Squamous cell carcinoma of the skin differential diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aditya Govindavarjhulla, M.B.B.S. [2], Raviteja Guddeti, M.B.B.S. [3]

Overview

Squamous cell carcinoma should be differentiated from melanoma and basal cell carcinoma. It accounts for 20% of all non-melanomatous tumors, and is fairly invasive contrary to its counterpart, basal cell carcinoma. Squamous cell carcinoma typically presents as a non-healing ulcer or growth on a sun exposed area of the skin.

Differentiating Squamous cell carcinoma from other Diseases

Diseases		Skin examination					Diagnosis		Additional findings
		Type	Color	Texture	Size	Distribution	Dermoscopic Findings	Histopathology
Cutaneous squamous cell carcinoma	SCC in situ (Bowen's disease)	Patch Plaque	Erythematous Skin colored	Scaly	Variable	Fair-skinned individuals: sun-exposed areas In black individuals: legs, anus, and areas of chronic inflammation	Presence of dotted and/or glomerular vessels White to yellowish surface scales Red-yellowish background	Keratinocytic dysplasia of the epidermis No infiltration into dermis Pleomorphic keratinocytes Hyperchromatic nuclei	Slow growth over the years
	Invasive squamous cell carcinoma	Papule Plaque Nodule	Skin colored	Indurated + hyperkeratotic (well differentiated) Soft + ulceration (poorly differentiated)	0.5 to 1.5 cm	Fair-skinned individuals: sun-exposed areas In black individuals: legs, anus, and areas of chronic inflammation	White circles White structureless areas Masses of keratin Hairpin and linear-irregular vessels	Keratinocytic dysplasia of the epidermis No infiltration into dermis Pleomorphic keratinocytes Hyperchromatic nuclei	May be painful or pruritic
Keratoacanthoma		Macule Papule May have telangiectasias	Skin-colored Mildly erythematous	Prominent keratinous core in the center of the nodule	1 to 2.5 cm	Sun-exposed areas Face, neck, hands, and arms	White circles Keratin Blood spots White structureless zones	Well-differentiated squamous epithelium Central keratin core Epidermal hyperplasia + large eosinophilic keratinocytes Dermal inflammatory infiltrate	Rapid growth (within weeks)
Merkel cell carcinoma		Intracutaneous nodule	Shiny Flesh-colored or bluish-red	Firm	< 1 cm	Sun-exposed areas Head and neck Upper limbs and shoulder Lower limbs and hip Trunk	Milky red areas Linear Irregular vessels Polymorphous vessels	Uniform cells with large basophilic nuclei Single-cell necrosis Frequent mitoses Lymphovascular invasion Perineural invasion Epidermal involvement via pagetoid spread	Older individuals with light skin tones Rapidly growing
Basal cell carcinoma	Nodular basal cell carcinoma	Papule	Flesh-colored	Small bump	Variable	Face	Focused, bright red, and branching arborizing vessels Loosely arranged blue-gray dots	Nest-like infiltration with basaloid cells	May have a "rolled" border
	Superficial basal cell carcinoma	Patch	Erythematous	Scaly	1 to > 10 cm	Sun-exposed areas Head (cheek and nose) Trunk	Superficial fine telangiectasia Shiny white to red, translucent or opaque structureless areas Multiple small erosions	Large, hyperchromatic, oval nuclei Minimal cytoplasm Small basaloid nodules	Higher incidence in men
	Sclerosing basal cell carcinoma (morpheaform)	Papule Plaque	Flesh-colored Slightly erythematous	Firm Indurated Indistinct borders	Variable	Sun-exposed areas	Whitish backround Few fine arborizing vessels Multiple brown dots Ulceration	Thin columns + small nodules Highly collagenized stroma	Expression of smooth muscle protein alpha-actin in tumor stroma
Prurigo nodules		Dome-shaped nodule	Flesh-colored Erythematous Brown/black	Firm	Few millimeters to several centimeters	Extensor surfaces of the arms and legs and on the trunk Upper back, abdomen, and sacrum	White "starburst pattern" surrounding red/brown/yellow crusts Erosions Hyperkeratosis	Thick and compact orthohyperkeratosis Irregular epidermal hyperplasia Focal parakeratosis with irregular acanthosis Nonspecific dermal infiltrate containing WBCs	Nodules range in number from few to hundreds Worsened by heat, sweating, or irritation from clothing
Melanoma	Melanoma in situ (Lentigo Maligna)	Macule	Variable (from light to dark brown, black, pink, red, or white)	Smooth	Around 1 cm	Sun-damaged skin of the head or neck	Asymmetric, pigmented follicular openings Gray angulated lines Gray areas, dots, and globules Circle within a circle	↑ atypical spindle shaped melanocytes Arranged in single cells or in small nests along the dermal-epidermal junction	Darkening of pigmentation, sharpening of borders, or emergence of nodular areas are signs of progression to lentigo maligna melanoma
