Oral cancer differential diagnosis

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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]


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

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
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
  • 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
  • Some tumors can be bilateral
Biopsy chows:
Epithelial precursor lesions --- --- --- Smoking Seen in the entire digestive tract Biopsy shows:
Proliferative verrucous leukoplakia and precancerous conditions --- ---
  • Average age at diagnosis is 62 years
  • Women are more commonly affected (ratio, 4:1)
Unknown An aggressive form of oral leukoplakia with considerable morbidity and strong predilection to malignant transformation Biopsy shows:
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: 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:
Condyloma acuminatum 2nd and 5th decade with a peak in teenagers and young adults
  • HPV- most common sub-types: 6, 11, 16 and 18
  • 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

  • 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
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
  • The overlying epithelium is of normal color or may be slightly pale
Biopsy shows:
Keratoacanthoma --- 8071/1
  • Occurs more often in


  • Twice as frequent in

men as in women

Associated with uptake of carcinogens (e.g. via particular smoking habits) Biopsy shows:
Papillary hyperplasia --- --- Affects all age groups Associated with: 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:
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 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 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

Predominantly solid variant shows peri- and intraneural invasion



8562/3 --- Unknown --- --- ---
Clear cell carcinoma,


8310/3 Unknown --- --- ---
Basal cell


8147/3 Rare in minor glands Unknown 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 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 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 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 --- ---
Basal cell adenoma 8147/0 20% of minor gland tumors Unknown --- They are histologically

similar to those in major glands.

Cystadenoma 8149/0 7% of benign minor gland tumors Uknown --- ---
Kaposi sarcoma --- --- Biopsy of all 4 types show:
Lymphangioma --- 9170/0
  • Appear mostly in the head and neck area but may be found in any other part of the body
  • Circumscribed painless swelling
  • Soft and fluctuant on palpation
  • Irregular nodularity of the dorsum of the tongue
Biopsy shows:
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:
Focal oral mucinosis (FOM) --- ---
  • The lesion affects all ages
  • Rare in children
  • There is no distinct sex predilection.
Unknown Asymptomatic fibrous or cystic-like lesion Histopathology is characterized by:
  • 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 Solitary, somewhat edunculated fibroma-like lesion, attached to the alveolar ridge near the mid-line
Hematolymphoid tumors Non-Hodgkin lymphoma --- Second most common cancer of the oral cavity
  • There is no known etiology in most patients
NHL of the lip presents with:

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:
  • Jaw bone
  • Intra-oral soft tissues
  • Gingiva
Common oral symptoms


Biopsy shows ovoid Langerhans cells

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

Hodgkin lymphoma --- Strongly associated with Epstein- Barr Virus Most patients present with localized disease (stage I/II), with ---
Extramedullary myeloid


9930/3 --- History of acute myeloid leukaemia,

predominantly in the monocytic or myelomonocytic sub-types

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

sarcoma / tumour

  • Tumor of adulthood
  • Affects wide age range
History of underlying hyaline-vascular Castleman disease The patients usually present with a painless mass Biopsy usually exhibits

borders and comprises:

  • 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:


  • Floor of mouth
  • Biopsy:
  • S100 positive
  • Negative for cytokeratins
  • More specific markers include:
  • HMB45
  • Melan-A or anti-tyrosinase