Esophagus

Carcinoma

Squamous cell carcinoma


Editorial Board Member: Wei Chen, M.D., Ph.D.
Deputy Editor-in-Chief: Catherine E. Hagen, M.D.
Xiaoqin Liu, M.D., Ph.D.
Aaron R. Huber, D.O.

Last author update: 7 December 2021
Last staff update: 7 December 2021

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PubMed Search: Squamous cell carcinoma of the esophagus[TI] "last 5 years"[DP]

Xiaoqin Liu, M.D., Ph.D.
Aaron R. Huber, D.O.
Page views in 2021: 14,131
Page views in 2022 to date: 15,540
Cite this page: Liu X, Huber AR. Squamous cell carcinoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/esophagusscc.html. Accessed December 7th, 2022.
Definition / general
  • WHO definition: a malignant epithelial tumor displaying squamous cell differentiation characterized by keratinocyte type cells with intercellular bridges or keratinization
Essential features
  • Esophageal squamous cell carcinoma (ESCC) is the most common esophageal cancer worldwide
  • Distinct from esophageal adenocarcinoma in terms of cell origin, epidemiology, etiology, pathogenesis and location in the esophagus
  • Rich lymphovascular network facilitates early tumor spread
  • Early diagnosis is critical to improve survival and endoscopic surveillance with biopsy evaluation is the standard of care in high risk groups
ICD coding
  • ICD-O: 8070/3 - squamous cell carcinoma, NOS
  • ICD-11: 2B70.1 - squamous cell carcinoma of esophagus
Epidemiology
  • Incidence worldwide, the most common esophageal cancer
  • Great regional and ethnic variation
  • Highest incidence regions (> 50 cases/100,000 person years) stretching from Eastern to Central Asia
  • Intermediate rates (10 - 50 cases/100,000 person years) observed along the Indian coast of Africa, in southern Brazil and Uruguay and in parts of the Caribbean
  • Trending down and less common in the U.S., Europe, Australia and many other Western countries than esophageal adenocarcinoma
  • Predominates in Eastern Europe, Japan and South America (Gastroenterology 2018;154:360)
  • Age
    • Rare before 30 years
    • Median age: 65 years
  • Sex
    • Overall, male predominant
    • Ratio varies with the M:F ratio reaching 4:1 in low risk areas (such as U.S.) and the ratio being lower or even exceeding 1:1 in high incidence areas of China and Iran (Gastroenterology 2018;154:360)
  • Ethnicity
Sites
  • Most commonly in middle third of esophagus, followed by lower third and upper third, respectively
Pathophysiology
  • Develops by stepwise progression, with accumulating genetic abnormalities driving progression from histologically normal squamous mucosa to low grade intraepithelial neoplasia (dysplasia) to high grade intraepithelial neoplasia and finally to invasive squamous cell carcinoma
  • TP53 mutation is a key early driver mutation developing at the stage of intraepithelial neoplasia
  • Other key genetic abnormalities, including cell cycle regulators (e.g., CDKN2A [p16], RB1, NFE2L2, CHECK1, CHECK2, CCND1, CKD4, CDK6 and MDM2), EGFR signaling pathway, PI3Kinase signaling pathway, histone modification, NOTCH and WNT pathway, Hedgehog signaling and other genetic changes, including aneuploidy, copy number alterations (Ann N Y Acad Sci 2018;1434:342)
  • Specific mutations required for the invasion beyond the basement membrane are still unknown
  • Acquisition of invasive and migratory capability via epithelial mesenchymal transition is important; EIF5A2 amplification has been shown to be a factor in inducing this phenotype
Etiology
  • Multifactorial and strongly population dependent
  • Low socioeconomic status is one of the most consistent factors, even after adjusting other confounding factors (e.g., tobacco use and alcohol consumption)
  • Tobacco use
    • Remains a key risk factor in developed countries but a weaker effect in developing countries
    • Dependent on both exposure duration and intensity, with duration outweighing intensity
    • Tobacco specific nitrosamines (TSNA) and polycyclic aromatic hydrocarbons (PAH) are thought to be the major carcinogenic substances in tobacco
  • Alcohol beverage
    • Alcoholic beverage consumption has been causally linked to ESCC by International Agency for Research on Cancer (IARC)
    • Consumption of > 3 drinks per day is associated with a risk almost 5 times that in individuals who consume 1 drink per day
    • Acetaldehyde, a metabolite of ethanol, is linked to the increase in risk of ESCC, particularly in Eastern Asian population, which was found to exclusively have ALDH2 and ALDH1A1 mutations leading to accumulation of acetaldehyde following alcohol consumption
  • Other risk factors: betel quid, diets low in fruit and vegetables, pickled vegetables, deficiency of selenium or riboflavin, hot foods and beverages, PAH, increased BMI, poor oral health
  • Associated medical conditions: Plummer-Vinson syndrome, achalasia, caustic ingestion injury, radiotherapy to the chest area and Fanconi anemia
  • Esophageal leukoplakia or epidermoid metaplasia has been associated with esophageal squamous cell carcinoma and dysplasia (Mod Pathol 2014;27:38)
  • Genetic factors: tylosis, a keratosis disorder caused by an autosomal dominant mutation in RHBDF2al, 17q25.3, is highly associated with ESCC (> 90% of patients develop ESCC by the age of 65 years)
  • HPV infection is unlikely to be a substantial risk factor in the current consensus
  • Reference: Gastroenterology 2018;154:360
Diagrams / tables

