohistochemistry is not routinely performed; however, CD34, CD31, erythroblast transformation specific related gene (ERG), alpha smooth muscle actin (SMA) and muscle specific actin (MSA) highlight the prominent vasculature throughout the mass
WT1 (Ann Diagn Pathol 2020;46:151506)

Negative stains

Videos

Histopathology of pyogenic granuloma

Clinical and etiologic features

Sample pathology report

Gingiva, excision:
- Pyogenic granuloma

Differential diagnosis

Peripheral ossifying fibroma:
- May be clinically identical
- Only on the gingiva / alveolar ridge
- Differentiated based on histopathologic examination
  - Peripheral ossifying fibroma demonstrates the presence of bone, at least focally, within the mesenchymal stroma
Peripheral giant cell granuloma:
- May be clinically identical
- Only on the gingiva / alveolar ridge
- Differentiated based on histopathologic examination
  - Presence of osteoclast type multinucleated giant cells
Parulis:
- May be clinically identical, although may express red-yellow fluid on palpation
- Associated with an adjacent nonvital tooth or inflamed periodontal pocket
- Can be traced using gutta percha to reveal the inflammatory origin
- Differentiated based on histopathologic examination
  - Accumulations of neutrophils arranged in a linear fashion
Metastatic disease:
- May be clinically identical
- Differentiated based on histopathologic examination
Gingival squamous cell carcinoma:
- May be clinically identical, although often demonstrates a granular or papillary surface architecture (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009;107:92)
- Differentiated based on histopathologic examination
  - Invasive islands of squamous epithelium arising from surface
Spongiotic gingival hyperplasia / localized juvenile spongiotic gingival hyperplasia:
- Papillary / pebbly surface architecture
- Recalcitrant to oral hygiene measures
- < 1 cm in size (J Cutan Pathol 2019;46:839)
- Traditionally localized, although multifocal examples have been noted
- Histopathologic examination reveals papillary proliferation of spongiotic, nonkeratinized squamous epithelium with elongation of rete ridges, intermixed capillary vessels and neutrophilic exocytosis
Angiosarcoma:
- Rare in the oral cavity (Int J Oral Maxillofac Surg 2014;43:917)
- Differentiated based on histopathologic examination
  - Infiltrative
  - May demonstrate rounded, polygonal or spindled cells, often with an epithelioid morphology (Lancet Oncol 2010;11:983)
  - Brisk mitotic rate with atypical mitotic figures or pleomorphism
  - Forms vascular sinusoids and less clearly defined vascular spaces (Lancet Oncol 2010;11:983)
  - May demonstrate keratin or EMA positivity
Kaposi sarcoma:
- Often multifocal or associated with diffuse violaceous gingival enlargement (JAMA Dermatol 2019;155:370)
- Associated with AIDS (JAMA Dermatol 2019;155:370)
- Differentiated based on histopathologic examination
  - HHV8 positive

Additional references

WHO Classification of Tumours Editorial Board: Soft Tissue and Bone Tumours, 5th Edition, 2020

Board review style question #1

The above mass is found on the gingiva. What is true regarding this diagnosis?

This entity is more commonly found in pregnant women
This entity is more commonly found in men
This entity is more commonly found in patients who are taking long term steroids
No treatment is indicated for this particular entity; clinical diagnosis is sufficient

Board review style answer #1

A. This entity is more commonly found in pregnant women

Comment Here

Reference: Pyogenic granuloma

Board review style question #2

The above images are of a pedunculated red, lobulated mass on the dorsal tongue. What is the diagnosis?

Angiosarcoma
Epithelioid hemangioendothelioma
Granular cell tumor
Lobular capillary hemangioma (pyogenic granuloma)

Board review style answer #2

D. Lobular capillary hemangioma (pyogenic granuloma)

Comment Here

Reference: Pyogenic granuloma

Pyostomatitis vegetans (pending)

[Pending]

Salivary duct cyst

Table of Contents

Definition / general

Reactive lesion to salivary gland duct obstruction and buildup of trapped mucin within

Essential features

Mucus trapped within lumen secondary to salivary gland duct obstruction
Severe obstruction can lead to squamous or oncocytic metaplasia of duct epithelial bilayer
Found on oral mucosal sites with minor salivary glands or parotid gland
May become secondarily infected around sialolith, which acts as a nidus

Terminology

Salivary retention cyst
Mucus retention cyst
Mucus duct cyst
Sialocyst
Reactive oncocytoid cyst (if epithelial lining has oncocytic metaplasia)
Not to be confused with mucocele / mucus extravasation phenomenon / ranula / plunging rannula / mucus escape reaction

ICD coding

ICD-10: K11.8 - other diseases of salivary glands

Epidemiology

M = F (Arch Otolaryngol Head Neck Surg 1987;113:51)
Some reports have found a slight female predilection (Arch Otolaryngol Head Neck Surg 1987;113:51)
Adults with median age of 56 years from 177 cases (Head Neck Pathol 2017;11:469)
Rarer than the oral cavity mucocele (Pediatr Dermatol 2008;25:308)

Sites

Minor salivary glands of the floor of mouth, vestibule (mucobuccal fold), buccal mucosa, upper labial mucosa (Head Neck Pathol 2017;11:469)
Parotid is the most commonly associated major salivary gland (J Oral Sci 2001;43:9)
Rare in the lower lip (Pediatr Dermatol 2008;25:308)

Pathophysiology

Salivary duct occlusion leading to reactive ductal ectasia (Diagn Cytopathol 2015;43:495)
True developmental cyst with epithelial lining unlike the oral cavity mucocele (Head Neck Pathol 2017;11:469)

Etiology

May be associated with sialoliths, mucus plugs, postoperative or postinflammatory stricture (J Oral Sci 2001;43:9)
Distal obstruction of a salivary duct leads to retention of secretion within the duct (Diagn Cytopathol 2015;43:495)

Clinical features

Dome shaped, sessile, slow growing but asymptomatic nodule (Oral Surg Oral Med Oral Pathol 1984;58:692)
1 - 3 cm but have been reported to grow up to 10 cm (J Oral Sci 2001;43:9)
Fluctuant to palpation but usually painless, some may feel firmer especially if a sialolith is present (Oral Surg Oral Med Oral Pathol 1964;18:191)
Mucus or pus may be expressed from dilated ductal orifices when palpated if secondarily infected (Oral Surg Oral Med Oral Pathol 1984;58:692)
Blue tinge due to Tyndall effect
Do not typically wax and wane over time (Arch Otolaryngol Head Neck Surg 1987;113:51)

Diagnosis

Based on patient reported history and clinical examination, definitive diagnosis made by histopathologic evaluation under light microscopy

Radiology images

Images hosted on other servers:

Nonhomogenous parotid lesion

Prognostic factors

Benign with good prognosis

Case reports

15 year old boy with a 3 month history of a left lower labial mucosa swelling (J Oral Maxillofac Pathol 2014;18:S151)
30 year old man with a left submandibular swelling only noticeable on swallowing and nose blowing (J Laryngol Otol. 2000;114:305)
56 year old man with an obstructive mass at the vallecula (Arch Otolaryngol Head Neck Surg 1989;115:1254)
63 year old man presenting with an enlarging left preauricular swelling (J Clin Imaging Sci 2013;3:3)
78 year old man with a firm swelling at the left upper labial mucosal (Indian J Pathol Microbiol 2013;56:163)

Treatment

Complete excision along with the feeding minor salivary gland is curative (Arch Otolaryngol Head Neck Surg 1987;113:51)
- Iatrogenic intraoperative damage to neighboring salivary gland parenchyma may contribute to the development of postoperative mucocele (Oral Surg Oral Med Oral Pathol 1964;18:191)
Partial or total removal of feeding major salivary glands may be required (Pediatr Dermatol 2008;25:308)
Chlorhexidine mouth rinse or oral antibiotics for secondarily infected salivary duct cysts (Oral Surg Oral Med Oral Pathol 1984;58:692)
Sialagogues may decrease the risk of salivary stasis within dilated ducts by stimulating salivary flow

Clinical images

Images hosted on other servers:

Labial mucosal bluish nodule

Parotid salivary gland swelling

Smooth firm labial nodule

Gross description

Nodular mass with soft texture

Gross images

Images hosted on other servers:

