Oral cancer differential diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:  Omodamola Aje B.Sc, M.D. [2]; Grammar Reviewer: Natalie Harpenau, B.S.[3]

## Overview

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There are different types of cancers of the oral cavity and oropharynx. It is important that they are differentiated from one another.

## Oral cancer differential diagnosis

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The table below outlines the different types of tumors/cancers present in the oral cavity and oropharynx and how they can be differentiated from one another.

Type of cancer  | Subtype  | ICD-O Code  | Epidemiology  | Etiology  | Localization  | Clinical features  | Diagnostic procedures

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Squamous cell carcinoma

* Basaloid squamous cell carcinoma
* Papillary squamous cell carcinoma
* Spindle cell carcinoma
* Acantholytic squamous cell carcinoma
* Acantholytic squamous cell carcinoma
* Adenosquamous carcinoma

| Verrucous carcinoma | 8051/3  |

* Older males
* 5th and 6th decades of life
* Males are affected more often than females

* Tobacco smoking and alcohol
* Chronic smokeless tobacco
* HPV 16 and 18

* Lip SCC arise almost exclusively on the lower lip
* Buccal mucosa
* Upper and lower gingiva

* Hard palate
* Anterior two-thirds of the tongue, including dorsal, ventral and lateral surfaces, and the floor of mouth

* Often asymptomatic or may present with vague symptoms and minimal physical finding

| Biopsy shows:

Thickened club-shaped

papillae and blunt stromal invaginations

of well-differentiated squamous epithelium with marked keratinization

Lymphoepithelial carcinoma |  | 8082/3  | 0.8-2% of all oral or oropharyngeal cancers  | EBV |

* Tonsil and tongue(90%)
* Palate and buccal mucosa (others)

* Intraoral mass, which may be ulcerated.

* Some tumors can be bilateral

| Biopsy chows:

* Syncytial sheets and clusters of carcinoma cells with vesicular nuclei

* Prominent nucleoli and ill-defined cell borders
* A rich lymphoplasmacytic infiltrate is present

Epithelial precursor lesions  | \
  | \
  | \
  | Smoking | Seen in the entire digestive tract |

* White patches (leukoplakia)
* Red patches (erythroplasia/erythroplakia)
* Mixed red and white lesions

| Biopsy shows:

* Hyperplasia
* Dysplasia / squamous intraepithelial neoplasia / atypical hyperplasia
* Carcinoma in-situ

Proliferative verrucous leukoplakia and precancerous conditions | \
  | \
  |

* Average age at diagnosis is 62 years
* Women are more commonly affected (ratio, 4:1)

| Unknown  |

* Buccal mucosa in women
* Tongue in men.

| An aggressive form of oral leukoplakia with considerable morbidity and strong predilection to malignant transformation | Biopsy shows:

* Extensive, thick, white plaques
* Hyperplasia and dense hyperkeratosis
* Verrucous surface with hyperkeratosis, hypergranulosis and a dense inflammatory infiltrate in the corium

Papillomas | Squamous cell papilloma and

verruca vulgaris

|  |

* Common in children and in adults in the 3rd to 5th decades

* Almost equal sex incidence with a slight male predominance

| HPV sub-types

2, 4, 6, 7,10, and 40

| Any oral site may be affected mostly:

* Hard and soft palate

* Labial mucosa
* Tongue
* Gingiva

| Soft, pedunculated lesions formed by a cluster of finger-like fronds or a sessile, dome-shaped lesion with a nodular, papillary or verrucous surface  | Biopsy shows:

* Exophytic and comprise folds of hyperplastic stratified epithelium
* Cluster of finger-like projections

Condyloma acuminatum |  | 2nd and 5th decade with a peak in teenagers and young adults  |

* HPV\- most common sub-types: 6, 11, 16 and 18

* Labial mucosa
* Tongue
* Palate

* Painless, rounded, dome-shaped exophytic nodules

* 15 mm in diameter

* Have a broad base and a nodular or mulberry-like surface that is slightly red, pink or of normal mucosal color.