	Lentigo maligna melanoma	Macule	Brown/tan	Freckle-like	Variable	Chronically sun-damaged areas	Asymmetric, pigmented follicular openings Gray angulated lines Gray areas, dots, and globules Circle within a circle	"Star-burst giant cells" in epidermis "Swallow's nest" sign along the dermal-epidermal junction Minimal cytoplasm Pale nucleus with small nucleoli	Usually in older individuals
	Superficial spreading melanoma	Macule Plaque with irregular borders	Variably pigmented (red, blue, black, gray, and white)	Thin	1 mm to > 1 cm	Anywhere but usually: Back (men and women) Lower extremities (women)	Asymmetry of shape > 2 colors Asymmetry of structures	Asymmetric Poorly circumscribed Lack cellular maturation	Lateral (radial) growth before vertical (invasive) growth
	Nodular melanoma	Polypoid nodule	Dark color	Lump	6mm to > 1 cm	Trunk Head Neck	Pigment network or pseudonetwork Aggregated brown or black globules Blue pigmentation within lesion Small dotted or comma vessels	Cells proliferate downwards through the skin Dermal growth in isolation or in association with an epidermal component	Two-thirds arise in normal skin, the rest in existing moles Rapidly enlarging
	Acral lentiginous melanoma	Macule Patch	Dark brown to black	Raised areas Ulceration Bleeding	Variable	Palmar Plantar Subungual Mucosal surfaces	Parallel-ridge pattern Irregular diffuse pigmentation	Asymmetric proliferation of single melanocytes at dermoepidermal junction	Most common among dark skinned individuals
	Amelanotic melanoma	Patch	Skin color	Slightly elevated borders	Around 6 mm	Sun-exposed areas	No melanin pigmentation Dotted vessels Linear irregular vessels		Lesions not pigmented since they don't produce melanin
Common nevus		Dome-shaped nodules	Hypopigmented	Smooth surface Terminal hairs often present	1 cm to > 20 cm	Sun-exposed areas above the waist	Comma-shaped or curved vessels Structureless light brown background Residual brown thick circles around the hair follicles	Multinucleated melanocytes Melanocytes diffusely infiltrate dermis	Also called Miescher nevus
Blue nevus		Macule Papule	Blue	Smooth	Variable	Head and neck, Dorsal aspect of the distal extremities Sacral area	Structureless blue pigmentation Structureless blue and white or blue and brown on some occasions	Proliferation of dendritic, dermal, melanin-producing melanocytes	Also called Mongolian spots
Spitz nevus	Nonpigmented Spitz nevus	Nodule	Pink	Smooth	< 1 cm	Cheek	Coiled vessels White network over a pink to reddish background		In children and adolescents
	Reed-like Spitz	Papule	Heavily pigmented	Smooth	< 1 cm	Head and neck Upper and lower extremities	Structureless black to gray center Hypopigmented follicular openings Peripheral streaks Pseudopods Globules	Enlarged spindle melanocytes with polyangular form "Ground glass" cytoplasm	Most commonly develops in children, adolescents, and young adults.
Solar lentigo		Multiple spots	Brown	Smooth	Around 5mm	Sun-exposed areas	Faint pigmented fingerprint structures Structureless pattern Light brown pseudonetwork with well-defined borders and a "moth-eaten" edge	↑ melanin deposition in keratinocytes ↑ linear arrangement of melanocytes at the dermal-epidermal junction	Associated with UV exposure and skin aging
Sebaceous hyperplasia		Papule	Skin-colored to brownish	Umbilicated	2 - 6 mm	Forehead Nose Cheeks	Structureless yellow to whitish center surrounded by short linear "crown vessels"		Usually in middle-aged or older patients
Lichen planus-like keratosis		Papule Plaque	Gray to brown	Prominent	Variable	Upper trunk	Shows a coarse or fine, gray to blue, granular pigmentation Diffuse brownish gray granules	Hypergranulosis Epidermal hyperplasia Superficial bandlike infiltrate Melanophages	Appearance depends on stage of evolution

A few conditions that mimic Squamous cell carcinoma include the following;

• Actinic keratosis (also called solar keratosis, or AK) is a premalignant condition consisting of one or multiple thick, scaly, or crusty patches on the skin. It is most common in fair-skinned people who are frequently exposed to the sun, due to lack of the protective pigment called melatonin. Actinic keratosis are pre-malignant lesions caused by solar damage that can progress to squamous cell carcinoma, and should therefore be treated.It usually is accompanied by solar damage.