Smooth firm labial nodule

Microscopic (histologic) description

Mucoid secretion surrounded by a bilayer of cuboidal or columnar stratified salivary duct epithelium (Oral Surg Oral Med Oral Pathol 1964;18:191)
- Cyst lining may have papillary folds into the lumen (Head Neck Pathol 2017;11:469)
May have squamous or oncocytic metaplasia of cyst lining, especially with more severe obstruction (Oral Surg Oral Med Oral Pathol 1964;18:191)
Sialolith and bacteria causing secondary infection may be present among the submitted tissue (Head Neck Pathol 2017;11:469)
Feeding salivary gland, if included, has obstructive changes with variable ductal dilation, lymphocytic infiltrate with periductal pattern and fibrosis (Oral Surg Oral Med Oral Pathol 1984;58:692)

Microscopic (histologic) images

Contributed by Vancouver General Hospital

True cyst removed intact

Squamous metaplasia, ruptured cyst

Positive stains

Negative stains

CD68

Sample pathology report

Right upper labial mucosa, exision:
- Salivary duct cyst (mucus retention cyst)
- Minor salivary gland parenchyma showing chronic sialoadenitis

Differential diagnosis

Mucocele/mucus extravasation phenomenon/ranula/plunging rannula/mucus escape reaction
- There is no true salivary gland duct epithelial lining and instead this is mimicked by epithelioid macrophages (muciphages) at the periphery of the extravasated mucin
Warthin tumor (papillary cystadenoma lymphomatosum)
- Lymphoid stroma in the cyst wall and multiple papillary infoldings with a bilayer of columnar and oncocytic epithelial lining
Papillary cystadenoma
- The lining epithelium has an adenomatous proliferation forming multilayered plaques of columnar or oncocytic salivary duct lining with papillary infoldings
Gingival cyst of the adult
- These occur only on the gingiva which has no minor salivary glands

Board review style question #1

A 66 year old female presented with a firm, painless, localized swelling with pustular discharge at the upper labial mucosa. The biopsy is shown above. Which immunohistochemical finding would one expect?

CD68 positive
Cytokeratin positive
PAX8 positive
S100 positive
SMA positive

Board review style answer #1

B. Cytokeratin positive

Comment Here

Reference: Salivary duct cyst

Board review style question #2

Dorsal tongue
Gingiva
Intrabony
Maxillary sinus
Parotid gland

Board review style answer #2

E. Parotid gland

Comment Here

Reference: Salivary duct cyst

SCC-general

Table of Contents

Definition / general

Squamous cell carcinoma (SCC) is a malignant neoplasm that arises from the mucosal epithelium of the oral cavity and shows variable squamous differentiation

Essential features

Most common cancer of the oral cavity, with a variable clinical appearance and a predilection for the ventrolateral tongue
Associated with tobacco, alcohol and betel quid
Malignancy of squamous cells with varying degrees of keratinization

ICD coding

ICD-10: C00 - C14 - malignant neoplasms of lip, oral cavity and pharynx

Epidemiology

> 90% of cancers in the oral cavity are SCC
Globally, the highest rates are seen in Melanesia and South Central Asia; it is the leading cause of cancer related death for men in India (CA Cancer J Clin 2021;71:209)
For the United States, the American Cancer Society estimates ~58,000 new cases of oral and oropharyngeal cancers in 2024 with 12,230 deaths (American Cancer Society: Key Statistics for Oral Cavity and Oropharyngeal Cancers [Accessed 2 February 2024])
M > F
Average age is 63
Can occur in younger patients, especially in the setting of dyskeratosis congenita or Fanconi anemia (J Pediatr Hematol Oncol 2019;41:501, Head Neck Pathol 2021;15:1099)

Sites

Can occur at any oral mucosal site (mucosal lip, buccal mucosa, alveolar ridge, floor of the mouth, hard palate, mobile tongue)
Classic high risk locations are ventrolateral tongue and floor of mouth
Patients can develop second primaries, synchronous or metachronous, with field cancerization as a probable hypothesis (Head Neck 2020;42:1848, Oral Oncol 2015;51:643)
Proliferative (verrucous) leukoplakia lesions have a high risk of malignant transformation, especially in locations such as the gingiva (Head Neck Pathol 2021;15:572)
Spread typically occurs via the lymphatic system to cervical lymph nodes

Pathophysiology

Multifactorial with accumulation of genetic alterations
- Loss of function of TP53 mutations and CDKN2A inactivation are frequently seen (Nature 2015;517:576)
Oral potentially malignant disorders, many of which harbor some degree of epithelial dysplasia, are associated with a risk of malignant progression (Head Neck Pathol 2019;13:423)

Etiology

Tobacco (Int J Cancer 2008;122:155)
Alcohol (Lancet Oncol 2021;22:1071)
Significantly higher risk with synergistic consumption of alcohol and tobacco (Clin Oral Investig 2019;23:2849)
Betel quid, gutka, pan masala (Curr Oncol Rep 2019;21:53)
Smokeless tobacco products (Nicotine Tob Res 2019;21:1162)
Ultraviolet (UV) radiation for lip squamous cell carcinoma (Laryngoscope 2018;128:84)
High risk human papillomavirus (HPV) is strongly associated with oropharyngeal squamous cell carcinoma; in contrast, 4.4% of oral squamous cell carcinoma cases are associated with high risk HPV (Braz J Otorhinolaryngol 2021;87:346)
Controversy regarding oral lichen planus and malignant transformation is unresolved (Oral Surg Oral Med Oral Pathol Oral Radiol 2016;122:332)
Due to confounding variables, chronic mechanical irritation has not been established as an independent risk factor (Bosn J Basic Med Sci 2021;21:647)

Clinical features

Varied clinical presentation, including exophytic, endophytic, white (leukoplakia), red (erythroplakia), nonhealing ulceration
May be preceded by or associated with an oral, potentially malignant disorder
Clinical factors associated with malignancy include nonhomogenous leukoplakia, erythroplakia, induration, deep ulceration, exophytic component and pain (Oral Surg Oral Med Oral Pathol Oral Radiol 2020;130:264)
Patient factors associated with malignant transformation include heavy tobacco smoking (> 20 pack years), heavy alcohol consumption (> 14 drinks/week for women and 21 drinks/week in men), immunosuppression (Head Neck 2021;43:3552)
Firm, fixed, nontender cervical lymph nodes may indicate regional spread

Diagnosis

U.S. Preventive Services Task Force concludes that for primary care providers, current evidence is insufficient to assess balance of benefits and harms of oral cancer screening in asymptomatic adults (Ann Intern Med 2014;160:55)
Visual and tactile exams of the oral cavity are often performed by oral health care providers and otolaryngologists
Immediate tissue biopsy with histopathologic examination for definitive diagnosis (J Am Dent Assoc 2017;148:712)
48.4% of cases are regional at diagnosis (NIH: Oral Cavity and Pharynx Stage Distribution of SEER Incidence Cases, 2011-2020 [Accessed 2 February 2024])

Radiology description

Invasive, advanced tumors may be detected on dental radiographs as destruction of underlying bone producing an ill defined radiolucency
Positron emission tomography (PET), computed tomography (CT) and magnetic resonance imaging (MRI) can be used to determine the presence and extent of disease
Carcinomas arising in the jaw bones without a mucosal origin are primary intraosseous squamous cell carcinoma and are not discussed here (Head Neck Pathol 2021;15:608)

Radiology images

Contributed by Sarah Glass, D.D.S.

Mandible invasion

Prognostic factors

5 year survival rate of 68.5% (NIH: Cancer Stat Facts - Oral Cavity and Pharynx Cancer [Accessed 2 February 2024])
Depth of invasion (DOI) and extranodal extension (ENE) were added to the AJCC staging 8th edition and are associated with upstaging (Oral Oncol 2018;85:82)
Bone invasion is correlated with a worse prognosis (and invasion through cortical bone into medullary bone provides the tumor with AJCC stage T4a) (Arch Pathol Lab Med 2019;143:439)
Noncohesive pattern of invasion is an adverse prognostic factor (Arch Pathol Lab Med 2019;143:439)
Perineural invasion is associated with poor disease specific survival (J Oral Pathol Med 2020;49:994)
Lymphovascular invasion may serve as a prognostic predictor of metastasis (Oral Surg Oral Med Oral Pathol Oral Radiol 2021;131:319)
Margin of < 1 mm is associated with increased risk of local recurrence (JAMA Otolaryngol Head Neck Surg 2017;143:1166)

Case reports

28 year old woman with asymptomatic tumor of the left mandibular gingiva and Fanconi anemia (Case Rep Dent 2021;2021:5571649)
63 year old man with pain and swelling on the right lower jaw (Head Neck Pathol 2021;15:1313)
66 year old woman with fungating ulcerative mass on the left lateral tongue (Head Neck Pathol 2017;11:552)
70 year old woman with ulcerated mass on the lateral border of the tongue (Head Neck Pathol 2018;12:580)

Treatment

Early staged lesions are often treated with surgery
Patients with early stage cancer may benefit from elective neck dissection (N Engl J Med 2015;373:521)
Moderate staged lesions are often treated with surgery, radiation therapy or chemotherapy
Patients with recurrent or metastatic head and neck cancer may benefit from immunotherapeutic agents (J Immunother Cancer 2019;7:184)

Clinical images

Contributed by Sarah Glass, D.D.S.