* Lesions may be multiple and are then usually clustered

| Biopsy shows:

Several sessile, cauliflower-like swellings forming a cluster

Focal epithelial hyperplasia | \
  | Disease of children, adolescents and young adults  | HPV sub types:

13 and 32

* All areas of the oral cavity
* Labia
* Buccal mucosa
* Tongue

* Multiple asymptomatic lesions

* Soft rounded or flat plaque-like sessile swelling.
* Usually pink or white in color
* 2-10 mm in diameter

| Biopsy shows:

* Rounded sessile swelling formed by a sharply demarcated zone of epithelial acanthosis

* Koilocytes similar to those of squamous papilloma are usually present

* “Mitosoid bodies”, which are nuclei with coarse clumped heterochromatin resembling a mitotic figure

Granular cell tumor | \
  | 9580/0  |

* Arise in all age groups, with a peak between 40 and 60 years
* Females are affected more often than males with an M/F ratio of 2:1

| No etiological factors are known  |

* Tongue is the most common single site
* Buccal mucosa
* Floor of oral cavity
* Palate
* Salivary gland

* Lesion presents as a smooth, sessile mucosal swelling
* 1-2 cm in diameter with a firm texture

* The overlying epithelium is of normal color or may be slightly pale

| Biopsy shows:

* Plump eosinophilic cells with central small dark nuclei and abundant granular cytoplasm

Keratoacanthoma | \
  | 8071/1  |

* Occurs more often in

whites

* Twice as frequent in

men as in women

| Associated with uptake of carcinogens (e.g. via particular smoking habits)  |

* Skin of the face, including the lips
* Mucocutaneous linings may also be involved

* Verrucous, speckled or ulcerated lesions

* Deep projections, which extend through minor salivary glands and underlying bone

| Biopsy shows:

* Verrucous surface, keratinized clefts and penetrating squamous rete processes
* Minimal atypia seen

Papillary hyperplasia | \
  | \
  | Affects all age groups  | Associated with:

* Wearing ill-fitting dentures
* Xerostomia
* Individuals with a high-arched palate
* HIV infection

| Palate | Asymptomatic nodular or papillary mucosal lesion | Biopsy shows:

* Parakeratinisation or less frequently orthokeratinisation

Median rhomboid glossitis  | \
  | \
  | \
  | Associated with chronic candidal infection | Dorsum of the tongue at the junction of the anterior two-thirds

and posterior third

| Forms a patch of papillary atrophy in the region of the

embryological foramen caecum

| Biopsy shows:

* Psoriasiform hyperplasia

* Areas of pseudoepitheliomatous hyperplasia
* Atypia may be present

Salivary gland tumors | Acinic cell carcinoma | 8550/3  |

* 2-6.5% of all intra-oral salivary gland tumors
* Age range from 11-77 years, with a mean of 45 years
* Male to female ratio of 1.5:1

| Unknown  |

* Buccal mucosa
* Upper lip
* Palate

| Tumors usually

form non-descript swellings

| Biopsy shows:

* Solid sheets of epithelium with secretory material
* Ductal differentiation in tumors

Mucoepidermoid carcinoma | 8430/3  |

* 9.5-23% of all minor gland tumors

| Unknown  |

* Palate (most common site)
* Buccal mucosa
* Lips: upper>lower
* Floor of oral cavity
* Retromolar pad

* Asymptomatic
* Bluish, domed swellings that resemble mucoceles or haemangiomas
* High-grade tumors result in ulceration, loosening of teeth, paraesthesia or anaesthesia

| Low power microscopy shows low-grade tumor with both cystic and solid areas and an inflamed, fibrous stroma
Adenoid cystic carcinoma  | 8200/3  |

* 42.5% of minor gland tumors

| Unknown  |

* Tongue
* Tonsil
* Oropharynx
* Cheek
* Lips
* Retromolar pad and gingiva

* Slow growing sub-mucosal masses and ulceration may be seen, particularly in the palate
* Pain, or evidence of nerve involvement, is usually only present in advanced tumors