• Atopic dermatitis (Atopic Eczema) is a hereditary, non-contagious skin disease characterized by chronic inflammation of the skin.
• Atypical fibroxanthoma is a tumor that occurs primarily in older individuals when the skin of their head and neck area is exposed to sun and/or therapeutic radiation. Clinically, lesions usually are suggestive of malignancy because they arise rapidly in skin where other cancerous lesions have been found and treated. Clinical presentation is a red, beefy, sessile nodule. Solar telangiectasias can be found around the lesions.
• Bowenoid papulosis presents as papules on the genitalia of both sexes and is induced by infection with HPV. Many of these lesions are benign, but there are case reports of malignant transformation (2.6%).
• Contact dermatitis
• Erythroplasia of Queyrat is squamous cell carcinoma in situ of the penis.
• Keratoacanthoma is a low-grade malignancy of the skin. It originates in the pilo-sebaceous glands, and is similar in its clinical presentation and microscopic analysis to squamous cell carcinoma, except that it contains a central keratin plug. Statistically, it is less likely to become invasive than squamous cell carcinoma.
• Bowen's disease is a sunlight-induced skin disease, and is considered to be an early form of squamous cell carcinoma.
• Marjolin's ulcer is a type of squamous cell carcinoma that arises from a non-healing ulcer or burn wound.
• Melanoma
• Basal cell carcinoma is the most common skin tumor accounting for 80% of all non-melanomatous tumors of skin. It is a malignant epithelial cell tumor that begins as a papule (a small, circumscribed, solid elevation of the skin) and enlarges peripherally, developing into a crater that erodes, crusts, and bleeds
• Pyoderma gangrenosum is an uncommon ulcerative condition associated with systemic disease in at least 50% of cases. This condition is a diagnosis of exclusion.

Squamous cell carcinoma of the mouth must be differentiated from other mouth lesions such as oral candidiasis and aphthous ulcer

Disease	Presentation	Risk Factors	Diagnosis	Affected Organ Systems	Important features	Picture
Diseases predominantly affecting the oral cavity
Oral Candidiasis	Dysphagia or odynophagia White patches on the mouth and tongue	Newborn babies Denture users Poorly controlled diabetes As a side effect of medication, most commonly having taken antibiotics. Inhaled corticosteroids for the treatment of lung conditions (e.g, asthma or COPD) may also result in oral candidiasis which may be reduced by regularly rinsing the mouth with water after taking the medication. People with poor nutrition, specifically vitamin A, iron and folate deficiencies. People with an immune deficiency (e.g. as a result of AIDS/HIV or chemotherapy treatment). Women undergoing hormonal changes, like pregnancy or those on birth control pills. Organ transplantation patients	Clinical diagnosis Confirmatory tests rarely needed	Localized candidiasis Oral and esophageal candidasis Candida vulvovaginitis Chronic mucocutaneous candidiasis Invasive candidasis Candidaemia Candida endocarditis Candida osteoarticular disease	Oral candidiaisis is a benign self limiting disease unless accompanied by immunosuppression.	Tongue infected with oral candidiasis - By James Heilman, MD - Own work, CC BY-SA 3.0, httpscommons.wikimedia.orgwindex.phpcurid=11717223.jpg
Herpes simplex oral lesions	Fever Sore throat Painful ulcers	Stress Recent URTI Female sex	Physical examination Viral culture Tzanck smear	Orofacial Infection Anogenital Infection Ocular Infection Herpes Encephalitis Neonatal Herpes Herpetic Whitlow Herpes Gladiatorum	The symptoms of primary HSV infection generally resolve within two weeks	Oral herpes simplex infection - By James Heilman, MD - Own work, CC BY-SA 3.0, httpscommons.wikimedia.orgwindex.phpcurid=19051042.jpg
Aphthous ulcers	Painful, red spot or bump that develops into an open ulcer	Being a female Between the ages of 10-40 Family history of aphthous ulcers	Physical examination Diagnosis of exclusion	Oral cavity	Self-limiting , Pain decreases in 7 to 10 days, with complete healing in 1 to 3 weeks	By Ebarruda - Own work, CC BY-SA 3.0, httpscommons.wikimedia.orgwindex.phpcurid=7903358