Images hosted on other servers:
8th edition TNM categories

8th edition TNM categories

Clinical features
  • Most common symptom is progressive dysphagia and weight loss
  • Insidious onset with dysphagia to solids, followed by dysphagia to all food
  • Chest pain, painful swallowing and weight loss can also present
  • Usually advanced at presentation
  • Chronic gastrointestinal blood loss from ESCC is common and may result in iron deficiency anemia
  • Hoarseness or cough may occur if the recurrent laryngeal nerve is invaded
  • May erode the esophageal wall, causing fistulas; the adjacent respiratory tree, causing pneumonia; the aorta, causing exsanguination or the mediastinum and pericardium
  • Horizontal and longitudinal spread are facilitated by rich lymphovascular network
  • Lymph node metastases vary by region:
    • Upper third: cervical nodes
    • Middle third: mediastinal, paratracheal and tracheobronchial node
    • Lower third: gastric and celiac nodes
  • Most common sites for distant metastasis are the lungs, liver, bones, adrenal glands, kidneys
  • References: Goldblum: Rosai and Ackerman's Surgical Pathology, 11th Edition, 2017, UpToDate: Clinical Manifestations, Diagnosis, and Staging of Esophageal Cancer [Accessed 28 October 2021]
Diagnosis
Radiology description
  • Fluoroscopy / barium swallow
    • Irregular stricture
    • Prestricture dilatation with hold up
    • Shouldering of the stricture
  • CT is the best initial modality for detection of distant metastasis, gross direct invasion and enlarged lymph nodes
    • Eccentric or circumferential wall thickening > 5 mm
    • Periesophageal soft tissue and fat stranding
    • Dilated fluid and debris filled esophageal lumen is proximal to an obstructing lesion
    • Tracheobronchial invasion appears as a displacement of the airway as a result of mass effect by the esophageal tumor
    • Aortic invasion
  • Endoscopic ultrasound is the most sensitive modality for assessment of the depth of invasion and regional enlarged lymph nodes
    • Approximately 20% of squamous cell carcinomas are superficial and frequently multicentric
    • Early lesions: nodule, polyp, plaque
    • Advanced tumors: exophytic, ulcerative, infiltrative
  • PET has a primary role in the depiction of distant sites of metastatic disease; also can be useful for restaging after the initial neoadjuvant therapy
  • References: Radiographics 2009;29:403, AJR Am J Roentgenol 2020;215:1072
Radiology images

Contributed by Xiaoqin Liu, M.D., Ph.D. and Aaron R. Huber, D.O.
Obstructing lesion of esophagus

Obstructing lesion of esophagus

Eccentric esophageal wall thickening

Eccentric esophageal wall thickening

Prognostic factors
Case reports
Treatment
  • Early lesion (T1) can be managed by endoscopic submucosal dissection or esophagectomy
  • Neoadjuvant chemoradiation followed by esophagectomy is widely accepted for advanced lesion (Surg Clin North Am 2019;99:479)
  • Definitive chemoradiation is an acceptable alternative in patients who are not surgical candidates or patients who wish to avoid surgery (Surg Clin North Am 2019;99:479)
  • Although salvage therapy is a viable option, longterm outcomes are unclear but it can be considered in select patients (Surg Clin North Am 2019;99:479)
  • By integrating molecular profiling as part of the management of patients with esophageal cancer, future treatment guidelines will provide a more personalized and effective approach to this disease
Clinical images

Contributed by Xiaoqin Liu, M.D., Ph.D. and Aaron R. Huber, D.O.
Mucosal tearing and ulceration

Mucosal tearing and ulceration

Gross description
Gross images

Contributed by Xiaoqin Liu, M.D., Ph.D. and Aaron R. Huber, D.O.
Fungating / exophytic lesion