Exophytic mass lateral tongue

Ulceration ventrolateral tongue

Red-white maxillary gingiva

Gross description

Site of involvement, tumor laterality and operative procedure should be communicated from the surgeon (Arch Pathol Lab Med 2019;143:439)
Gross examination of a specimen may not entirely reflect microscopic tumor extent, as dysplasia, ulceration or inflammation may appear as tumor on macroscopic examination (Arch Pathol Lab Med 2019;143:439)
White infiltrating tumor on cross section

Gross images

Contributed by Kathleen Higgins, D.D.S., M.S., Stephen Roth, D.D.S. and Kathleen Schultz, D.M.D.

Glossectomy specimen

Glossectomy specimen cross section

Resection
lateral view

Resection superior view

Resection anterior view

Glossectomy specimen

Frozen section description

Frozen section analysis can be used to evaluate tumor diagnosis and margin status
- Results are highly specific but only moderately sensitive when compared with final margins (Laryngoscope 2000;110:1773)

Frozen section images

Contributed by Kathleen Higgins, D.D.S., M.S. and Kathleen Schultz, D.M.D.

Tumor with margins

Invasive carcinoma

Microscopic (histologic) description

Dysplastic stratified squamous epithelium that extends through the basement membrane and into the underlying fibrous connective tissue without attachment to the surface
Malignant epithelial cells show eosinophilic cytoplasm, hyperchromatic nuclei, pleomorphism, mitotic activity, individual cell keratinization and intercellular bridging
Superficial or microinvasion can be used to describe the earliest moment of invasion
Malignant epithelium can invade fibrous connective tissue in islands, cords or individual cells
Keratin pearls of round, eosinophilic, concentric layers of keratin can be seen and are associated with well differentiated tumors
3 histologic grades for conventional squamous cell carcinoma include well, moderately and poorly differentiated based on amount of keratinization, mitotic activity, cellular and nuclear pleomorphism, pattern of invasion and host response (Arch Pathol Lab Med 2019;143:439)
Histologic variants are listed below (Arch Pathol Lab Med 2019;143:439)
- Verrucous squamous cell carcinoma
- Papillary squamous cell carcinoma
  - Exophytic growth demonstrating multiple, thin keratinized papillary projections with fibrovascular cores or rounded, bulbous projections with nonkeratinized epithelium
  - Malignant epithelial cells show an increased N:C ratio, prominent nucleoli and mitotic figures
  - Obvious invasive components uncommon (Ann Diagn Pathol 2013;17:18)
- Spindle cell squamous cell carcinoma
  - Also called sarcomatoid
  - Monoclonal, evolving from conventional squamous carcinoma with dedifferentiation (Head Neck Pathol 2010;4:265)
  - Often polypoid configuration on biopsy; tumor may be ulcerated
  - Overlying epithelium may show carcinoma in situ or dysplasia with elongation and spindling of the basal epithelial cells
  - Nest of moderately or poorly differentiated conventional squamous cell carcinoma may be intricately mixed sarcomatoid component
  - High mitotic count with bizarre, atypical mitotic figures
  - Dense and eosinophilic cytoplasm
  - Cells can be arranged in various patterns with variable amount of intervening matrix, which can mimic mesenchymal malignancies
  - Metaplastic mesenchymal elements such as bone or cartilage not identified
- Carcinoma cuniculatum
  - Well differentiated squamous epithelium with minimal to no cytologic atypia
  - Unique deeply infiltrative, large sized, branching, keratin filled cavities, resembling rabbit burrows (Head Neck Pathol 2022;16:213)
  - Lymphocytic infiltrate surrounding epithelial tunnels and intraepithelial neutrophilic microabscesses
- Basaloid squamous cell carcinoma
  - Lobules, nests or cribriform patterns of small basaloid cells with peripheral palisading and a thick basement membrane
  - Cells have minimal cytoplasm, are moderately pleomorphic with hyperchromatic nuclei and often abruptly transition to squamous epithelium
  - Single cell necrosis and comedonecrosis are common; often contiguous with carcinoma in situ in surface epithelium
  - Frequent mitotic activity, stroma is often hyalinized or myxoid; variable pseudoglandular spaces resembling adenoid cystic carcinoma
  - Rarely has a spindle cell component (Arch Pathol Lab Med 1995;119:181)
- Acantholytic squamous cell carcinoma
  - Pseudoglandular structures, dyskeratotic cells and prominent acantholysis within tumor islands (Head Neck Pathol 2022;16:388)
- Adenosquamous cell carcinoma
  - Distinct squamous and glandular differentiation in close proximity with blending and intermixing
  - Typically presents as a superficial squamous cell carcinoma transitioning to a deeper adenocarcinoma (Head Neck Pathol 2018;12:576)
- Lymphoepithelial carcinoma
  - Undifferentiated squamous cell carcinoma associated with a prominent, nonneoplastic lymphoplasmacytic cell infiltrate (Head Neck Pathol 2020;14:1001)
  - Definitive squamous differentiation may be present but is usually limited, while a basaloid morphology can be identified (Head Neck Pathol 2012;6:445)
  - Epstein-Barr virus (EBV) associated
  - Morphologically indistinguishable from undifferentiated nasopharyngeal carcinoma (Head Neck Pathol 2020;14:1001)
Although more often seen in salivary gland neoplasms and odontogenic tumors, oral squamous cell carcinoma may rarely show clear cell change (Cureus 2022;14:e25057)
American Joint Committee on Cancer (AJCC) 8th edition is currently used for staging (see Staging - oral cavity)
College of American Pathologists (CAP) protocol including TNM (CAP: Protocol for the Examination of Specimens from Patients with Cancers of the Lip and Oral Cavity [Accessed 2 February 2024])
Data set elements: operative procedure, specimens submitted, tumor dimensions, histologic tumor type, histologic tumor grade, pattern of invasive front, bone invasion, perineural invasion, lymphovascular invasion, margin status, pathologic staging (Arch Pathol Lab Med 2019;143:439)

Microscopic (histologic) images

Contributed by Kathleen Higgins, D.D.S., M.S., Duane Schafer, D.D.S., M.S. and Sarah Glass, D.D.S.

Tumor with margins

Basement membrane breach

Keratin pearl

Muscle invasion

Individual cell keratinization

Impressive pleomorphism

Surrounding nerve

Scattered malignant cells

Basaloid variant

Adenosquamous variant

Verrucous carcinoma

Papillary variant

Acantholytic variant

Spindle variant

Cuniculatum variant

Cytokeratin positive

Cytology description

Cytology is not routinely recommended for evaluation of intraoral lesions suspicious for malignancy (J Am Dent Assoc 2017;148:712)
Fine needle aspiration can identify regional spread to cervical lymph nodes

Positive stains

Cytokeratin stains are positive: AE1 / AE3, CK5/6, p63, p40 (Arch Pathol Lab Med 2019;143:439)
- This can be helpful to support epithelial origin in poorly differentiated tumors

Negative stains

Pathologists should not routinely perform high risk HPV testing on patients with nonoropharyngeal primary head and neck tumors (Arch Pathol Lab Med 2018;142:559)

Molecular / cytogenetics description

Due to advances in targeted therapy, some centers are evaluating the mutational profiles of tumors (Nat Rev Dis Primers 2020;6:92)

Sample pathology report

Right lateral tongue, incisional biopsy:
- Squamous cell carcinoma, well differentiated (see comment)
- Comment: Tumor islands are present at all surgical margins. Depth of invasion is at least 3 mm. Perineural and lymphovascular invasion are identified.

