Squamous cell carcinoma

Topic Completed: 1 February 2014

Minor changes: 17 August 2021

Copyright: 2003-2021,, Inc.

PubMed Search: Squamous cell carcinoma of the esophagus[TI] free full text[sb]

Elliot Weisenberg, M.D.
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Cite this page: Weisenberg E. Squamous cell carcinoma. website. Accessed September 19th, 2021.
Definition / general
  • WHO definition: a malignant epithelial tumor with squamous cell differentiation, microscopically characterized by keratinocyte-like cells with intercellular bridges or keratinization
  • Worldwide, the most common esophageal epithelial malignancy
    • In the developed world, its incidence is now less than adenocarcinoma
  • Great regional and ethnic variation in incidence with different risk factors
  • In western Europe and North America (low risk regions), 90% of cases are related to ethanol or tobacco consumption
    • Heavy tobacco smoking results in a 400 to 800% increase in risk that decreases over time with smoking cessation
    • High tar and unfiltered cigarettes may be more oncogenic and pipe smoking may also increase risk
    • Effect of alcohol is synergistic with that of tobacco
    • In the United States, there is a strong male predominance and the incidence in African American men is 2 to 5 times that of white men
  • Highest risk areas are parts of eastern China, Iran, parts of Kazakhstan and (for men) Zimbabwe; these areas have recently reported a decline in incidence
  • Intermediate risk areas are parts of east Africa, South America, China, the Caribbean and Southern Europe
  • Most commonly in middle third of esophagus; upper third is least common
  • Invasive carcinoma arises from squamous cell carcinoma in situ as part of the dysplasia-carcinoma sequence
  • Especially in high risk areas, a lack of fruits and vegetables causing deficiencies of vitamins A, B6, C, riboflavin, thiamine, zinc and molybdenum are likely involved
  • Other risk factors: betel nuts, fungal contamination, hot foods and beverages, nitrates / nitrosamines (in fermented corn, well water contaminated by animal / human wastes and produced by fungal contaminants), polycyclic aromatic hydrocarbons in China (Hum Pathol 1998;29:1294), urban environment
  • Other risk factors: achalasia, celiac disease, corrosive strictures, epidermolysis bullosa, esophagitis (chronic), lye stricture, Plummer-Vinson syndrome, radiation therapy, squamous cell carcinoma of other aerodigestive sites, tylosis palmaris et plantaris (palmoplantar keratoderma, BMC Cancer 2005;5:90)
  • HPV has been implicated by some investigators, especially in high risk regions with detection rates from 0 to 66% (Hum Pathol 1994;25:920, World J Gastroenterol 2005;11:1200, Hum Pathol 1997;28:174, Hum Pathol 1998;29:266, Scand J Gastroenterol 2000;35:123) but most authorities do not believe HPV is etiologically related to the majority of squamous cell carcinomas
  • Rarely associated with Barrett esophagus (Mod Pathol 1989;2:2)
Clinical features
  • Usually advanced at presentation
  • Horizontal and longitudinal spread are facilitated by rich lymphovascular network
  • Insidious onset with dysphagia to solids, followed by dysphagia to all food
  • Extreme weight loss due to loss of nutrition and tumor itself
  • May erode the esophageal wall causing fistulas, the adjacent respiratory tree causing pneumonia, the aorta causing exsanguination or the mediastinum and pericardium
  • Lymph node metastases vary by region: upper third - cervical nodes; middle third - mediastinal, paratracheal and tracheobronchial node; lower third - gastric and celiac nodes
  • May be associated with other malignancies of the upper aerodigestive tract
  • Rarely is multifocal in esophagus
  • Most common sites for distant metastasis are the lungs, liver, bones, adrenal glands, kidneys
  • Metastasis to the central nervous system may occur
  • Recurrences are common
  • Tissue biopsy
  • Exfoliative cytology may be useful, although concurrent biopsy is recommended
Prognostic factors
  • Stage is most important (Am J Clin Pathol 1991;95:844)
  • Tumor grade (well, moderate or poorly differentiated) is not reproducible and not important unless tumor is anaplastic
  • Overall 5 year survival is ~9%, most patients do not survive 1 year
  • Early detection when the cancer is superficial improves survival to 75%, compared to 25% for curative resection for patients at advanced stage
Case reports
  • Patients are divided into two groups, those with potentially curable locoregional disease and those with advanced disease who receive palliative treatment
  • Rare patient with early stage disease or high grade dysplasia may undergo endoscopic mucosal resection
  • Patients in the curative intent group usually undergo esophagectomy
  • Radiation therapy or chemotherapy may be used for all stages or palliative treatment
Gross description
  • Fungating / exophytic / polypoid lesions (most common)
  • Ulcerative (primarily intramural with deep irregular ulcers, protuberant edges around ulcer, may perforate and enter trachea, aorta or mediastinum) or infiltrative (intramural causing thick, rigid esophageal wall with luminal narrowing, linitis plastica pattern and only minor mucosal defect, associated with stricture)
Gross images

