Esophagus
Carcinoma
Squamous cell carcinoma
Authors: Xiaoqin Liu, M.D., Ph.D., Aaron R. Huber, D.O.
Editorial Board Member: Wei Chen, M.D., Ph.D.
Deputy Editor-in-Chief: Catherine E. Hagen, M.D.
Last author update: 7 December 2021
Last staff update: 6 March 2024
Copyright: 2003-2024, PathologyOutlines.com, Inc.
PubMed Search: Squamous cell carcinoma of the esophagus
Table of Contents
Definition / general | Essential features | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Diagrams / tables | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Clinical images | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Positive stains | Negative stains | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Liu X, Huber AR. Squamous cell carcinoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/esophagusscc.html. Accessed April 18th, 2024.
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
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
- In the U.S., 2 - 3 times more common in African Americans than others (Cancer Detect Prev 2008;32:87)
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
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
- Upper gastrointestinal tract endoscopy and biopsy for histological analysis, with or without brushings for cytological examination (UpToDate: Clinical Manifestations, Diagnosis, and Staging of Esophageal Cancer [Accessed 28 October 2021])
- If metastases are present, by image guided biopsy of a metastatic site (UpToDate: Clinical Manifestations, Diagnosis, and Staging of Esophageal Cancer [Accessed 28 October 2021])
- CT and fluorodeoxyglucose PET are useful for staging more advanced disease and response after chemoradiation (AJR Am J Roentgenol 2020;215:1072)
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
Eccentric esophageal wall thickening
Prognostic factors
- Stage is most important; American Joint Committee on Cancer / Union for International Cancer Control (AJCC / UICC) TNM the 8th edition (2017) is the current staging system to predict prognosis (Ann Cardiothorac Surg 2017;6:119)
- Females have better outcomes than males in several studies (Thorac Cancer 2014;5:204)
- Tumor length is an independent predictor of mortality when controlled for depth of invasion in patients with localized disease (Thorac Cancer 2014;5:204, Cancer 2002;95:1434)
- TP53 hotspot mutation p.R213* and TENM3 mutation are reported as independent prognostic factors (Ann Oncol 2018;29:938)
- Pathologic response to therapy is an independent prognostic factor (Eur J Surg Oncol 2017;43:1607)
- Tumor grade and location do not significantly affect patient survival (Thorac Cancer 2014;5:204)
- Overall 5 year survival of all stages combined is 20% according to the Surveillance, Epidemiology and End Results (SEER) database (American Cancer Society: Survival Rates for Esophageal Cancer [Accessed 28 October 2021])
- Early detection when the cancer is localized improves survival to 47%, compared to 5% for patients with distant metastasis (American Cancer Society: Survival Rates for Esophageal Cancer [Accessed 28 October 2021])
Case reports
- 43 year old man with synchronous triple squamous cell carcinoma of the esophagus (Int J Surg Case Rep 2018;49:34)
- 56 year old woman with verrucous carcinoma of the esophagus (Surg Case Rep 2020;6:35)
- 58 year old woman with simultaneous esophageal squamous cell carcinoma and adenocarcinoma (Middle East J Dig Dis 2015;7:257)
- 64 year old man with esophageal squamous cell carcinoma with neuroendocrine, basaloid and ciliated glandular differentiation (Clin J Gastroenterol 2021;14:32)
- 67 year old man with esophageal squamous cell carcinoma arising from esophageal squamous papillomatosis (Int J Surg Case Rep 2020;71:335)
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
Gross description
- Fungating / exophytic / polypoid lesions
- Ulcerative or infiltrative (intramural causing thick, rigid esophageal wall with luminal narrowing, linitis plastica pattern and only minor mucosal defect, associated with stricture)
- References: Cancer 1983;51:2139, Goldblum: Rosai and Ackerman's Surgical Pathology, 11th Edition, 2017
Gross images
Contributed by Xiaoqin Liu, M.D., Ph.D. and Aaron R. Huber, D.O.
Fungating / exophytic lesion
Polypoid lesion
Ulcerated 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
- Grade 1 (well differentiated):
- 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
Moderately differentiated carcinoma
Poorly differentiated carcinoma
Carcinoma with pagetoid cells
Keratinizing well differentiated carcinoma
Desmoplastic changes
Lymphovascular invasion
p40 stain
Kreyberg stain
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
- Pseudoepitheliomatous hyperplasia:
- Lacks paradoxical maturation
- Intact basal layer
- High grade neuroendocrine carcinoma:
- Basaloid variant can resemble this entity
- Synaptophysin, chromogranin, CD56, INSM1 can be helpful
- Sarcomas and spindle cell melanoma:
- Immunohistochemistry for S100 for melanoma
- CD117 for gastrointestinal stromal tumor
- Squamous cell carcinoma from other sites:
- From lung with direct extension into esophagus
- Cannot be differentiated based on morphology or ancillary test
- Clinical history or imaging can be helpful
- Atypical regenerative hyperplasia in biopsy:
- No stromal infiltration
- Postradiation chemotherapy changes:
- Usually monomorphic and background has inflammation and granulation tissue
- Reactive changes in ulcer beds:
- Atypical mesenchymal cells in biopsy specimens are pleomorphic and hyperchromatic but usually not mitotically active, are cytokeratin negative
Additional references
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?
- Tis
- T1
- T2
- T3
Board review style answer #1
Board review style question #2
What is the most important prognostic factor for esophageal squamous cell carcinoma?
- Tumor grade
- Tumor length
- Tumor location
- Tumor stage
Board review style answer #2