Differential diagnosis

Pseudoepitheliomatous hyperplasia (Arch Otolaryngol Head Neck Surg 2003;129:127):
- Benign lesions in the oral cavity, such as granular cell tumor, may show pseudoepitheliomatous hyperplasia of the overlying squamous mucosa
- Granular cell tumors are S100 positive and occur on the dorsal tongue, an uncommon location for oral squamous cell carcinoma
Mucoepidermoid carcinoma:
- May be difficult to distinguish high grade mucoepidermoid carcinoma from squamous cell carcinoma, adenosquamous variant
- High grade tumors may show predominantly squamous and intermediate cells with infrequent mucous cells
Basaloid salivary gland tumors (Semin Diagn Pathol 2022;39:17):
- May be difficult to distinguish basaloid salivary gland tumors from squamous cell carcinoma, basaloid variant
- Basal / myoepithelial cell population can be evaluated with p40 / p63
Oral malignant melanoma:
- May be difficult to distinguish amelanotic melanoma from a poorly differentiated squamous cell carcinoma
- Positive melanocytic markers: S100, HMB45, MART1, SOX10
Epithelioid sarcoma (Ann Otol Rhinol Laryngol 2021;130:416):
- Epithelioid sarcoma may express epithelial markers but most importantly does not express INI1
Angiosarcoma (Head Face Med 2008;4:17):
- May be difficult to distinguish angiosarcoma from squamous cell carcinoma, acantholytic variant
- Expresses endothelial cell markers such as FLI1
Metastatic squamous cell carcinoma to the oral cavity:
- Metastases may involve the soft tissue or bone
- First manifestation of disease in 25 - 30% of patients (Head Neck Pathol 2022;16:802)
- Histopathology is variable
- Patient history can be helpful, especially the ability to compare histopathology of known primary with current specimen
- Overlying mucosa uninvolved with lack of overt surface dysplasia
Neuroepithelial structures, including the juxtaoral organ of Chievitz:
- Avoid misinterpretation as carcinoma showing neural invasion (Head Neck Pathol 2020;14:876)
- Located lingual to the mandible, buccal to the mandible and within the posterior tongue
- Smalls islands of squamoid epithelium in close association with small nerves or the taste buds
- Absence of keratinization, cytological atypia and mitotic activity

Additional references

WHO Classification of Tumours Editorial Board: Head and Neck Tumours, 5th Edition, 2024

Board review style question #1

A biopsy of a lesion from the lateral border of the tongue in a 63 year old man demonstrates the histopathology seen above. What is the diagnosis?

Epithelial dysplasia
Granular cell tumor
Mucoepidermoid carcinoma
Squamous cell carcinoma

Board review style answer #1

D. Squamous cell carcinoma. The histopathologic image shows well differentiated malignant squamous cells that have broken through the basement membrane and are invading the underlying connective tissue. Answer A is incorrect because the proliferation of abnormal squamous cells is not confined to the epithelium as seen in epithelial dysplasia. Answer B is incorrect because granular cells are not present in the connective tissue. Granular cell tumors may show pseudoepitheliomatous hyperplasia, which can be mistaken for squamous cell carcinoma. Answer C is incorrect because mucous cells and intermediate cells are not seen.

Comment Here

Reference: SCC-general

Board review style question #2

Which oral squamous cell carcinoma histologic variant is the most likely to show minimal to no cytologic atypia?

Adenosquamous cell carcinoma
Basaloid squamous cell carcinoma
Carcinoma cuniculatum
Spindle cell squamous cell carcinoma

Board review style answer #2

C. Carcinoma cuniculatum. This histologic variant shows minimal to no cytologic atypia. Architecturally, the tumor is described as resembling rabbit burrows. Answer B is incorrect because basaloid squamous cell carcinoma frequently demonstrates mitotic activity, pleomorphic nuclei and single cell necrosis. Answer D is incorrect because spindle cell squamous cell carcinoma frequently demonstrates bizarre, atypical mitotic figures. Answer A is incorrect because adenosquamous cell carcinoma typically displays classic features of both squamous cell carcinoma and adenocarcinoma.

Comment Here

Reference: SCC-general

Schwannoma

Smokeless tobacco keratosis

Table of Contents

Definition / general | Gross description | Microscopic (histologic) description | Differential diagnosis

Definition / general

Occurs in users of smokeless tobacco (snuff) or tobacco chewers
Severity related to length of exposure and tobacco brand
Reversible with cessation of use (Arch Pathol Lab Med 2004;128:e17)

Gross description

Filmy, gray-white opalescence at areas of contact with tobacco

Microscopic (histologic) description

Parakeratosis or hyperorthokeratosis with parakeratin spires ("chevrons"), acanthosis, mild chronic inflammation and PAS+ marked hyalin deposition resembling amyloid

Differential diagnosis

Hyalinosis cutis et mucosae:
- Deposition begins around vessels, eccrine glands and epithelial-stromal interface, then fills entire dermis of all oral mucosa, tongue, pharynx, larynx and vocal cords

Spongiotic gingival hyperplasia (pending)

[Pending]

Squamous papilloma

Table of Contents

Definition / general

Common, small, benign intraoral squamoproliferation
Most common papillary lesion of oral cavity

Essential features

Common, small (< 1.0 cm), benign intraoral squamoproliferation
Associated with HPV 6 and 11 in approximately 50% of cases
Commonly involves soft palate, tongue, lips, tonsils
Excisional biopsy curative with recurrences rare; no known association with oral or oropharyngeal squamous cell carcinoma
Squamous cell papilloma represents WHO 4th edition head and neck preferred nomenclature; however, in practice, squamous papilloma is commonly used

ICD coding

ICD-10:
- D10.0 - lip
- D10.1 - tongue
- D10.2 - floor of mouth
- D10.30 - unspecified part of mouth
- D10.39 - other, specified part of mouth

Epidemiology

Most frequently seen in third to fifth decades (Oral Surg Oral Med Oral Pathol 1980;49:419)
- Can occur at any age
No gender predilection

Sites

Soft palate / uvula, tongue, lips, gingiva most common intraoral sites (Semin Diagn Pathol 2015;32:3)
Also may occur in oropharynx, larynx

Etiology

Approximately 50% associated with HPV 6 and 11 (Eur Arch Otorhinolaryngol 2017;274:3477)
- Not associated with high risk HPV infection
Remaining cases may represent persistence of papillary epithelial architecture following viral clearance or may represent nonspecific epithelial alteration
No evidence of clonality

Clinical features

Majority < 1.0 cm in size and do not show persistent growth
In setting of immunosuppression, may be larger, multifocal, less obviously papillary, more aggressive clinically (J Oral Maxillofac Surg 2018;76:128)

Diagnosis

Frequently suspected clinically on basis of papillary appearance
Excisional biopsy necessary for diagnosis

Prognostic factors

Recurrence rate minimal and related to incomplete excision
Since mucosal HPV infections may persist for 1 - 2 years, patient may be at mildly elevated risk for additional squamous papillomas (Lancet 2013;382:877)
Dypslasia infrequently encountered in squamous papillomas; generally not considered premalignant condition
No known association with oral or oropharyngeal squamous cell carcinoma

Case reports

5 year old girl with recurrent palate papilloma (Niger J Clin Pract 2018;21:1674)
10 year old girl with hard palate mass (Int J Clin Pediatr Dent 2018;11:244)
14 year old boy with hard palate mass (Indian J Dent 2014;5:211)
21 year old man with uvula lesion causing sore throat (Malays Fam Physician 2019;14:74)
43 year old man with lesion causing airway obstruction during conscious sedation (Anesth Prog 2017;64:168)

Treatment

Excisional biopsy

Clinical images

Contributed by Ivan J. Stojanov, D.M.D., M.M.Sc.

Squamous papilloma of gingiva

Squamous papilloma of tongue

Squamous papilloma of soft palatal mucosa

Gross description

Papillary (cauliflower-like) and exophytic, tan-white lesion

Gross images

Images hosted on other servers:

Hard palate tumor

Microscopic (histologic) description

Papillary proliferation of stratified squamous epithelium with variable hyperkeratosis or parakeratosis (Oral Surg Oral Med Oral Pathol 1980;49:419)
- Hyperplasia and mitotic activity restricted to basal / parabasal layers
- Retention of cellular polarity and normal maturation in suprabasal layers
Papillary (finger-like) projections exhibit prominent fibrovascular cores
- Hyalinization at tips of cores may be seen occasionally
Often pedunculated but may be sessile
Koilocytes rare / absent
No endophytic component
Secondarily traumatized squamous papillomas may show spongiosis, leukocyte exocytosis and absence of surface keratinization
Dysplasia in squamous papilloma characterized by cytologic abnormalities typical for epithelial dysplasia

Microscopic (histologic) images

Contributed by Ivan J. Stojanov, D.M.D., M.M.Sc.