Squamous cell carcinoma	Non healing ulcer, nodule, indurated plaque or mass May involve skin, lips, inside the mouth, throat or esophagus	Chronic sun or UV exposure Fair skin Elderly age (>45 yrs) Male sex Smoking	Physical exam Biopsy	Oral Cavity Floor of mouth Lateral tongue Throat Esophagus	Malignant Can spread to TMJ Some times associated with leukoplakia	Squamous cell carcinoma - By Luca Pastore, Maria Luisa Fiorella, Raffaele Fiorella, Lorenzo Lo Muzio - http://www.plosmedicine.org/article/showImageLarge.action?uri=info%3Adoi%2F10.1371%2Fjournal.pmed.0050212.g001, CC BY 2.5, https://commons.wikimedia.org/w/index.php?curid=15252632
Leukoplakia	White leathery spots on the mucous membranes of the tongue and inside of the mouth Lateral borders of tongue	Atypical Tobacco use Chronic irritation Immunodeficiency Bloodroot (sanguinaria)	Physical exam Diagnosis of exclusion Biopsy	Vulvar lesions occur independent of oral lesions	Associated with HIV Persistant white spots Benign but can progress to carcinoma after almost 10 years Oral proliferative verrucous leukoplakia is an aggressive sub type with multiple lesions and higher conversion to warts or carcinoma	Leukoplakia - By Aitor III - Own work, Public Domain, https://commons.wikimedia.org/w/index.php?curid=9873087
Melanoma	A lesion with ABCD Asymmetry Border irregularity Color variation Diameter changes Bleeding from the lesion	UV radiations Genetic predisposition Old age Male gender Family or personal history of melanoma Multiple benign or atypical nevi	ABCD characteristics Bleeding or ulceration may show malignancy Serum LDH may be elevated in case of malignancy Biopsy	Can metastasize All UV radiation or sun exposed areas can be effected independently 1-2 to hundreds of granules	Neural crest cell derivative Development begins with disruption of nevus growth control Progression involves MAPK/ERK pathway N-RAS or BRAF oncogene also involved	Oral melanoma - By Emmanouil K Symvoulakis, Dionysios E Kyrmizakis, Emmanouil I Drivas, Anastassios V Koutsopoulos, Stylianos G Malandrakis, Charalambos E Skoulakis and John G Bizakis - Symvoulakis et al. Head & Face Medicine 2006 2:7 doi:10.1186/1746-160X-2-7 (Open Access), [1], CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=9839811
Fordyce spots	Rice-like granules or spots Small, painless, raised, pale, red or white 1 to 3 mm in diameter	Greasy skin types Some rheumatic disorders Hereditary nonpolyposis colorectal cancer Lower gingiva (gums) Vestibular mucosa	Physical exam Small keratin-filled pseudocysts May be seen on incidental mucosal biopsy Biopsy not done for them primarily	Oral cavity Vermilion border of the lips Oral mucosa of the upper lip Buccal mucosa in the commissural region often bilaterally Genitals	Benign neoplasms with sebaceous features Visible sebaceous glands No surrounding mucosal change Several adjacent glands may coalesce into a larger cauliflower-like cluster	Fordyce spots - Por Perene - Obra do próprio, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=19772899
Burning mouth syndrome	Burning or tingling on the lips, tongue, or entire mouth	Nutritional deficiencies Chronic anxiety or depression Diabetes type 2 Menopause Oral thrush or dry mouth, or damaged nerves transmitting taste Female gender Menopause	Presentation Physical exam	Oral cavity	Pain typically is low in the morning and builds up over the day Low dosages of benzodiazepines, tricyclic antidepressants or anticonvulsants may be effective
Torus palatinus	Bony growth on midline of the hard palate Nodular mass covered with normal mucosa	Genetic predisposition Autosomal dominant	Physical exam Types Flat tori Spindle tori Nodular tori Lobular tori	Hard palate	More common in Asian and Inuit populations Twice more common in females Repeated trauma can cause bleeding Surgery may be required in symptomatic	Torus palatinus - By Photo taken by dozenist, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=846591