Predominantly solid variant shows peri- and intraneural invasion

Epithelial-myoepithelial

carcinoma

| 8562/3  | \
  | Unknown  | \
  | \
  | \

Clear cell carcinoma,

NOS

| 8310/3  |  | Unknown  | \
  | \
  | \

Basal cell

adenocarcinoma

| 8147/3  | Rare in minor glands  | Unknown  |

* Palate
* Buccal mucosa
* Lip

| Asymptomatic, smooth or lobulated sub-mucosal masses | Microscopically similar to basal cell adenocarcinomas of the major gland
Cystadenocarcinoma | 8450/3  | 32% developed in the minor glands  | Unknown  |

* Palate
* Lips
* Buccal mucosa
* Tongue and retromolar regions

| Slow growing and painless but somepalatal tumors may erode the underlying bone-causing sinonasal complex  | \

Salivary duct carcinoma  | 8500/3  |

* Rare in minor salivary glands
* Age range is 23-80 years (mean is 56 years)

| Unknown  |

* Palate (65%)
* Buccal mucosa and vestibule (19%)

* Tongue (8%)
* Retromolar pad (4%) and upper lip (4%)

| Tumors form painless swellings but many in the palate can be painful and ulcerated or fungated withmetastases to regional lymph nodes | The range of

microscopical appearances is similar

to that seen in the major glands

Salivary gland adenomas | Pleomorphic adenoma | 8940/0  | 40-70% of minor gland tumors  | Unknown  |

* Palate
* Lips
* Buccal mucosa

| Painless, slow-growing, submucosal masses, but when traumatized may bleed or ulcerate | Biopsy shows cellular, and hyaline or plasmacytoid cell
Myoepithelioma  | 8982/0  | 42% of minor gland tumors  | Unknown  |

* Palate of younger individuals

| \
  | \

Basal cell adenoma  | 8147/0  | 20% of minor gland tumors  | Unknown  |

* Upper lip
* Buccal mucosa

| \
  | They are histologically

similar to those in major glands.

Cystadenoma | 8149/0  | 7% of benign minor gland tumors  | Uknown  |

* Lips
* Cheek
* Palate

| \
  | \

Kaposi sarcoma | \
  | \
  |

* Classic (elderly men of Mediterranean/East European descent)
* Endemic (middle-aged adults and children in Equatorial Africa, who are not HIV infected)
* Iatrogenic (Immunosuppressed, post-transplant)
* AIDS-associated (HIV-1 infected individuals)

* HHV-8
* Immunologic, genetic, and environmental factors

* Skin (most common)
* Mucosal membranes, such as oral mucosa, lymph nodes and visceral organs

* Purplish, reddish-blue or dark brown macules
* Plaques and nodules that may ulcerate

| Biopsy of all 4 types show:

* Vascular slits and sparsely distributed lymphocytes

Lymphangioma | \
  | 9170/0  |

* Pediatric lesions
* Present at birth or during the first years of life

* Appear mostly in the head and neck area but may be found in any other part of the body

* Developmental malformation
* Genetic abnormalities
* Turner's syndrome

| Tongue |

* Circumscribed painless swelling
* Soft and fluctuant on palpation
* Irregular nodularity of the dorsum of the tongue

| Biopsy shows:

* Thin-walled, dilated lymphatic vessels of different size, which are lined by a flattened endothelium

Ectomesenchymal chondromyxoid

tumour of the anterior tongue

| \
  | \
  |

* Age range varies from 9-78 years
* No distinct sex predilection.

| Unknown  | \
  | Asymptomatic, slow growing solitary nodule in the anterior dorsal tongue  | Biopsy shows:

* Round, cup-shaped, fusiform, or polygonal cells with uniform small nuclei and moderate amounts of faintly basophilic cytoplasm
* Some tumors may show nuclear pleomorphism, hyperchromatism, and multinucleation

Focal oral mucinosis (FOM)  | \
  | \
  |

* The lesion affects all ages
* Rare in children
* There is no distinct sex predilection.