Pedunculated

Sessile

Irritated

Fibrovascular cores

Tangentially sectioned

Hyalinization

Irritated

Mitotic activity

With acanthosis

Molecular / cytogenetics description

HPV ISH not routinely performed for diagnosis

Sample pathology report

Right soft palate, mucosa, excision:
- Squamous papilloma

Differential diagnosis

Verruca vulgaris:
- Hyperkeratosis with marked hypergranulosis including large keratohyaline granules
- Axial inclination of rete ridges
- Rarely pedunculated and attached to underlying epithelium by narrow stalk
- Relatively uncommon in oral cavity
Condyloma acuminatum:
- More significant epithelial hyperplasia
- Bulbous rete ridges, blunted tips of individual papillae
- Koilocytes always seen
- Relatively uncommon in oral cavity and clinical correlation beneficial
Giant cell fibroma:
- Nodular proliferation of densely collagenous fibrovascular tissue
- Lage stellate and occasionally multinucleated fibroblasts present, particularly in superficial lamina propria
- Surface epithelium thinly keratinized and frequently papillary
- Rete ridges often elongated and occasionally anastamosing
Verrucous hyperplasia:
- Verrucous epithelial architecture with surface keratosis representing dysplastic phenotype
- Epithelial dysplasia may or may not be present
- Epithelium often atrophic but may be hyperplastic
- Hyperkeratosis / parakeratosis and verrucous architecture often sharply demarcated
- No true fibrovascular cores
- May or may not be seen in setting of proliferative (verrucous) leukoplakia
Verrucous carcinoma:
- Generally indolent histopathologic variant of squamous cell carcinoma
- Verrucous architecture with prominent hyperkeratosis / parakeratosis
- Endophytic growth pattern involving deep lamina propria or skeletal muscle in the absence of frank invasion
- Minimal to modest epithelial atypia / dysplasia
Focal epithelial hyperplasia (Heck disease):
- Often multifocal
- Epithelial hyperplasia with subtle to absent papillary features
- Mitosoid bodies characteristic: karyorrhectic cells with fragmented chromatin
Inflammatory papillary hyperplasia:
- Reactive condition exclusively seen in denture wearers or mouth breathers
- Generally presents as diffuse involvement of hard palatal mucosa
- Nodular / papillary proliferation of fibrovascular tissue
- Variable lymphoplasmacytic infiltrate
- Epithelium exhibits leukocyte exocytosis and spongiosis
- Pseudoepitheliomatous hyperplasia may be present

Board review style question #1

A 45 year old man presents with a subcentimeter lesion of the soft palatal mucosa, for which a representative image from the excisional biopsy is shown above. Which HPV types are associated with this condition?

2 and 4
6 and 11
13 and 32
16 and 18

Board review style answer #1

B. 6 and 11. This is a squamous cell papilloma.

Comment Here

Reference: Squamous cell papilloma

Board review style question #2

Which is the most common papillary lesion in the oral cavity?

Condyloma acuminatum
Squamous cell papilloma
Verruca vulgaris
Verrucous hyperplasia

Board review style answer #2

B. Squamous cell papilloma

Comment Here

Reference: Squamous cell papilloma

Stafne defect (pending)

[Pending]

Staging features

Table of Contents

Measurement of tumor metastasis

Cross sectional diameter of the largest lymph node metastasis (not the lymph node itself) is measured in the gross specimen at the time of macroscopic examination or if necessary, on the histologic slide at the time of microscopic examination (AJCC: Cancer Staging [Accessed 20 September 2018], CAP: Protocol for the Examination of Specimens From Patients With Cancers of the Pharynx [Accessed 20 September 2018])
Measurement of the metastatic focus in the lymph nodes is based on the largest metastatic deposit size, which may include matted or fused lymph nodes

Isolated tumor cells

Isolated tumor cells (ITCs) are single cells or small clusters of cells ≤ 0.2 mm in greatest dimension
While the generic recommendation is that lymph nodes with ITCs found by histologic examination, immunohistochemistry or nonmorphologic techniques (e.g. flow cytometry, DNA analysis, PCR amplification of a specific tumor marker), be classified as pN0 or pM0, evidence for the validity of this practice in head and neck squamous cell carcinoma and other histologic subtypes is lacking
In fact, rare studies relevant to head and neck sites indicate that isolated tumor cells may actually be a poor prognosticator in terms of local control

Extranodal extension

AJCC 8th edition introduces the use of extranodal extension (ENE) in subcategorizing the "N" category for metastatic cancer to neck nodes
Effect of ENE on prognosis in head and neck cancers is profound, except for those tumors associated with high risk HPV
Pathological ENE also must be clearly defined as extension of metastatic tumor (tumor present within the confines of the lymph node and extending through the lymph node capsule into the surrounding connective tissue, with or without associated stromal reaction)
Histopathologic designations for ENE are as follows (Amin: AJCC Cancer Staging Manual, 8th Edition, 2018):
- ENE_n (none)
- ENE_mi (microscopic ENE ≤ 2 mm)
- ENE_ma (ENE > 2 mm or gross ENE)
ENE_mi and ENE_ma are used to define pathological ENE nodal status
ENE_mi versus ENE_n will affect current nodal staging but data collection is recommended to allow standardization of data collection and future analysis (AJCC: Cancer Staging [Accessed 20 September 2018])
ENE does not appear to be as prognostically relevant for HPV mediated / p16+ and nasopharyngeal cancers
While it may be recorded, it is not required under AJCC 8th edition guidelines
However, ENE is still required for pN categorization of HPV unrelated (p16-) squamous cell carcinoma and hypopharyngeal carcinomas

TNM descriptors

By AJCC / UICC convention, the designation "T" refers to a primary tumor that has not been previously treated
"p" symbol refers to the pathologic classification of the TNM, as opposed to the clinical classification and based on clinical stage information supplemented / modified by operative findings and gross and microscopic evaluation of the resected specimens
pT entails a resection of the primary tumor or biopsy adequate to evaluate the highest pT category
pN entails removal of nodes adequate to validate lymph node metastasis and pM implies microscopic examination of distant lesions
Clinical classification (cTNM) is usually carried out by the referring physician before treatment during initial evaluation of the patient or when pathologic classification is not possible
Pathologic staging is usually performed after surgical resection of the primary tumor
Pathologic staging depends on pathologic documentation of the anatomic extent of disease, whether or not the primary tumor has been completely removed
If a biopsied tumor is not resected for any reason (e.g. when technically unfeasible) and if the highest T and N categories or the M1 category of the tumor can be confirmed microscopically, the criteria for pathologic classification and staging have been satisfied without total removal of the primary cancer

Staging terminology

Additional change in AJCC 8th edition is the elimination of the pT0 category for all oral cavity, skin, larynx, HPV- oropharynx, hypopharynx and sinus
- This change affects cases where a cervical lymph node has metastatic squamous cell carcinoma but no primary tumor is identified despite thorough history, examination and available imaging studies
- Assigning these cases to a specific head and neck site is not possible
- Previous editions of TNM staging included a pT0 category in each of these disease sites
- However, it is seldom used and if it is, the cancer could not be assigned to a stage group
- Therefore, for the 8th edition, the expert panel eliminated the pT0 category from the head and neck staging systems
Use of HPV+ or EBV+ pharyngeal "pT0" (AJCC: Cancer Staging [Accessed 20 September 2018], CAP: Protocol for the Examination of Specimens From Patients With Cancers of the Pharynx [Accessed 20 September 2018]):
- Risk of regional (cervical neck) nodal spread from cancers of the pharynx is high
- Majority of metastatic carcinomas to the cervical lymph nodes take origin from a head and neck primary carcinoma
- Most common histologic type of carcinoma to metastasize to cervical neck lymph nodes is squamous cell carcinoma
- Cervical nodal metastases may occur in the setting of an unknown primary carcinoma referred to as metastatic cervical carcinoma with an unknown primary
- As per AJCC 8th edition guidelines, 3 separate approaches are employed to stage patients who present with an occult primary tumor
- Primary T category is described as pT0 and the pN category is designated according to the respective anatomic site based on Epstein-Barr virus (EBV) and HPV status:
  1. Patients with EBV related cervical adenopathy use the pN classification of nasopharynx
  2. Patients with HPV mediated (positive) cervical adenopathy use the pN classification of HPV mediated / p16+ oropharyngeal cancer
  3. All other patients with EBV unrelated and HPV unrelated cervical adenopathy use the generic pN classification used for the other head and neck sites and for unknown primary