Diseases involving oral cavity and other organ systems
Behcet's disease	Painful mouth sores Acne like skin lesions Headache, fever, poor balance, disorientation Abdominal pain, diarrhea or bleeding Uveitis Joint swelling and joint pain Genital sores wit pain and scaring Aneurysms	Over active immune system	Physical examination	Mouth Genitals GIT Eye Joints Skin Vascular system Brain	Outbreaks of exaggerated inflammation Affects smaller blood vessels	Behcet's disease - By Ahmet Altiner MD, Rajni Mandal MD - http://dermatology.cdlib.org/1611/articles/18_2009-10-20/2.jpg, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=17863021
Crohn's disease	Chronic, episodic diarrhea or constipation Abdominal pain Vomiting Weight loss or weight gain	Smoking Whites and European Jews Hormonal contraception Diets high in microparticles, sweet, fatty or refined foods Industrialized country	Typical history and symptoms Skip lesions on biopsy Anti-Saccharomyces cerevisiae antibodies (ASCA) Anti-neutrophil cytoplasmic antibodies (ANCA)	Eyes Joints Skin	May lead to Obstructions Abscesses Free perforation Hemorrhage
Agranulocytosis	Fever or chills Frequent infections Unusual redness, pain, or swelling around a wound Mouth ulcers Abdominal pain Burning sensation when urinating Sore throat	Medications Cytotoxic chemotherapy Hematologic malignancies Autoimmune disorders	Neutropenia <100 cells per micro litre Eosinopenia Basopenia	Oral cavity Skin GIT Urinary system Conjunctiva	Immunocompromization Types Drug-induced Malignant Autoimmune
Syphilis	Chancre Regional lymphadenopathy	Multiple sexual partners Illicit drug use Unprotected sex Men who have sex with men Residence in highly prevalent areas HIV infection Presence of other STIs Previous history of STIs Intravenous drug use	Darkfield microscopy Non treponemal tests like VDRL and RPR test) Treponemal testsFTA-ABS tests, (TP-PA) assay, enzyme immunoassays, and chemiluminescence immunoassays)	Oral cavity Penis Cervix Labia Anal canal Rectum CNS CVS	Primary syphilis Chancre Secondary syphilis Condylomata lata Latent syphilis Asymptomatic Tertiary syphilis Gummas Neurosyphilis	oral syphilis - By CDC/Susan Lindsley - http://phil.cdc.gov/phil_images/20021114/34/PHIL_2385_lores.jpg, Public Domain, https://commons.wikimedia.org/w/index.php?curid=2134349
Coxsackie virus	Fever Sores in the mouth Rash with blisters Aches	Pregnancy immunodeficiency	History and Physical exam Throat swabs Swabs from the lesion Tzanck test	Oral cavity Skin	Symptomatic treatment	Hand-foot-and-mouth disease - adapted from atlasdermatologico.com
Chicken pox	Conjunctival symptoms Catarrhal symptoms Characteristic spots on the trunk appearing in two or three waves Itching	Pregnancy Premature infants born to susceptible mothers All infants born at less than 28 weeks gestation or who weigh =1000 grams Immunocompromised	History and physical exam PCR to detect VZV in skin lesions (vesicles, scabs, maculopapular lesions)	Oral cavity Skin	Sodium bicarbonate in baths or antihistamines for itching Paracetamol (acetaminophen) for fever Prednisolone is contraindicated	Chickenpox - By James Heilman, MD - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=52872565
Measles	Fever Rash Cough Coryza (runny nose) Conjunctivitis (pink eye) Malaise Koplick spots in mouth	Unvaccinated individuals Crowded and/or unsanitary conditions Traveling to less developed and developing countries Immunocompromized Winter and spring seasons Born after 1956 and never fully vaccinated Health care workers	History and examination PCR for Measles-specific IgM antibody PCR for Measles RNA	Oral cavity Skin Respiratory tract Eyes Throat	Caused by Morbillivirus Primary site of infection is the respiratory epithelium of the nasopharynx Transmitted in respiratory secretions, via aerosol droplets containing virus particles	Koplick spots (Measles) - By CDC - http://phil.cdc.gov/PHIL_Images/20040908/4f54ee8f0e5f49f58aaa30c1bc6413ba/6111_lores.jpg, Public Domain, https://commons.wikimedia.org/w/index.php?curid=824483