| Unknown  |

* Gingiva (most common site)
* Palate
* Cheek mucosa
* Tongue

| Asymptomatic fibrous or cystic-like lesion  | Histopathology is characterized by:

* Well-circumscribed area of myxomatous tissue

* Fusiform or stellate fibroblasts

* Absent or sparse reticular fibers

* Mucinous material shows alcianophilia at pH 2.5

Congenital granular cell epuli  | \
  | \
  |

* Affects newborns
* Females are affected ten times more often than males

| Etiology uncertain  |

* Maxilla

* Mandible

| Solitary, somewhat edunculated fibroma-like lesion, attached to the alveolar ridge near the mid-line  |

* Ultrasound for prenatal diagnosis
* Immuno-histochemically, the tumor cells are positive for vimentin and neuron specific enolase
* No reactivity with cytokeratin, CEA, desmin, hormone receptors or S-100

Hematolymphoid tumors  | Non-Hodgkin lymphoma | \
  | Second most common cancer of the oral cavity |

* There is no known etiology in most patients

* Underlying immunodeficiency state (e.g. HIV Infection)
* Strong association with EBV

* Palate

* Tongue

* Floor of mouth
* Gingiva
* Buccal mucosa
* Lips
* Palatine tonsils
* Lingual tonsils
* Oropharynx

| NHL of the lip presents with:

* Ulcer
* Swelling
* Discoloration
* Pain
* Paresthesia
* Anesthesia
* Loose teeth

Biopsy shows:

* Large cells with predominantly round nuclei and membrane-bound nucleoli, consistent with centroblastic morphology.

* Predominantly medium-sized cells with abundant pale cytoplasm.
* Large cells with round or multilobated nuclei

Langerhans cell histiocytosis | 9751/1  | \
  | Associated with:

* Eosinophilic granulomas
* Multifocal multisystem disease

* Jaw bone
* Intra-oral soft tissues
* Gingiva

* Palate
* Floor of mouth
* Buccal mucosa

* Tonsil

| Common oral symptoms

include:

* Swelling
* Pain
* Gingivitis
* Loose teeth
* Ulceration

| Biopsy shows ovoid Langerhans cells

with deeply grooved nuclei, thin nuclear membranes and abundant eosinophilic cytoplasm

Hodgkin lymphoma |  | \
  | Strongly associated with Epstein- Barr Virus |

* Waldeyer ring, particularly the palatine tonsil
* Oropharynx
* Alveolar crest of mandible
* Maxillary gingiva

| Most patients present with localized disease (stage I/II), with

* Chronic tonsillitis or tonsillar enlargement with or without enlarged cervical lymph nodes

| \

Extramedullary myeloid

sarcoma

| 9930/3  | \
  | History of acute myeloid leukaemia,

predominantly in the monocytic or myelomonocytic sub-types

* Palate

* Gingiva

| Isolated tumor-forming intra-oral mass  | Biopsy shows an Indian-file pattern of infiltration
Follicular dendritic cell

sarcoma / tumour

| 9758/3  |

* Tumor of adulthood

* Affects wide age range

| History of underlying hyaline-vascular Castleman disease |

* Tonsil
* Palate
* Oropharynx

| The patients usually present with a painless mass  | Biopsy usually exhibits

borders and comprises:

* Fascicles
* Whorls

* Nodules

* Storiform arrays
* Diffused sheets of spindle to ovoid tumor cells sprinkled with small lymphocytes

Mucosal malignant melanoma  | \
  | 8720/3  |

* 0.5% of oral malignancies
* Incidence 0.02 per 100,000

| No known etiological factors associated with oral melanoma  | 80% arise:

* Palate
* Maxillary alveolus or gingivae
* Mandibular gingiva

Others:

* Buccal mucosa

* Floor of mouth

* Tongue

* Asymmetric with irregular outlines
* Macular pigmentation
* Nodular growth
* Ulceration
* Melanosis

* Biopsy:
* S100 positive
* Negative for cytokeratins

* More specific markers include:
* HMB45

* Melan-A or anti-tyrosinase

|  |  |  |  |  |  |

## References

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