Additional TNM descriptors

For identification of special cases of TNM or pTNM classifications, the "m" suffix and "y" and "r" prefixes are used; although they do not affect the stage grouping, they indicate cases needing separate analysis
"m" suffix indicates the presence of multiple primary tumors in a single site and is recorded in parentheses: pT(m)NM
"y" prefix indicates those cases in which classification is performed during or following initial multimodality therapy (i.e. neoadjuvant chemotherapy, radiation therapy or both chemotherapy and radiation therapy)
cTNM or pTNM category is identified by a "y" prefix
- ycTNM or ypTNM categorizes the extent of tumor actually present at the time of that examination
- "y" categorization is not an estimate of tumor prior to multimodality therapy (i.e. before initiation of neoadjuvant therapy)
"r" prefix indicates a recurrent tumor when staged after a documented disease free interval and is identified by the "r" prefix: rTNM

Staging-mucosal melanoma

Table of Contents

Definition / general | Primary tumor (T) | Regional lymph nodes (N) | Distant metastasis (M) | Anatomic stage / prognostic groups

Definition / general

This staging is appropriate for all Head and Neck sites. It is still PENDING for the AJCC 8th Edition.

Primary tumor (T)

T3: mucosal disease
T4a: moderately advanced local disease - tumor involving deep soft tissue, cartilage, bone or overlying skin
T4b: very advanced local disease - tumor involving brain, dura, skull base, lower cranial nerves (IX, X, XI, XII), masticator space, carotid artery, prevertebral space or mediastinal structures

Regional lymph nodes (N)

NX: regional lymph nodes cannot be assessed
N0: no regional lymph node metastases
N1: regional lymph node metastases present

Distant metastasis (M)

M0: no distant metastasis
M1: distant metastasis

Anatomic stage / prognostic groups

III:	T3	N0	M0
IVA:	T4a	N0	M0	or	T3 - 4a	N1	M0
IVB:	T4b	any N	M0
IVC:	any T	any N	M1

Staging-oral cavity

Table of Contents

Definition / general

Staging of definitive resections for carcinoma (squamous cell carcinoma, neuroendocrine carcinoma and minor salivary gland carcinoma) of the oral cavity should use this system (AJCC: Cancer Staging [Accessed 21 September 2018], CAP: Protocol for the Examination of Specimens from Patients with Cancers of the Lip and Oral Cavity [Accessed 29 December 2020])
Oral cavity extends from the portion of the lip that contacts the opposed lip (wet mucosa) to the junction of the hard and soft palate above to the line of circumvallate papillae below and to the anterior tonsillar pillars laterally (AJCC: Cancer Staging [Accessed 21 September 2018], CAP: Protocol for the Examination of Specimens from Patients with Cancers of the Lip and Oral Cavity [Accessed 29 December 2020])
Staging system name "oral cavity" reflects the focus on all of oral cavity, which includes mucosa of lip but not the external (dry) lip
- External lip, including the dry vermillion border, has a more similar embryologic origin to skin and its etiology, which is based on ultraviolet exposure (AJCC: Cancer Staging [Accessed 21 September 2018], CAP: Protocol for the Examination of Specimens from Patients with Cancers of the Lip and Oral Cavity [Accessed 29 December 2020])
Staging protocols, such as those of CAP, are to document procedure, tumor site, tumor laterality, tumor focality, tumor size, histologic type, histologic grade where applicable, margin status, lymphovascular invasion, perineural invasion, regional lymph node findings and summarize these pathologic findings using TNM system (CAP: Protocol for the Examination of Specimens from Patients with Cancers of the Lip and Oral Cavity [Accessed 29 December 2020])
See also Head and neck staging features

Essential features

AJCC 7th edition staging was sunset on December 31, 2017; as of January 1, 2018, use of the 8th edition is mandatory
2 key significant alterations in the 8th edition for lip and oral cavity are the incorporation of depth of invasion (DOI) into T stage and extranodal extension (ENE) into N stage
- In essence, DOI increases the T category by 1 for each 5 mm of tumor depth (until ≥ 10 mm)
- Similarly, pathologic ENE+ will increase the nodal category by 1 (AJCC: Cancer Staging [Accessed 21 September 2018], CAP: Protocol for the Examination of Specimens from Patients with Cancers of the Lip and Oral Cavity [Accessed 29 December 2020])
Use of the CAP protocol is not required for recurrent tumors or for metastatic tumors that are resected at a different time than the primary tumor
- Use of this protocol is also not required for pathology reviews performed at a second institution (i.e. secondary consultation, second opinion or review of outside case at second institution) (CAP: Protocol for the Examination of Specimens from Patients with Cancers of the Lip and Oral Cavity [Accessed 29 December 2020])
Carcinomas of minor salivary glands of the upper aerodigestive tract site, including the oral cavity, are staged according to schemes corresponding to the anatomic site of occurrence
- There is no currently accepted staging for central (primary intraosseous) salivary gland tumors (CAP: Protocol for the Examination of Specimens from Patients with Cancers of the Lip and Oral Cavity [Accessed 29 December 2020])
Reporting of surgical margins for carcinomas of the minor salivary glands should follow those used for squamous cell carcinoma of oral cavity (CAP: Protocol for the Examination of Specimens from Patients with Cancers of the Lip and Oral Cavity [Accessed 29 December 2020])
CAP oral cavity staging protocol: CAP: Protocol for the Examination of Specimens from Patients with Cancers of the Lip and Oral Cavity [Accessed 29 December 2020]
Alternatively for providers practicing in different geographic regions, there may be interest in the International Collaboration on Cancer Reporting (ICCR) guidelines: ICCR: Carcinomas of the Oral Cavity (TNM8) [Accessed 29 December 2020]