Fungating / exophytic lesion

Polypoid lesion

Polypoid lesion

Ulcerated lesion

Ulcerated lesion

Cavitary lesion

Cavitary lesion

Microscopic (histologic) description
  • Essential diagnostic criteria: histological evidence of vertical and horizontal growth of neoplastic squamous epithelium, with definite evidence of invasion
  • Staging (TNM) (J Thorac Oncol 2017;12:36)
    • Should be staged using the 8th editions (2017) of the UICC / AJCC cancer staging manual
    • Depth of invasion provides a clinically relevant division of esophageal squamous cell carcinoma into superficial (or early) disease versus advanced (or late) disease
    • Superficial disease is invasion restricted to the mucosa and submucosa; it has a low risk of regional lymph node metastasis
    • Advanced disease is invasion beyond the muscularis propria, with a high risk of regional or systemic metastasis
  • Grading is based on the degree of cytological atypia, mitotic activity and presence of keratinization
    • Grade 1 (well differentiated):
      • Contains enlarged cells with abundant eosinophilic cytoplasm and keratinization
      • Cytological atypia is minimal and the mitotic rate is low
      • Invasive margin is pushing and the cells remain well ordered
    • Grade 2 (moderately differentiated):
      • Has evident cytological atypia and the cells are less ordered
      • Mitotic figures are easily identified
    • Grade 3 (poorly differentiated):
      • Consists predominantly of basal-like cells forming nests with or without central necrosis
  • Treatment effect often involved in both tumor cells and the peritumor stroma
    • Cellular changes include nuclear enlargement or shrinkage, nuclear vacuolation, apoptosis and necrosis
    • Neutrophilic or chronic inflammatory cell response may be seen
    • There is fibrosis and sometimes stromal elastosis
  • Subtypes:
    • Verrucous squamous cell carcinoma: usually at the gastroesophageal junction, associated with reflux; shows a very well differentiated histology with a pushing border and surface papillary projection and metastases are uncommon
    • Spindle cell squamous cell carcinoma: biphasic morphology with conventional squamous cell carcinoma and a high grade spindle cell component with heterogeneous differentiation
    • Basaloid squamous cell carcinoma: shows a solid or nested growth pattern of basaloid cells, sometimes with central comedonecrosis and occasionally with pseudoglandular cribriform formations
Microscopic (histologic) images

Contributed by Xiaoqin Liu, M.D., Ph.D. and Aaron R. Huber, D.O.
Well differentiated carcinoma Well differentiated carcinoma

Well differentiated carcinoma

Moderately differentiated carcinoma Moderately differentiated carcinoma

Moderately differentiated carcinoma

Poorly differentiated carcinoma

Poorly differentiated carcinoma

Carcinoma with pagetoid cells

Carcinoma with pagetoid cells


Keratinizing well differentiated carcinoma

Keratinizing well differentiated carcinoma

Desmoplastic changes

Desmoplastic changes

Lymphovascular invasion

Lymphovascular invasion

p40 stain

p40 stain

Kreyberg stain

Kreyberg stain

Virtual slides

Images hosted on other servers:
Pseudosarcomatous squamous cell carcinoma

Pseudosarcomatous
SCC

Squamous cell carcinoma

SCC

Invasive basaloid squamous cell carcinoma

Invasive basaloid SCC

Invasive moderately differentiated squamous cell carcinoma (pT2)

Invasive moderately differentiated SCC (pT2)

Cytology description
  • Nuclear membrane alterations, nuclear hyperchromasia and enlargement, loss of nuclear polarity, prominent nucleoli
Positive stains
  • Immunohistochemistry is useful in confirming poorly differentiated and spindle cell squamous cell carcinoma
  • Pancytokeratin, CK5/6, p63, p40
Negative stains
  • Negative Kreyberg or mucicarmine stain can help to rule out poorly differentiated adenocarcinoma
  • Negative synaptophysin and chromogranin stains can help to rule out neuroendocrine carcinoma
Molecular / cytogenetics description
  • At present, no molecular tests are required
  • TP53 mutation found in 59 - 93% of all cases
  • NOTCH1 and NOTCH3 mutations detected in up to 28% of cases
  • EGFR overexpression reported in 59.6 - 76% of cases
  • Mutations or amplification in RAS and AKT family seen in at least 75% of cases
  • Genetic alterations involved in cell cycle regulation, epigenetic factors, copy number alterations, chromosome aneuploidy (in particular, gains in chromosome 3, 10, 12 and 20) were reported
  • Associated with tylosis and Fanconi anemia
Sample pathology report
  • Esophagus, at 35 to 28 cm, biopsy:
    • Invasive moderately differentiated squamous cell carcinoma (see comment)
    • Comment: Immunohistochemical / special stains were performed and show the tumor is positive for p40 and negative for Kreyberg for intracellular mucin. The morphology and immunoprofile are consistent with squamous cell carcinoma.
Differential diagnosis
Board review style question #1

A 65 year old man presented with progressive dysphagia and weight loss. Esophageal biopsy confirmed squamous cell carcinoma and esophagectomy was performed. What is the T staging according to the H&E section above?

  1. Tis
  2. T1
  3. T2
  4. T3
Board review style answer #1
Board review style question #2
What is the most important prognostic factor for esophageal squamous cell carcinoma?

  1. Tumor grade
  2. Tumor length
  3. Tumor location
  4. Tumor stage
Board review style answer #2
D. Tumor stage

Comment Here

Reference: Squamous cell carcinoma
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