AFIP images

Fungating / exophytic

Upper esophagus

Middle esophagus

Lower esophagus


Small tumor of mid esophagus

Prominent edges surround ulcer

Huge ulcerating carcinoma


Elevated plaque

Carcinomatous stricture


Pseudosarcomatous squamous cell carcinoma

Contributed by
Dr. Mark R. Wick

With lymph node metastasis

Squamous cell carcinoma

 Contributed by
 Dr. Elliot Weisenberg

Squamous cell carcinoma

Images hosted on other servers:

Fungating / exophytic

Large mass with fungating pattern


Distal esophagus

Exophytic ulcerated mass


Granular surface

Microscopic (histologic) description
  • Usually moderate to well differentiated (based on mix of undifferentiated / primitive basal cells, large flat squamous cells and keratinized foci)
  • Tumor clusters may be present distant from main mass (intramural metastases) due to lymphatic spread through submucosa
  • Tumor cells often exhibit keratinization and have intercellular bridges
  • Angiolymphatic invasion (75%)
  • Mitotic rate usually correlates with percent basal cells
  • May have focal glandular or small cell differentiation or lymphoid stroma
  • Occasionally intraepithelial component resembling Paget disease
  • Desmoplasia most common with adventitial penetration
  • Lamina propria invasion: elongated rete-like projections which may bud and then break off; little desmoplasia
  • Intramucosal: does not penetrate below lamina propria
  • Submucosal invasion: often pushing type border with expansion circumferentially; variable desmoplasia
  • Note: in situ carcinoma can also invade submucosal ducts without being considered true invasion
Microscopic (histologic) images

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AFIP images

Well differentiated

Moderately differentiated: trabecular growth

Moderately to poorly differentiated

Poorly differentiated:
without clear
cut squamous

Infiltration of lamina propria

Carcinoma without desmoplasia

Desmoplastic stroma in adventitia

Expansile growth pattern

Infiltrative growth pattern

Focal glandular component

Small cell type

Lymphatic invasion

Intramural venous invasion

Radiated tumor cells

Intramural invasion likely due to lymphatic spread

With possible incipient invasion at base

In situ carcinoma and submucosal invasion

In situ carcinoma

Ulcer associated
florid regenerative

Pseudosarcomatous squamous cell carcinoma

Stromal differentiation

Contributed by Dr. Mark R. Wick


Keratinizing type

Squamous cell carcinoma

Contributed by Dr. Elliot Weisenberg

Squamous cell carcinoma

Images hosted on other servers:

Well differentiated

Well differentiated

Moderately differentiated pink cytoplasmic keratin

Undermining surface epithelium

Infiltrating nests of tumor

Intercellular bridges

Perineural invasion

Lymphatic invasion

Residual tumor after radiation therapy

Cytology description
  • Cells have enlarged nuclei, multiple and enlarged nucleoli, loss of nuclear polarity in cell clusters
  • Similar features also present in reparative epithelium
Positive stains
Electron microscopy images

Images hosted on other servers:

Desmosomes and tonofilaments (site unknown)

Molecular / cytogenetics description
  • 2/3 are aneuploid
  • Most have high levels of epidermal growth factor receptor (EGFR)
  • Genetic alterations include mutations or amplification of p53, p16INK4a, cyclin D1, cyclin E, c-MYC and EGFR; KRAS and APC mutations are rare (World J Gastroenterol 2007;13:1438)
  • p53 and other mutations may be detected in precursor dysplastic lesions
Differential diagnosis
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