Terminology

Anatomic boundaries and primary site(s): the oral cavity extends from the portion of the lip that contacts the opposed lip (wet mucosa) to the junction of the hard and soft palate above, to the line of circumvallate papillae below and to the anterior tonsillar pillars laterally; it is additionally divided into multiple specific sites listed below (AJCC: Cancer Staging [Accessed 21 September 2018], CAP: Protocol for the Examination of Specimens from Patients with Cancers of the Lip and Oral Cavity [Accessed 29 December 2020], see figure 1 in Diagrams / tables)
- Mucosal lip:
  - Begins at the junction of the wet and dry mucosa of the lip (the anterior border of the portion of the lip that comes into contact with the opposed lip) and extends posteriorly into the oral cavity to the attached gingiva of the alveolar ridge
  - Dry vermilion lip and vermilion border are staged using the chapter on cutaneous carcinoma of the head and neck; this is a change from past AJCC editions where the dry vermilion was included in the lip and oral cavity chapter
- Buccal mucosa:
  - Includes all the mucous membrane lining of the inner surface of the cheeks and lips from the line of contact of the opposing lips to the line of attachment of mucosa of the alveolar ridge (upper and lower) and pterygomandibular raphe
- Lower alveolar ridge:
  - Refers to the mucosa overlying the alveolar process of the mandible, which extends from the line of attachment of mucosa in the lower gingivobuccal sulcus to the line of attachment of free mucosa of the floor of the mouth
  - Posteriorly, it extends to the ascending ramus of the mandible
- Upper alveolar ridge:
  - Refers to the mucosa overlying the alveolar process of the maxilla, which extends from the line of attachment of mucosa in the upper gingivobuccal sulcus to the junction of the hard palate
  - Its posterior margin is the upper end of the pterygopalatine arch
- Retromolar gingiva (retromolar trigone):
  - Attached mucosa overlying the ascending ramus of the mandible from the level of the posterior surface of the last lower molar tooth to the apex superiorly, adjacent to the tuberosity of the maxilla
- Floor of the mouth:
  - Crescentic surface overlying the mylohyoid and hyoglossus muscles, extending from the inner surface of the lower alveolar ridge to the undersurface of the tongue
  - Its posterior boundary is the base of the anterior pillar of the tonsil
  - It is divided into 2 sides by the frenulum of the tongue and harbors the ostia of the submandibular and sublingual salivary glands
- Hard palate:
  - Semilunar area between the upper alveolar ridge and the mucous membrane covering the palatine process of the maxillary palatine bones
  - It extends from the inner surface of the superior alveolar ridge to the posterior edge of the palatine bone
- Anterior two - thirds of the tongue (oral tongue):
  - Freely mobile portion of the tongue that extends anteriorly from the line of circumvallate papillae to the undersurface of the tongue at the junction with the floor of the mouth
  - It is composed of 4 areas: the tip, the lateral borders, the dorsum and the undersurface (nonvillous ventral surface of the tongue)
  - Undersurface of the tongue is considered a separate category by the World Health Organization (WHO)
Tumor thickness (TT) versus depth of invasion (DOI) (AJCC: Cancer Staging [Accessed 21 September 2018], CAP: Protocol for the Examination of Specimens from Patients with Cancers of the Lip and Oral Cavity [Accessed 29 December 2020]):
- Tumor thickness is usually measured from the mucosal surface of the tumor to the deepest point of tissue invasion in a perpendicular fashion with a measuring instrument
- DOI is measured from the basement membrane of an adjacent normal to the deepest point of invasion of the tumor
  - DOI assesses the invasiveness of a carcinoma, regardless of any exophytic component
  - It is measured by first finding the "horizon" of the basement membrane of the adjacent squamous mucosa
  - Perpendicular "plumb line" is established from this horizon to the deepest point of tumor invasion, which represents DOI
  - DOI is recorded in millimeters
- See figures 2A and 2B in Microscopic (histologic) images
- Extrinsic tongue muscle (ETM) invasion (AJCC: Cancer Staging [Accessed 21 September 2018], CAP: Protocol for the Examination of Specimens from Patients with Cancers of the Lip and Oral Cavity [Accessed 29 December 2020]):
  - No longer used as a component of pT4 staging because this is a feature of DOI
  - No longer a staging criterion for T4 designation in oral cavity because depth of invasion supersedes it and extrinsic muscle invasion is difficult to assess (both clinically and pathologically)
Surgical margins (AJCC: Cancer Staging [Accessed 21 September 2018], CAP: Protocol for the Examination of Specimens from Patients with Cancers of the Lip and Oral Cavity [Accessed 29 December 2020]):
- Definition of a positive margin is somewhat controversial given the varied results from prior studies
- However, overall, several studies support the definition of a positive margin to be invasive carcinoma or carcinoma in situ / high grade dysplasia present at margins (microscopic cut through of tumor)
- Furthermore, reporting of surgical margins should also include information regarding the distance of invasive carcinoma, carcinoma in situ or high grade dysplasia (moderate to severe) from the surgical margin
Tumor bed versus specimen margins:
- Regarding what actually represents the relevant margin status, it becomes increasingly clear that margins obtained from the main resection specimen are of more reliable prognostic value
  - Clinical value of tumor bed margins (i.e. margins taken separately) is often undermined by their uncertain origin with respect to the main resection, infrequent orientation as to the new margin surface and fragmentation
  - Nonetheless, tumor bed margin status is still utilized in various practice settings for patient management
  - However, the challenge for pathologists is to arrive at a "final" margin status, integrating both tumor bed and specimen margin status
  - As it is in multipart resections, the pathologist's ability to confidently establish the relationship between the main resected specimen and additional, separately submitted parts and to assess the adequacy of excision is compromised
- To optimize reporting, both specimen margin and tumor bed margin status should thus be reported separately
  - "Final" margin status then becomes a multidisciplinary integration of these findings
  - For instance, in cases with differing margin statuses (i.e. resection specimen margin positive, corresponding tumor bed margin negative), the small size and lack of orientation of the tumor bed margin may preclude a reliable conversion to final negative margin
  - Conversely, in some cases the tumor bed specimen (e.g. revision of margin) may be a reliable indicator of a true final margin
  - This is a judgment call that requires close interaction between the surgeon and pathologist but generally, the following basic requirements are met:
    1. Tumor bed margins are quite large (i.e. thick enough to be readily processed as radial margins and large enough to match the corresponding aspect of the main specimen margin)
    2. Are oriented as to the new true margin surface (by ink or stitch)
    3. Physical relationship between the main resection specimen and additional tumor bed margins is confirmed by pathologist and surgeon (usually through unequivocal labeling and even fitting the tumor bed margin to the main specimen)
  - In such a case, the tumor bed margin could be considered a final margin
Worst pattern of invasion (WPOI) (AJCC: Cancer Staging [Accessed 21 September 2018], CAP: Protocol for the Examination of Specimens from Patients with Cancers of the Lip and Oral Cavity [Accessed 29 December 2020]):
- Validated outcome predictor for oral cavity squamous carcinoma patients in multivariate analysis
- To simplify prognostication and enhance adaptation, the only cutpoint recommended for assessment is whether or not WPOI-5 is present
- WPOI-5 is defined as tumor dispersion of ≥ 1 mm between tumor satellites
- Tumor dispersion is assessed at the advancing tumor edge
- To some, WPOI can be viewed as redundant and only optional for reporting purposes, as extratumoral perineural invasion or extratumoral lymphovascular invasion also count as WPOI-5

ICD coding

C00.3: Mucosa of upper lip
C00.4: Mucosa of lower lip
C00.5: Mucosa of lip, NOS
C00.8: Overlapping lesion of lip
C00.9: Lip, NOS
C02.0: Dorsal surface of tongue, NOS
C02.1: Border of tongue
C02.2: Ventral surface of tongue, NOS
C02.3: Anterior 2/3 of tongue, NOS
C02.8: Overlapping lesion of tongue
C02.9: Tongue, NOS
C03.0: Upper gum
C03.1: Lower gum
C03.9: Gum, NOS
C04.0: Anterior floor of mouth
C04.1: Lateral floor of mouth
C04.8: Overlapping lesion of floor of mouth
C04.9: Floor of mouth, NOS
C05.0: Hard palate
C05.8: Overlapping lesion of palate
C05.9: Palate, NOS
C06.0: Cheek mucosa
C06.1: Vestibule of mouth
C06.2: Retromolar area
C06.8: Overlapping lesion of other and unspecified parts of mouth
C06.9: Mouth, NOS

Primary tumor (pT)

TX: Primary tumor cannot be assessed
Tis: Carcinoma in situ
T1: Tumor ≤ 2 cm with depth of invasion (DOI)* ≤ 5 mm
T2: Tumor ≤ 2 cm with DOI* > 5 mm and ≤ 10 mm or tumor > 2 cm and ≤ 4 cm with DOI* ≤ 10 mm
T3: Tumor > 2 cm and ≤ 4 cm with DOI* > 10 mm or tumor > 4 cm with DOI* ≤ 10 mm or any tumor
T4: Moderately advanced or very advanced local disease
- T4a: Moderately advanced disease
  - Tumor > 4 cm with DOI* > 10 mm or
  - Tumor invades adjacent structures only (e.g. through cortical bone of the mandible or maxilla or involves the maxillary sinus or skin of the face)
- T4b: Very advanced disease
  - Tumor invades masticator space, pterygoid plates or skull base or encases the internal carotid artery

Notes:

*DOI is depth of invasion and not tumor thickness, see above Terminology section for definition
Superficial erosion of bone / tooth socket alone by a gingival primary is not sufficient to classify a tumor as T4

Pathological regional lymph nodes (pN)

NX: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastasis
N1: Metastasis in a single ipsilateral lymph node, ≤ 3 cm in greatest dimension and extranodal extension (ENE)-
N2: Metastasis in a single ipsilateral lymph node, ≤ 3 cm in greatest dimension and ENE+ or > 3 cm but ≤ 6 cm in greatest dimension and ENE-; or metastases in multiple ipsilateral lymph nodes, none > 6 cm in greatest dimension and ENE-; or in bilateral or contralateral lymph nodes(s), none > 6 cm in greatest dimension and ENE-
- N2a: Metastasis in either
  - Single ipsilateral lymph node that is ≤ 3 cm and ENE+ or
  - Single ipsilateral lymph node that is > 3 cm but ≤ 6 cm in greatest dimension and ENE-
- N2b: Metastasis in multiple ipsilateral lymph nodes, none > 6 cm in greatest dimension and ENE-
- N2c: Metastasis in bilateral or contralateral lymph node(s), none > 6 cm in greatest dimension and ENE-
N3: Metastasis in a lymph node > 6 cm in greatest dimension and ENE-; or in a single ipsilateral node > 3 cm in greatest dimension and ENE+; or multiple ipsilateral, contralateral or bilateral nodes, any with ENE+; or a single contralateral node of any size and ENE+
- N3a: Metastasis in a lymph node that is > 6 cm in greatest dimension and ENE-
- N3b: Metastasis in either
  - Single ipsilateral lymph node, > 3 cm and ENE+ or
  - Multiple ipsilateral, contralateral or bilateral lymph nodes, any with ENE+ or
  - Single contralateral lymph node of any size and ENE+

Notes:

Designation of "U" or "L" may be used for any N category to indicate metastasis above the lower border of the cricoid (U) or below the lower border of the cricoid (L)
Per AJCC 8th edition, for pN, a selective neck dissection ordinarly will include 10+ lymph nodes and a comprehensive neck dissection (radical or modified radical neck dissection) ordinarily will include 15+ lymph nodes
Negative pathologic examination of a smaller number of nodes still mandates a pN0 designation
Midline nodes are considered ipsilateral nodes

Distant metastasis (M)

M0: No distant metastasis
M1: Distant metastasis

Notes:

Metastasis found on imaging is considered cM1
Biopsy proven metastasis is considered pM1

AJCC prognostic stage grouping for oral cavity

Stage 0:	Tis	N0	M0
Stage I:	T1	N0	M0
Stage II:	T2	N0	M0
Stage III:	T3	N0	M0
	T1 - 3	N1	M0
Stage IVA:	T4a	N0 - 1	M0
	T1 - 4a	N2	M0
Stage IVB:	Any T	N3	M0
	T4b	Any N	M0
Stage IVC:	Any T	Any N	M1

Registry data collection variables

Extranodal extension (ENE) clinical (present versus absent)
ENE pathological (present versus absent)
Extent of microscopic ENE (distance of extension from the native lymph node capsule to the farthest point of invasion in extranodal tissue)
Perineural invasion
Lymphovascular invasion
p16 / HPV status
Performance status
Tobacco use and pack year
Alcohol use
Depression diagnosis
Depth of invasion (mm)
Margin status (grossly involved, microscopic involvement)
Distance of tumor (or moderate / severe dysplasia) from closest margin
Distance of moderate / severe dysplasia from closest margin
Worst pattern of invasion - 5

Histologic grade

Gx: Cannot be assessed
G1: Well differentiated
G2: Moderately differentiated
G3: Poorly differentiated

Notes:

For histologic types of carcinomas that are amenable to grading, 3 histologic grades are suggested, as shown below (AJCC: Cancer Staging [Accessed 21 September 2018], CAP: Protocol for the Examination of Specimens from Patients with Cancers of the Lip and Oral Cavity [Accessed 29 December 2020])
- For conventional squamous cell carcinoma, histologic grading as a whole does not perform well as a prognosticator
- Nonetheless, it should be recorded when applicable, as it is a basic tumor characteristic
- Selecting either the most prevalent grade or the highest grade for this synoptic protocol is acceptable
- Variants of squamous cell carcinoma (i.e. verrucous, basaloid, etc.) have an intrinsic biologic potential and currently do not appear to require grading
Histologic (microscopic) grading of salivary gland carcinomas has been shown to be an independent predictor of behavior and plays a role in optimizing therapy
- However, most salivary gland carcinoma types have an intrinsic biologic behavior and attempted application of a universal grading scheme is merely a crude surrogate
- Thus a generic grading scheme is no longer recommended for salivary gland carcinomas
- Carcinoma types for which grading systems exist and are relevant are incorporated into histologic type
- 3 major categories that are amenable to grading include adenoid cystic carcinoma, mucoepidermoid carcinoma and adenocarcinoma, not otherwise specified
In some carcinomas, histologic grading may be based on growth pattern, such as in adenoid cystic carcinoma, for which a histologic high grade variant has been recognized based on the percentage of solid growth
- Those adenoid cystic carcinomas showing ≥ 30% of solid growth pattern are considered to be histologically high grade carcinomas
- Histologic grading of mucoepidermoid carcinoma includes a combination of growth pattern characteristics (e.g. cystic, solid, neurotropism) and cytomorphologic findings (e.g. anaplasia, mitoses, necrosis)
- Adenocarcinomas, not otherwise specified do not have a formalized grading scheme and are graded intuitively based on cytomorphologic features

Histopathologic type

Carcinoma of the oral cavity
- Squamous cell carcinoma (conventional)
- Verrucous squamous cell carcinoma
- Papillary squamous cell carcinoma
- Spindle cell squamous cell carcinoma
- Acantholytic squamous cell carcinoma
- Lymphoepithelial carcinoma
- Basaloid squamous carcinoma
- Adenosquamous carcinoma
- Carcinoma cuniculatum
Carcinoma of minor salivary gland
- Acinic cell
- Adenoid cystic
- Adenocarcinoma, NOS
- Basal cell adenocarcinoma
- Carcinoma ex pleomorphic adenoma
- Carcinoma type cannot be determined
- Carcinosarcoma
- Clear cell adenocarcinoma
- Cystadenocarcinoma
- Epithelial myoepithelial carcinoma
- Mammary analogue secretory carcinoma
- Mucoepidermoid carcinoma
- Mucinous carcinoma
- Myoepithelial carcinoma
- Oncocytic carcinoma
- Polymorphous adenocarcinoma
- Salivary duct carcinoma
Neuroendocrine carcinoma
- Well differentiated neuroendocrine carcinoma (typical carcinoid tumor)
- Moderately differentiated neuroendocrine carcinoma (atypical carcinoid tumor)
- Poorly differentiated neuroendocrine carcinoma, small cell type
- Poorly differentiated neuroendocrine carcinoma, large cell type
- Combined (or composite) neuroendocrine carcinoma (specify types)
Carcinoma type cannot be determined
Mucosal melanoma

Diagrams / tables

Images hosted on other servers:

Figure 1

Microscopic (histologic) images

Images hosted on other servers:

Figure 2A

Figure 2B

Board review style question #1

A 2.4 cm primary gingival carcinoma was resected in continuity with the underlying posterior mandible. Which of the T category criteria in the 8th edition AJCC staging guide is satisfied by the examination of the microscopic sections above?

T1 by depth of invasion
T2 by depth of invasion
T3 by mandibular medullary bone invasion
T4 by mandibular medullary bone invasion

Board review style answer #1

D. T4 by mandibular medullary bone invasion

Comment Here

Reference: Pathologic TNM staging of lip & oral cavity, AJCC 8th edition

Staging-oropharynx & hypopharynx

Table of Contents

Nonneoplastic lesions	ICD-O	ICD-11
Necrotizing sialometaplasia		DA04
Multifocal epithelial hyperplasia		1E82.0
Oral melanoacanthoma		2E90.3
Epithelial tumors
Papillomas
Squamous papilloma	8052/0	2E90.3 & XH50T2
Oral potentially malignant disorders and oral epithelial dysplasia
Oral epithelial dysplasia	8077/0, 8077/2
Proliferative verrucous leukoplakia		DA01.00
Submucous fibrosis		DA02.2
HPV associated oral epithelial dysplasia
Squamous cell carcinomas
Oral squamous cell carcinoma	8071/3	2B6E.0
Verrucous carcinoma of the oral cavity and mobile tongue	8051/3	2B66.0 & XH5PM0
Carcinoma cuniculatum	8071/3	2B6E.0
Tumors of uncertain histogenesis
Congenital granular cell epulis		KC23
Granular cell tumor	9580/0, 9580/3	2E90.1
Ectomesenchymal chondromyxoid tumor	8982/0
Melanotic neuroectodermal tumor of infancy	9363/0	2D42 & XH6C72
Hematolymphoid proliferations and neoplasia
Burkitt lymphoma
EBV positive mucocutaneous ulcer
Extranodal marginal zone lymphoma of mucosa associated lymphoid tissue
Myeloid sarcoma
Plasmablastic lymphoma
Primary mucosal CD30 positive T cell lymphoproliferative disorder

Benign oropharyngeal lesions	ICD-O	ICD-11
Hamartomatous polyps		DB35.3
Epithelial tumors
Squamous cell carcinoma, HPV associated	8085/3	2B6A.0 & XH0EJ7
Squamous cell carcinoma, HPV independent	8086/3	2B6A.0 & XA4J67 & XH4CR9

Stage I:	T0 - 2	N0 - 1	M0
Stage II:	T0 - 2	N2	M0
	T3 - 4	N0 - 1	M0
Stage III:	T3 - 4	N2	M0
Stage IV:	Any T	Any N	M1